Segment 2 Of 2     Previous Hearing Segment(1)

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    Mr. PORTER. Dr. Olden, thank you for that fine opening statement. You already answered my first question, which was how long is it going to take to actually achieve the use of transgenics in lieu of conventional rodent assays and one to two years is what your answer was, I thought.

    Dr. OLDEN. Yes. But I can add that the Food and Drug Administration will already accept an alternative model. The model has to be an animal, though; it is not an in vitro model. And in most cases, it is the transgenic animal models that they will accept.

    So it is already being used. In other words, FDA will accept one test in a conventional animal model, and then one in a transgenic. And that, in itself, is a major advance.


    Mr. PORTER. All right, let me change the subject and ask you a question that arose at a forum I had last Monday night. This may be a little out of your field, but it relates to the idea that we are creating cancers and negative health effects by spraying pesticides that are used for insect control. I assume that the EPA has jurisdiction over pesticide chemicals?

    Dr. OLDEN. They do over the regulation of pesticide chemicals.

    Mr. PORTER. Do you have responsibility for testing those chemicals?
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    Dr. OLDEN. We have responsibility for probably more than 50% of the research on pesticides. And as Dr. Klausner will testify when he comes here, we have a collaboration with NCI and EPA. We have what we call an agricultural health study that we have been conducting now for over five years.

    And what we are doing for the first time in the case of non-cancer end points is to look at—determine—what the health effects of exposures to agricultural chemicals really are. And the emphasis is on developmental issues, immune issues and respiratory issues.

    This is a ten year study that is being supported by all three of us. And for cancer, this will be a definitive study. We have a number of other studies ongoing to investigate the health effects of pesticides.

    For example, the National Academy reported to us about three years ago now that the impact of pesticides on children was a serious public health issue. So we initiated studies in the National Toxicology Program to look at the effects of pesticides on the developing embryo and the early pups of mice once they are born.

    We look at the effects of pesticides throughout the life history of the animal. We have a number of studies going on on the health effects of pesticides.

    Mr. PORTER. Would it be a fair statement to say that for many of the pesticides in common use in the United States today, we do not know whether they are carcinogens or not?
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    Dr. OLDEN. Some of the ingredients in pesticides we know are carcinogens at high levels. We do not know about low levels, the level at which most of us are exposed. But the truth is, we do not know anything about the toxicity or carcinogenicity of most of the components of pesticides.

    So your statement is a fair statement.

    Mr. PORTER. Then at the close of the ten year study, presumably we are going to know a lot more?

    Dr. OLDEN. Absolutely.

    Mr. PORTER. And that would then, presumably, be a basis for regulation by the EPA of these substances?

    Dr. OLDEN. In the case of cancer, I think that the studies will be fairly definitive in terms of whether there are increased cancer risks from exposures to pesticides. We are looking at pesticide applicators on farms. We are looking at the farmers themselves, the male, the female and the children, the offspring.

    In a case of end points other than cancer, however, this represents the first major study. So what we are doing mostly in the case of non-cancer end points is hypothesis building rather than really testing hypotheses because we just do not have adequate information.

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    So in the case of non-cancer end points, additional studies will clearly be required before we can make any recommendations to you or to the regulatory agencies such as EPA and FDA about the health effects of pesticides.

    Mr. PORTER. Well, to get a little more specific, my home State of Illinois, in anomaly of constitutional law created mosquito abatement districts years ago. They spray larvacides and they also spray pesticides, and they spray the pesticides directly into the foliage in cities.

    Dr. OLDEN. Yes.

    Mr. PORTER. Is it a fair statement to say that they may be spraying chemicals that may be carcinogenic and may be a threat to children?

    Dr. OLDEN. That is a fair statement.


    Mr. PORTER. Why do we allow the use of chemicals that we do not know whether they are harmful or not?

    Dr. OLDEN. Well——

    Mr. PORTER. I know this is a little bit out of your bailiwick.

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    Dr. OLDEN. Yes, my opening statement was a bit long, so I cut it down a little bit last night, and I would have said that the Environmental Defense Fund and the National Research Council of the National Academy of Sciences have both reported that, of the high use, high volume chemicals in use in the United States, toxicity and carcinogenicity testing has not been performed—none—on more than 75 to 78% of those chemicals.

    So, in most cases, we simply do not have the toxicity data in place to tell you whether those components of pesticides cause harm or not. Now we know that many of them do. We have tested many of them.

    As a matter of fact, we have tested over 500 chemicals in all in the National Toxicology Program. And of the 500 tested, 68, or 14 to 15% of those are listed in the report on carcinogens. So we know something about many of them.

    Mr. PORTER. But we also know that there are a number of chemicals that are not carcinogenic.

    Dr. OLDEN. Absolutely, but they could affect development, and we know that some do. A number of chemicals affect development. As a matter of fact, the major concerns about children are asthma, lead exposure, and number three would be pesticide exposure because of the impact on development.

    I indicated that we are doing studies in the National Toxicology Program where we are looking at the effect on developing embryos in mouse model systems. And indeed, we are detecting problems in development.
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    Mr. PORTER. Well, this again is outside of your responsibility, but why couldn't your Institute recommend to EPA the chemicals that appear most benign at this point in time, and why couldn't we limit the spraying of those chemicals even though we do not know for sure that they are benign and not allow the spraying of those we do not know anything about?

    Dr. OLDEN. Well——

    Mr. PORTER. Or do we already do that?

    Dr. OLDEN [continuing]. The strategic investments that I outlined, Mr. Chairman, would allow us to provide you and regulatory agencies with that kind of information. One of the investments that I identified was the need to determine exactly what it is that the American people are exposed to.

    What body burdens do all of us have? That investment would allow us to know whether to prioritize. In fact, that is what it would do, would allow us to set some priorities as to which chemicals are likely to be harmful to humans based on actual uptake into our bodies and into cells and tissues.

    Without the kind of data that I outlined in the strategic investments, we simply do not have the information.

    Mr. PORTER. So what you're saying is our knowledge base is just not strong enough yet, but we are working on it. We will have some answers as a result of this survey?
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    Dr. OLDEN. The first exhibit talks about the gap. It indicates there is a major gap between public policy and science. Public policy is, in almost all cases, out in front of the science.

    And that simply is a reflection of the fact that we have not made the investment to answer some of the fundamental questions and issues that ought to be answered about the environment.

    Mr. PORTER. If we doubled the resources at your disposal over the next five years, presumably you would be able to speed up the process of discovering the answers to these questions.

    Dr. OLDEN. Absolutely. We have had this discussion with Dr. Varmus. And with the budget increases that the President proposes, we plan to invest in those issues that we have outlined in the strategic investments.

    Mr. PORTER. Thank you, Dr. Olden.

    Mr. Stokes.

    Mr. STOKES. Thank you, Mr. Chairman.

    Dr. Olden, nice to see you and your colleagues.

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    Dr. OLDEN. Thank you.


    Mr. STOKES. Let me start by asking you about lung hemorrhage in infants. Is that a matter of which your institute has become aware? As you may know, about one-third of the cases, nationally, are in the Cleveland area, and about one-half of them are around the Great Lakes area. Can you tell us whether or not this is a matter that you have inquired into or conducted any research?

    Dr. OLDEN. Yes, we are aware of it. We know that it is caused by a mold due to dampness, damp conditions. And we have provided some support to a physician in the Cleveland area to look into this issue and mostly to generate case reports.

    Dr. Fauci probably would be the person who is doing the most because it is a biological, although we certainly are making some investments. We are providing one physician in the Cleveland area with some resources to build a database.

    Mr. STOKES. Has any part of your budget been directed to support this operation?

    Dr. OLDEN. Yes, a very small portion. And I do not know how many dollars we are providing the physician, but that would be the only portion of our budget that is going into this effort.

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    But we looked into it about two years ago when it first appeared.


    Mr. STOKES. Okay. We will probably pursue this further with Dr. Fauci when he comes up.

    Dr. Olden, as you are keenly aware, environmental justice remains a primary concern, especially as it relates to children's health. Environmental hazards must be clearly defined. What type of projects are needed to provide the database to facilitate the identification of environmental hazards that threaten children's lives, or rather, their health?

    Dr. OLDEN. As I indicated in part to my answer to Congressman Porter, the major threat to children is lead poisoning. And we have a number of research efforts to address that, and let me come back to it.

    Asthma would probably be second. Exposures to pesticides would be third. There we are concerned about cognitive development and embryonic development. And the fourth would be susceptibility, and we are addressing all of those—susceptibility in terms of behavior, susceptibility because of differences in metabolism.

    And we have research programs to address all of them, Congressman Stokes. With 15 other institutes in the National Institutes of Health, we initiated a study to look at the genetic basis for susceptibility.

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    We are supporting research grants to look at the effect of behavior on exposure and, in other words, uptake due to children's behavior is very different. We have a number of projects on asthma.

    We are collaborating with the National Institute of Allergy and Infectious Diseases on the Inner City Asthma Study and two asthma research centers. For example, we have three centers in New York.

    They are in the Manhattan area at Columbia University, Harlem Hospital, Albert Einstein College of Medicine, and one is in the Bronx at Mt. Sinai. And they are looking at the health effects of asthma.

    Air pollution is another major problem in children with asthma, and so we have a number of research efforts, as you know, to look at the health effects of particulates and ozone and acid aerosols on respiration and pulmonary dysfunctions.

    So we have a substantial program, and I think we are addressing the four or five major health threats to children.


    Mr. STOKES. How about those children who are classified as being socioeconomically disadvantaged? Is there any emphasis on that category?

    Dr. OLDEN. Yes we have one special asthma project called The Five-Cities Study that focuses exclusively on children that are socioeconomically disadvantaged. But I would say the overall thrust of our inner-city asthma project is focused on socioeconomically disadvantaged children.
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    The lead studies focus on socioeconomically disadvantaged children because that is where the problem is today. It is not a problem of middle class families as a rule. It is in the inner city—it is an urban problem.

    Asthma the same way; it is thought to be mainly associated with indoor household allergens, such as cockroach allergens. Such allergens may not be a major problem that we have in middle class communities.

    Well, many years ago, we felt that there was a connection between the fact that poor people, socioeconomically disadvantaged people, live and work in the most hazardous environments and surely those exposures are at least in part responsible for the disparities in health outcomes.

    And so we created three to four programs to address that issue. One, we created a developmental Centers Program to encourage academic health science centers to go into low income communities to address some of the health problems encountered there.

    We have three such centers—the center at Harlem—collaboration between Harlem and Columbia University is one such center. We also have a center in New Orleans that is also of that type. We also created a grants program to encourage partnerships between academic health science centers and communities.

    One example, we have such a grant in upstate New York that is looking at the effects of PCB's in pregnant women on development of the fetus. And that is funded by us through the partnership. We have a partnership in California at the University of California at Davis that is focusing on the health effects of pesticides on farm workers, which are about 90% minority and poor and Hispanic.
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    That center has developed a test to improve or standardize—a test called acetylcholine esterase which is a biomarker for exposure to pesticides. So the University of California at Davis scientists have developed a test that is now used by the state to—that is more reliable than the previous test to estimate exposure to pesticides.


    Mr. STOKES. Dr. Olden, as the Nation prepares for the new millennium and Congress debates the need to nearly double the NIH budget, what is the condition of the basic and clinical biomedical researcher's pipeline as it relates to the researchers under the purview of your institute?

    Well, I guess what we would like to examine what your institute is doing to promote increased biomedical research opportunities?

    Dr. OLDEN. Well, first of all, we are participating in all of the programs that are sponsored by the NIH—for example, the MARC and MBRS programs. We are also supporting a program that I think is unique and very promising called the Meyerhoff Program at the University of Maryland—Baltimore.

    We are providing support for that program. And that program has been very successful. I think it is a national model as to how to get minority children into biomedical research.

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    We also are creating a new program called the ARCH Program. And that program is created to form a partnership between a research intensive university and a minority serving institution.

    For example, we expect organizations like the institution Morehouse in the Atlanta area to form partnerships with an institution like Emory, or Meharry to form partnerships with organizations like Vanderbilt.

    But the objective of the ARCH Program is threefold. And one is to increase quality teaching and research at the minority serving institution. It is to provide a larger pool of qualified applicants for the research intensive university.

    And in the end, we hope we will establish an infrastructure, a partnership, between a research intensive university and a minority serving institution that will be long lasting. And think, if every state just provided training to two nationally competitive minority scientists per year, we would not be having the problem that we are talking about today—just two.

    So we hope that after our grants programs are no longer in place, that these partnerships between institutions, let us say between like Meharry and Vanderbilt, will be long lasting.

    Mr. STOKES. Thank you.

    Mr. PORTER. Thank you, Mr. Stokes.
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    Mr. STOKES. Thank you, Mr. Chairman.

    Mr. PORTER. The Chair would like to exercise a prerogative and recognize some students over in the corner who are here under the Close Up Program from the 10th congressional district of Illinois. We welcome you.

    Mr. Hoyer.

    Mr. HOYER. Who represents the 10th district of Illinois?

     Mr. PORTER. I cannot imagine. (Laughter.)

    Mr. HOYER. They are well represented, the 10th district of Illinois, I can tell them that.

    Mr. PORTER. Thank you, sir.


    Mr. HOYER. Mr. Chairman, thank you.

    Dr. Olden, I apologize for being late. I was chairing the Caucus which ran a little over time.

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    You mention Pfiesteria in your statement, and you mention the eastern shores of our country, the Atlantic coast. Obviously the Eastern Shore for a Marylander is the Maryland Eastern Shore; for Virginia, the Virginia Eastern Shore.

    But North Carolina, Virginia, Maryland in particular, as you point out in your statements, had a real problem. We have tried to get some additional funds made available to CDC and to other agencies.

    Could you bring me up to date on where you think we are on Pfiesteria?

    Dr. OLDEN. We started working on Pfiesteria in 1993, I believe, when there was an outbreak in North Carolina. We joined forces with Dr. Joanne Burkholder, who is the scientist who first identified this organism.

    Mr. HOYER. Right.

    Dr. OLDEN. And we have to date succeeded in isolating at least two fractions. There is a dermonecrotic fraction, and then there is a neurotoxic fraction. And so we have those two fractions isolated.

    We have with other institutes in the National Institutes of Health—and there are at least four of us involved in these efforts—initiated studies. The bottleneck had been having the isolated, purified fractions in large enough quantity that we could do toxicity studies.

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    And we now have those fractions and we have them in large enough quantities to do toxicity studies. We are now doing studies in sheep—inhalation studies, for example. We are also doing studies in mice and rats—memory studies using skin paint.

    Some clinical studies using PET scans have been done at University of Maryland-Baltimore and Johns Hopkins, and these studies were supported by a number of institutes and not just NIEHS.

    So the problem is the following: Pfiesteria has 24 life stages, and we can only recognize one of them. So what we need to do is develop a biomarker to identify all 24 life stages. So there needs to be an effort to maybe clone the genome of Pfiesteria.

    And so that is one thing that is being proposed, and obviously all 24 different life cycles will have the same genome. Whereas, any other biomarker may not work.

    The other issue that needs to be worked out is what are the growth conditions. Exactly what conditions promote the growth and proliferation of the infectious form? And we do not know what that is. But now we are beginning to grow the organism under laboratory conditions where we can control the nutrients and we can figure out what the growth conditions are accurately.

    Mr. HOYER. Doctor, obviously this is a very timely issue in terms of the nutrients and what is causing it as it impacts farmers——

    Dr. OLDEN. Yes.
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    Mr. HOYER [continuing]. Who raise livestock or have livestock, whether it is chickens or pigs or other farm animals on their property and the nutrients that flow into the Chesapeake Bay or to other tributaries or other waterways.

    Dr. OLDEN. Yes.

    Mr. HOYER. How soon do you think we are going to have answers which can be relied upon by policy makers as definitive enough to make policy?

    In other words, I know you will not be sure 100%, but policy makers will be making judgements at the Federal level and certainly in our state, and I know in North Carolina, Virginia and other states as well.

    Dr. OLDEN. Well, this is a guess and I probably should not do that. My guess is in one to two years we will understand the health effects of the isolated chemicals and we will know what the growth conditions are.

    Mr. HOYER. Okay.

    Dr. OLDEN. And if we choose to go after the genome, we can also isolate that.

    Mr. HOYER. Okay. Well, I think that is helpful in terms of policy makers knowing what time frame they are dealing with. And maybe they are going to have to act sooner than that without full knowledge acting safe—I frankly think Governor Glendenning, for instance, acted correctly.
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    We do not have all the facts, but if the worst case scenario turned out——

    Dr. OLDEN. Right.


    Mr. HOYER [continuing]. Then we would be lamenting the fact that we did not act waiting for definitive answers. So I thank you for that, Dr. Olden.

    Doctor, let me follow up. Obviously asthma is of great concern to you. I have asthma. Vic Fazio, one of my closest friends in the Congress who is leaving, is also a asthma sufferer. Both of us came from, I would presume, relatively middle class homes. Not advantaged homes by any stretch of the imagination, but middle class homes.

    I lived in New York City until I was nine. I lived in Greenwich Village in housing that was decent housing, not bad housing. One of the things that interests me and I talked to doctors about it is the extent to which you believe there is a psychological component of asthma.

    I have found the more traumatic environment in which I am living at a given time, the more likely I am to have an asthmatic problem. And I do not know whether that is psychosomatic or whether it is in fact a causation.

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    Dr. OLDEN. Well, I am not the person to comment on that. But let me just say——

    Mr. HOYER. You mean personally diagnose me? No, I was not looking for that. [Laughter.]

    And I thank you for your forbearance.

    Dr. OLDEN. Having a child who is asthmatic, it does appear to be a stress related issue. But asthma is not an illness that is limited to one socioeconomic class versus another.

    Now it is a fact, however, that in urban, inner city areas, that asthma is in crisis proportion. For example, in some parts of New York City. And that is probably environmentally related. The New York Times has been running a series of articles recently about the conditions in New York.

    And in some parts, it is two or more times higher than the national average. However, the incidence of asthma is very high in regions of New York that are mixed use—where there is housing, there is industry, there are waste facilities.

    And so it is probably related to diesel exhaust, soot, particulates, acid aerosols, as well as kids having the predisposition, as many of us might have. And if we are placed because of socioeconomic reasons in environments in inner city, we might have an allergic response.
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    Mr. HOYER. Doctor, last question because, as you know, the EPA has recommended tighter standards for air quality. In the course of that consideration, one of the things that the opponents of the tightening of regulations have argued is that as the air has gotten cleaner, more particulate free, asthma statistics have gone up.

    Now, I do not know that you can. Obviously, I do not necessarily believe you can have a correlate between the two, but how would one view those statistics, as unrelated and irrelevant to one another?

    Dr. OLDEN. Well, it is a fact that nationwide the air quality has greatly improved, and nobody can deny that. But in some inner cities automobile use, diesel buses, dilapidated housing, and poverty are also risk factors.

    And that may be what is occurring now. I mean, if you look in the parts of New York City where asthma is in epidemic proportions, all of those factors are involved. If cockroach allergens are important, and our studies demonstrate that indeed they are, that is a major problem in upper Manhattan and the Bronx.

    Particulates that EPA wants to regulate are certainly a huge problem because of use of diesel buses and automobiles, incineration and other issues. So it is not clear why asthma rates are increasing because the air is indeed getting cleaner.

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    Mr. HOYER. Thank you, Doctor.

    Thank you, Mr. Chairman.

    Mr. PORTER. Thank you, Mr. Hoyer.

    We will have a second round. Are each of you going to stay for the second round? I understand Mr. Stokes will.

    Mr. HOYER. I have to go in ten minutes.

    Mr. PORTER. Pardon me?

    Mr. HOYER. I have to go in ten minutes, but I do not have any additional questions.

    Mr. PORTER. All right. We will then divide the remaining time.

    Mr. Stokes, do you have another place where you are expected?

    Mr. STOKES. I am going across the hall to another hearing.

    Mr. PORTER. Then why don't you proceed right now for seven or eight minutes.

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    Mr. STOKES. Fine. Thank you, Mr. Chairman.

    Dr. Olden, recently, there has been a growing effort by some persons in the environmental community to have Congress establish a National Institute for the Environment, particularly over on VA/HUD appropriations subcommittee on which I sit.

    Are you aware of this?

    Dr. OLDEN. Yes, I am.

    Mr. STOKES. This issue continues to be brought before Congress, particularly those of us who serve on that subcommittee.

    I just wondered if, in your professional judgement, you can give us some insight as to whether you see a need for both a National Institute for Environmental Health Research and a National Institute for the Environment, separate from the NIEHS; and if so, why?

    Dr. OLDEN. Let me comment on the need for the science and limit my remarks to that.

    There is a need for additional research in the Federal Government on ecological issues. That is an area of research in the environment that is indeed under funded. It is presently supported, to the extent that it is supported, by the EPA and NSF.
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    It appears to me that infusion of resources to either one or both of those agencies could get the science that is needed done. There is a need for the science. Do we need another agency? There are two agencies that are already in place.

    And certainly the NSF has an excellent track record of supporting peer reviewed research like the NIH, and so that would be, in my estimation, a reasonable place to put such a program.


    Mr. STOKES. Okay, thank you.

    Let me ask you this. There have been some recent articles noting an association between miscarriages and the byproduct of water chlorination. Tell us what research is underway at the NIEHS to help address this public health problem.

    Dr. OLDEN. Yes, there is a report out of California that was conducted by the State Department of Health demonstrating that increases in trihalomethane levels in the drinking water has increased miscarriages by about twofold.

    Now, that is a preliminary result and it needs to be confirmed. However, in our National Toxicology Program, we have for a long time been looking at chlorination and other disinfectant by-products.

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    At the present time, we have about 14 such products under study in the National Toxicology Program. We are looking at carcinogenicity, as well as reproductive health problems.

    So it is a major effort underway in NIEHS, and we have asked NTP to look at these disinfection by-products. And some of them have indeed been demonstrated to be toxic. Trihalomethanes, for example, at very high doses, are certainly carcinogenic, as are other by-products.

    But the point is that the levels at which we are exposed are important. The real issue is dose-response relationships and the NTP is studying this.


    Mr. STOKES. I notice, Dr. Olden, that the highest reduction in research grant award success rates over the last ten years occurred in NIEHS. The rate reduced by half from 28% in 1990 to an estimated 14% in 1999.

    Tell us what has caused this decrease and whether it is a reflection of a reduced priority in environmental health research project grants.

    Dr. OLDEN. No, it is not the latter.

    In 1991, about 300 plus grants were referred to the institute through the NIH review mechanism for funding decisions. Now about 900 grants are referred to our institute for funding decisions. So the number of grants referred to the institute have gone up about threefold.
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    Now the budget has gone up significantly during the same period of time, but obviously I think it reflects that the institute has attracted many more outstanding investigators. We have expanded our mission in sense of our priorities. I would say in '91, '90 we mainly focused on cancer as the disease end point.

    And I promised you five or six years ago in 1992 that we were going to begin to emphasize other disease end points such as asthma, reproductive health, and immune toxicity. And we have done that.

    And as we have done that, we have begun to attract scientists who are also co-funded or funded by other institutes in the National Institutes of Health. For example, we have attracted a number of new grantees who are funded by Child Health, for example, as we broaden our interest to developmental problems.

    So I think it is a reflection mostly of increased interest on the part of the scientific community in the research objectives and mission of NIEHS.

    Dr. VARMUS. May I comment briefly, Mr. Stokes, about this?

    Mr. STOKES. Sure, Dr. Varmus.

    Dr. VARMUS. The NIH is acutely aware of the problem faced by an investigator whose grant is assigned by our Center for Scientific Review to an institute whose success rate may not be as high as another institute which might legitimately also fund a grant in that area—for example, a grant on the effect of environmental agents on development.
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    At last year's leadership retreat, the Institute directors discussed this problem. We have agreed that, in addition to the existing mechanisms for possible co-funding of grants and for sharing of grants, we would find some way to make completely transparent to all Institutes those grants that are falling below the pay line in other Institutes so that there can be an easier mode of access for investigators to have access to the resources of an Institute to which their grant was not initially assigned.

    Mr. STOKES. Thank you, Dr. Varmus.

    Thank you, Dr. Olden.

    Thank you, Mr. Chairman. I have a number of other questions which I will submit for the record.

    Mr. PORTER. Thank you, Mr. Stokes.


    Mr. HOYER. Mr. Chairman, could I ask one question before I go?

    Mr. PORTER. Absolutely, Mr. Hoyer.

    Mr. HOYER. Doctor, I did not follow up on the question I should have. On the Pfiesteria issue, would it be useful, would it accelerate, would it in any way enhance the dealing with Pfiesteria if you had additional resources? In other words, could they be applied to some meaningful objective that you cannot now——
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    Dr. OLDEN. Well, I think the NIH and the department—and that case needs to be made—have made a substantial contribution to our understanding of the Pfiesteria outbreak. And I think the issues that need to be addressed in this area are being pursued by agencies in the department.

    Mr. HOYER. So could the department use more resources?

    Dr. VARMUS. You can say yes. [Laughter.]

    Dr. OLDEN. Yes, and I think the department has an outstanding record of performance on this issue, and we have done well.

    Mr. HOYER. Thank you, Doctor.


    Mr. PORTER. Thank you, Mr. Hoyer.

    Dr. Olden, several years ago we talked about the mutations of animals that had been found. One was a frog mutation discovered by Minnesota school children in 1995, and then there was a book that came out that described other mutations that had been discovered.

    What can you tell us about our knowledge base in reference to that issue or question?
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    Dr. OLDEN. Well, this has been an interesting year in that regard. We, as I indicated to you a year ago, I believe, had developed a partnership with the State of Minnesota.

    That is not the only state where deformed frogs have appeared. I think 32 such states have reported frogs that are deformed or have extra limbs.

    But we tested the water from various sites in the state in the region where deformed frogs were found and, under laboratory conditions, we were able to demonstrate that the water indeed would cause deformities.

    We do not know what the causative agent is, however. Studies are underway now in collaboration with the Environmental Protection Agency and CDC to figure out what the causative agent is.

    Turns out that very slight manipulations, for example, of the salt balance, can create deformities so it is not going to be easy to figure out, but I think it will be resolved in a cooperative fashion in a very short period of time.

    Mr. PORTER. So when I ask the question next year, you will have the answer?

    Dr. OLDEN. I should hope so.

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    Mr. PORTER. If there is an answer.

    Dr. OLDEN. I should hope so.


    Mr. PORTER. In your budget justification, your institute, the EPA and CDC are spearheading a large children's program in response to the President's Executive Order on Children's Health and the Environment.

    Centers will be established which will focus on environmental influences on asthma and other respiratory diseases, childhood learning, and growth development. Planning a new program provides you with a prime opportunity to implement the Government Performance and Results Act. What performance standards and outcomes measurements are being established to comply with GPRA in this new program?

    Dr. OLDEN. Mr. Porter, NIEHS, like all the other institutes, has a planning process and we have documents that are developed in response to that. However, we have not set specific goals because we have gone in with the other institutes, all 24 units of the NIH, to establish aggregate targets and goals.

    And I think that is appropriate given that the three activities that NIH is involved in—research, training and support facilities—is not something that is limited to the boundaries of institutes.

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    So we are required to contribute to the NIH goals and priorities. And so I think it is appropriate that our goals and priorities be folded into the NIH aggregate goals and priorities.

    Mr. PORTER. But if you have a new program that you are jointly sponsoring with several other institutions, could not that program and should not that program have performance measures and standards written into it at the time the initiative is set up?

    Dr. OLDEN. Yes, sir; and we do.

    Dr. VARMUS. Perhaps I should comment briefly about this.

    Mr. PORTER. Please.

    Dr. VARMUS. We did not talk about GPRA yesterday.

    One of the things that we have done is to establish what we call ''means goals''. That is, goals for those components of our activities that are required to achieve the goals of understanding, preventing, treating disease.

    Among those might be, for example, the means goals of establishing a certain number of centers under this program, reviewing a certain number of projects, establishing activities. We think those are very useful indicators of how well the agencies are functioning.

    In that case, NIEHS would obviously be a component of the mechanism used to achieve those means for achieving our long term goals.
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    Mr. PORTER. And I suppose outcome measures would be much more difficult or impossible to——

    Dr. VARMUS. They are more difficult.

    We have some cases where we believe the quantitation is appropriate, but those are a limited number of circumstances, to find those.

    For example, in the context of genomic work—where it is possible to say, as the Genome Institute has said, that we would like to establish the complete sequence of the human genome, all three million base pairs, by 2005—we can set up some milestones.

    The difficulty there is, of course, as you know, the GPRA plan calls for annual goals. But we can try to establish some milestones and we have done that in some cases. Or, in Dr. Olden's case, a similar kind of goal might be to say that we will have a certain number of newly developed transgenic models for more rapid environmental testing.

    Now that is a little different from saying we will have the new tests in place, but we will at least have the tools. And those kinds of measures in very limited circumstances, we think, are useful indicators for how well our scientists are doing.

    But we are much more reluctant to try to develop specific quantitative goals for achieving our long range objectives for improving health. It actually provides a very dangerous precedent for making our science conform to the regulatory process or to the oversight process rather than having the oversight process look at how well we do in——
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    Mr. PORTER. Discovery cannot be programmed according to a schedule, obviously.

    Dr. VARMUS. And we do not want it to end up being the tail that wags the dog.


    Mr. PORTER. Dr. Olden, you instituted two major external reviews of your institute this past year. One group is assessing the institute's research programs with special emphasis on the appropriate balance between extramural and intramural research. The other one is evaluating the epidemiology program to determine if the current resources and staff are appropriate to meet the challenges and opportunities developing in environmental epidemiology.

    When do you expect to have the results of these reviews? Do you plan to expand this concept to look at other management or scientific issues? What is the reason for undertaking this review? And are you aware of any other institutes undertaking similar reviews?

    I can go back through those one by one if you want.

    Dr. OLDEN. No, these two reviews represented the end of a long process. We started this process in 1991–92. We have had every single entity with one exception reviewed. The one entity that is yet to be reviewed, but we have been advised to have that group reviewed, is our extramural program, our grants program.
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    We will have that done. The epidemiology review is complete. It is in hand. And it was an excellent review. The overall review of the institute by the institute's advisory council—working group of the advisory council—is also in hand.

    And we just received it, and I forwarded it to Dr. Varmus about two weeks ago. We are preparing a response to that review. It was an outstanding review. It was good. It was thorough. It was comprehensive.

    And it was by an outstanding group of people, and they recommended things that we can do to make NIEHS the very best institute that it can be. And that is exactly what we asked. It was one of the charges that we gave to the committee. So we do not plan to have any other reviews because this was the end. Remember we had the National Toxicology Program reviewed. We reorganized the institute. We had the report on carcinogens reviewed.

    And so we think, with the final review, which is an over arching review, that we now have a blueprint to really move the institute forward in the year 2000 and beyond.


    Mr. PORTER. NIH also had a management and structure review by an outside consulting firm, did it not?

    Dr. OLDEN. Yes, it did.

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    Mr. PORTER. Presumably this management review gave advice not only to NIH generally, but to each of the institutes, is that correct?

    Dr. OLDEN. Yes.

    Mr. PORTER. Have you seen what advice they have given you?

    Dr. OLDEN. Yes.

    Well, one of the recommendations was that we use more service group units. In other words, the institutes come together, and rather than duplicating, we share services—centers.

    And we were already doing that. But I think we were already doing that in response to previous reviews. We have subjected our institute to an awful lot of reviews over the years. And we were already using service centers. We were servicing the human genome. We were using ones in Heart, Lung and Blood.

    So I think we had already had service centers. Over the years, I have been trying to find resources to do the important things that I talked about. In order to do that, we have taken a look at management to make sure that we are managing the organization as efficiently as possible.

    We are close to it. I think the final review made some recommendations, and we will follow them, absolutely. So we are using service centers.
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    Mr. PORTER. Dr. Varmus, are you satisfied with what NIEHS is doing in this area?

    Dr. VARMUS. They have been very active in review processes.

    I have mandated only a few kinds of reviews for all institutes to take part in, and one is review of their intramural program by experts in addition to those investigators who normally are serving as boards of scientific counselors and review of institute directors every five years.

    The other reviews are made in response to specific problems posed by certain institutes. For example, you may recall that four years ago we asked the Cancer Institute to carry out a review of the way in which it was organized and the way in which the intramural and extramural components were built into divisions.

    But Dr. Olden is to be congratulated for carrying out very vigorous reviews of many aspects of his program.

    Mr. PORTER. I think Dr. Olden thinks he is over reviewed. [Laughter.]

    Dr. OLDEN. I do not, but some people in the Institute think so. We are never over reviewed. [Laughter.]

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    Mr. PORTER. Dr. Olden, one final question. There are thousands and thousands of chemicals in use in America today.

    Dr. OLDEN. Right.

    Mr. PORTER. When you discover a chemical that is a carcinogen, can't industry simply create another one? And if this is the case, can you ever catch up with this game, or can you isolate chemicals by groups and say that if, for example, they contain chlorine—the whole group is likely carcinogen and should not be used?

    How do you address that?

    Dr. OLDEN. That is exactly what is occurring. Industry clearly—it is not in their best interest from a profit point of view to create products that have to be removed from the market or products that harm people.

    And that is not their intent. So now there is close collaboration discussions between Government and industry, and we are using the same resources, and we are trying to identify those chemical groups that are problems.

    And although I did not talk about them here today, we are developing tests to predict toxicity in advance of synthesizing and making a chemical. Industry is in partnership with us, EPA and FDA to do that work.
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    So we will be able to predict and know in advance so that industry will not, in the future, create as many harmful products as we have in the past.

    Mr. PORTER. Is there any way to give us a time line as to when we will be at that point?

    Dr. OLDEN. Well, our predictive capabilities are very sophisticated already. When we will be able to never make a product that is harmful, that we can never guarantee down to every single chemical because the capacity of industry to make chemicals now is unbelievable.

    I heard a number, something like seventy to eighty thousand new chemicals can be made now by industry pharmaceuticals in one year because, you know, they just make slight permutations of a chemical and they have a way of doing that that we did not have a few years back.

    So we must be more sophisticated in predicting toxicity because otherwise we are just going to be swamped with a mountain of things that we do not know anything about the toxicity of.

    But I am optimistic that we are going to do the science that I outlined on that board. It is going to get us through testing for all the things that have been made in the past, and there are seventy-five or eighty thousand chemicals out there that we know very little about.
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    Mr. PORTER. Well, Dr. Olden, I think you have made an excellent presentation of your Institute this morning. I think that if people look at the responsibilities you have, your Institute can make an excellent argument that more resources will bring more results. And obviously there is a lot of risk out there that if we can understand it better, we can protect people and their health in the future. So, Dr. Varmus, I think you should use Dr. Olden and his Institute, as a prime example of why more resources will mean more results.

    Thank you very much.

    Dr. OLDEN. Thank you very much.

    [The following questions were submitted to be answered for the record:]
    "The Official Committee record contains additional material here."

Wednesday, March 11, 1998.





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    Mr. PORTER. We are pleased to welcome the new Director of the National Institute on Deafness and Other Communication Disorders, Dr. James F. Battey. This is his first appearance before the subcommittee. Dr. Battey, we are delighted to see you. Would you introduce the people who are with you and then proceed with your statement, please?

Introduction of Witnesses

    Dr. BATTEY. Thank you very much, Mr. Porter.

    It is indeed a pleasure to be here and have an opportunity to present our research to the subcommittee. On my far left is Ms. Patience Sparks, who is our budget officer of the NIDCD; Mr. David Kerr, who is our Executive Officer; Dr. Donald Luecke, who is the Deputy Director of NIDCD. And of course you know Dr. Varmus and Mr. Williams on my right.

    I am really honored to have an opportunity to appear before you today as the newly appointed Director of the National Institute on Deafness and Other Communication Disorders.
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Opening Statement

    And I am pleased to be able to present the President's budget request for the NIDCD for fiscal year 1999 representing the sum of $213.8 million dollars which is an increase of roughly $15 million above the FY 1998 appropriation.

    Communication skills will be central to a successful and fulfilling life in the new century for all Americans. For the 46 million Americans with communication disabilities, however, facing each day can be a challenge. The simple acts of speaking, listening or making their wants and needs known are often impossible for these individuals.

    For those who cannot speak without stuttering, or for those who are unable to express ideas clearly after suffering a stroke, or those who cannot use their voices to talk with a friend on the phone due to a voice disorder, or the devastation of throat cancer, each day poses a challenge.

    Similar challenges are faced by children who have autism and consequent language disabilities, as well as for their families who must care for these children. For an older person, loss of their sense of balance can result in falls and fractured bones, and a loss of hearing can result in isolation.

    For the young child who begins a struggle with language acquisition that without proper intervention will be a lifelong struggle, communication disabilities pose a constant challenge.
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    The NIDCD has made important progress in understanding and helping to develop better treatments for these disorders of human communication this year, and we have identified new targets, new tools and new teams to accelerate discovery in fiscal year 1999.

    For example, we now are using the advanced neuroimaging tools to image the brain at work during normal and disordered human communication. These studies have taught us that much of the brain is used for hearing, balance, voice and speech, and the manipulation and production of language, as well as the ability to smell and taste.

    Having the ability to image brain activity patterns during various communication events or disorders such as stuttering, or aphasia, or ringing in the ear or tinnitus, or imaging the use of Americans using American sign language is revolutionizing our understanding of normal and disordered processes of human communication.

    In one of many remarkable advances this year, NIDCD scientists have been able to visualize brain activity that is correlated with tinnitus or ringing in the ear.

    In another remarkable study, an intramural investigator showed that individuals who stutter have a completely different brain activity pattern associated with speech production whether or not they are fluent or dysfluent.

    NIDCD supported scientists are determining the properties of remarkable and unique sensory cells of the inner ears that we call hair cells that are shown on the electron micrograph to my left. And I think if you look at the cell, which is really very unique, you can understand why biological scientists call it a hair cell.
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    It is that hairy structure or cluster of sterocilias that is absolutely critical for auditory signal transduction. When the tips of those stereocilia get deflected, that results in an electrical stimulation of the cell which sends the electrical information into the brain, and that is in fact how we hear and how we maintain balance.

    Very often, it is the loss of these unique hair cells in the inner ear that lead to hearing impairment and balance disorders. And our scientists are working hard to try to understand what the molecular mechanisms might be that would allow these cells to regenerate.

    We know that in birds, these cells can regenerate. And within the last year, even in some mammals, scientists have been able to effect regeneration of hair cells after they have been damaged. And we think this is a very exciting new area of research.

    Now in a very different way, NIDCD scientists are also trying to restore hearing through support and development of the cochlear implant, and this has been research that has been ongoing for the last several decades.

    The cochlear implant is a sensory neural auditory prosthesis that we now know improves the economic and social outcomes for postlingual hearing impaired individuals. And I direct your attention to the second exhibit on my left.

    Let me tell you a little bit about how the cochlear implant works. If you look at item number one, you have a microfilm that detects the sound. The sound is then sent to item number two, which is a speech processor.
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    And that speech processor converts the sound into electrical energy; which is then sent to number three, which is a radio transmitter; which transmits the information across the skin into a receiver, which is item number four; then sends the information to an array of electrodes, sometimes as many as 22 electrodes, which a surgeon has inserted into the cochlea, which is the structure in the inner ear where the hair cells are where the hearing happens.

    And these electrical impulses are changed with a time—with a doubling time of less than a millisecond so that the information is now being delivered to the cochlear structure in a way very similar to the way that information was delivered before the hair cells were lost.

    This device is truly remarkable. And individuals who lose their hearing, suddenly, they are able to stay in their jobs. And in fact, over 60% of them are still able to use the telephone after they have had the cochlear implant installed and had proper training in its use.

    NIDCD continues to investigate the development of language in children who are deaf or hard of hearing. We now know that, within the first six months of life, there is a critical window of opportunity for language acquisition, either spoken or signed.

    As I am sure you are well aware, a number of states are currently implementing universal newborn hearing screening which begins with a test for auditory function very soon after birth.

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    In 1998, NIDCD supported scientists will complete a five year study showing that two methods, measurement of otacoustic omissions, which are sounds that those hair cells make themselves, or auditory brain stem responses, which is the electrical activity moving through the brain stem associated with hearing—we can use these tools to accurately identify infants in the newborn nursery who have hearing impairment.

    And this, we believe, will stimulate clinical research into what the proper intervention strategies might be to help these infants get the greatest language acquisition ability that they can have as they progress through life.

    Our institute has also made progress in studying specific language impairment. Specific language impairment is a deficit in language acquisition that is present in about eight percent of American school age children.

    And what it is, is a deficit in language acquisition that is independent of any other cognitive defect. It is very frustrating for these children. They often get turned off to schools or maybe leave school earlier than they would have because they struggle with these language disabilities.

    What we have learned is that specific language impairment is often caused not by any sort of language problem per se, but it is an inability of these individuals to process rapidly changing auditory information which occurs during normal human speech.

    What that suggests is maybe, by slowing down the rate at which the auditory information comes in, we may be able to train these individuals to improve their language acquisition skills and hopefully restore a language acquisition in these children.
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    I am sure every one of us who is a parent in this room is aware that otitis media, or middle ear infection, is the most frequent reason why a sick child visits either an emergency room or a pediatrician's office.

    The estimated total cost for otitis media is about five billion dollars a year. And the organisms that cause it are proving to be increasingly resistent to the conventional antibiotic therapy that has been used to manage this disorder.

    We continue our research efforts to try to develop vaccines against the organisms that cause otitis media. And we have observed that one of the most difficult aspects of treating otitis media is it so often relapses within days or weeks of when the antibiotics are taken off some of the children who develop otitis media. And we are currently investigating why these infections are both recurrent and resistent to treatment.

    In addition to new targets and new tools, new teams of scientists are providing collaborations to help us progress.

    Molecular genetics is now revealing the identity of genes involved in many disorders of human communication. The search for hearing impairment genes has been enormously facilitated by timely collaboration and information exchange among many of the NIH institutes and both our intramural and extramural laboratories.

    We see an opportunity to support teams who will work together now to understand the biology and genetics of voice, speech and language disorders and translate this into improved diagnostic and better intervention strategies in such disorders as velocardiofacial syndrome and autism.
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    New tools, new targets and, most importantly, new teams will be needed to rapidly and effectively seize the remarkable opportunity before us. We look forward to expanding our understanding of the biology and genetics of human communication disorders and to translate that knowledge into better strategies for diagnosis, early intervention and treatment.

    And I would like to thank you for your kind attention. And I, with my colleagues, would be happy to try to answer any questions you might have. And I would also bring to your attention this little box that I brought with me.

    Inside it has a metal cast of a human cochlea so you can see what it looks like and how small it is, as well as the electrode array from the cochlear implant that is actually inserted into the cochleas and the radio receiver that is implanted in the skull immediately behind the ear.

    So if you are curious to see it, I would be delighted to let you have a look.

    [The prepared statement follows:]
    "The Official Committee record contains additional material here."

    Mr. PORTER. Dr. Battey, thank you for your very fine statement. How long have you been with the institute?

    Dr. BATTEY. I have been at the NIH since 1983 and have been in a number of institutes. I arrived at NIDCD in 1995 when I was appointed by Dr. James Snow, my predecessor, as the institute's Director of Intramural Research or Scientific Director.
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    Mr. PORTER. When we met yesterday I said that you have great enthusiasm for your new job, and I think that is evident in what you told us this morning. You were in the room when Dr. Olden was testifying. I am struck by the fact that Dr. Olden's responsibilities seem more at the beginning of discovery, and your institute has come a long way toward reaching solutions to many of the problems of deafness and communication disorders. Do you see it that way also?

    Dr. BATTEY. I believe that there has been great progress. And the cochlear implant, I think, is one such manifestation of that progress. But I would be wrong in telling you that we have licked the problem.

    As I am sure you are aware, 20 million Americans or more have hearing impairment. Many of them would benefit from the use of a hearing aid. Only about five million of those individuals actually use the hearing aids.

    And the reason is that they do not like them. And they do not like them because they do not do what—they do not restore what is missing in these hearing impaired individuals. What has happened in the hearing impaired individuals is that the dynamic range of their ability to hear has shrunk.

    What do I mean by that? I mean that the difference in sound intensity between a sound that can barely be heard and one that is intolerably or painfully loud is teeny compared to the size in a normal individual.
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    So if you just put a device and a hearing aid that linearly amplifies everything—in order to hear the sounds you need to hear to communicate, you are going to amplify the louder sounds so much that they are painful and disturbing to the user.

    So clearly a lot of work needs to be done to design devices that more accurately replace the hearing loss that is missing.

    In the area of the genetics of hereditary hearing impairment, we are making progress, but we have a long way to go. As I am sure you are aware, roughly one child in a thousand is born with profound hearing impairment at birth.

    And all together too often, the cause is a genetic cause.

    Roughly 30 genetic loci have been identified by gene mapping studies to have hearing impairment genes. Within the last year, we have gone from locating to identifying about a half dozen of these genes.

    And there are a remarkably diverse group of proteins that do many different sorts of things within the cell that we can talk about in detail if you are interested, but I am just struck by how diverse they are.

    We need to find the rest of the genes. We need to determine what their importance is in auditory function. We need to determine why it is that they clinically manifest their genetic problem only in the inner ear and not elsewhere in the body; the same mutant genes are everywhere else.
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    Is it because they are only expressed there, or is it because their expression or function is somehow rate limiting in the inner ear? We then need to use this information ultimately when gene therapy moves from being really a laboratory exercise to reality towards the long term goal of maybe someday replacing these broken genes with functional genes and hopefully restoring the ability to hear in these individuals, assuming we do not get to them too late and the hair cells are not already gone and we cannot bring them back.


    Mr. PORTER. Where at NIH were these sites discovered? Were they discovered through Dr. Collins' work or your institute's work or a collaborative way?

    Dr. BATTEY. All of the above.

    It would have been impossible to discover any of these genes without the infrastructure laid down by the Human Genome Project. The nearly million expressed sequence tags in gene databases make the search in a large megabase interval of DNA for genes now possible simply by sampling DNA sequence within the interval.

    The mapping that I talked about of the 30 genes is only possible because we have evenly spaced markers or sign posts throughout all the chromosomes which allow us to determine a linkage or association between that sign post that we know where it is and the hearing impairment gene.

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    Now having said that, let me tell you a story about one of these genes called the DFNB4. The B stands for—it means it is an autosomal recessive which means you need to inherit a bad gene from both your mom and your dad to get the disorder.

    DFNB4, it turned out, our intramural scientists discovered, but only after Eric Green in the National Human Genome Research Institute cloned the gene for Pendred's Syndrome, which is a disorder of the thyroid abnormality that sometimes has hearing impairment.

    When we heard of Eric's discovery, we noted that the Pendred's gene was located in essentially the same place as DFNB4. And in advance of publication, Eric provided us with the sequence information of the gene that allowed us to determine that different mutations in that same gene caused non-syndromic hereditary hearing impairment.

    So in the genetic arena, there really are no institute boundaries. The scientists move very freely. And progress in one institute almost inevitably will lead down the road to progress in another.

    That is part of the excitement of doing that work.

    Mr. PORTER. Thank you.


    I have a question for Dr. Varmus that I do not want him to answer right now, but let me ask it right now.
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    In listening to Dr. Battey, it seems to me that, as a result of the mapping of the human genome, a couple that might be contemplating marriage will be able, at some point in time in the future, to determine whether they contain in their genome, defects that can lead with some degree of probability to an outcome that a child would be hearing impaired or have a particular disease or be susceptible to that disease.

    I wonder what the implications are for policy. I don't want you to answer it now because it is a rather long question, but sometime I would like to discuss it with you further. There are already bills introduced on genetic discrimination and the like, but I wonder what the implication of this might be in the future.

    Dr. VARMUS. It is not in the future, Mr. Porter; it is already here——

    Mr. PORTER. It is already here.

    Dr. VARMUS [continuing]. In some cases.


    Mr. PORTER. Yes, we will have to talk about it.

    Dr. Battey, you mentioned hair cell regeneration and it seems to me that I recall three years ago, maybe it was two years ago, when there was great criticism of a study that was being made of birds—I think it was canaries—in regeneration of hair cells. This was one of the issues that was highlighted on PrimeTime Live by Sam Donaldson as being charged with wasting of public money. Do you want to comment on that a little bit?
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    Dr. BATTEY. Yes, I would like to comment on that specific example, but then I would like to comment, if I could, on the use of animal models in biomedical research in general.

    First of all, I think that it is—hopefully it is obvious from my earlier comments that often animal models provide us with the means to discover important new ways to deal with human disorders that cannot be appreciated in human populations.

    And I think the hair cell regeneration in birds is a great example. Not only do we know that hair cells can be regenerated based on these studies done in birds, but the more important fact is that once the hair cells come back, they rewire and send their information into the central nervous system in a way that results in restoration of normal auditory function.

    And that is what is absolutely astounding to me is that either the cells can find a way to not only grow back, but to send the information in right; or the brain is sufficiently plastic, that it can readjust to this new set of regenerated hair cells and restore auditory function.

    Mr. PORTER. So the criticism that this was a waste of money may, in the end, prove to be one of the most important expenditures of money for science because this may lead to a discovery to regenerate hair cells and restore hearing in humans?

    Dr. BATTEY. That is absolutely true.

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    And let me cite another example because I think it is very important for our understanding of the genetics of hereditary hearing impairment. It turns out that, although much smaller than us, the ears of mice work pretty much the same way as the ears of humans.

    Now they can hear at somewhat higher frequencies, and that is an interesting question all unto itself. But other than that, structurally and functionally, they are really very similar. What does this mean?

    This means that we can use mice to help us identify the genes for human hereditary hearing impairment. And in fact, we are currently supporting a contract to screen all of the mice in the largest mouse repository in the world, the Jackson Labs, to identify strains of mice that have hereditary hearing impairment.

    And lo and behold, it is the same loci that we are mapping in humans, are mapping to their syntenic or similar locus in the mouse. In the mouse, as Dr. Olden showed you earlier, with much less expense, we can rapidly zero in on the location of the gene, enormously facilitating the time and the expense otherwise required to positionally clone those genes.

    The other thing we can do in the mouse which we will probably never be able to do in the human is we can prove it is the right gene and we can do that—I am sure you have heard of gene knock outs. Well, I am going to tell you about a gene ''knock in.''

    We can knock the functional gene back into the mouse genome and restore hearing. And in fact, one of our intramural scientists did that with another hereditary hearing impairment gene just within the last two months.
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    Mr. PORTER. That is truly exciting.

    Thank you, Dr. Battey.

    Mrs. Northup.


    Ms. NORTHUP. Thank you, Doctor. I have a couple of questions. First of all, I did notice that you all have done some work on SLI, the specific language impairment?

    Dr. BATTEY. Yes.

    Ms. NORTHUP. It affects three to six percent of our children that are in school. I was wondering, first of all, at what age can we diagnose that a child has that specific problem?

    Dr. BATTEY. I'm not a speech pathologist, so I'll merely speculate, and give you my—the best understanding that I have. But I think that problem can be diagnosed pretty much at the same time as language acquisition begins to come on board, which would be around two to three years of age.

    Ms. NORTHUP. I have a number of questions to follow up. For example, should schools be making this diagnosis? Should we screen every child? Is there an affordable test that would make it possible to efficiently screen every child for this type of disability?
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    It's clear to me that many of the children that have this, that are diagnosed with dyslexia, and we know that dyslexia often isn't diagnosed when it needs to be, at five years old, and so forth. It's much later. And that's very troubling to many children who don't read. Because they pick up bad eye patterns, and so forth.

    And unlearning is as hard as it is to learn the correct way to read. I wondered if you're communicating your findings on SLI to those whose primary role it is to educate our children. And if you're developing or testing strategies for remediation of these children, how do we apply that understanding of their difficulty in distinguishing phononyms, to how we teach them, then, in first grade, how to read.

    And if you were working at all with the panel that was established between the Department of Education and NICHD last year, to communicate on what the emerging science is regarding children that have learning disabilities, and what we do in our schools, in practice, you know?

    How do we connect what we learn with how we apply it?

    Dr. BATTEY. That is a large number of very important questions. I guess I'll answer the ones which I feel I'm best able to respond to directly.

    One of the exciting things about our determining, that in fact, it's an auditory processing defect that's behind specific language impairment offers an opportunity for us to more accurately make the diagnosis, and distinguish it from other things that can cause language delay.
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    So, I think that the recent break-throughs in research will provide a more accurate diagnosis. And were it appropriate to do screening, would provide a more accurate way to do the screening.

    As to who ought to do the screening, my understanding of the testing, and given the fact that it is an auditory problem, I would think that speech language pathologists and audiologists would be the appropriate group to be involved in doing such a screening.

    And as far as translating results into the public domain, we do that—scientists do that by virtue of publishing their results in peer review journals, thereby making the information available to health care professionals in other arenas. And that's been the traditional way that information has moved from the research arena, and into the—hopefully development of better treatment strategies.

    One investigator in particular, Paula Tallal, feels that a strategy for improving the language abilities of these children involves a strategy she calls fast forward. And what happens in that strategy is, the speed at which the language phonemes come in are slowed down with a computer.

    And in some of the studies she's done, and these are preliminary, and they have not yet been replicated by another investigator, so I hasten to place too much weight on them just yet. But if her results are right, they're very exciting.

    She is able to improve the language acquisition skills, by doing exactly that, by slowing down the rate at which the phonemes are introduced into the auditory system. And I think that if that holds up, that's pretty exciting, for either six or eight percent, depending on how, I guess, you diagnose them, of school age children with specific language impairment.
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    Ms. NORTHUP. When you have children that are dyslexic, what you find out is that there is an array of signs. And not all—all of them have a different collection of those signs. They are visual, you know? They're reversal. Everybody think dyslexics reverse—reverse letters.

    And actually, some do. But they don't all. Some are dysgraphic. And some, actually, you say, go to bed, and they think you said, the goat is dead. And you can understand why a child that works through this has reading problems.

    And you know, what we found last year is, that the Department of Education really was largely unaware of the research that was being done by NICHD.

    And that was the reason that this committee set up that panel, to make sure emerging research joined with the people that—whose real dedication in life is helping children all be successful.


    Do I have time for one more question? I have several friends that have been very involved in the Louisville Deaf Oral School, in Louisville, Kentucky.

    And one of the complaints that a number of those parents have is that the screening that is supposed to go on at birth, a very preliminary screening, was not picked up. Children that were really pretty severely deaf.
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    And so, they lost those very early years, when communication skills, and developing language patterns are so important. And they were at the Louisville Deaf Oral School for a longer time, due to that, and had some developmental problems that early diagnosis could have helped with.

    I just wondered what sort of confidence you have in the national effort to screen children, babies, newborn, in the hospital, before they go home. And if there is anything we should do to improve that screening?

    Dr. BATTEY. A number of states are already implementing universal newborn hearing screening. I think New York is one of them. I believe Colorado is one of them. And the State of Rhode Island would represent a third.

    In hearing the presentations by individuals that are associated with these screening efforts, they feel that the screening methodology is there, that it works. It's satisfactory.

    So, technologically, we can do it. The big issues are implementing it across all of the states, who will pay for it. The test costs $30–$35 an infant to do the screening, with the current technology.

    But most importantly is follow-up. In that it does no good to screen if you don't get the child back for appropriate intervention. And that then brings us to the final area, where I think NIDCD has a big responsibility, and that's proper early intervention.
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    We're going to be finding children that have mild to moderate hearing impairment at birth. And we do not know today what the optimal intervention strategy is. There are ideas out there, and many things in practice. But none of them have been validated by really well controlled clinical trials.

    And we feel that a big responsibility of our institute is to stimulate that clinical research, and to support it. And I think we're actually playing catch-up on that, because those infants are going to be found within the next couple of years.

    Ms. NORTHUP. Okay. Thank you. Thank you, Mr. Chairman

    Mr. PORTER. Thank you, Mrs. Northup. Mr. Stokes.


    Mr. STOKES. Thank you, Mr. Chairman, Dr. Battey. You may have gotten into this. I've had to be between two subcommittees this morning, and you may have gotten into this. If you have, just tell me, and we'll skip on to something else.

    But have we talked about whether or not we're getting closer to unraveling the cause of hereditary hearing impairments?

    Dr. BATTEY. There has been remarkable progress in the last year. And we talked a little bit about it, but maybe I can quickly summarize it for you.
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    Mr. STOKES. I'd appreciate it if you would.

    Dr. BATTEY. I'd be happy to do that. Last year, when Dr. Snow appeared before you, we knew the map location of maybe 15 or 20 genes involved in so-called non-syndromic hereditary hearing impairment. That's hearing impairment without any other obvious clinical manifestation.

    We now know the location of over 30 genes that cause non-syndromic hereditary hearing impairment. But more importantly, within the last year, we not only know where a half dozen of them are, we know what they are. We have cloned the genes.

    Much of this is through NIDCD supported efforts, or collaborations between NIDCD investigators, and investigators supported by other mechanisms.


    Mr. STOKES. My next question is, what major activities are under way in autism research? And what is the size of our investment there?

    Let me share this with you, before you try to answer my question. Cleveland newspapers have just recently had a very interesting story about a young African-American kid who is eleven years old, in middle school, who is described as being a spelling wizard.

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    He recently competed in the school spelling bee, and would have proceeded on to the next stage of competition, at Cleveland State University. But, in the final questions put between he and one other young person who was competing with him, he was asked the question, to spell sachet.

    And he did not think to ask for a description of the word, which he was entitled to do. And so, he thought of sachet meaning to walk casually. He spelled it S–H–A–Y. And they were really referring to sachet, the French word for small bag, S–A–C–H–E–T. And so, they disqualified him on the basis of it.

    Since then, it has been determined that he should have been permitted to ask for a description. If he didn't, he should have been told, when two words fall into the same category of that sort.

    So, they reinstated him in. And he is now back in the competition at Cleveland State University. And of course, the newspapers had another big article about the fact that he had now sacheted back into the competition. [Laughter.]

    But I'd appreciate it if you would talk about autism research, and what we're doing.

    Dr. BATTEY. I'm very excited about the NIH's efforts in autism. And I say NIH, because NIDCD is one of four institutes, including NIDCD, NINDS, NICHD, the Child Health Institute, and NIMH, the Mental Health Institute, which are collaborating on funding a series of centers to take a comprehensive approach to autism.
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    Understanding the genetics of autism. If you look at identical twins, the concordance for autism is 70 percent in identical twins. Whereas in non-identical twins, it's three percent. What does that tell us about the importance of genetics in autism? Got to be pretty important.

    They're looking into the diagnosis. Is it one disorder, or is it a spectrum of disorders? And how can we more precisely classify these individuals to optimize the proper intervention and treatment?

    We are very close, I believe, to identifying the map location for at least one major locus involved in autism, based on discussions I've had with investigators working in these centers. And I think it's one of the more important areas of research that NIDCD supports.

    If autism is anything, it is a communication disorder. And that is the fundamental sine qua non of autism. So, I view it as very important. And if I'm remembering correctly, the aggregate support from the four institutes for these centers is about $23 million.


    Mr. STOKES. Okay. To what degree, Dr. Battey, does your institute collaborate with the Department of Education? It seemed to me that there should be some type of collaborative effort here.

    Dr. BATTEY. One recent example of our collaboration with the Department of Education, as well as the Department of Labor, is a workshop that we co-sponsored on the economic and social realities, for individuals with communication differences and disorders.
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    I learned at that workshop that, in the early part of this century, most individuals were in jobs that involved physical labor, and very little communication and information processing skills.

    But as we move into the next millennium, 90 percent or more of the jobs, jobs that give—put money in people's hands, that make them feel satisfied with their lives, involve communication and information processing and exchange.

    Clearly, communication disorders are going to be a more important problem in the next millennium, than they were in this millennium. And they're already a pretty severe limitation. If you look at how difficult it is for an individual with hearing impairment to keep a job, or to get another job after they've lost their job.

    So, yes. We are very interested in working with people in the Department of Education, and Labor. And they help provide a very important perspective on the importance of our research.


    Mr. STOKES. Dr. Battey, one of the areas that I've maintained interest in over the years are ear infections. And as we know, doctor's offices, emergency rooms, are filled constantly with children with ear infections.

    Is this an area in which we're making any progress in terms of research?
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    Dr. BATTEY. Mr. Stokes, my background is in pediatrics. So, I am very much very aware of ear infections. And in fact, my eleven year old son was treated over 40 times with antibiotics for otitis media during the first eight years of his life.

    So, I know what a problem it is. And it's a big problem. Because antibiotics, in the case of my son, were not a very satisfactory way to manage the problem. It's a big problem, because the organisms, strep pneumoniae, non-typable haemophilus influenza, and Moraxella, that caused the disorder, are appearing in antibiotic resistant forms, which will require the use of more expensive and sophisticated antibiotics to treat these organisms.

    And it's a problem because, even when you treat them with antibiotics, the infection comes back. Some of the progress that's been made by NIDCD investigators in this area, involve a better understanding of why the infection occurs.

    An investigator at the University of Pittsburgh, Dr. Garth Erlich, has shown, using molecular biology assay, called the polymerase chain reaction, that organisms are—remain in the middle ear after treatment, and that these organisms are in relatively indolent, slowly dividing forms. Which explains why they're resistant to antibiotics, because most antibiotics kill bacteria only when they divide.

    And these—these little sort of niches hiding away in the middle ear are called bacterial bio-films. Bio-films is an emerging area of importance in the infectious disease arena. And I think that as we better understand how these organisms can hide, and evade our abilities to treat inner ear infections, we will be able to develop better treatments, maybe antimicrobials that don't require cell division to kill the bacteria.
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    But the ultimate solution is a vaccine. And our institute, both intramurally and extramurally, supports research to develop vaccines against otitis media. And the intramural research program, it's a lipooligosaccharide, which is a sugar molecule on the outside of the bacteria, of the non-typable haemophilus, that we couple to a protein called tetanus toxoid.

    And this antigen has provided protective immunity in a variety of animal—systems, including direct bacterial challenge to the middle ear, in the chinchilla, within the last year. And we are moving this forward, into a phase one clinical trial, in the NIH's clinical center, hopefully before the conclusion of this fiscal year.

    Extramurally, individuals are looking at the fimbrin protein, which is a protein on the outside of the bacteria, that allows it to stick to surfaces. And that's, in fact, how we think the middle ear gets seeded with bacteria.

    These investigators are exploring whether or not developing vaccines using the fimbrin antigen might not be effective in treating, or excuse me, vaccinating, and providing protection against otitis media.


    Mr. STOKES. I was just thinking as you were speaking, about your previous comments to my question about, what's going to happen in the new millennium, the year 2000 and beyond. We talk about 90 percent of the jobs requiring communications skills, as opposed to what it has been in the past.
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    Obviously what we're talking about is social and economic costs that attaches, then, to communications disorders, is that right?

    Dr. BATTEY. Yes. I think if you look at it carefully, you will conclude, as I have, that the cost to do the research today, to alleviate the communication disorders of tomorrow, will more than pay us back, both in the economic contributions, and the employability of the individuals with these communication disorders.

    Going beyond the fact that you provide these people with good self-esteem, and the satisfaction that comes from being a productive, full player in the American work force.

    Mr. STOKES. Mr. Chairman, I guess my time is expired.

    Mr. PORTER. Thank you, Mr. Stokes.

    Mr. STOKES. Thank you very much.

    Mr. PORTER. Dr. Battey, I'm very impressed with your broad knowledge, and as I said earlier, your enthusiasm for your new position. I think you're doing a fine job and we appreciate very much your very detailed and direct answers to our questions, as well as your fine opening statement.

    I have a lot more questions, and I wish I had more time to talk with you, but we'll have to put these in the record, because the second bell has rung for the vote. We wish you well in your new position and look forward to talking to you again soon. Thank you so much.
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    Dr. BATTEY. Thank you, Mr. Porter. And I'd like to thank the committee for their support.

    Mr. PORTER. Thank you very much. The subcommittee will stand in recess until 2:00 p.m.

    [The following questions were submitted to be answered for the record:]
    "The Official Committee record contains additional material here."

Thursday, March 12, 1998.







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    Mr. PORTER. The subcommittee will come to order.

    We continue our hearings on the National Institutes of Health and the fiscal year 1999 budget request of the National Heart, Lung, and Blood Institute. We're pleased to welcome Dr. Claude Lenfant, the Director of NHLBI.

    If you would introduce the people who are with you, Dr. Lenfant, and then proceed with your statement, please.

    Dr. LENFANT. Thank you, Mr. Chairman. On my far left is Dr. John Watson, who is the Acting Deputy Director of the Institute; next to him is Ms. Sheila Merritt, who is the Executive Officer of the Institute; and then next is Dr. Carl Roth, the Associate Director for Scientific Program Operations; and here on my immediate left is Jim Wehling, who is the Budget Officer of the Institute; and, of course, you have met Dr. Varmus and Mr. Williams.


    Mr. Chairman, I am really very pleased to be here today and this year, I would say. As you know, 1998 is a very special year for the Institute. It is the year that we are celebrating our golden anniversary.
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    In the next few minutes, I would like to highlight some of our accomplishments, and then focus on the opportunities for further progress—opportunities I should say which would have been unthinkable ten or fifteen years ago.

    As you can see on chart 1 here, when the Institute was created in 1948, that the Nation was witnessing an epidemic of heart disease which was causing an ever-increasing death rate from this condition in men and in women as well. With the support that we received from this committee and from the Congress and the Administration, plus the work of the scientific community, we have seen in the next 50 years the occurrence of many life-saving treatments as well as we have learned how to prevent some of these diseases. As a result, we have witnessed a very significant decline in the death rate from heart disease; see chart 2.

    As a result of that, the life expectancy of the American people has increased by approximately six years, as you can see here on chart 3, during the years 1965 and 1995. But the thing that I would like to underscore is that approximately 60 percent of this increase in the life expectancy is due to the decline in death rate from cardiovascular diseases—coronary heart disease, the most important, stroke, and other heart and vascular diseases.
    "The Official Committee record contains additional material here."

    I should also point out that some of the increasing life expectancy can be accounted for by decline in death rates from perinatal diseases, some of them being within the purview of the National Heart, Lung, and Blood Institute, especially neonatal respiratory distress syndrome.
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    I should say, however, Mr. Chairman, that we must not become complacent, as heart disease and disease of the lung and of the blood remain the most important public health problem that we have in this country in terms of morbidity and mortality.

    Fortunately, we have before us opportunities which, if they are pursued, will lead to even more improvement in the health of the American people. And I would like to spend a moment talking about a special case, which is that of thrombosis.

    Thrombosis, or the formation of blood clots, is a very important health problem in this country. When blood clots are inappropriately formed, as you can see on chart 5, they are responsible for a host of life-threatening events—heart attack, stroke, pulmonary embolisms, and deep vein thrombosis—which affect millions of people in this country. However, today, the discovery of compounds and molecules in the bloodstream, molecules and compounds which promote thrombosis, coupled with advances in the genetics of thrombosis, gives us the opportunity to learn more about this condition and actually to develop some very effective interventions.

    In fact, I would say that the case of thrombosis is truly a paradigm of how we can use human genetic and genomic research to approach the disease problems which are within the mandate of our Institute.

    One of the first things that we can learn to do from this research in human genetics is to identify the susceptibility to disease. And let me explain what I'm saying by that. Two individuals may smoke during their entire life; one of them will have all these elements that we know so much about and I'll discuss so much today, but one may not get a disease. And that is basically because of a difference in susceptibility.
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    Knowing more about the susceptibility to disease, we can, of course, develop some prevention intervention which would be much more effective than the kind of shotgun approach that we are using today. As well, we can make early diagnoses and develop a prognosis for this condition, we can predict disease manifestation, we can, of course, understand the mechanisms of disease, and we can tailor our pharmacological interventions specific to individuals. Already, we know of a case coming from the work of the Institute where we know that some individuals with asthma are responsive to a specific medication where other individuals may not be responsive to this medication.


    Finally, I would like to demonstrate a new avenue of research which may have a very remarkable impact on the well-being of many patients. When I presented to you the contributions to a change in life expectancy, I did not say anything about chronic obstructive pulmonary disease. As you can see on chart 3 here from this chart, chronic obstructive pulmonary disease, or emphysema, has a negative impact. Basically, what it means is that the morbidity and mortality of this condition keeps on increasing in contrast to what we have seen in the cardiovascular area.

    Now, chronic obstructive pulmonary disease, or emphysema, is responsible for the destruction of the lung tissue and in so doing impedes normal breathing. I would like to illustrate that on this chart which shows some work from an animal model.

    Here is a normal lung. And as you can see, all these little spaces are called air sacs. That is where oxygen goes into the blood and the carbon dioxide is eliminated. In the case of emphysema, as you can see, all these little air sacs disappear and are now replaced by larger spaces, open spaces. That is why the breathing and the transfer of oxygen is impeded.
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    Recently, it has been found that if a lung with emphysema is treated with a certain retinoic acid, you can witness the restoration of the air sacs that you find in the normal lung. That is quite an interesting new avenue of research which we believe offers new prospects for all these patients affected by this condition.

    So, Mr. Chairman, during the last few minutes I've recited to you some opportunities which certainly will bring to the patients hope for a better life and a healthier life as well.
    "The Official Committee record contains additional material here."

    I'll be pleased to answer your questions.

    [The prepared statement follows:]
    "The Official Committee record contains additional material here."

    Mr. PORTER. Thank you, Dr. Lenfant.

    Before I begin questions, let me take just a minute to introduce and welcome James Beckman, a student at Glenbrook South High School in the tenth congressional district, who is here with the Congressional Youth Leadership Conference. He's from my district. [Laughter.]


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    Dr. Lenfant, you're asking for a 7.7 percent increase for the next fiscal year, including the OAR transfer. Many of us in Congress want to see an even greater rate of increase over the following five years. A great deal of progress, obviously, has been made in reference to diseases of the heart and blood and of the lungs. Can you reasonably use a doubling of your budget over the following five years after this fiscal year? What would you do with the additional money?

    Dr. LENFANT. I believe so, Mr. Chairman. Let me try to convey this feeling that we have in the various communities which are served by the Institute. Today, the opportunities are limitless. When we look back at what has been happening during the year past, much progress has been made, there is no doubt, but we have failed to understand the mechanisms of many of the conditions which are before us. In certain other instances, we have uncovered in great part these mechanisms but we haven't been able to develop therapies and cures to address these problems.

    The case of thrombosis that I just mentioned to you is one example. We're putting together all that we have learned, plus bringing into the areas which are of interest to our Institute molecular medicine. And I could say that heart, lung, and blood medicine are now moving to the forefront of molecular medicine. By bringing these techniques, we can make immense progress and I believe reduce the morbidity and the mortality of these conditions as well as finding cures. I would like to underscore the word ''cures'' as opposed to treatments. Often a treatment is something that you have to do forever because, in fact, you haven't cured the condition.

    I think that today there are a number of conditions which eventually can be cured as a result of the research that we can do using these new approaches and combining that with what we have learned about the physiology and pathophysiology of the organs in which we are interested.
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    Mr. PORTER. Could you explain what age-adjusted is in reference to the charts. How do you adjust for age to get the data?

    Dr. LENFANT. Well, to adjust for the age means that we make the data that you see today comparable; you can compare the data that you had seen 10 or 15 years ago or even that you would see 10 or 15 years from now.

    Mr. PORTER. Why does the data require adjustment?

    Dr. LENFANT. Because the size of the population for different age brackets changes. Today, we have many more people above 60 years old than we had 30 years ago. The adjustment allows you to make that comparison in spite of the shift in the demographics of the population.


    Mr. PORTER. I see. Dr. Lenfant, you state in your testimony that a highly sensitive anti-hepatitis C test implemented in 1992 is estimated to have prevented 33,000 cases of hepatitis annually, resulting in savings of $323 million in health care costs. Dr. Satcher, our new Surgeon General, testified last week that many Americans infected with hepatitis C are unaware that they have the disease. The recommendation is that anyone who had a blood transfusion prior to 1990 should be tested for the disease.
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    In light of your testimony, shouldn't the recommendation be for anyone who received a blood transfusion prior to 1992?

    Dr. LENFANT. Yes, Mr. Chairman. Attached to my testimony is a graph which shows the declining risk of post-transfusion hepatitis. I should say that all the steps that you have seen here between 1960 and now are, in fact, the result of some of the research that has been supported by the Institute.

    As you can see, in 1980, we estimated that approximately 7 or 8 percent of the transfused population might have been at risk of hepatitis. And so, therefore, there is no question that if we want to ascertain the situation of these transfused people in the year past, we have really to go back past 1990 and even 1992.
    "The Official Committee record contains additional material here."


    Mr. PORTER. Through your studies several less invasive imagining techniques have emerged as potential screening techniques for coronary arterial blockages. One of these techniques is retinal scanning which detects early signs of systemic vascular damage in the blood vessels of the eye. Do you expect that someday a test like this will be used as a component of a routine physical exam?

    Dr. LENFANT. Yes. Yes. I think that will become possible. But I think that the technique at this time needs to be considerably improved, first of all, to make it better, more reliable, and, perhaps more importantly, so that the cost of the equipment which is necessary decreases in order to make it available to a greater population.
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    Mr. PORTER. After two decades of decline in deaths from stroke and heart disease, we are seeing a small increase in stroke deaths and a leveling off of mortality from heart disease. In addition, congestive heart failure in end-stage kidney disease is on the rise. This has caused the Institute to update the 1993 guidelines and, for the first time, provide recommendations about which drugs should be used to treat which patients. The new guidelines will also recommend for the first time ways to control blood pressure using diet.

    Do you think this is a trend for the future? Will we be seeing new guidelines making specific recommendations for other diseases?

    Dr. LENFANT. Yes. If I may, Mr. Chairman, I'd like to say a few words about the findings in the research that dietary intervention may be quite effective for the treatment of, say, a condition like high blood pressure. Indeed, we have conducted a fairly large study of hypertensive subjects treating them only with a dietary intervention which included a diet low in fats, rich in fruits and vegetables. And, indeed, after I think it was five years, we saw a very significant decline in the hypertension in the blood pressure of these patients. My recollection is that it was in the order of 5 or 6 percent of the number, the blood pressure, which is a fairly significant decline.

    Your question, as I understand it, was whether such dietary intervention can be applied to other conditions as well. And I think that the answer is certainly true. We do know, for example, that coronary heart disease can be prevented or certainly reduced in severity by way of dietary intervention which requires limitation of saturated fat. We know also that in many cases of cancer, dietary interventions are very important to prevent the occurrence of this cancer. So I think the answer to that is yes.
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    Admittedly, there are some conflicting signals which are coming from various studies. In fact, at the request of Dr. Varmus, we are looking at these conflicting signals to see how we can reconcile all the information that is coming from different sources.


    Mr. PORTER. Although this isn't your direct responsibility, it seems to me that more than any other disease, coronary heart disease tends to be a disease of lifestyle. We seem to know a great deal about the positive effects of exercise, of a diet low in fat and rich, as you say, in fruits and vegetables. And we know a great deal about the effects of tobacco use over a long period of time on the heart.

    What do you do to interface with the CDC and others who are attempting to influence people in choosing a healthy lifestyle? And what should we be doing that we aren't doing in that regard?

    Dr. LENFANT. Well, let me first say, Mr. Chairman, that as we look at the things which we believe we can do to improve the cardiovascular health of the American people, we do include exercise as one of the issues that we are interested in. Now having said that, we do work fairly closely with the CDC, the Centers for Disease Control and Prevention and we cooperate on many activities to basically make sure that the outcome of our research programs is communicated to the people and, more specifically, to the communities, because we do believe that programs which are at the community levels are often much more effective than a program that results from a centralized intervention.
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    The other aspect of your question, what should we do, I think the answer to that is simple. We should intensify that because we believe that lifestyle is a key aspect, a key thing that we can do to prevent the development of many conditions which are within our mandate, certainly heart disease, blood pressure elevation, the complications of which may be heart disease, or stroke. And dietary intervention, I think the American people have got to be ''educated'' or informed about these things. But I have to tell you it is very, very difficult to do.

    Mr. PORTER. I think it's obvious that it's very difficult to do because, although tobacco use has been curtailed a great deal in our country, we now seem to be on the problem of over-weight and out of shape even to our young children. Somehow we've got to get a handle on that because, if we could turn those kinds of things around, we could save a huge number of lives and a great deal of health care costs that are reflected now in our system.

    Dr. LENFANT. On Tuesday when Dr. Varmus appeared before you the issue of obesity was brought up. I can only underscore again what he said, that obesity is the only risk factor for cardiovascular diseases on which we not only have made no progress, but the issue and the problem has worsened over the years. It is an issue of tremendous concern that, as you heard Dr. Varmus say, is addressed by several Institutes and we are one of them. In fact, we have now a task force which is just about to report on some guidelines for the prevention and the approach to obesity.

    Mr. PORTER. Thank you, Dr. Lenfant.

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    Ms. DeLauro.

    Ms. DELAURO. Thank you very much, Mr. Chairman.


    Thank you, Dr. Lenfant, for your testimony. It's good to see you back here. Last year, I asked you about Cooley's anemia and I would like to talk a little bit about the disease again. As you know, Cooley's anemia disproportionately affects people of the mediterranean heritage, particularly Italian-Americans. Twenty years ago the average life expectancy of someone with Cooley's anemia was mid-teens. Now, most of those patients live to their thirties. I applaud the progress and want to continue to do better.

    In the conference report last year for Labor, HHS, the report endorsed a recommendation of a September 1996 special emphasis panel that the National Heart, Lung, and Blood Institute create a network, if you will, of collaborative clinical centers to address the special research related to Cooley's anemia. As I understand it, another special emphasis panel which met last September endorsed the creation of that same kind of a network. What action has been taken to establish the network of clinical centers?

    It is also my understanding that people who suffer from Sickle Cell anemia can benefit from the same kinds of treatment that Cooley's anemia patients use. Have you expanded the research or undertaken any new efforts toward improving treatment of those patients?

    Dr. LENFANT. Let me first answer the second part of your question, which is whether we have expanded the research portfolio on this condition. The answer to that is, yes, yes, yes; a big yes, actually. We have initiated a new research program on the clinical aspect of Cooley's anemia. A solicitation was issued by the Institute shortly after the hearing last year, I would say, in part, in response to your comments and your interest, and looking again at the report of these panels which you mentioned. We did issue that solicitation. The applications have been received and they are in the process of being reviewed. I think that review is going to be completed within a couple of weeks or something like that.
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    I can tell you that the applications that we have received, there are I think a dozen or so, all are extremely interesting. If they are judged meritorious by the review process that we have, I think that will contribute greatly to move the research several steps ahead.

    The applications focus on the induction of fetal hemoglobin, as you know, which is a possible treatment for this condition, on the assessment of iron deposits especially in the heart, there are also some projects on the development of new cheleators, which are the compounds that can help remove excess iron, and then also there is some work which is quite interesting and concerns the feasibility of exchange transfusion in these patients. So that's the answer to the second part of your question.

    Ms. DELAURO. You said you received a dozen or so applications?

    Dr. LENFANT. We have a dozen applications. I don't know how many will be funded because it depends on the quality of the applications.

    Ms. DELAURO. And you expect the results or the applications within the next couple of weeks to be determined what will be accepted or not.

    Dr. LENFANT. Yes. And then it has to go to our national advisory council, the next meeting of which is in May. But after May, the applicants will be advised. From what I've heard, I hope I'm not speaking too fast and out of turn, but I'm fairly confident that we will end up with a very reasonable program.
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    Ms. DELAURO. Terrific.

    Dr. LENFANT. Now the first part to your question was have we initiated or given further thought to the clinical network. We haven't initiated it but we have given much more thought to it. In fact, we have budgeted in the 1999 budget an allocation for the development of this clinical network. The details of it are not developed as yet. Most likely, it will be a clinical network which will be joint for Cooley's anemia and Sickle Cell disease because there are so many similarities between these two conditions.

    Ms. DELAURO. What is your sense of timing on the development of the centers? And is it a question of resources? What has held up you're doing that?

    Dr. LENFANT. Well, let me tell you, Ms. DeLauro, the issue is not one of resources, because the Institute is, and has always been, very committed to this condition. The issue was the practicality and the feasibility of developing these centers. It is the support of an infrastructure. It's like buying a building, if you will, but if nobody goes and works in the building, what's the point of having the building? And the question that we had is whether there would be enough patients in some sites, whether there would be enough interest for the comparisons between the different sites to support this infrastructure. After looking into it and making the decision that we would combine that with Sickle Cell disease, we have come to the conclusion that that was a reasonable thing to do.

    You asked me the time frame for that. I would think that in one year from now I could give you some reasonably good news about it; in other words, the process would be on its way in one year from now. Whether they would be awarded or not, we would be approximately six months into fiscal year 1999 in one year from now, we could have made the award or we would be very close to making the awards.
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    Ms. DELAURO. I'm sure I'll ask the question again the next time.

    Dr. LENFANT. I am confident.


    Ms. DELAURO. Again as you know, heart disease is the number one killer of women. Can you tell us about the progress that you have made in the last year in the study of so-called designer estrogens which appear to protect women from heart disease. Are you doing any research toward developing a similar drug or therapy that would protect from heart disease without the side effects of estrogen in terms of breast cancer, blood clot formation?

    Dr. LENFANT. That's a very difficult question. One thing I can say is, yes, the Institute's tests supported for years the development of designer estrogen, actually a specific one, one which would be derived from plants. In fact, last night I was watching the national news and heard that the FDA has just approved a designer estrogen which is derived from soybeans. I don't know if that's a result of our own research, but we have done research on that for a number of years.

    The second part of your question was whether that has modified prescriptions and what happens in the real world and in the practice of medicine. I don't know. Within the studies that the Institute is supporting, especially I would say the Women's Health Initiative, which, you may know, has been transferred to our Institute, we are not using a designer estrogen because that would affect the continuity of the study. We cannot just change the estrogen which is being used for the simple reason that, as yet, there is very little data on the effectiveness and the use of these new medications and, therefore, we cannot replace something with which we have considerable experience with something else with which we have much less because we don't know what impact it might have on the study.
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    But there is another issue. The advent of all these new compounds and new hormonal products is of some concern. The Institute actually is in the process of working with the other Institutes at NIH which are interested in this issue to develop a group to monitor the effectiveness of these new designer estrogen compounds and see whether they could eventually be used to replace what we are using now. So it's kind of a long winded answer to your question because so far nothing has clearly been done at least within the purview of the Institute. But we are looking at it and are getting prepared to take action if warranted and appropriate.

    Ms. DELAURO. Just a quick comment, Mr. Chairman, I know my time is up.

    Again, with the eye toward looking at how we deal with the side effects of estrogen, which is a scare with regard to breast cancer and blood clots, we're trying to figure out how we lessen those side effects as well with what we're doing here; is that part of——

    Dr. LENFANT. The issue is that we don't know as yet. What we have learned about the estrogens which are being used now is the result of years of observation and research. With regard to the designer estrogens, we do not have these years of research and observation.

    Ms. DELAURO. Thank you very much, Mr. Chairman.

    Mr. PORTER. Thank you, Ms. DeLauro.
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    Mrs. Northup.

    Mrs. NORTHUP. Thank you.


    Thank you, Doctor. I would like to ask you about a couple of things. First, I know that more and more people that are suffering from heart disease and heart problems are depending increasingly on sensors and artificial valves and pacemakers. I just wondered what the Institute was doing in terms of interdisciplinary studies to look at micro fabrication and engineering sensors in order to make sure that the medical community and the engineering community put these things together, and whether your Institute is engaged heavily in that.

    Dr. LENFANT. Our Institute is, indeed, very much engaged in bioengineering research. In fact, Dr. Watson, whom I introduced earlier as the Acting Deputy Director of the Institute, is a bioengineer of very long experience and has driven the Institute down the path of bioengineering research for 20 or some years. So all that is to say that we are very much abreast and informed of what's going on in the bioengineering world.

    In fact, the Institute does a number of studies which use some devices which are either for the sake of support or substitutions when there is failing, say, of the heart. The Institute has been really the agency of the department which is developing the artificial heart, the total replacement heart now, but also what is called the assist device which is, as its name says, to assist the failing heart. We also have been very much involved with the development of pacemakers and defibrillators, devices which now are implanted in a number of patients who have conditions which warrant the implantation.
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    Dr. VARMUS. Could I make just one additional comment?

    Mrs. NORTHUP. Yes.

    Dr. VARMUS. Dr. Watson just last week co-chaired a large bioengineering symposium at the NIH, organized by a group called BECON, for Bioengineering Consortium, that the Office of the Director at NIH recently developed to involve virtually all of the Institutes in bioengineering. Senator Frist came out to give the keynote address. Bioengineering is a very lively activity at the moment at the NIH.

    Mrs. NORTHUP. That's reassuring. We talked about diabetes yesterday and we know that there are assist devices. It is of concern that medicine is talking about genes, and what you eat, and how you exercise, and the body, and it's important that we also make sure that we advance and marry, if you will, the artificial supports besides just drugs and medicines.

    Dr. LENFANT. I may add, Mrs. Northup, that relative to Cooley's anemia, which we were discussing just a moment ago, that, as, in diabetes there is need to have a pump that infuses drugs called the chelators, and that is also the result of bioengineering development. These patients with that condition have benefitted from that for years.


    Mrs. NORTHUP. Okay. I'm sorry that I had another hearing and was not here for the genome testimony. But, in particular, I have a strong interest in what your Institute does in terms of genetics and heart disease, heart problems. I assume that there is quite a bit of coordination between other genome research, in particular heart disease.
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    Dr. LENFANT. Yes. We do work very closely with the Genome Research Institute. And, yes, the Institute is moving in a big way into applying the molecular genetic approaches to our problems. Already, quite a bit of progress is being made. I believe I heard Dr. Varmus on Tuesday mention the gene for the long QT syndrome, which is a heart disease with an irregular heart beat, and that now hopefully will be treated much more effectively in the future.

    There are a number of cardiovascular conditions which are due to one gene which is an alteration or a mutation. One of them is hypertrophic cardiomyopathy, for example. That one is fairly well known by the public because one of its manifestations is sudden death, and when that occurs in athletes, basketball players, in particular, everybody recognizes the problem.

    But here there is an extensive amount of work which is being done in some of the institutions that we support and I would say in our Institute as well. In fact, our Institute, in our internal programs, has been at the forefront of these conditions for I believe 40 years. Now, we are bringing molecular genetics into it in association with the Genome Research Institute.

    Mrs. NORTHUP. Certainly, the genetic side of heart problems often does result in sudden deaths, sort of maybe unpredictable sudden deaths; certainly, athletes are one of those groups. And prevention would be connected to testing ahead or something that's predictive, so I'm interested in that.

    Dr. VARMUS. Can I make one additional comment, Mrs. Northup. I don't want to suggest that Dr. Lenfant is being unduly modest, but he should take credit for the fact that his Institute has been in the leadership on the rat genome project, which is very important for the study of many physiological problems including cardiovascular disease.
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    Mrs. NORTHUP. Thank you.

    Dr. LENFANT. I just wanted to add one thing. I gave as a couple of examples diseases which are determined, if you will, by one gene and its function. But, by and large, most cardiovascular diseases are polygenic; that is, there are an array of genes which intervene in these conditions. That's why they are called complex diseases from the genetic viewpoint. Lots of work is needed to understand these conditions and be able to address them. I am saying that because that was, in fact, what the Chairman was asking me at the beginning, do we have anything else to do? The answer is, yes, indeed.

    Mrs. NORTHUP. Thank you. Thank you, Mr. Chairman.

    Mr. PORTER. Thank you, Mrs. Northup.

    Mr. Stokes.


    Mr. STOKES. Thank you very much, Mr. Chairman.

    Dr. Lenfant, as Dr. Varmus just commented about how modest you were, I'm reminded that a few days ago when Dr. Varmus was testifying I made the comment to him that seated next to him and behind him were some of the finest scientists and doctors in the world. I was uniquely aware of the fact that you were one of those seated immediately behind him. I think that all of us are very proud of what you represent in the medical profession, and I've enjoyed the opportunity over the years to sit across the table and have various discussions with you regarding medical problems that confront this country.
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    Let me start out by making reference to a disease that you and I have discussed often. When Ms. DeLauro was talking about Cooley's anemia, which uniquely affects persons of Italian extraction and Middle East origin, I thought about Sickle Cell disease which we know affects African Americans in the same manner. You and I have talked about it for many, many years right here in this hearing room. Are we anywhere near reaching a cure for this devastating disease?

    Dr. LENFANT. I think we are getting closer to it. When it will be at hand, I don't know. I wish I could tell you next year or five years from now, but I cannot tell you that. But one thing I can tell you is that each year when I come and appear before you I have some new advances to report to you which I think are of immense benefit to this population.

    Mr. Stokes, before you came, I was showing what has happened to cardiovascular diseases the 50 years before the Institute was created and the 50 years since the Institute has been created. If you would look at Sickle Cell disease 50 years ago, patients with severe Sickle Cell disease were dying in their teens or in the sub-decades of their life. Today, these patients are living to their 50s and 60s, living a productive life. Undoubtedly, the quality of that life is often affected by their condition, but they are alive. That is a result of the research that we have supported, and I should say in great part because of your support. And for that, in fact, when we celebrated the 25th anniversary of the National Sickle Cell Disease Research Program last fall the entire audience stood up and saluted you for the support that you have given for that research.

    Mr. STOKES. I'm the first to acknowledge that we have obviously made great progress, particularly over the last ten years. Yet, one just has to wonder will we ever find a cure for this disease. That's what's so troubling to me.
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    Dr. LENFANT. A cure for this disease I am confident will happen but I just cannot tell you when. There are lots of people and the best minds in this country working on gene therapy which would produce if you will the ultimate cure for this condition, but, as my colleagues have said during the last couple of days and as you will hear more during these hearings for the NIH, it is a very difficult problem, very difficult problem.

    But meanwhile, I do have some good things to tell you that I didn't tell you last year.

    Mr. STOKES. I want to get into that. And since you're suggesting it, why don't you just do it right now? [Laughter.]

    Dr. LENFANT. Okay. Well, the first good thing that I want to tell you is that infants and children who have Sickle Cell disease have the risk of two very major complications. One is infection, and you may recall that three or four years ago I came here and I told you how we could prevent this infection. The second one was the development of stroke. We talk a lot about strokes here in this room, but here we are talking about strokes in kids who are in their teens, which is, of course, a terrible human problem.

    This year we have reported the result of a study that has shown that we can, in effect, prevent the occurrence of stroke in these children because now we are able to detect how the blood flow is in their brain and, if some abnormal blood flow is detected, we can initiate a therapy that will prevent the occurrence of a stroke because the abnormal blood flow is actually a precursor sign of a stroke to come.
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    The treatment in question is blood transfusion, to initiate blood transfusion very early. That, indeed, prevents the occurrence of a stroke. Approximately 90 percent of the kids who have been treated did not develop a stroke compared to a group which was not treated. There are problems with that treatment that need to be addressed. Now, we have put into place a research program to address these problems. But at least these children do not have a stroke. So that's one thing that's happened since last year.

    As you may recall, Mr. Stokes, you asked me over the years about bone marrow transplantation and I told you that it was emerging in Europe as an approach but coming along very slowly in this country because I suppose physicians in this country are perhaps more conservative than those in Europe.

    Today, I can tell you about an experience of 37 children who have been bone marrow transplanted here in this country, and the good thing is that 95 percent of them are still alive and that 80 percent of those appear to be free of their condition. So here is an approach which I believe opened the door on opportunities. Bone marrow transplantation is not a benign procedure. It's not like injecting blood or injecting a medication; it has its own risk. That is under study and I believe that in the years to come a larger population study will be reported and we will see a continuation of the success that we have in this small population.

    The third thing that I would like to mention is that two years ago I came here and told you about a result that we had with hydroxyurea in adults. You may be interested to know that two or three weeks ago the Food and Drug Administration approved that drug for use in adults. Meanwhile, we have initiated a study in children giving them hydroxyurea and so far, so far, the results are quite satisfactory.
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    So here are three examples of progress which I can report to you and that I did not mention to you the year before.

    Mr. STOKES. Obviously, we are making significant progress, as you've stated. Let me ask you, Dr. Lenfant, with respect to medical schools at Historically Black Colleges and Universities, to what extent are they directly involved in the basic applied and clinical Sickle Cell disease research that is under the purview of your Institute? Tell us what is the size of the investment in this area.

    Dr. LENFANT. Three of these colleges have a medical school—Howard University, Meharry, and Morehouse. Two that I know of have at the present time support from the Institute for Sickle Cell disease research. Unfortunately, this support will not continue past a few months from now because the competition was not favorable to permit this continuation.

    Having said that, we are working with these institutions in the hope of fostering some other activities in Sickle Cell disease research.

    Mr. STOKES. Okay. I heard the bell, but let me just make this comment, Mr. Chairman, if I may. That's an area in which I hope that the Institute will work with those particular schools to try and help them be able to qualify. I think it's extremely important that the Historically Black Colleges and Universities be involved in research and the things that are necessary relative to diseases that particularly and uniquely affects African Americans. That is imperative. Thank you.
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    Mr. PORTER. Thank you, Mr. Stokes.

    Ms. Pelosi.


    Ms. PELOSI. Thank you, Mr. Chairman.

    Dr. Lenfant, thank you very much for your testimony and for your leadership at the National Heart, Lung, and Blood Institute.

    Following up on Mr. Stoke's questions about involving our institutions of higher learning and training across the board, I wanted to ask you about behavior change and research training. To seriously address many of the leading causes of death in this country, we need to improve our understanding of the factors involved in initiating and sustaining positive changes in behavior. In addition, and this is my point, it is essential that increased attention and resources be given to training a new generation of behavioral scientists to focus on these questions especially in the prevention area.

    Can you tell me more about your prevention research efforts and your involvement in professional training of investigators?

    Dr. LENFANT. The Institute pursues several avenues to foster prevention research including, of course, behavioral research for the purpose of adopting different lifestyles and so forth. First of all, we support a number of training programs in I believe three or four institutions in the country. We have a number of research projects in more institutions which combine biomedical as well as behavioral approaches, seeking some new regimens and interventions to develop preventive regimens. And then, thirdly, I should tell you that just a few months ago the Institute released a blueprint of behavioral research as adapted to the needs of the Institute in heart, lung, and blood research basically with the expectation that that will stimulate further work from the interested community.
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    Ms. PELOSI. I appreciate that. Dr. Varmus, the other day when you were presenting your initial testimony, the flagship testimony, you mentioned in the category of talent—you said, ''We will fund innovative research training programs that emphasize transdisciplinary work. We propose to increase by 25 percent the stipends that we provide to graduate students and post-doctoral fellows, and we will create a research environment that offers improved stability and the likelihood of research funding that was true in the early years of this decade.'' Bravo.

    Do you have the resources to do that?

    Dr. VARMUS. We will under the President's budget. As a result of the healthy increases we received this year, we have already started to do some of these things, particularly create the healthy research environment. The decision to increase stipends would not apply until fiscal year 1999.

    Ms. PELOSI. And then, hopefully, all the things that Mr. Stokes talked about might be captured by that into the communities that are——

    Dr. VARMUS. Certainly, some of the new training programs we're envisioning would be directed toward our continuing concern about the number of biomedical investigators who come from minority populations.

    Ms. PELOSI. You will have outreach in that group?

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    Dr. VARMUS. Absolutely.

    Ms. PELOSI. Could you just tell me, is the term of art now transdisciplinary?

    Dr. VARMUS. I don't know the subtlety that might distinguish interdisciplinary from transdisciplinary.

    Ms. PELOSI. Okay. I just didn't know if I was missing something.

    Dr. VARMUS. We can send this as a letter to Mr. Safire and he can help us with it. [Laughter.]

    Ms. PELOSI. Yes, he's good at that.

    Dr. LENFANT. Although I may say that when it comes to prevention research, multidisciplinary rather than transdisciplinary is quite an important, I would say necessary, way to approach the problem. Because as you pointed out in your question actually, to achieve prevention takes change in lifestyles but also some change in what you eat. Basically, the biology of it needs to be known as well as the behavioral approaches to achieving that. So here is an example I suppose of a multidisciplinary approach combining biology with behavioral.

    Ms. PELOSI. Well, as I said when I was invited to UCSF when they were announcing an interdisciplinary multi or transdisciplinary approach to their cancer project, I said at that time, Mr. Chairman, that I found it fascinating because knowing the coordination that it would take among the departments. I commended the chancellor for a level of political skill that was a game we were not familiar with here. I imagine that that would be a challenge. But you seem to have a comfort level with it and I'm encouraged by that.
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    Dr. VARMUS. You know my lineage, Ms. Pelosi, so you can see where I developed those instincts.

    Ms. PELOSI. Yes, indeed.


    I applaud all of your work, Dr. Lenfant, and successes with securing a safe blood supply for all of us. Thank you. I understand that your budget request for your efforts on AIDS research is contained in the Office of AIDS Research budget proposal. But I wonder if you can tell us about the recent work by your Institute in the area of AIDS and the potential this work has to expand our ability to address other serious illnesses. Can you give me an example of how broader understanding of HIV disease has improved our ability to fight a broad range of diseases affecting the circulatory system?

    Dr. LENFANT. The AIDS program of the Institute is basically related to the heart, to the lung, and to the blood, with the bulk of it making sure that we keep a safe blood supply. The research that we do is really to develop better and further tests to detect the presence of antibodies which are the result of a viremic infection, AIDS or any virus.

    In fact, the Institute is now initiating some new programs where we hope to be able to detect the nucleic acid which is part of the DNA of the virus which would allow us to reduce the window between the infection and when the antibodies occur. Our expectation is that if we are successful, we may reduce that window to only a few days, where now, depending on the virus that has infected the subject, it may be several weeks. So that would be a tremendous advance in safety, if you will, from that viewpoint.
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    Now with regard to, say, the heart, now that patients with AIDS are surviving much longer, many of these patients are developing some heart complications. Our research program is to assess the extent of these complications, to understand them and see how we can develop some therapies which are independent of the therapy that is given for the AIDS infection.

    With regard to the lung, it's also the same kind of approach. Many of these patients with AIDS in the terminal phase of their disease die from pulmonary infection. We are studying the defense mechanisms of the lung against these infections.

    Ms. PELOSI. I really appreciate your very thorough response and all that is implied by it. Thank you for your attention to this, Doctor.

    Mr. Chairman, next week I'll probably ask Dr. Varmus to tell us more about the active collaboration among universities, government, industry, and how such interactions are vital to our efforts to control disease. But I probably don't have time to do that today.

    Mr. PORTER. You have 36 seconds.

    Ms. PELOSI. Would you like to comment on that, Dr. Varmus?

    Dr. VARMUS. I think we could do that in a little more leisurely way.

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    Ms. PELOSI. Okay. Thank you very much, all of you. Thank you, Mr. Chairman.

    Mr. PORTER. We're going to have a second round, also.


    Dr. Lenfant, on retinoic acid, if I understand it correctly, the tests have occurred only in animals. Is that correct?

    Dr. LENFANT. That's correct.

    Mr. PORTER. We haven't yet done it with human beings. How far are we from doing that?

    Dr. LENFANT. Well, if I may expand on that. It has been done only on animals, rats and mice. It is now being done on nonhuman primates. But the results have been so spectacular, so spectacular in the rats, in particular, that I know that some investigators in the country are in the process of initiating a clinical study that is to give retinoic acid to patients who have those conditions.

    Mr. PORTER. Since retinoic acid is a derivative of Vitamin A, what does this mean for people who are at risk for chronic lung disease, like smokers? If they take Vitamin A they might reduce the risk? Does it have any meaning that way?

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    Dr. LENFANT. Well, if they are still smokers, I think it wouldn't do too much good. If they had been smokers and have developed a lung disease like, say, emphysema, whether it will work or not, I don't know. But that is what is going to be tested by these investigators who are interested in doing it.

    Mr. PORTER. But could Vitamin A then be considered a means of protecting against the damage of smoking perhaps?

    Dr. LENFANT. I think it requires that it be retinoic acid because the retinoic acid, my biochemistry here is going to be challenged, but I think it is a precursor of the development of Vitamin A, and it is that precursor which is the active compound and not the Vitamin A itself.

    Mr. PORTER. I see.

    Dr. LENFANT. Was that the correct answer?

    Dr. VARMUS. That's correct.


    Mr. PORTER. Dr. Varmus agrees. I've read that several school districts in Minnesota have delayed the start of the school day for high school students and have seen a remarkable change in student attitudes, test scores, and discipline problems. It is believed that melatonin which induces sleepiness is secreted later in the evening in older teens. The result is that high school students are starting class in the morning before their body's biological clocks have woken them up. Have you studied this phenomenon in your Sleep Disorders Center? Do you agree with this theory? And would delaying the start of the school day for high school students give them a better chance to succeed?
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    Dr. LENFANT. I cannot agree with that. I think the only thing that I know about that is from having read about this report. I have to admit that it is fairly impressive. Now the issue of melatonin is a very interesting one. We are discussing within the Institute whether a carefully controlled study should be done. In fact, we are discussing that with the Office of Alternative Medicine. As yet, I am not personally aware of any controlled study using melatonin. But the statements which are made that you reported are making a good deal of sense.


    Mr. PORTER. Dr. Varmus, from time to time there are hot drugs, for want of a better term, that are sold in health food stores and other places. Do we have any kind of program within NIH to quickly look at the efficacy and safety of these kinds of things, or is that something that the FDA—well, the FDA doesn't do that.

    Dr. VARMUS. No, they don't. As I think you and I may have discussed once or twice in the last year, we have decided to give a more vigorous role to the Office of Alternative Medicine in sorting out some of these claims.

    The most prominent study of that sort is one that is now being carried out in a collaboration of the Office of Alternative Medicine with the National Institute of Mental Health to support a clinical trial at Duke to study St. John's Wort in depression. Several other similar studies are actually in formulation, including one to look at chondroitin sulphate in osteoarthritis.
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    We are giving very careful attention, as Dr. Lenfant mentioned, to some studies of melatonin, both in sleep cycling and in treatment of jet lag. A number of other medications that are fashionable and used without FDA imprimaturs are going to be the subject of rigorous clinical trials through the OAM and other Institutes.

    Mr. PORTER. The OAM, it seems to me, could perform a great service to American society by taking these matters up very quickly when they begin to break and give some guidance to people as to whether these things are worth anything.

    Dr. VARMUS. I agree entirely. This represents a bit of a change in tactics. While we are still supporting some centers to develop scientific expertise among those people who are interested in alternative therapies, we also feel that it is important to use the money that goes to the Office of Alternative Medicine to allow traditional clinical trialists to do definitive trials of some of these medications.

    I also should draw to your attention, Mr. Porter, to the fact that in the last several months I have developed a transagency group that includes representatives from the FDA, from AHCPR, from CDC, and from many of the NIH institutes to identify candidate therapies for such trials. That group has met. We have quite a dossier of recommendations, and Dr. William Harlan, who runs our Office of Disease Prevention and has immediate oversight over the Office of Alternative Medicine—OAM—is working with the OAM to try to develop the appropriate set of trials in conjunction with the categorical institutes.

    Mr. PORTER. A lot of the medical newsletters take these matters up and get them to what I would judge to be a fairly educated audience. But the vast majority of people, it seems to me, aren't reading those kinds of things and don't know what they really ought to do.
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    Dr. VARMUS. The fact is that although there may be discussions in such newsletters, in the vast majority of cases, there have not been well-designed definitive trials.

    Mr. PORTER. No, but they can raise issues and give people caution. I agree with you that they don't have any definitive answers necessarily, but they sometimes will say this hasn't been tested, you ought to——

    Dr. VARMUS. I agree, a more balanced presentation than you might find in an advertisement.

    Dr. LENFANT. If I might say something here with regard to retinoic acid, which is actually available over the counter. When the initial study was published, which was maybe a year ago or so, it was picked up by many of these information publications just mentioned. As a consequence, the Institute must have received maybe 200 or 300 letters from patients with emphysema asking if they should start taking retinoic acid. Of course, our response was we don't know and we don't think you should do it, certainly without consulting your physician. But it is sometimes a real problem because everything jumps ahead of the scientific knowledge.


    Mr. PORTER. Dr. Lenfant, a three-year study comparing the two most popular approaches to treating abnormal heart rhythms was halted because of overwhelming results. The study was comparing commonly prescribed heart drugs to an implantable device that corrects abnormal heart rhythms. An early analysis of the data showed significantly better survival rates in those who had the devices. In addition, the drugs can have serious side effects.
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    It has been almost a year now since you announced the findings of the study. Has the medical community used the results? Have you seen a trend toward the use of more implants?

    Dr. LENFANT. Yes. Maybe to a fault. We are concerned with that because the study was not to establish that all patients with heart beat disorder should be implanted with one of these devices. And so now we are in the process of having further studies to really clarify or specify more precisely which patients should be receiving these devices.

    I can understand why the reaction has been what it is because the results have been quite spectacular. There were two groups, as you may know, one treated with medication, and one with these devices. And 98 percent of the patients having a device were free of further problems, whereas it was not the case in the medication treated group. Incidentally, I should say that this study has since been corroborated by a similar study conducted in Canada. So we think that these are pretty good results. But we need to become more specific as to which patients are eligible.

    Mr. PORTER. When we're talking about the drugs, are we talking about beta blockers and similar type drugs?

    Dr. LENFANT. Yes. Yes, that's what it is.


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    Mr. PORTER. Dr. Lenfant, I asked Dr. Collins this morning the question, ''When the genome project reaches the point where clinical trials are appropriate, do you envision your Institute actually conducting the trials or relying on the clinical trial expertise of other Institutes?'' In Dr. Collins' response, he described some promising work his Institute was collaborating on with your Institute on hemochromatosis. Maybe you could give us your views on this question as well.

    Dr. LENFANT. I think, first of all, that's a condition which is around but it's not terribly common. You may know also that it is more prevalent in men than in women. It is, indeed, an inherited condition. The gene has been uncovered, and the issue today, and that's what Dr. Collins and I are discussing, is to develop a study to assess the effectiveness of screening for this condition.

    Dr. Collins asked our Institute to conduct the study, and we are now in the process of developing the protocol in consultation with him, I should say. But we will be conducting the study which is actually an epidemiological study, it is not a clinical trial at this time, it's an epidemiological study. Our Institute has a very significant portfolio and expertise I would say in epidemiology. So we think, and I personally think that this collaboration between the Genome Institute and NHLBI—where basically something that he knows best, which is the genetics of this condition, is capitalized on with what we also know best—is quite a very fruitful marriage.


    Mr. PORTER. Last year we also discussed a new noninvasive technology, the magnetic resonance imaging angiogram which can be repeated without any danger to the patient and cost five to six times less than conventional angiograms. Has this technique developed to a point of widespread use?
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    Dr. LENFANT. No, not yet. But it is getting closer to it. In fact, I don't know if you heard about it, but our Institute, where we are doing lots of work in this area, is now in the process of developing a collaboration with the hospital which is just across the street from the NIH in order to have access to a larger number of patients and to assess the effectiveness of this technique. So that's one thing that we are going to do in our Institute. And I would anticipate that within some period of time, I'm not prepared to say how long that's going to be, it will become a routine way to assess patients.

    Mr. PORTER. The Bethesda Naval Hospital?

    Dr. LENFANT. No, no. It is Suburban Hospital.

    Mr. PORTER. Suburban Hospital.

    Dr. LENFANT. It's a community hospital where there is a continuous flow of patients with coronary heart disease and stroke. The National Institute of Neurological Disease and Stroke is also involved in this project. I think it is a very exciting thing.


    Mr. PORTER. We're seeing more and more evidence that a daily dose of aspirin reduces the risk of heart attacks, especially in men. Do you think enough evidence exists to recommend that everyone take a low dosage and topically coated aspirin a day, or, at the very least, all those who are at higher risk of heart attacks?
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    Dr. LENFANT. Well, I take it. [Laughter.]

    I think that, yes, people should do that. The issue is how much they take. There have been some problems reported. Aspirin is a drug, so you have to know what you are doing. Some people think that taking 300 milligrams a day is better than taking 80 milligrams a day. The fact of the matter is that for this purpose that is not correct. It should be a low dose. What is usually advocated is 80 milligrams a day, which is what I'm taking, that does not make it necessarily right, but I think it certainly puts me out of the kinds of possible complications with taking too much aspirin.

    Mr. PORTER. When I talked to another of your Institute directors, that director said that you should only take it five days a week and not seven because of the effect on your stomach. Do you agree with that?

    Dr. LENFANT. Oh, 80 milligrams won't cause any stomach problems. I feel very strongly about that.

    Dr. VARMUS. Some advise every other day.

    Mr. PORTER. He advised five days a week, not on weekends.

    Dr. LENFANT. But when it's every other day, it is usually 150 milligrams. I am talking about 80 milligrams a day.

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    Mr. PORTER. You're saying it is too low a dosage to have any effect on your system?

    Dr. LENFANT. Yes. I have been taking it for ten years. I am still looking for any bad effects. But my heart is okay.

    Mr. PORTER. Is there any problem with skipping a day now and then?

    Dr. LENFANT. Oh, no. Of course not.

    Dr. VARMUS. The clinical trial in which I was a subject personally, the Physicians' Health Study carried out by Dr. Hennekens at Harvard, involved the use of aspirin every other day.

    Mr. PORTER. Okay. We're getting free medical advice here. [Laughter.]


    Mr. PORTER. It was reported for the first time in November—and this is my last question, then Mr. Stokes will have the second round as well—that cholesterol-lowering drugs could help even healthy middle-aged people with ordinary cholesterol levels reduce their risk of heart trouble by more than one-third. This announcement came from a study paid for by a drug manufacturer and could impact an additional 8 million Americans. Do you agree with the findings of this study? Are there other scientific studies to support this recommendation?
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    Dr. LENFANT. Yes. Certainly, I agree with it. I think it was a wonderful study. Let me give you just a little bit of background on the cholesterol debate. Ever since these drugs appeared on the market there have been debates as to who should take it, should people take it at all, and so forth. Little by little, I think all specialists in the field would tell you that if you have had a coronary event, it does not have to be a heart attack, but angina or whatever, you should take it. That is pretty much accepted in medical practice.

    If it is after a coronary event, it's called secondary prevention. That is, you know you have the disease, some manifestation of the disease and you want to limit further development of that condition.

    The study you are talking about was looking at primary prevention. That is, it was a study that was done on military personnel, I think that is the one that you are talking about that was reported in November, and they took healthy, normal men with normal cholesterol and they gave them this cholesterol-lowering medication and then they observed them as well as observing a group of similar kinds of individuals for I think it was five years. At the end of it, the ones who had taken the medication for five years, with no evidence of coronary heart disease, had something like 60 percent fewer heart events than those who had not taken the drug.

    Mr. PORTER. Thank you.

    Mr. Stokes.

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    Mr. STOKES. Thank you, Mr. Chairman.


    Dr. Lenfant, despite the progress that has been made, claiming a life every 33 seconds, cardiovascular diseases now account for about 42 percent of all deaths in the United States. More than one in five Americans suffer from cardiovascular diseases, at an estimated cost of $274 billion in 1998 in medical expenses and lost productivity. I understand further that from ages 35 to 74 the age-adjusted death rate from coronary heart disease for African American women is more than 71 percent higher than that of their white female counterparts. What major research is underway to address this enormous health disparity gap, and what is the size of that investment?

    Dr. LENFANT. The specific amount of money on this particular problem, I think I would like to provide that later.

    Mr. STOKES. If you could provide that for the record.

    Dr. LENFANT. Yes. How much we are spending on heart disease in the African American population, specifically in women; is that the question?

    Mr. STOKES. Particularly in African American women for that particular problem.

    [The information follows:]
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    The Institute's investment in clinical research to address the health disparity in African American women was about $25 million in FY 1997, an estimate based on the representation of African American women as research subjects in its portfolio of human-subject-based studies.

    Dr. LENFANT. The amount of money I don't know, but I do know that there are many, many programs which are involving and studying this cardiovascular condition in African American women, men and women, I should say.

    Mr. Stokes, I wish I could come here and tell you we are making progress. We are making some but certainly not as fast as we could or should. Now, what are the barriers to that? I think, as has been discussed here before, many of the issues about cardiovascular diseases involve what you do for yourself. Therefore, we have to be able to communicate to the population where you want a change to occur, what needs to be done. That is very, very difficult. But it is possible. In fact, just yesterday, and not in preparation for this hearing, but because we were talking about these things, I heard about some data which I would like to share with you which will show you that it is not a hopeless situation.

    You know about the stroke belt, the 11 Southeast States where there is a very high prevalence of stroke. I have discussed that here year after year. Well, yesterday I was informed of the impact of the program that we have had there, which is a program of building coalitions to work with the people, with the cities, the communities, and church leaders to really help people to do something about this condition. That's what we have been doing for better than 12 years. The result that I heard yesterday is that we have seen a decline of stroke in that population which was 17 percent in the white population in these 11 States. That compares with 18 percent for the Nation as a whole.
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    Now, in the black population there, the decline of death rate from stroke was 31 percent—31 percent, about twice as much as what we saw in the white population, and that compared with a decline for the U.S. black population as a whole of 26 percent.

    So the meaning of all that is that by having some very active intensive programs of getting the community involved and the patients involved, outreach, you can succeed and you can do something. Here, again, we have a decline of stroke mortality in these 11 States which is higher than the U.S. population as a whole, and also higher than the white population which was not specially targeted in this project.

    Mr. STOKES. So, there's a direct relationship or ratio in terms of saving lives and education?

    Dr. LENFANT. I think there is no question that the issue of communication and getting the people or the patients to be to participate is absolutely critical to be successful.


    Mr. STOKES. Very good. Let me ask you this question, Dr. Lenfant. About 50 million Americans age 6 and older suffer from high blood pressure which also disproportionately affects African Americans. What is the extent of high blood pressure in children ages 6 to 19, and what do we know about the early onset of this health condition? Is it a condition that is more concentrated within this specific age group of children?
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    Dr. LENFANT. It is known to be higher in the African American children than it is in the Americans from European descent. The prevalence in children is not as high as it is in adults. Indeed, in adults, especially African American adults, the prevalence of high blood pressure is much higher.

    Last November, we issued some new guidelines on the diagnosis, treatment, and prevention of high blood pressure. On that occasion, we noted that we have seen a decline in the rate of awareness and control of high blood pressure in the American population, black and white. We are exceedingly concerned to see that because for years we had seen a continuous decline in the prevalence of high blood pressure and all of a sudden during the last few years we are beginning to see an increase again. The Institute is talking a lot about what to do next to address this problem. But here, again, is an issue of the patients themselves participating in this effort.


    Mr. STOKES. Let me ask you this also with regard to children. In light now of findings that there are strong relationships between poor diet and exercise and high blood pressure, what is being done to encourage healthy eating in school lunch programs, in WIC services, and physical education activities in our schools?

    Dr. LENFANT. A lot, actually. For years the Institute supported a study which involved several school districts in several States, there were four or five States, to see if we could make these schools adopt a dietary pattern which was different from what they had, and whether these kids would continue to accept these new dietary habits that they did not have before.
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    That has been very, very successful, so much so that all the approaches and methods which have been developed in that study have been widely distributed and now are adopted, as I understand it, by school districts in States which were not even involved in the initial study. We hope that will have an impact. But, again, here is an issue of education which must be fostered and encouraged as much as we can.

    Mr. STOKES. Mr. Chairman, I have a number of other questions which I will submit for the record. Dr. Lenfant, thank you very much.

    Dr. LENFANT. Thank you, sir.

    Mr. PORTER. Thank you, Mr. Stokes.

    I also have a number of other questions for the record.

    Dr. Lenfant, thank you for your excellent testimony, your direct answers to our questions, and the fine job you're continuing to do at NHLBI.

    The subcommittee will stand in recess until 10:00 a.m. Tuesday next.

    [The following questions were submitted to be answered for the record:]
    "The Official Committee record contains additional material here."

Thursday, March 19, 1998.
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    Mr. PORTER. The subcommittee will come to order. We continue our hearings with the National Institutes of Health and the budget of the National Institute on Drug Abuse. We are very pleased to welcome Dr. Alan Leshner, who always has interesting things to tell us. Dr. Leshner, it is very good to see you, sir.

    Dr. LESHNER. Very nice to be here.

    Mr. PORTER. Would you introduce the two people who are with you and then proceed with your statement, please.
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Introduction of Witnesses

    Dr. LESHNER. Sure. I would like to introduce Donna Jones, who is the NIDA Budget Officer; Laura Rosenthal, who is the Executive Officer. You know Dr. Varmus, Mr. Millstein, the Deputy Director of NIDA, and you know Dennis Williams. I think you have met.


    I am very pleased to report that the National Institute on Drug Abuse has had another outstanding year. NIDA-supported researchers continue to make enormous strides toward improved understanding, prevention, and treatment of one of our country's most serious public health problems— drug abuse and addiction.

    As just one example, we have moved this year beyond the single snapshots of a brain high on drugs that I have shown you in past years to now being able to actually look at the dynamic changes that occur in the brain as an individual has a drug experience.

    We can observe the different brain changes that occur as a person experiences the rush, the high, and, finally, the craving of a commonly abused drug like cocaine.

    In addition to that, we are continuing to use brain-imaging techniques to understand the neurochemical changes that are occurring during the process of addiction. This first poster shows you your brain on tobacco smoke.

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    These PET scans show, for a cigarette smoker on the top and a nonsmoker on the bottom, the levels of an enzyme known to be important in the breakdown of the neurotransmitter dopamine. This enzyme is called Monoamine Oxidase A. Red and yellow on the chart is more MAO–A, green is less.

    Here you see that being a heavy smoker results in lower levels of MAO–A, which means higher levels of dopamine, because it is not there in order to break the dopamine down. People very much like having higher dopamine levels, and they do not like it when dopamine levels fall.

    So, actually, maintaining these higher brain dopamine levels which occur via these changes in MAO–A may be one of the mechanisms that keep smokers smoking. They may be trying to keep their dopamine levels up by reducing their MAO–A levels.

    As you know, brain dopamine also plays a key role in another of our country's most serious emerging drug problems, the spread of methamphetamine abuse.

    As you can see from the second poster, which I hope you can see, the use of methamphetamine, this highly addictive substance, first was a major problem in limited, isolated cities like Philadelphia in the early 1980s.

    In the 1990s it became predominant in the Southwest, and it is now spreading rapidly eastward across the country and becoming a major problem in previously untouched cities. This is particularly disturbing in light of recent research that shows the drug's actual neurotoxic effects.
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    Now, NIDA has mounted a major science-based initiative to help avert a greater national methamphetamine crisis. We are working on methamphetamine-focused public education and prevention campaigns. We are working aggressively to develop more effective behavioral treatments and new medications to treat both methamphetamine addiction and methamphetamine overdose.

    We are confident that we will be able to develop more effective treatments for methamphetamine abuse, just as we have for other addictions like heroin and nicotine.

    I can also tell you that we are beginning to see some real progress in our search for an anti-cocaine medication that we have talked about in years before. This remains one of our country's greatest needs and one of NIDA's highest priorities.

    The good news this year is that we are now about to begin our first ever large-scale, multi-center clinical trial of a very promising anti-cocaine addiction compound called selegeline. I have learned in the last couple of weeks that we actually have five or six other compounds that are waiting in line for additional trials.

    We are optimistic that this trial will not only lead to an effective cocaine medication, but will also serve as a first step in launching what, ultimately, will become a national drug treatment clinical trial network.

    This network will take new behavioral and pharmacological therapies that have been shown to be effective in small-scale, academic studies and evaluate them in large-scale, multi-site clinical trials conducted in real-life treatment settings.
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    Through this network, we hope to more rapidly and systematically bring science-based treatments into actual practice.

    We have learned that in the drug addiction arena, we cannot just disseminate findings through traditional routes like journal articles. This is one of the reasons we will be holding the National Conference on Drug Addiction Treatment next month, for which we already have over 650 registrations.

    We will be bringing together treatment researchers, practitioners, and policy-makers to discuss the best that science has to offer in drug treatment.

    We are also continuing to take our science to the American public. We are about to have our seventh town meeting on April 2nd with the citizens of Boston. This is going to follow closely on, and be coordinated with, a March 29th premiere of a five-part series on addiction that Bill Moyers of National Public Television has produced using, I might say, NIDA technical assistance.

    We are also providing communities with the tools they need to prevent drug use in their own neighborhoods. Last year we debuted here what has now become one of our most popular publications, ''Preventing Drug Use Among Children and Adolescents.'' Over 150,000 copies of this document have been sent to communities across the country to use as they develop and evaluate their own prevention programs.

    All of these exciting research efforts are moving us closer to truly understanding drug abuse and addiction and what to do about it. NIDA will continue to bring multi-disciplinary strategies to bear on these issues, will continue to build on our past accomplishments and to exploit the many new scientific opportunities we now have to help this country gain control over one of the most complex and pressing issues we all face.
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    I will be happy to answer any other questions you might have.

    [The prepared statement follows:]
    "The Official Committee record contains additional material here."


    Mr. PORTER. Dr. Leshner, obviously, your responsibilities are primarily in the research area, but you have been doing, as you mentioned, a great deal to spread the word on the effects that use of drugs have on health and particularly using very graphic demonstrations as to the effect on the brain.

    It seems to me that this problem is probably the most important one to address of all and that somehow we have got to get to the young people of this country with a real message that this is not something they want to do.

    I think it is great that Bill Moyers is going on National Public TV, but I will bet you the audience that watches that show will not be the audience that we want to really reach. The watchers will be people who already understand the dangers of the use of drugs. While they may be opinion leaders and help put pressure on the system to raise this to a higher priority, somehow we have got to get to young people.

    TV seems to me to be the most important way. Town meetings are good, but how many people can you reach at a town meeting. Unless the message goes on TV, how many young people can you reach? We have to set the message on the kind of TV that young people really watch.
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    So how do we get these brain pictures on MTV? How do we get them on the shows that are watched by our youth in this country? How do we get the message from your brain into their brain that this is something that is just not for them to do.

    Dr. LESHNER. Well, we actually have been very fortunate to have a number of very effective collaborators, mostly in the private sector, who have been working with us to spread that information.

    In October, we released a set of science-based materials for middle school kids at the National Association of Biology Teachers meeting. Because the response to those materials was so tremendous we are now placing those materials, which are very graphic and very descriptive, into every middle school in the United States.

    In addition to that, as you may recall, two years ago we put out a brochure made specifically for young people—''Marijuana: Facts for Teens''—and 1,500,000 copies have been distributed. I notice that the Partnership for A Drug Free America in its print ads uses that brochure as the focal point.

    I will not go into others in great detail, but your point about the need is unquestionably true. We are working hard at it. I think working with some of the anti-drug coalitions around the country has been another vehicle that we have been using. But the core issue has got to be, obviously, to get the science into the hands of the people and to kids in particular.

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    Mr. PORTER. If you were to identify an agency of Government that ought to take the lead on this, who would you identify?

    Dr. LESHNER. We have had an interesting collaboration. As you know, we collaborate with many other NIH Institutes. We have tremendous relationships with both the Department of Education, through their Drug-Free Schools program, and with multiple parts of the Department of Justice. We have been working heavily with SAMHSA to help and inform some of their prevention activities and some of their media activities.

    The other obvious arm of Government that has taken major leadership in this area is the Office of National Drug Control Policy (ONDCP), which has its media campaign. We work very closely with them to make sure that the messages that are conveyed through that media campaign are scientifically accurate.

    We do not pretend to be advertising experts, but we are science experts. We do, in fact, review the content—not the concept—for all of the ads the Partnership for a Drug Free America—all of their ads—and for this ONDCP campaign.


    Mr. PORTER. How much of your budget is spent on education? I am sure it is not a very large portion.

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    Dr. LESHNER. Sadly, it is not.

    Mr. PORTER. Because it is not your primary responsibility.

    Dr. LESHNER. It is hard to give you a precise number. Our best estimate is about $8.5 million out of our total of $527 million, but it is distributed across public education campaigns, where we take science to the public, and our science education program, which is, again, drug-specific, which has produced a number of materials that are used widely. So about $8.5 million.

    Mr. PORTER. If you take a look at the total that we spend—what is spent by General McCaffrey, what is spent by you, what is spent by numerous agencies—in fact, I think there is some drug money in every department of Government. It seems to me though, that funding is tilted toward prosecution, interdiction, and treatment and not much, relatively speaking, for education.

    It seems to this observer that we can spend all of the money we want to try to interdict or stamp out the growing of the sources of drugs, we can prosecute all we want, we can treat all we want, but if the demand remains in the United States, somehow the drugs are going to get in and somehow they are going to be used. So it seems to me that the real effort ought to be to teach our young people that they do not want them and dry up the demand, and then you will dry up all of the rest.

    I wonder what the results would be if the Federal Government was to give one of our agencies a large sum of money, probably small relative to what is being spent on this entire effort, and we said, go out and buy some time on MTV, go out and buy some time on the major shows that young people watch and put on Alan Leshner's information in a graphic way that will hit people between the eyes as to what they are doing to themselves when they use drugs. Do you think that would be money well spent or not?
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    Dr. LESHNER. Well, I am a big supporter, as you may know, of ONDCP's public media campaign, which is literally doing that with $195 million; that is to say, they are taking ads from the Partnership for a Drug-Free America and trying to adhere to the science as much as possible in the production of those ads, and we are all very hopeful that they will be productive.

    I think there is no question that educating people about drugs is ultimately the best tool we are going to have in combatting the problem. I also believe that it is a complex issue that requires complex strategies. Sadly, no matter how good a job I do, I will never come up with a magic bullet. We are going to need multiple strategies.


    Mr. PORTER. Can you give us a profile of a marijuana user and a profile of a hard drug user? Who is using these drugs or does it go all of the way across all kinds of different strata of society?

    Dr. LESHNER. The bad news is that drug use in this country is an equal opportunity destroyer. Drug use among young people is actually as high or higher in affluent communities than it is in poor communities. People have trouble remembering that fact.

    In addition to that, the majority of even hard-core drug users are white, people who may have begun in the middle class. The truth is minority and ethnic groups are over-represented among hard-core drug users as adults, as a percentage of the society, but, in fact, again, even for adults, drug use, including addiction, is an equal opportunity destroyer and affects people of all varieties.
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    Mr. PORTER. Some of those teachers who might be given the materials might, in fact, be drug users themselves; is that possible?

    Dr. LESHNER. Absolutely. Yes, sir.


    Mr. PORTER. It seems to me that we spend a great deal of resources on this problem. Let me put this in the form of a question. Can you tell me whether you see a lot of progress being made and whether you are encouraged or discouraged? Are we doing things better now than we did them five years ago and ten years ago? Obviously, we know more, but are we doing a better job get the message across to people?

    Dr. LESHNER. I am fond of saying that advances in science over the course of the last decade have totally revolutionized our fundamental understanding of the nature of the phenomenon. When I came to NIDA, I had a sort of slogan: Science must replace ideology. I have now changed that slogan; that is, that science can replace ideology, and I think we have a science base on which to base what we do in this country.

    Having said that, I also have been committed to trying to change public understanding, and I hope I am not deceiving myself that we are beginning to see more and more people feed back to us information about what the science has taught about drug abuse and addiction. It is a slow process.

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    But I do believe, and I do take heart in the thought that we are starting to make some progress, and I think that certainly the way in which the Administration has structured changes in the budget this year, not necessarily at all absolute levels, clearly reflects an understanding among Dr. Shalala, General McCaffrey, and others about what some of the science is teaching us.

    Mr. PORTER. Thank you, Dr. Leshner.

    Mr. Hoyer.


    Mr. HOYER. Thank you very much, Mr. Chairman.

    Dr. Leshner, welcome. We are pleased to have you here.

    I sit on the Treasury Postal Committee which oversees the budget of the ONDCP.

    We now have a strategy which is a ten-year long-term, five-year short-term strategy. Would you tell me your view of that strategy and of the probability or the appropriateness of the objectives that are set forth in that strategy and the probability of success that you foresee for that strategy.

    Dr. LESHNER. One of the things that I particularly like about this strategy is that it uses science very heavily, probably for the first time in our history of developing such strategy. Science is a core element of each of the major goals, and it is a core element of each of the major objectives that lie under them.
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    I am very supportive of each of the goals. I am particularly enthusiastic about Goal No. 1, which relates to Mr. Porter's question about work with our youth. We have been working closely with ONDCP and other agencies on that goal.

    The second has to do with public health consequences, both for the individual and for society, of drug use. My own view is that it is a rational strategy that attempts to take a rational, focused approach to the problem. I am, of course, very pleased that there is a heavy science complement to it.

    Mr. HOYER. Doctor, the strategy, as you know, has been characterized as a timid, weak, defeatist policy. Would you tell me whether or not you agree with that characterization and, if not, why not?

    Dr. LESHNER. My own view is that this is the most complex problem facing humankind. It is a social issue. It is a health issue. It affects parents. It affects children. It affects everybody in the society. I believe the only way we will ultimately get a handle on it is when our strategies are as complex as the problem that we are trying to address.

    Having said that, I think, A, there will never be a magic bullet and, B, the solutions will not come very quickly.

    My own view of the strategy—which, again, we have had a part in the production of—is that it is a rational, systematic approach to getting a handle on the problem. It is complex, and it does use multiple elements. My own view is that it is a good strategy.
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    Mr. HOYER. Would I be correct, then, Doctor, that you do not think it is a timid strategy?

    Dr. LESHNER. No, sir, I do not.

    Mr. HOYER. And you do not think it is a weak strategy?

    Dr. LESHNER. No, sir.

    Mr. HOYER. And you do not think it is a defeatist strategy?

    Dr. LESHNER. No, sir. I see it as a positive strategy.

    Mr. HOYER. I do not want to get you in an argument with the Speaker of the House of Representatives——

    Dr. LESHNER. Thank you. [Laughter.]


    Mr. HOYER [continuing]. But, frankly, I agree with the Chairman's views that has expressed, as opposed to the Speaker's view, which I think was simplistic and wrong and not helpful to the fight against drugs, to which this administration and this budget has applied $17.1 billion.
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    Chairman Porter observed that perhaps too much of that is for enforcement and interdiction, which is critically important, in my opinion.

    If we do not get people off drugs, particularly hard-core users, who are the biggest consumers and, therefore, the biggest buyers, and, therefore, the biggest drive of demand and, therefore, the biggest drive for people to create supply, we are not going to win and winning is not, obviously, 100 percent.

    But do you think the goals are reasonable goals then? I ask that in this context: We had a long discussion with General McCaffrey on this issue. One of the criticisms is that the goals are not high enough. In other words, the reductions are not high enough. Notwithstanding the fact that they are substantially lower by a point, point-and-a-half, two points, than the lowest use rates that have been recorded over the last 15 years.

    Do you think the goals are sufficiently low or high, depending upon what we are looking for, to be, in effect, worthwhile goals and achievable goals?

    Dr. LESHNER. Again, I think that the strategy, as it is laid out, is as realistic as we can be, given what we know and what we know how to do at this point.

    I hope that by the time those five years are up I will have provided you, through the research that we support, new tools and techniques that we have not even thought of today, that we will be able to use to speed up the pace.

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    Mr. HOYER. That is a good point. On an annual basis we will look at these goals as it relates to our capabilities to see whether or not, we ought to raise the bar as to what we want to accomplish. I think that makes a lot of sense.

    Doctor, I want to say that I know General McCaffrey believes you are a critically important component.

    It is a complex problem, and one of the great things I think about President Clinton's appointment of General McCaffrey, who is a nonpolitician, not involved with any parties, the most decorated soldier in America, and clearly somebody who has been given some of the highest responsibilities when the United States was at risk in terms of a military perspective, has come into this and has applied a very rational, considered, long-term view, while at the same time wanting to reach short-term objectives.

    But I know that he believes you are a critically important component of this because without the medical intervention, without getting people off drugs and having effective rehabilitation strategies, we are just not going to win this thing.

    I talk to police officers in Prince George's County, and they say—and, Mr. Chairman, I am sure you have talked to police officers that say the same thing—you could be in the corner of the room over here arresting somebody for a 15-year penalty for selling crack and in that corner you will have somebody else selling crack, because the profits are so high.

    So we are not stopping people because of incarceration. What we need to do is make sure that we stop the buyers because, as the Chairman points out, if we educate them on how dangerous this activity is, we can find a way to get the ones who have already gotten hooked off.
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    I have three daughters who smoke. One has now stopped because she had a child and, in the process, obviously, stopped smoking and continued not to smoke. But I have two other daughters who continue to smoke and I bring home all of this information that you folks give me. I show them these pictures and all of that and I have a 26-year-old daughter who looks me in the eye and she says, Dad, I do not want to stop smoking. It is the toughest thing I have ever tried to do, and she says it with tears in her eyes. She is hooked on those cigarettes, and she cannot get off. I have never smoked. Judy never smoked.

    So God bless you.

    I do not know whether my time is up. Is my time up?

    Mr. PORTER. You have 20 seconds.

    Mr. HOYER. Let me try one question then.

    Mr. LESHNER. I will answer quickly.


    Mr. HOYER. Obviously, we are having a major medical cost impact with prenatal cocaine exposure on the development of a child. Can you discuss that in 20 seconds.

    Dr. LESHNER. Let me give you the quick answer, if I may, but it is an issue, I think, of tremendous importance.
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    One of the problems, by the way, that we have had is that we have had an unusual pendulum swing in this country that is making me, at least, extremely uncomfortable. We began with abject hysteria about crack babies in the late 1980s when we first saw that they were born with low birth weight and a number of other problems.

    Now we have had a pendulum swing in the other direction of what I call excess sanguine feelings about crack babies; that is, everybody thinks they are just fine.

    What we have discovered, and I might tell you that in September of this year the New York Academy of Sciences, with our support, held the first-ever meeting bringing together basic and clinical scientists to address this problem.

    What we are seeing is some very important latent and subtle effects, so that some children, not all children, but some children prenatally exposed to cocaine develop attentional problems that are not expressed until ages five to six.

    They develop learning and cognitive disabilities that do not emerge until they are 10 to 12 years old. Now, these are subtle changes. They are not very dramatic. But a study was done at Brown University that showed in the aggregate the mean IQ of the prenatally exposed kids, opposed to the general population was three IQ points, lower which for any individual child is in the noise. It is a testing error.

    But when you look at moving the mean three IQ points, it is 14 thousand kids who need intervention because of their prenatal cocaine experience. Therefore, we have increased our efforts looking at the 12 cohorts that we are now studying who were prenatally exposed to cocaine; to figure out first the nature of the problem, obviously, and, secondly, what we can actually do about it without stigmatizing those many thousands of babies who were born prenatally exposed who might not be affected.
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    So it is a very complex problem, both from a scientific and from a public health point of view.

    Mr. HOYER. Thank you, Doctor, and thank you, Mr. Chairman.

    Mr. PORTER. Thank you, Mr. Hoyer.

    Mrs. Northup.


    Mrs. NORTHUP. Doctor, I agree that we have to reduce the demand. We also have to reduce the supply. I think it is sort of interesting that we would ever diminish either one of those. We are certainly not doing that in tobacco.

    I notice that we are not just educating kids not to smoke. We are also going after the people that make it attractive and make it available as aggressively as we can, and that is what a two-pronged approach is. I agree that we have to do both of those well.

    Since you are talking about the medical side of it and not the enforcement side of it, I will keep my point structured to that, but I would not want it at all to be assumed that I did not think that reducing the supply was very important, too.

    Reducing the demand has got to be done at every level, and I think that education is important. We could put ads on television. It is not the only way of approaching it, and I just wondered how closely you work with those agencies that are both involved in prevention and in education, particularly SAMHSA, and whether or not you have ongoing conversations about your work and what might be applicable to their work in prevention.
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    Dr. LESHNER. Let me mention, first, that we have a very close relationship with the Department of Education, since you mentioned education. The Drug-Free Schools Unit within the Department of Education, which has been distributing our prevention brochures everywhere around the country trying to make sure that it, in fact, gets used.

    We have a number of interactions with various elements within SAMHSA, and you may know that the new SAMHSA CSAP director is a NIDA grantee, Karol Kumpfer, and so we are very hopeful that we will actually have even more relationships developing over time, where we would, of course, be looking at ways to implement that which has been discovered in the scientific research that we produce.


    Mrs. NORTHUP. I think that the Chairman had a real point when he said the demand is created at sort of every level, every strata of society, and every age. I have talked to a couple of organizations, businesses, that have put in very effective no-use policies, and I wondered if you have done any studies that would show what the best practices are that exist in drug-free workplaces that would help other companies and other communities that are trying to implement a no-use policy.

    Dr. LESHNER. Let me say two things, if I may, about that; one, we do have some research going on now about workplace drug prevention. I would not want to create the impression that we have a formula that could be used. However, first, just to have the presence of drug testing, to have the presence of drug prevention programs in workplace environments is very important.
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    The second thing I would mention is drug treatment. Many employed individuals are, in fact, addicted—and it is hard for people to remember that something like 70 percent of the addicts in this country are, in fact, employed. Employee Assistance Programs within work environments have been developing more, and better, and more effective treatment programs to help people return to functionality.

    A finding I think was just published—it may be about to be published—showed that in the Employee Assistance modality you can, in fact, literally match the service needs of a particular individual to the services being offered. This may sound obvious, but it is actually a change from historic practice—and increase the efficacy of the intervention by 20 percent.


    Mrs. NORTHUP. It is a tough issue because we know that to overcome whatever challenges each of us face, there has to be a strong inner motivation, too. I think the threat of losing your job is part of making sure there is some intervention, but there is the opportunity for treatment, the opportunity for survival in your job, even if you fail the first time.

    I also happen to know of a number of people that have been young adults, they used drugs, but the opportunity to have a really good job and know that they were going to have to take a drug test and then be tested at random after that was just enough to stop use. I do not think we would classify them as addicted, but they are part of the reduced use, reduced demand that helps eliminate the market that we are trying to eliminate.
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    Those type of best practices, I think, are very important and very important that we make them available.

    I am also interested in what goes on in schools and what type of grassroots efforts are being used. If you believe that it has to be a multifaceted campaign as I do, then you agree that maybe some mass media is important.

    I also believe that what we have done in communities regarding smoking is a pretty good model, and that is the grants that exist in every state for grassroots planning. They compete for them. I think half of them come through HHS and half of them come through CDC.

    But they are a grassroots organization, a coalition to reduce smoking. They are the coalitions, in most States, that have pressed for strong public policy, that have pressed for strong education programs, that have met youth where youth are, in terms of both physically and mentally. I wondered if there is any effort that you see going on to create that same sort of grassroots organization in all of our states regarding the drugs.

    Dr. LESHNER. Actually, there is a phenomenon that has been going on for the last five years in this country. Just to give you a very large number, there are now 4,000 anti-drug coalitions in communities around this country. They are organized collectively in something called the Community Anti-Drug Coalitions of America, and you may know that Mr. Portman was influential in a bill to provide support for those communities.

    Mrs. NORTHUP. Right.
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    Dr. LESHNER. Well, one of the nice things that has been happening is we have been working very closely with CADCA, and they have developed a program called, ''The Practical Theorist,'' where they take our scientific findings and actually translate them, with our participation, into a format that then is circulated to these 4,000 coalitions and then gets diffused out into the community setting.

    The first issue they did was on our prevention activities, and they are co-sponsors in our Treatment Conference next month, and we are very hopeful that that will be another vehicle, whereby communities can get their hands on the best of what we have. Again, I do not want to create the impression we know everything, but we do have a lot to offer.

    Mrs. NORTHUP. Well, I think you do. The advantage, though, of the State grants, and I am searching for the name of those two—ASSIST, one of them is ASSIST, and I cannot think of what the other one is. The advantage is that they provide not that much money, but enough to bring together a lot of coalitions, the PTA and so forth, to have sort of an organized approach, and I just have wondered if that would not be valuable.

    It is very hard. I was very involved in the tobacco one in Kentucky. There are a lot of diverse groups, a lot of volunteers, a lot of people that already have other responsibilities, and the planning grant actually helped move them from Point A to further down the line very fast. I would just be interested in whether that model would help give us an impetus.

    Dr. LESHNER. I do think that these coalitions have been tremendously effective.
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    Mr. PORTER. Thank you, Mrs. Northup.

    Mrs. Lowey.

    Mrs. LOWEY. Thank you, Mr. Chairman.

    Again, I would like to welcome you, Dr. Leshner, Dr. Varmus.

    Dr. LESHNER. Thank you.

    Mrs. LOWEY. Because time is limited I will submit some questions for the record.


    Mrs. LOWEY. I am particularly interested in discussing your statements in your initiative called Genetics of Addiction Initiative, and your comments regarding the complexity of addiction.

    When you think about this, and the interaction, the interrelationships between food addiction, and alcohol addiction, and drug addiction, and the cost to society today in health, in criminal activity, I think it is probably one of the most important things we can do.

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    When you look at our prisons, you see that 90 percent of the people are there as a result of drug addiction and related crimes.

    So I am very interested in the results of that initiative, which I will ask you to discuss at another time.

    My colleague, Mr. Hoyer, talks about his daughters. I do not smoke. My husband never smoked. Neither of us ever smoked, and we have the same situation, they all got off cigarettes, but they also said to me it was the hardest thing they ever did in their life.

    The reason your research concerning the biological basis for drug addiction is so interesting to me, there has been a longstanding perception that drug addiction, for example, is more prevalent in low-income communities. You say it is an equal opportunity addiction, which is true. We see it at all levels.

    If this is the case and if there is a biological basis for addiction, then it is a very important message to us here and that how do you deal with it? What is the interaction between the socioeconomic forces and the biological basis? Do we treat everyone who is arrested for drug addiction as a sick person? And considering the cost to society, as someone who has been so involved with DARE and peer assistance programs, why can we not do something that is successful?

    Steny Hoyer has talked for years, and I have been very involved with him as well, in comprehensive programs in the school. We have loads of these programs, although not the ones he is talking about, and I support that. But the numbers of users may dip a little bit, but basically it is rising.
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    So my question is, perhaps, briefly, where is this study going? Is the interaction based upon information now between the biological basis for addiction and the socioeconomic forces, and what are we learning about it? What are we doing about it?

    Dr. LESHNER. I may have to sort those two parts; what we are learning and what we are doing.

    Vulnerability to addiction is, obviously, a tremendously complex phenomenon, but there is no question in 1998 that it is the result of the intersection between genetics and environmental influence; that is, that every twin study or adoption study that has been done shows amazingly high levels of heritability of the vulnerability to being addicted.

    The numbers that I have been given recently approximate 50 to 70 percent of the vulnerability as contributed by genetic factors. Now, we have not studied that in enough depth for me to be confident that that will prove to be the number forever, but it is showing us a tremendous influence.

    Having said that, obviously, not everyone who carries the genetic load becomes addicted and, therefore, we have to look at the intersection between genetic vulnerability and the expression of that genetic vulnerability and actually being addicted.

    Therefore, our own work—apropos what are we learning about it—is trying to look at this area; and we are about to mount a major initiative looking at the genetics of vulnerability. We will look at that as an element, then look at the environmental determinants, and then look at the intersection between the two of them.
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    I think among the things that we all need to address, obviously, is the issue of what do we do with that information once we have it, given that not everyone who is vulnerable will actually become addicted. Therefore, we will need to have, as our markers for vulnerability get better over time, just as we have new strategies for dealing with social environmental markers, we will need to have new strategies for knowing whom to interview with and how to intervene with those people once we understand the nature of the relationship.

    Mrs. LOWEY. We have to go vote, but I am very much interested in this, and I would like to have a further discussion because knowing that people have a predisposition towards depression, predisposition towards many other mental illnesses, and the interrelationship between the biological basis, certainly, for drug addiction and the other mental illnesses certainly leads me to say we have to just do a better job of detecting this in our young people today, not only to ensure that they have a successful, healthy life, but because the cost to society is enormous. We know that once a youngster is addicted, the numbers are not very good.

    I have worked with Phoenix House and so many of the programs within my district, and it all leads to you having to figure it out early, detect those youngsters early because once they are addicted, the recurrence rate, as you know, is extraordinarily high.

    We are out of time, and so I will save the rest of my questions, but I just want to——

    Mr. PORTER. Mrs. Lowey, I am sorry we are not going to be able to save questions because we have Dr. Gordis to testify yet.
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    Mrs. LOWEY. No, no. I mean I will just submit them for the record. I just wanted to emphasize this is an area that I, personally, am very interested in because I think it is so important as a public health issue, as a cost issue and, although, we have done so much, and I think you have heard the frustration of so much of us, there are so many successful programs yet we cannot replicate them on a large enough scale to really be successful.

    I want to thank you for the very important work you are doing, and I look forward to hearing more about your success.

    Dr. LESHNER. Thank you.

    Mrs. LOWEY. Thank you.

    Mr. PORTER. The Chair would like to also say that you are doing a superb job at NIDA, Dr. Leshner, and all of us appreciate that and want to give you the resources that you need to do it even better.

    Dr. LESHNER. Thank you, sir.

    Mr. PORTER. We will do our best. I am very sorry we do not have enough time. It is a scheduling problem for us. We are attempting to move our hearings along a little bit faster than last year and it sometimes simply is too compact, for which we apologize.

    Thank you very much for appearing and testifying.
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    Dr. LESHNER. Thank you, sir.

    Mr. PORTER. The subcommittee will briefly stand in recess.

    [The following questions were submitted to be answered for the record:]
     "The Official Committee record contains additional material here."

Thursday, March 19, 1998.








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Opening Remarks

    Mr. PORTER. The subcommittee will come to order.

    We continue our hearings on the National Institutes of Health with the National Institute on Alcohol Abuse and Alcoholism. We are pleased to welcome Dr. Enoch Gordis, the Director.

    Dr. Gordis, it is good to see you and if you will introduce the people that you brought with you and then proceed with your statement, please.

    Dr. GORDIS. Thank you, Mr. Porter.

    Starting from that end of the table is Mr. Steve Long who is head of our Office of Policy Analysis; Mr. Martin Trusty, our Executive Officer; Ms. Carmen Richardson, our Budget Officer; Dr. Mary Dufour, our Deputy Director of the Institute and I think you know everybody else at this table.

    Before I begin on my remarks about Institute activities, I would like to join the other colleagues at NIH who, over the last few days, have had an opportunity to congratulate Mr. Stokes on his distinguished career and to wish him all the best in the years to come.
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    Mr. STOKES. Thank you very much, Dr. Gordis.

    Dr. GORDIS. The Fiscal Year 1999 President's budget request for our institute is $230,243,000, an increase of $17.5 million over the 1998 appropriation. Including the estimated allocation for AIDS, total support proposed for our Institute is $245,000,000, an increase of $18.6 million over the 1998 appropriation. Funds for NIAAA AIDS research are included in the Office of AIDS Research budget request.

    The problem of alcohol is immense in this country, Mr. Chairman. Fourteen million Americans have been diagnosed as having alcohol abuse or alcoholism. It is by far the leading drug of abuse in this country, especially among the youth. One-quarter to one-half of all hospital beds in urban hospitals are occupied by people being treated for the medical consequences of their drinking. It causes 100,000 deaths annually and in 1992 the estimated cost to society was over $100,000,000,000.


    As a result of our extensive epidemiological work, an important addition to our knowledge appeared this year. The first poster shows that when we analyzed the relationship between the age of onset of drinking and the odds of becoming a diagnosable clinical alcoholic as an adult, each year that the age of onset was delayed decreased the risk 14 percent compared to the year before. Forty percent of the people who start drinking below the age of 15 will have a diagnosis of alcoholism some time in their adult life, while starting later reduces that risk to about 10 percent.
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    Now, of course, the appearance of alcoholism in adulthood is only one reason for being concerned about adolescent drinking. Adolescent drinking causes highway deaths, destruction of school activities, date rape in colleges, binge drinking and all of the things that I think we are familiar with. But this is yet another reason to be very concerned about the onset of drinking in the young.

    The range of our research is from molecular biology through treatment, toxicology to organs including the fetus, prevention activities of all sorts and also a portion of work on the health benefits of drinking because, as a scientific agency, we have a responsibility to look at all aspects of the use of this substance.


    In the second poster, I am going to make the point in response to a question which is frequently asked and that is, how long does it take to get from the science to its useful application in treating patients? And what this shows here is that it depends on what kind of science you are talking about. The distance from science to clinical application is relatively short if we are talking about clinical trials. If we talk about neuroscience it is a bit longer. Exciting new approaches of medications development are just beginning to be seen and, in the case of alcoholism, the route from the genetic work, which I will tell you about shortly, to its applicability in the clinic is probably even longer still.

    Clinical trials, of course, include Project MATCH which is a randomized control trial of 1,700 patients that was just completed. Other work has shown that naltrexone, an opiate antagonist, is useful for the treatment of alcoholism—which led to the FDA approval of this drug three or four years ago.
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    A new drug in Europe called acamprosate is being widely looked at now in the United States and has become the subject of one of our new cooperative studies. And new drugs, such as amperozide and many others, which I will not take the time to go over, are on the horizon.

    But the important point is that these clinical trials have already been able to exploit the fruits of basic science in treating patients.

    When we get to neuroscience, we are learning what happens in the brain which will then provide us with the tools to provide new medications. Unlike the drugs of abuse, which Dr. Leshner discussed with you in the previous hour, alcohol affects virtually every receptor system in the brain which is studied. And one of the main issues in our research is to understand the common principles by which alcohol reacts with these receptors

    There are, in general, two ways we can look at the neuroscience of alcohol abuse. One is to look at what is called positive reinforcement. That is, what is there about drinking which is enjoyable? That involves one set of neurocircuits and one set of neurotransmitters.

    The other side of the coin is what is there about the discomfort of not having alcohol when one is dependent which leads to relapse? That involves other neurocircuits and other kinds of neurotransmitters. Both of these approaches have helped explain why the drugs that we have introduced are useful and promise a route to the discovery of new ones.

    Of course, we use all the high-tech approaches in neuroscience—imaging, using transgenics, and knock-outs, and site-directed mutagenesis, which is a technical method for changing the structure of receptors and seeing exactly where alcohol acts upon them. And if there is any interest in that I will be happy to respond.
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    The third one, new approaches to medication development is the following idea. In general new medications have been found in many areas of medicine by a combination of luck and accident on the one hand, by exploring off-the-shelf what is available as well as finding new uses for medications which are used for other purposes, and our field has benefitted from that as well.

    What is happening now in medication development is our ability to understand the three dimensional structure of body molecules such as proteins and enzymes which permit us to design beforehand which kind of medications would suit the fit of those molecules.

    A very exciting piece of work by a group of our grantees was the unraveling of, the crystalline structure of the molecule of aldehyde dehydrogenase, a key enzyme in the metabolism of alcohol.


    What it has helped explain is why the mutation, which had been previously identified in Asian people who often have a flush after drinking and, therefore, are in some ways protected against developing alcohol dependence, happens?

    Time does not permit me to go into this now but because of this particular structure which gives the shape, the coiling, the chains, the linking of the various parts of this molecule, we can now explain why that mutation causes the activity which it does, and it is a prototype of what is coming in the future of how this kind of approach will permit us to devise new medications.
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    The final arrow on the poster previous to this was about genetics. And I know that the Committee is interested in this, judging by the questions in the previous session. Our collaborative study on the genetics of alcoholism now is in its eighth or ninth year. And we are happy to report what will be in the press shortly, that we have found four chromosomal loci, so-called ''hot spots,'' for alcoholism in the genome, as well as other loci which relate to various electroencephalographic abnormalities which are risk markers for alcoholism.

    In the next few years we hope to identify the genes and get the rewards of this effort. The rewards of efforts in genetics really are to understand the function of the proteins which are abnormal and develop new medications, based on that understanding, to have more targeted prevention and finally to understand the relation between gene and environment more precisely.

    Our research includes a wide range of other activities in prevention, studying FAS and toxicity to other organs, youth drinking, public education both to the lay public and to physicians and other professionals and also to clarify the health effects of moderate drinking.

    I will be very pleased to answer any questions that you may have.

    [The prepared statement follows:]
    "The Official Committee record contains additional material here."
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    Mr. PORTER. Dr. Gordis, thank you very much for your excellent testimony. You were in the room when we were discussing with Dr. Leshner the problem of the substances under his jurisdiction that are abused and we talked about how much money is spent by the government in that area. I recall it being around $20 billion. Do you know how much does the government spend on alcohol abuse overall?

    Dr. GORDIS. No. I do not have that figure in front of me right now, Mr. Porter. I am sure, however, that it is considerably less despite the fact that alcohol is the number one drug problem in our country, especially among youth.


    Mr. PORTER. It seems to me that the problems that hard drugs cause in our society are severe, but the problems that alcoholism cause are much more severe as you just stated. We do not put nearly enough of our resources toward aiming at solutions that affect a much larger population in our country.

    Alcohol abuse and alcoholism are serious problems for our economy, for families, for addicted individuals and has a lot of deleterious effects on society.

    Let me I ask you, if we were to double your funding over five years, could you use those funds in a meaningful way to advance your research goals or would we simply be putting money out there that really would not do much?
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    Dr. GORDIS. I think we could use this kind of money in a very meaningful way. In view of the budget discussions which we have all been party to in the last months we have, obviously, like our sister institutes given a lot of thought to that kind of a question. And I believe there are many areas, greatly exciting, some of them novel, some of them elaborate continuations of what we are doing, where we could make some very meaningful advances in the field.

    I would be very happy to discuss some of them with you but the answer to your question is, yes.


    Mr. PORTER. In your opening remarks you mentioned two different types of, I think you called them, receptors. One had to do with the pleasure that people derive from drinking alcoholic beverages and the second had to do with the addiction to them. Is that correct?

    Dr. GORDIS. Well, the feeling of deprivation when it is not present.

    Mr. PORTER. Can you describe the research you are doing in both areas a little bit more? Do you ever see a situation where the pleasures that people associate with using alcoholic beverages could be cut after their use so that you do not get the effects of the alcohol and you do not get the dependence that often follows?
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    In other words, can you get part of the whole, the good part and not the bad part?

    Dr. GORDIS. This is a dream which man has had for a long time. [Laughter.]

    Mr. PORTER. Woman, too. [Laughter.]

    Dr. GORDIS. Just a short answer to the second part of your question because the first, I think, is more directly related to what we are doing now. Agents which reverse the intoxication from alcohol have been called amethystic agents. I think it comes from the Greek, amethyst which is a stone which in Greek mythology had the capacity of undoing drunkenness.

    So, these have been called amethystic agents. And there are none available right now. Whether it will be valuable to have one, I think, is a matter of some dispute because it involves certain aspects of social policy such as violence at home and highway deaths and so on. And it is a complicated issue.

    But for all practical purposes, there is no such agent now which undoes intoxication. Whether there will be an agent which permits one to enjoy the legitimate pleasures of alcohol without going on to addiction, I think in the future that is conceivable as we get to understand more of the mechanisms to which you alluded.

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    Let me just take a moment to clarify a little bit about these two kinds of circuits. I said pleasure but I was using a commonly used word. What I am talking about are circuits having to do with reward and reinforcement, that is those brain circuits which once a behavior has happened make it highly probable that it will be repeated.

    And this kind of activity can be studied both in people and especially in animals. The circuits which have been largely involved in that are the so-called mesolimbic systems involving circuits of the brain where dopamine is a key player but not the only one. Especially with alcohol we know that the opiate system, the GABA system, and the serotonin system are all involved in this. I could go into this in much greater detail; this is a very active area of work in understanding which receptors are involved in the nerve connections in the circuits that have to do with reward.

    In the last few years, the other side of the coin is becoming increasingly prominent as well. That is the so-called alcohol deprivation effect. That means that after an animal, for example, is permitted to get alcohol at will for a period of weeks or months sometimes, if it is terminated the drinking resumes at a very high amount. And this seems to involve somewhat different circuits than the reward circuits I just described. It is a circuit which produces the discomfort that the animal feels in the absence of alcohol which human patients also feel even when they are sober for many months. This feeling or ''craving'' is one of the things which antedates relapse.

    Here we know that different neurotransmitters are probably involved in part. Certainly, the NMDA receptor which is an excitatory neurotransmitter is involved because we know that acamprosate, which is a drug that is undergoing clinical trials now, as a matter of fact, does act at that receptor. In Europe acamprosate has had important effects in curbing the rate of relapse. I hope it will in America, too, when the clinical trial is over.
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    So, the answer to your question is we are actively engaged in research in both these aspects of neural control of alcohol-related behavior.


    Mr. PORTER. There are a lot of reasons why we have a separate Institute for Dr. Leshner and a separate Institute for you. One reason is historical and that is alcoholism and alcohol abuse was a problem in this country before the use of harder drugs.

    But there are several others and one is that alcohol is legal in this country, whereas the use of other drugs under Dr. Leshner's jurisdiction are not. And finally, and this is my own view of it, alcohol has been used throughout history as a social lubricant and, I think, in practically every society.

    In fact, if alcohol is used moderately and with some reasonableness it is viewed in a benign or even a positive way. There is also research saying that moderate use of alcohol can be healthful, but there are not such studies about the use of drugs that are illegal.

    Somehow, it seems to me, there has to be a separation between that benign or even positive use of alcohol and the over-use or misuse of alcohol and it seems to me that your research is terribly important in defining some way of drawing that line and preventing the negative effects of people who do not use alcohol in a reasonable way. That is why I am interested to know what kind of progress you are making.

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    If you look at your research, Dr. Gordis, are you optimistic that we are going to find some of these ways that will really make the use of this drug a more benign substance or the misuse of it less possible?

    Dr. GORDIS. Yes. I am optimistic about it. I think the work of the last 10 years has exploded in many fields, all of which contribute the kind of information which will lead to the answers to the questions you are asking.

    Our main goal is to understand why some people never get into trouble with alcohol while a minority do. Our genetics research is contributing to that; when we find the genes we will understand something about that. Our neuroscience is already trying to do that because even now we know that within the brain there are different regions where the neurotransmitters vary in their shape and their form and we are studying that.

    And the more we understand that I think we will be in a better position to be able to intervene early. Now, having said this—and I mentioned before why genetics is going to reveal the abnormalities in proteins in those who become addicted compared to those who do not and we will be able to develop medications based on that knowledge, too—I do not want to minimize the important side of the environmental influences here.

    There are many such influences in this country as we know. The parents' attitudes towards alcohol right from the start, including how the parents handled it, and whether they drink abusively or not is one. Friends and peer pressure are another influence. We have the issue of many young people having a misconception of how much drinking is really being done by their friends. We know that they all think their friends are drinking more than they are in many situations.
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    We have the immense power, of course, of the commercial interests and advertising—the industry and its advertising in all media. So, there are tremendous social influences which determine the use of alcohol and the question you are asking is really profound. One of the reasons why I believe our country has not come to grips with the alcohol question in a very serious way is because of these various aspects which you have pointed out in your question. It is legal, it has a legitimate use, it has been used throughout history and, therefore, it is harder for people to come to grips with the complexities of this issue.

    Nevertheless, I think one of these days the country is going to have to do that because as I said, it is the number one cost and killer among drugs of abuse.

    Mr. PORTER. Thank you very much, Dr. Gordis.

    Mr. Stokes.


    Mr. STOKES. Thank you, Mr. Chairman.

    Dr. Gordis, it is a pleasure to welcome you back before our subcommittee and thank you for your very kind remarks.

    When we left for this last vote, as we got into the elevator, we ran into one of our colleagues who had on her lapel a campaign button that said, ''Stop Cyber Booze.''
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    Some of us inquired as to what the button was about and she told us the story about how a minor had ordered a case of liquor on the Internet. When the case of liquor was delivered, the minor used his parent's credit card and paid for it. So, she has introduced some legislation to address that issue.

    And, so, the question I have for you is have we learned what impact the advertising of alcohol products and the drinking of alcohol in television shows and in movies and on references of alcohol in music impacts adolescent alcohol consumption?

    Dr. GORDIS. Thank you, Mr. Stokes.

    Let me lay out the main controversy that exists in this field because I think it gives shape to what I will tell you.

    Mr. STOKES. Sure.

    Dr. GORDIS. On one hand are many advocacy groups which believe that the industry is intentionally trying to advertise to cause young people to begin drinking when they have not been drinking before. That is one extreme. The other extreme is the industry's response which is that that is not their intention at all. Their intention is only to maintain brand loyalty and make sure people keep using the brand they happen to be manufacturing.

    Where does the truth lie in all of this? I think that is really the heart of the question you are asking.
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    Mr. STOKES. Sure.

    Dr. GORDIS. The fact is that we have hints there but we do not know the full answer. Let me give you a reasonable sequence by which advertising could have an effect and I will tell you what is missing in our ability to know the answer for sure.

    You have to see the ad, you have to be exposed to it, you have to understand it, you have got to remember it, and then following that, you have to have an attitude change toward alcohol as a result of it. That has to lead to an intention to drink and then you have to start drinking.

    In order to know the answer to your question ideally we would like to know the whole sequence and to be able to say that advertising has such and such a role in marching a young person through that sequence. We have pieces of it. The idea that expectancy is related to future drinking, that the expectancy of the good effects has been documented, I think, very persuasively.

    Also, there are studies which show that alcohol advertising does lead to expectancies and to a better attitude towards alcohol itself. And we know that very young children know a lot about the difference between brands and about beverages.

    So, why is the answer incomplete? The answer is incomplete for a couple of reasons. First of all, the same populations have, in general, not been followed longitudinally over a period of time so we know for sure that that is what is happening. We have chunks of information for one age group, we have chunks of other kinds of information for another and, therefore, we do not have the answer convincingly.
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    From what we do know it is not likely that advertising accounts for more than a minority of the variance in drinking. Although that is a good plausible answer, we are not absolutely sure of it.

    We will now be studying this in great detail. We have a request for applications out on this very topic in which the issue that you have just raised, Mr. Stokes, is going to be looked at extensively with longitudinal studies to finally sort of put the nail in this coffin, that is, to find out what is the role of advertising in the initiation of drinking in the young.


    Mr. STOKES. Now, I noted, Dr. Gordis, that in your congressional justifications the examination of data from the National Longitudinal Alcohol Epidemiologic Survey found that the age of onset of alcohol use is a strong predictor of future alcohol problems. The younger age of onset is associated with an increased likelihood of future alcohol and related problems. And you have already made some reference to that in your remarks here this morning.

    These findings indicate that there is an increased need for family-centered prevention programs. To what extent do these programs exist and how effective are they?

    Dr. GORDIS. To many people—not to you nor this committee—the idea that prevention can be actually researched so you can find what works has been a novel idea. But the fact of the matter is that just as a new medication can be researched, prevention can be researched also. It is possible to try interventions in one community with one group of kids and see if they have an effect compared to another group of kids or other communities which are not given that intervention.
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    And we have done that and we have had some positive results for several interventions in which the family plays a role. For example, in Project Northland in Minnesota, which examined the issue of drinking in an age group roughly from about 11 to 14, we found that a combination of family work, parents and children working together with assignments on this problem, school-based activities and several other details led to a reduction in the initiation of drinking in that group by about 25 percent. For any kind of a social effect this is really quite large.

    Those kids are actually being followed for the next three years and within about a year or so we expect to have the data. The interventions that one needs with somewhat older kids are less of the homework kind of stuff, these interventions tend to involve more community interventions. And we know from some of our other prevention trials that community interventions which involve many aspects of enforcement, of public activities about drinking and driving and so on, all have a role. For the record, I will be glad to give you the results of some of those other trials.

    But I want to just conclude this answer by pointing out that the cyber booze you are talking about—selling booze over the Internet is a minor issue but an important one because of the fact that there are many places in this country where an under-age kid can still go into a liquor store and buy it.

    This is where the rubber hits the road, as a matter of fact. And every single one of the community-based interventions which does not address this problem is not going to work.
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    Mr. STOKES. Well, in light of what you have just told us, Dr. Gordis, do you have some ongoing collaborative efforts with the Department of Education relative to the schools? What type of programs currently exist in the schools?

    Dr. GORDIS. Yes. We have several things going on that way. And we also are working with the Department of Justice, by the way, on the advertising issue that you spoke to us about. Mary, did you want to comment on the education efforts any further?

    Dr. DUFOUR. Just to say that most of the things are related to the issue of alcohol and adolescence and going from middle school through high school. We are especially interested in college issues because that has been a very difficult one.


    Mr. STOKES. Okay. Dr. Gordis, let me ask you this, the rise of managed care has increased the importance of primary care providers over the years. The Institute has emphasized that primary care providers could be a valuable and effective tool in talking to patients about alcohol consumption.

    With the restraints placed on physicians in terms of time spent with patients in many managed care arrangements, how likely is it that physicians will have the time for this type of discussion or that managed care administrators will provide physicians with additional time? Can you tell us what is being done to educate managed care plans about the benefits of this kind of dialogue?
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    Dr. GORDIS. You are absolutely correct that the primary care physician is the gatekeeper on making sure that a patient who has an alcohol problem is going to be identified and handled right. We have been very active in that. We have just published a physicians' guide to helping patients with alcohol problems and a similar booklet of training for primary care physicians. And I must say that the managed care firm, as well as ONDCP, has been very helpful to us in distributing this to almost 300,000 doctors across the country.

    Managed care, even when you consider that they do have bottom line interests, obviously are also interested in making sure that the patients who are being seen are not going to cost them more in the future. And one good way of doing that is intervening in alcohol problems early before they end up as a costly hospital admission.

    So, I would not be pessimistic that managed care organizations would want to deprive doctors who are working for them of the opportunity to do this kind of intervention you are talking about especially since the kind of interventions that we are talking about, of which this booklet is only one example, are designed to be rapid and efficient.

    Obviously, if you have 40 minutes to see a patient or half an hour, you are not going to devote 20 minutes to talking about alcohol when you have got many other things to talk about as well. So, you have to get into the topic in a way that is going to give you a high yield quickly. And we know two things about this from research on primary care.

    First of all, that it is very cost efficient in the sense that it is possible to have a non-physician do some of the counseling once the problem has been identified. This leads to a diminution in the rates of hospitalization which Dr. Fleming's study has shown in a very extensive study in Michigan. And secondly, Dr. Israel in Pennsylvania has shown that if you use the history of trauma as one of your first questions, you can identify about 60 or 70 percent of the expected number of alcoholics in your population without even mentioning alcohol first.
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    The point of all this is that with efficient interrogation methods there is no reason to assume that managed care folks would not be very happy to cut down the costs of the complications of alcoholism by giving the primary care doctors a chance to do it right.

    In line with your question, I just am reminded that the parity issue which is, of course, very much related to that is whether health care plans of all sorts are going to be required to take care of alcohol and drug questions to the same extent that they are now required to take care of mental health problems and in parallel to what they do for medical and surgical complaints.

    And certainly the science would support the wisdom of going that route for the reasons I have talked about; by preventing complications, the costs spent in treating these folks is saved many-fold over.

    Mr. STOKES. My time has expired.

    Thank you, Dr. Gordis.

    Dr. GORDIS. Thank you, Mr. Stokes.

    Mr. STOKES. Thank you, Mr. Chairman.

    Mr. PORTER. Thank you, Mr. Stokes.

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    Mrs. Lowey.

    Mrs. LOWEY. Thank you, Mr. Chairman.

    And welcome, Dr. Gordis.

    Dr. GORDIS. Thank you.

    Mrs. LOWEY. I thank you for your excellent presentation. I apologize that we are pulled in so many different directions. This morning we have been talking about the genetic basis of drug abuse and I am particularly interested in the growing evidence that alcoholism is genetic in nature, as well.

    And I was interested in your comments regarding the promise of research in that area. Perhaps you can update us on what progress has been made—and I know you feel they are at the beginning and there is a lot more that has to be done—what progress has been made on identifying genes that do influence behavior? And, in fact, I would be interested in the interaction between the genetic basis and the socioeconomic basis, as well.

    Dr. GORDIS. Sure.

    Mrs. LOWEY. And before you give that comment, I just have to react to the conversation before and your response in terms of under-age youth buying alcohol. What I think is truly unfortunate in this country is that you have bartenders who do not have to be 21 and it is very common, certainly in New York, for the local bars to have guest bartenders and bring your friend that night.
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    Now, if the bartender is 18 and he fills the bar up with his friends, I just wonder about the enforcement of the 21-year old drinking age.

    Dr. GORDIS. Well, I share that point of view.

    Mrs. LOWEY. And perhaps you can respond then to my question regarding genetics.

    Dr. GORDIS. Yes. Okay. The wisdom of Congress had led to the funding of a collaborative study on the genetics of alcoholism which is now in its eighth year. This is taking place at six centers across the country where diagnostic instruments for defining alcoholism were designed and arrived at. They have been found so useful they have been translated into eight or nine languages and used all over the world now.

    Thousands of potential probands, that is the initial case who has alcoholism in their families, have been interviewed and over the course of this time, this has been honed down to about 320 informative families, that is, families where you have multi-generational alcoholism, some with and some without, where the genetics studies can be done.

    The studies have progressed very well, indeed. And the first publications actually are appearing this spring. Four sites on the human genome that are so-called ''hot spots,'' locations within the chromosomes where the genes for the vulnerability to alcoholism have been found have been identified, chromosomes 1, 7, 8, and 16 for alcoholism itself.

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    In addition two other ''hot spots'' have been identified for certain kinds of brain wave abnormalities which are found in kids known to be high-risk who have never even used alcohol. These ''hot spots'' predict this as a high-risk group.

    And, so, the next five or 10 years, and I think that is part of what Mr. Porter was asking about regarding how we would spend more money, the goal is to actually find the genes, themselves, because now we only have their locations. We have other clues from animal work in genetics where some of these genes might be. But in the interest of time, if you are interested in that I will be happy to supply that for the record.

    So, we are very confident that over the next five or 10 years we are going to find genes that have to do with the vulnerability to alcoholism. And as has been said before and I will say it again, alcoholism is not only a genetic disease but the role that genes and environment have in any individual will vary from person to person. With a heavy genetic load it will not take much of an environmental push, with a lighter one you will need more of an environmental influence to shape that.

    So, clearly by knowing the genes, we are going to be able to define the environmental pressures even more accurately.

    Now, having said that I will give you one example of where we have a beautiful example of the question you are asking of the environment and the genes.


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    One of the striking triumphs of molecular biology and alcoholism is the identification of the mutation in the gene for an enzyme which, because of that mutation, leads to inadequate metabolism of alcohol and a very uncomfortable reaction from drinking.

    It is almost like you took antabuse, except you have a gene for it instead of taking the medicine. About half the Asian population has this mutation, which leads them to avoid alcohol. Among alcoholics in Japan, for example, this mutation while it is 40 to 50 percent through the whole population, you hardly ever find it in alcoholics because it seems to be protective, not because it protects against alcoholism, but because the initial experience with alcohol is so unpleasant you do not go further.

    Now, the interesting wrinkle about this is there is a mild form of this where you have one copy of the normal gene and one copy of the mutant gene but you do not have such a severe reaction. So, what has been looked at is how has the presence of this mild form of this genetic mutation changed over the 15 years that it has been looked at in Japan?

    That is the enzyme but it is not related really to the present discussion as I am answering Ms. Lowey's question.

    The fact of the matter is that the mild form of this mutation has been less and less effective in protecting people in Japan from drinking because it is mild enough that you can tolerate it and as the environmental and as the social pressures for westernization of drinking habits has increased since the late 1970s to now, you find more and more of the alcoholic population who have this mild form of the flushing reaction.

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    This is a beautiful example of how social pressures can overcome a mild genetic protective effect. And I am sure that when it comes to the vulnerability to alcoholism we are going to find very interesting interactions of this sort as well.


    Mrs. LOWEY. I really appreciate that and I am very interested in your statement as well, where you are pursuing research on reducing drunk driving, understanding the effects of alcohol advertising on our nation's youth, improving adolescent alcohol treatment and clarifying the health effects of moderate drinking.

    I guess I have been the villain today. There is a full-page ad taken by the liquor industry, the beer industry specifically against me. I feel so strongly that the alcohol abuse is such a cost to our nation but if people are going to drink they should just get their hands off the wheel of a car.

    And they are going to have to do what they want about their own alcohol problems and hopefully we can get some additional research to help them, but at least they should get their hands off the wheel of the car and I, frankly, feel that the government that acts in so many ways to move legislation forward should take positive action in that direction.


    Another totally unrelated question. I have been very interested in what we can do to stimulate more clinical research, certainly in this area and reverse the steep decline in MDs seeking research careers. There is concern that has been brought to our attention that psychiatrists are not being trained as researchers, specifically as clinical researchers. Could you just share with us what your institute is doing to encourage more psychiatrists to go into research?
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    Dr. GORDIS. Sure.

    We are very interested in this and, of course, we have participated with the American Psychiatric Association by bringing research to the meetings annually and meeting with young residents in psychiatry to interest them in research careers. Dr. Varmus, in his introductory remarks at his hearing a couple of weeks ago, of course, spoke about the new K mechanisms which are designed to increase the amount of clinical researchers who need the opportunity and support to learn how to do it right. And we are participating in that.

    Of course, we are a small institute so that we do not have large numbers of grants but we will be increasing the number of the new mechanisms, both the one that succeeds the K08 where several psychiatrists already have them with us as well as the middle level K24s for the mid-career people.

    And to the degree that it fits proportionally in the size of our institute, we will be very much going in that direction as well.


    Mrs. LOWEY. In a related question how do you provide physicians and other health professionals with the latest research findings? I often wonder what kind of delay there is from science to the bedside, from research science to the bedside?

    Dr. GORDIS. Well, there are various avenues for doing this. And the physicians and the health professionals are not the same folks, as you know. The physicians, generally read medical literature. So, that is certainly one route.
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    Most of them do not read the research literature. So, even there, there is a translation step from the research to the clinical literature, the standard medical journals. And for the people who are other health professionals, for example, counselors, social workers, or psychologists who are working in treatment programs, their literature has to be somewhat different. And for that reason we have a wide variety of publications.

    I mentioned before our physicians' guide, and we have publications for patients, both in English and Spanish about drinking and about drinking in pregnancy. For the counselors we have a variety of publications, for example, Alcohol Alert, which is a pamphlet circulated to about 100,000 people all over the country four times a year. It is designed to translate for the lay person or the educated lay person the findings of research in relatively non-technical ways.

    And, of course, we meet with a variety of constituency groups representing the various people throughout the year where people from the research community as well as from the Institute present the latest fruits of research.

    One interesting thing which we have afoot now are discussions in New York with the State authorities on alcohol and drugs about an interesting thing we would like to do. The commissioner came to us and asked for some help to see how the fruits of the research could be translated more effectively into treatment not only because it is a good idea but because it is a cost saving idea.

    We have been working on setting up a conference which we believe we will have next fall mostly for senior people who determine policy in their treatment programs. They are the ones who decide whether naltrexone or acamprosate is going to be used in the program and bring in new methods instead of the traditional old ones.
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    In addition to that discussion—that is coming along fine—are discussions to choose two or three programs who have volunteered to be demo programs in which we, with the help of some of our experts in clinical research, would actually go into the treatment programs and see if we can help them incorporate some of the new ideas and treatments into their programs.

    And we are very much looking forward to seeing that this comes to fruition.


    Mrs. LOWEY. Mr. Chairman, I just wanted to make one, brief comment apropos our conversation before about our children and smoking. We tend to personalize so many of these issues. The pamphlets concerning alcohol abuse and the damage to one's health are very clear and they have been out there a long time.

    And, speaking for my daughter who recently had a child, boy, she didn't have a drink for about a year-and-a-half when she became pregnant and also now that she is nursing. There was no question. And yet, these kids know or they should know that alcohol abuse can cause them bodily harm in so many other ways. If not, are we doing something wrong?

    And, so, for another time, I think it would be interesting to pursue the fact that when there is a powerful incentive, boy, they stop. But otherwise, we are not curbing drug and alcohol use as effectively as we should.
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    I thank you for your indulgence.

    And thank you, Dr. Gordis.

    Mr. PORTER. Thank you, Mrs. Lowey.

    Ms. Pelosi.

    Ms. PELOSI. Thank you very much, Mr. Chairman. Before I commend Dr. Gordis for his work, I want to commend my colleague for her leadership on this issue. Villain she may be to some, but heroine to most of us for her leadership on this issue. I am very proud of that attack they made on you this morning in the paper. [Laughter.]

    It demonstrates how effective you are on this issue and how necessary your initiatives are on it. Thank you. And as we compare photographs of our grandchildren, we all have a different perspective on some of these issues, and it is interesting to see what the responsibility is from a mother to a child in terms of carrying a baby and being responsible, knowing what we know today about the price that would be paid by a mother drinking excessively while pregnant.

    Dr. Gordis, thank you for your leadership. I am sorry I missed Dr. Leshner's presentation from National Institute on Drug Abuse, because his work is a priority for our office and always has been, and I commend him for his leadership.

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    I would like to submit some questions for the record to him, Mr. Chairman.


    Welcome, Dr. Varmus, again. And, Dr. Gordis, for your work. I wondered if any of you saw Nightline last night, because on the show it opens up by policemen banging in the door of someone's home. And the point is, as they said, police don't break into the homes of people who have cancer and they don't break into the homes of people who have heart disease or have a heart attack, but they break into the homes of people who have an addiction, whether it is a drug addiction—and then they go on further into the discussion about alcohol addiction.

    Perhaps you saw the show. If I mischaracterize it, please stop me. The point was that this is a health problem that America is facing, not that people are not responsible for their behavior, but nonetheless it is a health problem that they are facing. Even one of our colleagues was on the show as a person who had had a problem with alcohol, and from his own firsthand experience was talking about how the insurance industry, and how we as a society treat and regard people with an alcohol or a drug addiction.

    And I was thinking at the time what the Congress had done about the disabilities issue as relating to people with addiction with alcohol, which we have discussed here before, and I wondered, I know that we are each of us responsible, but then you have talked about the genetics of some of this. But do you think that as a society we should be addressing this issue completely differently as an affliction that people have? How much is behavior, how much is preordained?

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    Dr. GORDIS. You have asked a question, one of the profoundest issues in our fields, not only ours but the field that Dr. Leshner deals with, and that has to do with what kind of an affliction is it, since there is obviously some sort of volitional component to the behavior? After all, the muscles that you lift a drink to your mouth with are the same ones that you swing a baseball bat with, so they are called voluntary muscles.

    And I don't want to take too long at this, except perhaps to make two points briefly, and if you would like me to enlarge on that some other time I would be very happy to do so, either in writing or personally.

    At what point does alcohol use become involuntary? I think there is a trajectory in life where the initial exposure and the initial choice of using it is really a voluntary event. And so to what degree are you responsible for becoming alcoholic if you start drinking?

    Well, if you know nothing about anything, then probably you are not responsible at all. If you have a strong family history of alcoholism, I would say that it is the job of society or the parents, or yourself if you are 17 or 18, to realize that you are at risk. Therefore even at that point, drinking should be considered very seriously and maybe reflected on carefully if it begins to escalate.

    But as we move from this initial voluntary stage into the area of affliction or disease or disorder or whatever you want to call it, we are talking about voluntary behavior in a very narrow sense, but voluntary behavior determined by a motivational state which is so severe that it displaces the normal judgment that we have with voluntary behavior.
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    Now several of you mentioned the smoking issue and how difficult it was for your own offspring to stop, and we have all seen that in our families. It always surprises me to see how often the public can understand how difficult it is to stop smoking, and yet they cannot translate that into addictions which are equally strong and understand how difficult it is to stop using cocaine or alcohol.

    So we have a bit of a problem there in which the smoking is understood to be a hard habit to kick and the other ones are not, which is interesting, but nevertheless it is the same thing. We have seen people who are perfectly responsible, intelligent, competent, respected people, who can't give up smoking because there is a motivation here to use tobacco which defies their own judgment and knowledge, and that is what addiction is really all about.

    That is what we are trying to explain with the science, the kind of questions that I have been asked before by Mr. Porter: these various brain circuits which determine the state of desire for the substance or a feeling of deprivation when it is not there, which are so overwhelming to the people who are afflicted that even though there is a voluntary component to obtaining it and buying and so on, we are dealing with a very disordered motivational state, and I think that is the issue which you are trying to understand.

    Ms. PELOSI. I am glad you brought up the smoking issue, because I believe this is one of the points that they made last night, and that is, people smoke and then some get lung cancer, there is never any question that their insurance is going to cover their lung cancer if they have, you know, a comprehensive health insurance policy, even though smoking which was a so-called voluntary action caused their lung cancer.
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    So if we treat, if the insurance covers that, then why wouldn't there be some transfer over to treating addiction or the consequences of addiction, as well?

    Dr. GORDIS. Well, the consequences of addiction are being treated. You see, the analogy——

    Ms. PELOSI. By insurance, by private insurance?

    Dr. GORDIS. Sure. I mean, if you get cirrhosis of the liver, or you fall off a fifth floor story from drinking, you are still going to get covered by your insurance.

    Ms. PELOSI. Yes. Okay.

    Dr. GORDIS. The issue comes up with the treatment of the behavior itself, the drinking or the smoking or the drug addiction.

    Ms. PELOSI. Right, exactly.

    Dr. GORDIS. The complications are not the issue. The complications are being treated, whether they are lung cancer from smoking, cirrhosis of the liver from alcohol, or maybe a stroke from a cocaine use, those complications are not where the issue is. The issue is the behavioral treatment itself, and that is where the difficulties lie.

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    Ms. PELOSI. Yes, you are exactly right. Right. So do you have an answer for that?

    Dr. GORDIS. Yes. I think that science should dictate public policy, and science says that treatment for the addictions ought to be covered like any other illness.


    Ms. PELOSI. I completely agree with you. I thank you for that answer.

    Some other more specific questions, and forgive me, if these have been asked I will just read the record.

    I understand that the NIAAA National Advisory Council has just published an excellent document called ''A National Plan for Alcohol Health Services Research.'' Can you tell us about the major recommendations included in the plan and how you intend to respond to those recommendations?

    Dr. GORDIS. Yes. Well, the document you are referring to is here in the executive summary, but actually the committee which created this was created by our Advisory Council in order to guide us in how we should study the issues related to health services research: access, financing, managed care, and so on.

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    And this document does provide an extensive list of recommendations of which topics would be best to spend the Institute's money on, and they are a guide to some of the research which is already going on now. I think it is a very extensive document. I would be very happy to give you more details of that for the record, in fact, supply you with an executive summary of the proposal itself.


    Ms. PELOSI. Oh, I would love to see that. Thank you. Thank you.

    What does your Institute-supported research tell us about changing campus drinking culture? And perhaps you did address this earlier.

    Dr. GORDIS. The college drinking issue is a very big one. We have studies showing the various potential interventions that have been suggested to be useful on college campuses, both as far as changing the environment to a certain degree, but largely individual-based ones with college students to teach them what normal patterns are, to relieve them of misapprehensions as to how much their buddies are drinking, to explain to them what the effects of drinking on their risk for auto accidents and bad school work is, and so on.

    The fact of the matter is, we don't have a good research answer to a potent intervention on college now, in my view, and for that reason we are doing several things. The first thing is, we have a Request for Applications on this very topic.

    The second thing is, we are creating a subcommittee of our council, very much analogous to the one you just asked about in relation to health services research, on the issue of college drinking. This subcommittee will be chaired by Father Malloy, the president of Notre Dame, who was the head of the committee from CASA, Mr. Califano's unit in New York which published a study on college drinking, not terribly research-based but very reasonable. Father Malloy is going to be co-chairing our Council subcommittee, he is a member of our council—together with Dr. Mark Goldman, who is professor of psychology in Florida.
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    And we are going to be devoting the next couple of years to having a thorough analysis of what the research needs and opportunities are on this issue. Following that, we will embark in a major program of research in this area.

    I think we have bits and pieces of it, but frankly, judging by what we read about what is happening on college campuses, I cannot give you a totally convincing, plausible answer of what we ought to be doing. And partly that is because of the heterogeneity of college campuses: some are rural, some are urban, some are church-run, some are not, some are private and have a different ethnic group, and so on. I think as a result of these deliberations we will be in a much better position to create a program of research which will give us much-needed answers.

    Ms. PELOSI. I think it is so very, very important, and I am pleased that you are going down that path.

    I did have some more questions about how many of your trainees or young researchers are psychologists. I know a third of your grantees are psychologists, which I will submit for the record, also.


    Mr. PORTER. Ms. Pelosi, let me ask a question of Dr. Varmus at this point, because we have been here for the last hour talking about the effects on individuals, the huge burden on society, how it affects young people, and yet we spend in NIAAA less than half of what we are spending in NIDA, where the effects are narrower and not nearly as great on society.
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    Why are we spending so little on alcohol abuse and so much on hard drug abuse, and shouldn't we at least be spending the same amount, considering that alcohol is a much more abused subject with much greater burdens on society?

    Dr. VARMUS. Dr. Gordis welcomes that question. [Laughter.]

    I think you are raising a legitimate issue. On the other hand, we have to recognize that the problems that the NIDA is facing are more numerous—there are a number of drugs of abuse that NIDA is studying, ranging from heroin to cocaine to tobacco. Moreover what happens over the course of the history of an institute is the development of a cohort of investigators who may be doing things that have very wide applications to research across many domains. Certainly Dr. Gordis and Dr. Hyman and others depend a great deal on some of the neuroimaging and extramural activities that are being carried out through NIDA, and we see certainly a tremendous collection of exciting neuroscience going on within the Institute.

    Some would argue that understanding tobacco addiction in particular has enormous effects on health, that I think it very hard to compare the effects of drug or tobacco to alcohol. If one looks at the toll that any single behavior exerts on health, tobacco is the lead. There are of course other kinds of effects that alcohol has on our society. These things are very hard to compare, and I would rather try to evaluate the budget in relation to the quality of the science that is being done.

    Mr. PORTER. Well, I am sure there are explanations and reasons, but it seems to me that—and this predates your stewardship by a great deal——
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    Dr. VARMUS. But I would agree with you, Mr. Porter, that there is a great more to be done focusing particularly on the kinds of results that Dr. Gordis brings to us today, and that public advocacy of the kind we talked about earlier with Dr. Leshner is particularly important in getting the message out about alcohol abuse in adolescent years.

    Mr. PORTER. Yes, I think perhaps we ought to really look at what we can do in this area, because the effects on the economy and society are very large under the jurisdiction of Dr. Gordis, and I think we probably have not given the kind of attention overall within the government or the kinds of resources that we ought to place on this very, very serious problem for our country, and we ought to look at it again.

    Dr. Gordis, thank you for the fine job you are doing. We thank you for your testimony this morning.

    Ms. PELOSI. Mr. Chairman?

    Mr. PORTER. Ms. Pelosi.

    Ms. PELOSI. Would the gentleman yield?

    Mr. PORTER. Yes, of course.

    Ms. PELOSI. Just one point. I didn't think the point was that there would be less for NIDA——
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    Mr. PORTER. No, no, no.

    Ms. PELOSI [continuing]. But more for NIAAA.

    Mr. PORTER. Exactly, exactly.

    Ms. PELOSI. So we thank you, Mr. Chairman.

    Mr. PORTER. Thank you, Dr. Gordis.

    Dr. GORDIS. Thank you, Ms. Pelosi.

    Mr. PORTER. The subcommittee will stand in recess until 2:00 p.m.

    [The following questions were submitted to be answered for the record:]
    "The Official Committee record contains additional material here."

Wednesday, March 11, 1998.



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    Mr. PORTER. The subcommittee will come to order. We continue our hearings regarding the budgets of the National Institutes of Health and are pleased to welcome Dr. Phillip Gorden, the Director of the National Institute for Diabetes and Digestive and Kidney Diseases at NIH.

    Dr. Gorden, it's wonderful to see you.

    Dr. GORDEN. Thank you, sir.

    Mr. PORTER. Will you introduce the people who are with you and then proceed with your statement, please?

    Dr. GORDEN. Yes, Mr. Porter. To my far left is Mr. Charlie Zellers, our Budget Officer; to my immediate left is Mr. Earl Laurence, the Deputy Director; and of course, you know Dr. Varmus and Mr. Williams.
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    Mr. Chairman and Members of the Committee, I am pleased to testify before the Committee on behalf of the National Institute of Diabetes and Digestive and Kidney Diseases. The President in his FY 1999 budget has proposed that the NIDDK receive $927.5 million, an increase of $69 million over the comparable figure of 1998. Including the estimated allocation for AIDS, total support proposed for NIDDK is $944.3 million, an increase of $70.5 million over the FY 1998 appropriation. Funds for NIDDK efforts in AIDS research are included within the Office of the AIDS Research budget request.

    A major goal of the NIDDK is to make investments in innovative technologies and discoveries that can be directly applied to patients in clinical trials. These advances then have immediate application to patient care and to public health. This general process can be illustrated by examples in diabetes that clearly point to research advances and help chart our further progress.

    One of the most important objectives of our current research investment is to reduce the intensity and the duration of an individual's exposure to high levels of blood glucose and develop other risk reducing therapies. I'd like to give you one example of this approach taken from our diabetes research agenda. First, I must point out that diabetes is the most common cause of end stage renal disease, comprising one third of end stage renal disease in diabetic patients.

    I'd like to call your attention to the chart that you see on my left. This chart plots on the vertical axis the percent risk of developing renal failure in a type 1 diabetic patient as a function, on the horizontal axis, of years of exposure to diabetes risk. Please note the top blue line. This represents the cumulative risk of developing renal failure for a diabetic patient on general maintenance treatment. You note that this risk approaches almost 40 percent.
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    Now, if you will focus on the purple line just below, you will see the result of one of our recently completed clinical trials. A drug that was first introduced for the treatment of hypertension, called an ACE inhibitor, was found in experimental animals to interdict the course of diabetic renal disease independent of any effect that it had on blood pressure or the blood glucose concentration. Here you see the results of administering this drug at the earliest stages of renal disease. You see that it markedly decreases the risk of renal failure in these patients.

    Incidentally, a very recent analysis of this study has indicated that this maneuver alone saves over $189 million per year. This we call a form of tertiary prevention. Tertiary prevention means that the agent affects the end organ per se, that is, the kidney, independent of any systemic effect, that is, an effect on the blood glucose concentration or of the blood pressure. It's a major goal of our further technology development.

    Now, if you'll focus on the green line, you will see the results of adding to this study the results of our Diabetes Control and Complications Trial (DCCT). The DCCT was a form of secondary prevention in that it addressed the question of blood glucose control and demonstrated clearly that rigid control of the blood glucose concentration markedly ameliorates the complications of diabetes, not only with respect to the kidney, but also with respect to the eye and the nervous system.

    You see the results of these two trials are additive. Further, it is important to note that these trials are completed and their findings have been introduced into medical practice, but we must certainly continue to make them applicable to all patients with either type 1 or type 2 diabetes.
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    Now, I'd like to call your attention to the dashed red line at the bottom. This represents an ongoing trial of primary prevention. Primary prevention means that we have discovered ways to recognize the pre-diabetic state and can act to interdict the development of diabetes per se. I must be clear. We have no actual results from this study and the data shown are drawn from a model based on the statistical characteristics of the study. If we were to achieve the statistical result that would give us a positive study, then you would see the results shown here. To reiterate, in each of these three trials it was essential that we establish the technology for the intervention and the knowledge base required and that we demonstrate the efficacy of the approach directly in patients.

    This general approach is basically something that we can use for a number of other examples, but we wanted to illustrate it for type 1 diabetes. We could do exactly the same for type 2, except we would refer to our Diabetes Prevention Program which is a separate study of primary prevention in type 2 diabetes.

    Now with these studies that are completed and the one ongoing, we must improve on these successes. Patients and their families want better technologies that will produce easier and more effective treatments. To expand our therapeutic tools, we will pursue innovative strategies for achieving the diabetes research results and advances of the future.

    Let me give you just a few examples of these approaches and goals. We will continue to exploit the mechanism of interdicting immune destruction of the beta cell in Type 1 diabetes. We're using transgenic technology to create animal models to pinpoint mechanisms that will modulate the immune system, first in animals and then in patients who are at high risk for developing Type 1 diabetes.
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    We will attempt to identify viral or other environmental factors that may cause Type 1 diabetes including retroviruses.

    We will attempt to find factors that regulate the tissue-specific generation of insulin-producing cells including the possibility of stimulating a progenitor cell to produce insulin after mature cells have been destroyed.

    We will attempt to engineer insulin-producing cells using constructs that will confer specific properties on the cell, such as glucose-sensing or glucose recognition or other similar regulatory steps.

    To close the gap in the difficulty of administering insulin, we will foster research on a variety of glucose-sensing technologies. Further approaches to understand the cause of diabetes and its complication will be pursued by genetic techniques. Six known genes are involved in several forms of Type 2 diabetes. And several large-scale studies using ''high through-put genomics'' are attempting to find new genes and more conventional forms of Type 1 and Type 2 diabetes.

    We are also looking for diseases that relate to the complications of the disease such as diabetic renal disease. We will disseminate important research findings through the National Diabetes Education Program, which is making special efforts to reach minority populations disproportionately affected by Type 2 diabetes.

    For support of this program and for all of our activities to improve the health of minorities through NIDDK research, I would like to extend our sincere appreciation to Congressman Stokes. On a personal note, Mr. Stokes, I would like to thank you for your persistence and your patience and I'd like to assure you that the very high goals that you've set for us will be met.
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    Mr. STOKES. Thank you very much.

    Dr. GORDEN. Let me just give you a few other examples of important research needs and investments that we plan to pursue. Obesity is a major risk factor for Type 2 diabetes, lipid disorders, hypertension, cardiovascular disease and cancer. Through basic research, we've discovered multiple genetic loci for obesity in animals—with human parallels. The most dramatic discovery in the field of energy regulation was the identification of the first obesity gene and its protein product leptin.

    In Fiscal 1999, we will continue to expand our programs to explore the discovery of obesity genes and the complex neuroendocrine system that regulates both food intake and energy utilization. Most importantly, we are making plans to initiate a major clinical trial which we hope will show that the numerous health risks posed by obesity can be reduced by voluntary weight loss.

    Other diseases within the NIDDK mission on which we will intensify research include diseases such as hepatitis C, food-borne illnesses such as hemolytic uremic syndrome, and urologic diseases. We're promoting enhanced efforts to understand the biology of the bladder and the pelvic floor, and susceptibility to infection and inflammation—research that is very relevant to interstitial cystitis, urinary tract infections and urinary incontinence.

    Concomitantly, we are intensifying research on the biology of the prostate, which includes studies of benign prostatic hyperplasia, prostatitis, and prostate cancer, which we're conducting in collaboration with the National Cancer Institute.
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    In cystic fibrosis, we'll be exploiting newly discovered concepts about how chronic infection is initiated and perpetuated. In hematology, we have dramatic advances in our understanding of the iron-overload diseases, such as hemochromatosis, and new opportunities for treating these diseases.

    Underpinning these and other NIDDK programs to combat disease will be our continued strong support of basic research, which is the wellspring for clinical and medical advances.

    Mr. Chairman, I'd be very pleased to answer any questions that you and the committee may have.

    [The prepared statement follows:]
    "The Official Committee record contains additional material here."


    Mr. PORTER. Dr. Gorden, thank you very much for your opening statement.

    Could we go back to your chart for just a second? I have a related question. If you continued the chart out to the right, it looks as if, in Type 1 diabetes even with no interventions at all that the chart would indicate less than a 50 percent chance of developing kidney disease. Is that correct?
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    Dr. GORDEN. That's exactly correct, Mr. Porter.

    Mr. PORTER. Is that the same for Type 2 diabetes?

    Dr. GORDEN. It is the same for Type 2 if we take a very high-risk population. If we take the usual population of the entire mixture of the country, the risk is even lower.

    Mr. PORTER. It's a bell shaped curve in other words.

    Dr. GORDEN. It's a bell shaped curve in the sense that if you don't develop diabetric renal disease within 20 to 30 years, you essentially don't develop it. This a very interesting problem: how we distinguish an individual who will develop renal disease from one who will not is unknown to us at the present time and that's a major subject that we're taking up.

    Mr. PORTER. Does this chart represent seven years and does each line mark a year?

    Dr. GORDEN. No. The chart, the reason I've actually taken the numbers off this chart is because it's an attempt to compress all four data sets onto the same scale, so that patients enter this model at different times.

    If you take, for reference, the blue line, which is the untreated group, the usual way that that's portrayed is over about a 20 to 30 year exposure to diabetes. That is the period in which people develop all the complications including renal disease.
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    Mr. PORTER. Am I correct that you could look at half that length of time and if you hadn't developed diabetes by that time your risk begins to decline? Or does it begin to decline after the full length of time you're describing?

    Dr. GORDEN. It is likely that, if you're looking at the population at large, you would not know which individual would develop risk until you got out to approximately 20 years.

    In other words, you have markers that will begin to show up earlier, well before deterioration in kidney function and they are important markers for therapeutic intervention. In fact, in the second line the therapeutic intervention only started when patients had obvious renal disease and that's very late in the course of diabetes.

    Mr. PORTER. And the tertiary treatment is aimed not at diabetes, but at the effect of diabetes on the kidneys?

    Dr. GORDEN. Exactly. And this is exactly the approach we're taking in the eye. There are new agents that are being tested now to try to interdict the complication at the tissue level itself, independent of what we can do for overall metabolic control. That is a very powerful way to add to your therapeutic efficacy.


     Mr. PORTER. You can do the same thing for the eye?
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    Dr. GORDEN. You can do the same thing for the eye but not with this particular therapy—with a different therapy.

    Mr. PORTER. Different therapy.

    Dr. GORDEN. Exactly.

    Mr. PORTER. When you go to secondary treatment, you're adding glucose control?

    Dr. GORDEN. Exactly.

    Mr. PORTER. And at the primary treatment level you have those two plus——

    Dr. GORDEN. Plus the prevention of hyperglycemia itself. In other words, you find an individual that you know will develop diabetes within three to five years. That person has normal blood glucose concentration. You do an interdiction of some kind and you prevent hyperglycemia from occurring. The line is drawn indicating the expected success rate based on the statistics of the study. So you can see that what you achieve by all three of these means of prevention is really quite dramatic. This is really a major goal because to reduce the fundamental risk of complications is our primary goal in diabetes research at the present time. If we can interdict onset of the entire disease, that of course is the major goal, but this is something that we don't have evidence for at the moment.
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    Mr. PORTER. Well, aren't there other risks as well? Kidneys and eye complications are certainly two of the most prevalent ones, but what about heart disease, stroke?


    Dr. GORDEN. Yes.

    Mr. PORTER. How are we going to interdict those complications?

    Dr. GORDEN. The health issues with respect to the complications that I've described are what we call ''microvascular.'' Those are diabetes-specific complications. They do not occur in the absence of hyperglycemia at all. The risk for those begins when hyperglycemia begins.

    ''Macrovascular'' complications include vascular disease, myocardial infarction, stroke, and peripheral vascular disease. Fundamentally all of us are incurring some risk for these over a lifetime; diabetes imposes a greater risk.

    Now the idea here is to use all of the strategies that we've already learned, such as lipid control and hypertension control which have a dramatic effect, even more dramatic in diabetics, and to add glycemic control to that. That strategy is the subject of a major study that we're planning to do in collaboration with the Heart Institute and the subject of other studies that are on-going, either of a relatively short nature or studies that we're actually supporting in England right now to try to get a bit of a handle on how to approach this. This is a major area that we plan to attack now, to see if we can't reduce the cardiovascular mortality and morbidity of diabetes.
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    Mr. PORTER. Dr. Gorden, how long has NIDDK been in existence?


    Dr. GORDEN. We will be celebrating our 50th anniversary in the Year 2000. The bill creating the NIDDK was signed into law by President Truman in 1950.

    Mr. PORTER. Given that we have been doing diabetes research for a long time, where are you on the scale of optimism about real breakthroughs? Are we making any real progress? Is this still as elusive as it was 50 years ago? Are we close to where we are really going to see some progress made? Why don't you give us a greater description regarding diabetes.

    Dr. GORDEN. Mr. Porter, I think I could illustrate that to some extent by the chart again. I think what you see is a measure of the progress we've made. We know that with careful glucose control, as was achieved in the Diabetes Control and Complication Trial, we can markedly change the Complications rate. And if we could reduce blood glucose levels just a little bit more, if we could do just a little bit better, we would be approaching this primary prevention line. You see the difference between the green and the dashed line is not all that great. That's where we're trying to get to.

    I think we've made a considerable amount of progress. What we've got to do now is we've got to close the gap in the difficulty of achieving that. We know what can be achieved. We have achieved it. But we've got to close that gap in technology. For instance, we've got to have better ways to administer insulin or we've got to close some sort of glucose-senor loop, or we've got to have a cell-based therapy. We've got to now use these sorts of technology which I think are things that we've only been able to do for the last several years. So I think we know what can be achieved and I think we have all of the ingredients ready to go to accomplish the closing of that loop.
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    Mr. PORTER. In talking about glucose control, are you talking only about pharmaceuticals or are you talking about diet, exercise, control of weight? Is that all that's in that picture?

    Dr. GORDEN. If I were to have used a Type 2 diabetes model rather than the Type 1, I would have emphasized much more the issue of diet, exercise, and drugs. We do have a lot of evidence for the effect of diet, a lot of evidence for the effect of exercise, and we have at least four classes of drugs, including one very new one that's been introduced in the past year, that are quite efficacious.

    Mr. PORTER. Is that Rezulin?

    Dr. GORDEN. this is the troglitazone class—yes, Rezulin is the brand name. It has been introduced just in the past year. It's the first of the so-called insulin sensitizing drugs. That is, it decreases insulin resistance and it's the first time we've had a pharmacologic agent that we could use for that purpose, which is very, very important.

    So we have the ability to achieve these things or at least we know what will happen if we can achieve them. Now what we've got to do is to show that we can decrease that exposure to hyperglycemia further and we're attempting this prevention strategy. In other words, rather than to try a variety of other therapeutic strategies, we're going directly to an attempt at a prevention strategy for both Type 1 and Type 2 diabetes. That is the on-going program at the present time.

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    Mr. PORTER. Is there a lot of evidence that diabetes is genetically based?

    Dr. GORDEN. Yes, genetically based in the sense that it's a complex genetic disease. What we mean by that is that it is not a disease caused by a single gene, except in rare forms of the disease—that's where I mentioned we know what six of those genes are. Those reare forms represent maybe 5 percent of all of diabetes. Those are specific syndromes that are related to diabetes, but the vast majority of people with so-called Type 1 and Type 2 diabetes have presumably a number of genes that are interacting with each other and we're attempting to learn how this system works. It's a major issue for multiple diseases such as hypertension, dyslipideima, Alzheimer's disease and a whole variety of complex diseases. So this is an approach, and in diabetes, we're making a considerable amount of progress vis-a-vis all of the other complex genetic diseases, but it's a very difficult and complex problem.

    Mr. PORTER. Thank you, Dr. Gorden. Mr. Stokes?

    Mr. STOKES. Mr. Chairman, I think Mr. Hoyer was here ahead of me.

    Mr. HOYER. No, no, go ahead.

    Mr. PORTER. I think you were both here at the start of the hearing.
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    Mr. STOKES. Thank you very much, Mr. Chairman. Dr. Gorden, nice to see you and thank you for your very kind remarks. I appreciate that.

    Let me start with the Type 2 diabetes where you mentioned the clinical trials. Can you tell us a little bit about your interventions there, where the trial stands, and when we can expect the results?

    Dr. GORDEN. What we refer to as the Diabetes Prevention Program is a study that is underway that will include 4,000 Type 2 diabetics, at least 50 percent being minority. This is an example in which minorities are clearly over-represented as patients with Type 2 diabetes, and so, they are over-represented in the trial. We have to be certain that our strategies are going to be applicable to each particular group that participates.

    This study has four arms. It has a control arm. It has an arm related to intense diet and exercise that Mr. Porter just mentioned. It has two drug arms. One is using this new insulin-sensitizing drug Troglitazone and another drug that's been around for a little bit longer, called Metformin. We want to see if a strategy using the best diet and exercise program possible will achieve our goals of interdicting the conversion of so-called ''impaired glucose tolerance'' to overt diabetes, or whether a pharmacological approach will be required. So we've covered essentially all of those bases in this trial and it's moving forward. The recruitment has gone extremely well and we think that it will take about another four years before we will actually have enough definitive results to present.
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    Mr. STOKES. Both in your formal statement this morning and in your presentation here, you've mentioned the serious situation regarding African-Americans. According to your opening statement, between 1980 and 1994, the number of African-Americans with diabetes rose 33 percent, which is three times the rate of increase for all other Americans. In terms of trying to reach that target group, tell us what you're doing to address that type of national situation.

    Dr. GORDEN. I think there are three kinds of approaches, Mr. Stokes. First of all, we're very hopeful that the fundamental basic research that we're doing to try to understand insulin resistance and insulin secretion and the broad aspects of Type 2 diabetes will be even more applicable because of the higher risk in the African-American population.

    The second major tool that we're using is this prevention trial I've just described and the information that we will gain from it.

    The third is our newly inaugurated National Diabetes Education Program which will have a specific minority component that actually is going to be added this summer, to disseminate the information that we have and everything that we know about controlling moderate to mild diabetes, which we think we can do very well. We must be certain that the information base is out there where it really counts. We believe that those combined strategies will have a major impact on this issue. That is our goal and that's what we're trying to achieve.
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    Mr. STOKES. Dr. Gorden, let me ask you about hypertension related kidney disease. That obviously is another extremely tragic problem in the African-American community and I understand that you have a clinical trial underway relative to that.

    Dr. GORDEN. Yes.

    Mr. STOKES. Can you tell us about it?

    Dr. GORDEN. Yes. It was the recognition through United States Renal Data System that led us to understand that African-Americans who had hypertension developed renal failure at a rate that was markedly greater than any other population. We felt that we must find some way to interdict the course of this rapidly deteriorating renal disease. We inaugurated a clinical trial that basically has two different modalities of therapy. One modality is to try to understand what is the most optimal blood pressure for an African-American hypertensive patient. Is it what we call conventional normal or is it something that might actually be lower than that? That's one goal of this study.

    The second goal is to see if a different class of drugs may have a special effect, such as this so-called ''ACE inhibitor'' that I've described here, or other agents known as calcium channel blockers, or other types of drugs. There are at least three different types of drugs being tested and two different levels of blood pressure. We believe because we already have preliminary evidence in other situations that at least one of those two modalities is going to have an important effect, but we don't know which one. We really believe that this study will have a very important effect in ameliorating this incredible deterioration in kidney function that occurs once someone develops hypertension. We're very optimistic about this study giving us the kind of tool we need to interdict this problem.
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    Mr. STOKES. Let me ask you a little bit about obesity and diet pills. Can you tell us what type of research is being done on diet pills as it relates to persons trying to fight obesity, and diseases of that sort?

    Dr. GORDEN. Well, Mr. Stokes, obesity is a major problem in this country, and there have been a number of attempts to develop pharmacologic agents that will interdict the course of obesity or that will ameliorate it, and will help people lose weight.

    Thus far there's been only very limited success and there have been some very difficult problems in terms of drug toxicity. We believe that we are beginning to focus on the technology that will allow us to move ahead with this long-term risk-reduction trial that I was discussing in the opening statement.

    But the fundamental issue in obesity is our lack of a good technology, and that distinguishes obesity research from what we've done in hypertension, what we've done in hypercholesterolemia, and what we're doing in diabetes. This lack of a technology to treat obesity has really been the major obstacle, but we're beginning to close ranks. The success in basic science in the last three or four years in obesity has been absolutely phenomenal. We're hoping that we can capture that exciting science and apply it to things that are going to be clinically relevant. We must do that because if we don't do something clinically relevant, we're not going to be able to get ahead of this problem. We're really working very hard to make this true. We believe that we're getting closer, but we've still got a way to go.
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    Mr. STOKES. What about the relationship of genetics to obesity? Are we doing much there?

    Dr. GORDEN. We are doing a considerable amount of research. The real breakthrough in genetics has come from animal genetic studies from which we've had some extraordinarily exciting findings. It turns out that we're beginning to find that a certain number of the genes that affect the animals also produce specific syndromes in patients, and that's the first clue that this approach may be a useful approach.

    In addition, we're beginning to apply what we call the ''genomic approach,'' the ''whole genome search.'' This the sort of thing we're doing in diabetes, and that's being done in hypertension and a number of other diseases. We're getting to the point where we can actually do this kind of research in obesity, but obesity is a more difficult problem to attack genetically. We're really gratified about this analogy with the animal research that has been such a positive and useful thing. This gives us a lot of encouragement that we're moving in the right direction.

    Mr. STOKES. Thank you. Thank you, Mr. Chairman.

    Mr. PORTER. Thank you, Mr. Stokes. Mr. Hoyer.


    Mr. HOYER. Thank you very much, Mr. Chairman. Dr. Gorden, again, welcome to the committee.
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    I am not going to have some questions on diabetes, but I do want to congratulate you and the Institute on the work that you are doing. Many of my colleagues will ask those questions. It is obviously one of the critical problems that confronts all of our constituents in our country.

    Doctor, the question occurs to me and I want to ask you some questions on nutrition, but one of the challenges that confronted us in Judy's illness was her inability to eat which is common, obviously, to cancer patients. I'm wondering if you do any work because one of the things that we tried to get was things to allow Judy to eat. She wanted to eat. She knew she had to remain strong, but it was incredibly difficult for her. Do you do any work on that issue? Obviously, it's not a digestive disease. It is, however, an inability to have any psychological inclination, I suppose, for intake and then an inability to digest and use the food that is taken to remain strong. I'm wondering do you do any work in this Institute on that issue?

    Dr. GORDEN. Yes. This is an extremely important issue, Mr. Hoyer. There are really two fundamental issues here. One is the purely mechanical issue and that, of course, is a very difficult one. There are a variety of maneuvers that can be of some help. But the other one you refer to is really not mechanical, it is the simple situation of anorexia or simply not having any desire to eat.

    We're beginning, I believe, to understand something about what we call satiety or the regulation of why one wants to eat or when one feels satiated. Of course you could look at it the other way and say that one has no desire to eat.

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    It is likely that a similar set of control mechanisms is involved in both of those directions, and we're beginning to understand control sites in the brain that appear to regulate that. For instance, just in the past few weeks, there have been some important papers published about new peptides that have been found or receptors for those peptides that have been found in an isolated, very small area of the brain. When applied in animal studies, these peptides can cause feeding behavior. We already know of a number of so-called ''neuro peptides,'' meaning these hormone-like products that can be isolated from nervous tissue, that will stimulate appetite or will inhibit appetite. It is very likely that this kind of research, which is partly related to eating disorders, partly related to obesity, and partly related to the kinds of problems that you refer to will be extremely important in helping us overcome these problems.

    It's a terribly important area that we see in cancer and in a whole variety of other diseases that will certainly yield, I believe, to this kind of research.

    Mr. HOYER. Thank you. It was evident as we dealt with it that this was a very common problem and one which frustrated the doctors with whom we dealt very greatly.

    Dr. GORDEN. Yes.

    Mr. HOYER. I know how tough it was for Judy because she knew she had to eat and she couldn't eat.

    Dr. GORDEN. Absolutely. That nutritional support is so terribly important for maintenance and it is almost impossible to provide in some cases other than through parenteral nutrition, which is another issue.
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    Mr. HOYER. We ultimately went to that. Doctor, we mention in our report last year on E. coli, everybody is very concerned about E. coli, as well as other food-borne—obviously in our state, Pfeisteria, the fish, we worried about that.

    You were asked to report to us with recommendations for additional research that could be pursued. Can you tell us the status of that?

    Dr. GORDEN. Yes, this report has actually, I was just informed this morning, been sent to the Congress. You should be receiving the report very soon. It is through clearance.

    This is a rather large issue. The real focus from the point of view of NIDDK was on an outbreak of food-borne illness caused by a special type of E. coli that particularly contaminates meat. It turns out that it causes a rather severe form of diarrhea, but in children, particularly young children, it also causes a renal disease called a hemolytic uremic syndrome, which can cause acute renal failure in children and can actually lead to end stage renal disease and tragically in some instances, to death.

    That's been the focus for NIDDK research. The National Institute of Allergy and Infectious Diseases has a larger program with respect to a whole variety of bacteria that are involved in food-borne illnesses, but both the Allergy Institute and NIDDK and NICHD have a focus on this particular E. coli. We have a series of grants that we've awarded to address this problem specifically. We are augmenting those grants through our research centers mechanism. We are establishing a core in one of Digestive Diseases Research Centers to address this problem. We plan to add to this by an initiative that we're going to be talking to several other institutes about in FY 1999. It's an area that we feel is very important, and we feel that our role is to deal with the disease per se in ways of trying to both treat, interdict or prevent the actual disease. And of course there are multiple other parts of the government—the Department of Agriculture and others—that are involved in the whole food safety program, and we actually are coordinated with them through the Department and through the Department of Agriculture.
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    Mr. HOYER. That uses my time up. You reference this as an aside and obviously a lot of others deal with this. Do you deal with preventive nutrition? We talk a lot about diet in terms of what's bad and also obviously what's good in terms of being healthful, in terms of practice, behavioral, we talked about that yesterday.

    Do you deal with that in nutritional assessment of populations. Have you been making such assessments as well?

    Dr. GORDEN. Well, this is a trans-NIH issue and the NIDDK is the home of Dr. Varmus's Nutrition Coordinating Committee. So, although we're the lead institute for nutrition research, we actually coordinate this in a broader sense. Some of those things relate to NIDDK and some relate to more trans-NIH issues. The National Cancer Institute has a major interest in this area, as does the National Heart, Lung and Blood Institute. The National Institute of Child Health and Human Development addresses issues including folic acid and neural tube defects. All of these things come under this general purview of nutrition. We've been very much involved in developing, through the National Academy of Sciences the so-called RDAs, the Recommended Dietary Allowances for micronutrients such as vitamins. Of course, there's a broader aspect in terms of food composition, and all of these things from a purely research point of view are in the purview of this coordinating function at NIH and the purview of individual institutes. We are also very much involved in trying to develop strategies that will help us understand how food might be used as a disease preventive. There's been a lot of interest in the antioxidant agents such as vitamin E, vitamin C and vitamin A. We're trying to learn more about how these agents, these naturally occurring agents would not only prevent their own deficiency diseases, which have been a major focus, but would also at some level be preventive. This is a major area of research and I think that we will hopefully make some progress in this area, just as we have clearly made progress in understanding folic acid, and we've clearly made progress in understanding the need for enhanced levels of calcium. These are examples where we clearly have evidence that these agents, used in larger amounts, are preventive for diseases such as osteoporosis, neural tube defects, and perhaps cardiovascular disease.
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    Those are the examples.

    Mr. HOYER. Thank you, Doctor. Thank you, Mr. Chairman.

    Mr. PORTER. Ms. Northup.


    Ms. NORTHUP. Thank you, Doctor. I'd like to just ask, about the capacity that we have for diabetes research and for progress and in particular. It seems to me like diabetes is something that we treat and research in a variety of areas. We talked about that yesterday with Dr. Varmus, but I assume that your institute coordinates and watches what goes on in the other institutes and that there's good communication.

    In the last year, I believe that Medicare has expanded considerably the treatment that's available or the monitoring treatment for people with diabetes. Have you seen any differences, any improvements? Are there recommendations you would make to the Congress regarding extensions or obvious lack of coverage?

    Dr. GORDEN. Let me just address several points, Ms. Northup, first, in terms of coordination, one of the really important things that happened last year was that—with Dr. Varmus's help—we organized a trans-NIH conference to bring in people who had an interest that related to diabetes research in a number of different NIH institutes. Each institute has a special kind of expertise that actually strengthens the field as a whole. It's important to coordinate it, but it's important also to capture the strength that's across the NIH We've mentioned the issue of vascular complications in the National Heart, Lung and Blood Institute. We mentioned the issue in the immunology of the disease in NIAID. There's a lot of strength around NIH. And Dr. Varmus really helped us very much to capture and develop an enlarged focus. I think in that sense that we're moving in the right direction.
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    Your other question was related to Medicare and part of the Budget Reconciliation Act in which there were at least three important things that were related to diabetes. One was the new Medicare benefits that were allowed for diabetic patients, particularly Type 2 diabetic patients who were permitted to buy diagnostic strips and other types of materials that are important for their care, and a certain amount of educational support was given through Medicare. That was a major thing for Type 2 diabetics.

    There was a also a portion of the law related to Native Americans, and Native Americans have the highest rate of diabetes in the country. That portion of the law will largely be dealt with through the Indian Health Service in terms of community action, and things of that nature that deal with the Indian Health Service. And of course, the third part was related to Type 1 diabetes and that was put under the purview of NIH through Dr. Varmus by way of the Secretary. The NIDDK, as the lead institute, coordinates for Dr. Varmus the efforts in Type I diabetes. So there was a whole group of things that happened vis-a-vis the Budget Reconciliation Act that ranged all the way from Medicare changes to more direct kinds of NIH research. So I think that there's been a lot happening. Now the question. We have a lot of evidence, but not the kind of evidence that I feel comfortable in telling you about, about improvements—of course, these things are very new. We can't talk about what effect they have had, but we have evidence that things are actually getting better for patients. Because we've been instituting some of the things I mentioned over a period of at least a few years and even before that, we think that things are already getting somewhat better. We can point to certain studies, but they're not the kind of studies that I think would convince you. That's what I want to be able to do. I want to be able to present the kinds of studies that clearly can convince you that things really are getting better.

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    Ms. NORTHUP. We've touched on obesity drugs some, but there's obesity and then there are, all the vitamins and herbal remedies that are out in the market. I just wondered how involved you all are in looking at those particularly related to obesity and the fact that they don't have to be tested before they actually are on the market. And then you can extend that beyond that point. I sort of feel like everybody I know that's my age started with C and E and B complex and now it's Ginkgo and they all have a little bag they take on trips. I just sort have wondered what the recommendations is for those things, both the weight control drugs, in particular and others—what is the effect they have on the systems.

    Dr. GORDEN. Well, you're absolutely correct. Several years ago we established the National Task Force on the Prevention and Treatment of Obesity, which operates within NIDDK. It's a trans-NIH group, in order to be able to at least address some of these issues. It's impossible to address them all. They keep cropping up literally every minute. Each time you think you've put one in the basket, another one comes up.

    This task force has put out a number of papers that speak to some of these issues. They have to do with so called yo-yo dieting, the issue of weight going down and up, and they speak to——

    Mr. DICKEY. You just called my name.

    Dr. GORDEN. We have a publication for you, Mr. Dickey. And the papers speak to drugs, the use of pharmacologic agents. That was why we wanted a cross section of people who are not specifically coming from NIH or government representatives, but a variety of scientists to give us their best opinions. One of the real problems is that we've got to come up with alternative treatments, because every time we say these things don't matter, then we have to come up with an alternative for it, and that's what we're so much striving to do. Because what people grasp onto is whatever straw there is when there isn't something more substantial available. That's what so many of these things really are.
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    Of course, there's a tremendous advertisement for diet aids. There's a tremendous market for a variety of these agents. This is just the way our system is right now, and until we can really develop a rational approach that's easy for people to use, I'm afraid we're not going to be able to do very much about this overall problem. But we're going to try, and we're going to try, to educate people as best we can.

    Ms. NORTHUP. And you do look at the drugs we're talking about and the effects. You know, somebody might lose weight with chromium picolinate, but they might also ruin their kidneys.

    Dr. GORDEN. Exactly. In fact, it was because of this surveillance that we were able to address this so-called Fen-Phen issue, which causes this rather tragic situation with heart valves. We actually had surveillance mechanisms in place and we had the only control groups. One of the issues that comes up is what happens in the native state? That is, what does obesity per se do to heart valve thickening? If you don't know that, you can't know that the drug is really having some sort of an adverse effect.

    We had a mechanism in place through one of our Clinical Nutrition Research Centers to answer that question, and we answered it very quickly, so there was a very rapid response through the NIH and through the FDA that actually recognized this problem rather quickly and stopped the marketing of the drugs.

    We're proud of the fact we were able to do that. We would, of course, be prouder if we were able to do something positive, but that's the kind of surveillance that we're involved in.
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    Ms. NORTHUP. Thank you, Mr. Chairman.

    Mr. PORTER. Thank you, Ms. Northup. Ms. Lowey.


    Ms. LOWEY. Thank you, Mr. Chairman, and it's a pleasure to see you again, Dr. Gorden. I won't pursue Ms. Northup's line of questioning, but I've had some individual conversations with you and I think I said at one of the hearings that it's my understanding that a survey was done and most Americans get their health information from ER. This was actually a poll that was done and I have very similar questions to yours and I'm delighted that you are doing some work on, I believe it's St. John's wort and chondroitin glucosamine sulfate, you can correct the spelling for the record, but I think it is really a concern because we all know people who are getting this information, going around with a dozen pills and I often wonder about the interaction between a chromium picolinate and a ginkgo and a St. John's wort, etcetera. So perhaps we can—I know so many of us are interested in this. Perhaps we can have an informal conversation some time in the future about the scientific base of some of this alternative mediation and the current investigation that's going on, but to the issue today I want to just tell you that I'm very pleased to see the continued collaboration between your institute and the Office of Research on Women's Health focusing on cardiovascular disease in women with Type 1 diabetes and I understand that this is a long-term study. But can you share with us the progress that's been made thus far, and what you hope to accomplish in the coming year?

    Dr. GORDEN. There are really two aspects. We have a very active collaboration with the Office of Research on Women's Health. One collaboration is what we call the EDIC study, which is the long-term follow-up of the Diabetes Control and Complications Trial. That is, this group that I showed you on the chart under secondary prevention. We're continuing to follow all 1400 of those patients. Mr. Porter asked about macrovascular, or in other words, large vessel disease. One of the first things that this collaboration allowed us to do was to do a cross sectional measurement of blood vessels by a certain type of ultrasound technique so that we can get some idea about the progress of macrovascular disease in that population.
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    In addition to that, we have a number of other projects, including gestational diabetes, obesity control and several other projects that are ongoing with the Office of Research on Women's Health. It's been both of these types of projects, one on the vascular disease and the other on diseases related to pregnancy and other diabetes-related concerns that we continue to work with the Office on.


    Ms. LOWEY. I'm also aware that islet transplantation holds promise for the treatment of diabetes, particularly Type 1 or insulin-dependent diabetes. How would you assess the current state of research in this area?

    Dr. GORDEN. Well, it's an extremely exciting form of therapy. It would essentially take cells from the pancreas, isolate them, exploit their insulin-producing capacity and their glucose-sensing capacity, so that they can be then infused into a recipient individual. Then essentially these cells can take over for the cells that have been destroyed.

    The problems have been related to two things. One is that we really don't understand the requirements for growth and maintenance of isolated cells when they're transplanted, and we've not completely been able to deal with the immunologic issue. We know that when you transplant a whole organ, such as the pancreas, it works and it's fine. But when you isolate the cells out of that organ and transplant them, it's been very difficult. But this is something that we're continuing to work with. We have new technologies now that allow us to actually construct those cells out of cells that were never insulin-producing cells. We're hopeful that we can create a more rugged cell, so to speak, that will allow us to get around some of these growth properties. We have a lot of different opportunities now that we haven't had before.
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    The approach is an extremely valid approach, but it's clearly going to require further development in order to make it clinically useful. We're continuing to pursue that quite vigorously.

    Ms. LOWEY. I thank you and in another area, last year we learned of some promising advances in the fight against Crohn's disease. Could you briefly update us and give us an idea of your future research agenda with respect to this disease?


    Dr. GORDEN. This has been really a disease that is really quite severe. It's part of the so-called inflammatory bowel diseases. Crohn's disease is a disease of the small bowel. Ulcerative colitis is the disease of the large bowel. There have been some exciting therapeutic advances in the last year or two. One of the more exciting ones is the development of an antibody to something called tumor necrosis factor, which is a kind of a cytokine. It's a protein product of a cell that occurs during an inflammatory situation that can have a very negative effect on tissues. It turns out that infusing these antibodies has a major effect in people who are refractory to other treatments in Crohn's, so that helps us get a better understanding about the nature of the disease and also offers us other therapeutic options.

    There have been a number of other advances such as corticosteroid preparations that work locally or are not absorbed into the systemic circulation so that you can get the advantage of them. There have been drugs developed that have an aspirin-like quality to them that can be given, and they're used in a format that's not absorbed, so you can get the reaction to occur in the gastrointestinal tract.
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    We've made some progress in understanding some aspects of the genetics of the disease. There's no question that there's been a marked decrease in the actual morbidity and certainly the mortality, a tremendous reduction in mortality. It's really one area in which we've made great progress. We have a way to go. People who do have the refractory forms of the disease suffer a great deal, so there's still a lot to be done. I think that a lot has been done to help a larger and larger subset of people.

    Ms. LOWEY. Thank you very much and I thank you Mr. Chairman.


    Mr. PORTER. Thank you, Ms. Lowey. Mr. Dickey.

    Mr. DICKEY. Dr. Gorden, how are you doing? What I'd like to do is have short questions and short answers. I'll try to live up to my side of it. Some of the things we talked about yesterday, but I'd like to know within a reasonable medical certainty how many diseases are related and caused by or are increased by obesity?

    Dr. GORDEN. There are at least eight, maybe ten.

    Mr. DICKEY. Can you name some of them, please?

    Dr. GORDEN. Certainly obesity is a risk factor for diabetes, heart attacks, stroke, the lipid disorders, the arteriosclerosis, in general, and certain forms of cancer, gallstones and at least two or three other things that certainly are related, such as osteoarthritis, and in other words, any kind of condition involving pressure on joints. There would be a variety of those related conditions.
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    Mr. DICKEY. Cancer?

    Dr. GORDEN. Cancer, yes, at least certain forms of cancer.


    Mr. DICKEY. Do you know the economic costs to our society of obesity?

    Dr. GORDEN. We don't really know exactly. There are numbers that have been actually produced that are in the range of just under $50 billion in direct costs; an estimate of $47 billion is a number that one could produce some evidence to support. And there's another number for indirect costs, so that the numbers that are out there are in the range of about 68 or just under $70 billion with respect to direct and indirect costs of obesity.

    Mr. DICKEY. Now if we're looking at avoiding obesity as our target, controlled nutrition and activity are two cures for obesity. Is that a fair statement?

    Dr. GORDEN. Yes.

    Mr. DICKEY. Which affects obesity more?

    Dr. GORDEN. Nutrition.

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    Mr. DICKEY. Okay, now I notice the increase of funding at least between 1995 and 1996 of the nutrition research amount went up only 2.5 percent.

    Dr. GORDEN. I don't actually have the percentage. We do have the actual nutrition numbers. The 1997 total NIH nutrition number is $452.8 million.

    Mr. DICKEY. What was it in 1996?

    Dr. GORDEN. The 1996 comparable figure is $438,812,000.

    Mr. DICKEY. Okay, so there was an increase, but not a great deal of increase.

    Dr. VARMUS. The number projected for 1999 is $507 million.

    Mr. DICKEY. What percent increase is that, Dr. Varmus?

    Dr. VARMUS. Seven percent over 1998.

    Mr. DICKEY. Okay, so that's in keeping with the overall NIH increase.

    Dr. VARMUS. That's correct. Actually, the numbers overall are not out of sync with the overall increase.
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    Dr. GORDEN. These increases are pretty much keeping pace with the average.

    Mr. DICKEY. Is part of that money going to the research of what causes food addiction?

     Dr. GORDEN. Well, this is a total NIH nutrition research figure and included in that would be the kind of research that relates to issues such as food addiction or terms that we've talked about, that relate to craving for food. So a subset of that research would relate to what you asked, yes.

     Mr. DICKEY. Is there any other agency that you know of that's doing the same thing, studying nutrition from the standpoint of an addiction or why we eat so much?

    Dr. GORDEN. Yes, the Department of Agriculture has a rather substantial research program related to this. There are also programs in the Veterans Administration. There are programs in the Department of Defense that relate to this general area of energy utilization and obesity, the broad term that we're discussing.

    Mr. DICKEY. Does the CDC have anything going in that relationship?

    Dr. GORDEN. The CDC's Work is more related to translational issues, not so much related to research per se.
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    Mr. DICKEY. What is translational?

    Dr. GORDEN. Translational issues have to do with taking information and trying to use state health departments or other kinds of community action to disseminate it and to get some sort of community effect. That is the area that they work in mostly.

    Mr. DICKEY. All right, now do you think we have too much duplication?

    Dr. GORDEN. I don't really think so, in terms of duplication. I think the agenda here is quite different. As I mentioned, the CDC's and the NIH's agendas are quite different. We have, I think, very good coordination in terms of the two major Federal components, the Department of Agriculture and the HHS. I think we have excellent coordination, and that also works through Dr. Varmus' Nutrition Coordinating Committee where we're represented in this broader context within the Department and with Agriculture. And we have contacts with the other agencies, such as the VA and the DOD.


    Mr. DICKEY. We've done a good job of explaining obesity, and informing people of the potential dangers to their health. Then we have a lot of companies and efforts being made at least on TV to get us to exercise more and to eat less. Now there's something missing here and I'm going to suggest that it's the incentives that we're missing. In other words, we know why we need to lose weight and we know how to do it, and yet we're not doing it. Isn't obesity on the rise in America?
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    Dr. GORDEN. Yes.

    Mr. DICKEY. Okay, now what is the problem and what can we do through the funds that we give to you to try to solve it? Can you be brief on that one?

    Dr. GORDEN. I think honestly, Mr. Dickey, we're going to have to have a technology, a drug, something like that. That's where our success has come in other areas. Until we develop this kind of intervention, we're not going to be totally successful. We're going to try prevention strategies; we're going to do everything we can, because once the obese state occurs, it's very difficult to reverse it. But prevention is also very difficult. We can talk about it but it's very difficult to achieve.

    We've got a number of pilot things that we're trying to do to see if we can't at least get that approach moving in a better way. If we're going to be as successful as in hypertension or in the lipid disorders or as we are now becoming more successful in diabetes, we've got to have a new technology. That's why we want to begin to try to test some of this now to see if we could demonstrate to you that we can decrease these morbidities, in other words, all these health risks that I've said. That would have an enormous effect and that would give us something to build on. That's the general approach that we're taking to do.

    Mr. DICKEY. But the reduction is completely up to us and as a nation, we're deciding to be obese.

    Dr. GORDEN. Well, I guess that's true in one sense, but it's very complex in another because——
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    Mr. DICKEY. I know that for a fact.

    Dr. GORDEN. We know, for instance, from our research that there are individual people who are more fuel efficient than others. What I mean by that is the same as an automobile that's more fuel efficient. If you want to use gas, you don't want to have a fuel inefficient automobile. We're built like that too. Why exactly we're like that, we don't know. We suspect that some of that is genetic, but we can measure that, and we know that an individual that falls into this more fuel efficient category is prone to gain weight. We've done those kinds of studies and we know at least seven or eight risk factors for gaining weight. We can measure a number of those things. Each time we understand one of them it gives us a potential point of interdicting in a more specific way.

    These are the ways that I think this problem is going to be solved, and I think our basic approach is still the best one, because we simply can't make an absolute overreaching step right now and make the problem go away.

    Mr. DICKEY. Can I ask one more question? Dr. Gorden, there's a company in Dallas, it's a health clinic actually, that uses financial incentives. They gave out $33,000 in one year of incentives, with individual employees receiving all the way up to $300, depending on what their baseline health statistics were and what they did as far as improvement. They saved $117,000 in health claims in that one year. Now what I'm saying is this problem, as I can see it, has a lot to do with economics. The incentives that were given for that clinic could reduce health premiums in the national work force level, the federal work force level or it could be just outright cash or vacations or whatever. Obviously, we've got to have something to dynamite the logjam and get people to take what they know and what's available and do something about it.
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    Now is there anything, can you put any faith in financial incentives working in this area?

    Dr. GORDEN. I can only point to the analogies that have been done in research and various forms of behavior modification. Certain types of rewards and types of approaches as you indicate are used and they're used with some success.

    Now, how to do that on a national or global basis from a reward point of view, I don't know. Scientists have suggested that perhaps, rather than a cigarette tax, we need a tax on some sort of fast food restaurants or things of that nature, and these have been suggested. I don't honestly know myself. I'm just——

    Mr. DICKEY. That's a negative. I'm talking about positive incentives such as giving money to people.

    Mr. PORTER. Would the gentleman yield on this?

    Mr. DICKEY. Sure.


    Mr. PORTER. Perhaps this is a suggestion. A lot of our obesity problems that are not related to disease or related to genetics would be better addressed by teaching good eating habits at a very young age.
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    Dr. GORDEN. Yes.

    Mr. PORTER. Maybe we should put money into a children's health initiative that educates parents and kids on good eating habits and gets them started early and on the right path, so they don't develop the kinds of habits that lead to health problems. Actually, the most recent statistics show all of our young kids are already overweight.

    Dr. GORDEN. That's correct.

    Mr. PORTER. So bad eating habits seem to start very early in life and carry through the rest of life. If we can catch them before they start, then I think we've got a good chance of reducing them.

    Mr. DICKEY. That's an excellent point because we learned that in cigarettes. The cigarette industry made the decision that if they got someone under 18 they would get them for life. Now I don't think there's any food conspiracy here. Maybe there is. But I'm just saying you've got an excellent point in that we may be losing the battle if people haven't been reached by the time they get out of college.

    Dr. GORDEN. Yes, there have been studies, Mr. Porter, to suggest that the vast majority of adults who are overweight were not overweight as children. On the other hand, if you're overweight as a child, you have double the chance of being overweight as an adult. So what you say is absolutely true. We know in certain studies that the problem begins in childhood. We know in others that it begins in adolescence. If you look at the incremental weight that these individuals gain after they're 20, they're not different from a control. All of that happens while they're adolescents. So we know that there are different factions, but it clearly happens at a young age and then there are a multiple other things that happen when one is older. So it's a very complex issue. There are multiple different things at play here and I'm quite sure that some of these strategies are going to work for some people. No question.
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    Dr. VARMUS. May I make one brief comment about this? I noticed when you asked Dr. Gorden about the relative importance of exercise and diet he said diet and this is probably accurate. But the importance of exercise should not be underestimated. In my readings of this literature, the most successful attempts to gain control of weight in children have occurred when family units have learned exercise patterns that are sustained over years; they are much more important than either drug use or temporal changes.

    Mr. DICKEY. Does that suppress appetite?

    Dr. VARMUS. It probably has an effect on the amount of food that's taken in proportion to caloric intake and in proportion to how much exercise is undertaken, but I just want to stress this because in addition to teaching proper nutrition in school, it seems to me it's important that we perhaps place less emphasis on winning teams and more emphasis on being sure that all children who go to school acquire exercise patterns that will last them throughout their lifetime.

    Mr. DICKEY. Excellent.

    Mr. PORTER. Thank you, Mr. Dickey.

    Mr. DICKEY. Thank you, sir.


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    Mr. PORTER. Dr. Varmus, a question for you, if I may. You have decided, more or less, that all disease has some genetic base that can be ultimately discovered. Is that a fair statement or not?

    Dr. VARMUS. We believe that, possibly excepting certain forms of trauma, there probably is a genetic contribution to all disease.

    Mr. PORTER. Then the question is, are we putting all other research approaches on hold and telling the Institutes, until we can unlock the genetic keys you should be looking at what the diseases do to us and what can be done to prevent the damage that they cause us? Is that happening?

    Dr. VARMUS. Absolutely no.

    Mr. PORTER. I knew you were going to say no. I want to know why.

    Dr. VARMUS. In fact, as you probably will hear from Dr. Collins tomorrow when you hear testimony from the National Human Genome Institute, we are actually worried about the difficulty of identifying the genetic contributions made to complex diseases. That's going to be difficult in the case Type II diabetes, I believe. It's going to be difficult in the case of hypertension and many other disorders. We're just beginning now to have a look at that by identifying the so-called polymorphisms that are scattered around human chromosomes, but this is going to be a 20 or 30 year struggle, in my mind, to identify those markers. And even then it may be difficult to know how to act on that information to carry out gene-based diagnostic, or preventive, or therapeutic maneuvers. So there's very much to be gained by looking at kinds of interdictions that are being thought about in the context of obesity and behavioral changes. In short, we are trying to understand the genetic basis of disease and it's going to make a very important contribution, especially to those so-called unigene diseases, but other things must continue in parallel.
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    Mr. PORTER. Thank you. Dr. Gorden, it was reported in Science Magazine that researchers had developed a genetically engineered injectable vaccine that prevents urinary tract infections in mice. The vaccine must still be tested in humans, but holds promise for the 8.5 million people in the U.S. alone that suffer from urinary tract infections. How long do you think it will be before we will know if this discovery is effective in humans?

    Dr. GORDEN. I can't give you an exact time frame, Mr. Porter, but I would like to elaborate on the problem. Antibiotics have certainly been extremely helpful for the treatment of urinary tract infections, but there are a number of individuals who are really plagued with recurring urinary tract infections. This is an intriguing observation that was made by a group of our scientists. The bacteria have a particular kind of protein that's involved in attaching to a particular part of the bladder wall and the isolation of this protein has permitted this vaccine attempt. If the vaccine is given, at least in experimental animals, then this protein that is necessary for attachment to the bladder wall to produce the infection can't take place. This is an extremely promising approach and it uses concepts that have been built on basic science that comes from plant biology: a product of plants known as lectins have to do with the binding to particular kinds of carbohydrate components of proteins. It is really one of those phenomenal things coming out of very basic research, now used in the experimental animal model for a very important disease. Now scientists will be moving towards the human application of that finding, but I can't tell you exactly when. Usually it takes several years before clinical application would be possible.

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    Mr. PORTER. Can you tell me where we are with respect to research on interstitial cystitis? Have we made a lot of progress in that disease?

    Dr. GORDEN. I think that the real progress that's been made is in terms of categorizing a variety of disorders that cause extreme pain that are related to the bladder. One of the ways we've gone about this is to deal with it directly, clinically, by establishing a group of clinical centers that recruit individuals who have the characteristics that are associated with interstitial cystitis and attempting to assess each one of them. We now have a battery of biopsied material and material from cultures to put together. We've just recompeted this group of centers because we thought this was an extremely valuable program. We've just recompeted it to try to see if we can develop therapeutic strategies to treat some of these individuals. We have some ideas about how to go about that. This has been a really debilitating disorder for many people. We are working with the community and we just had our second international conference sponsored with the Interstitial Cystitis Society. Our program director, Dr. Lee Nyberg, was very much involved in this, and we think we both developed a tremendous rapport with the community. We have addressed their problems and we're trying very hard to make this something that could be therapeutically important.


    Mr. PORTER. Since you raised rapport with the interstitial cystitis community, how about your rapport with the diabetes community? I'm talking about the Juvenile Diabetes Foundation, the American Diabetes Association and others. Where are you with them? Is it a good, close relationship?
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    Dr. GORDEN. Well, this year has been a phenomenal year for diabetes, for patients, for researchers and for all of us at NIH and so I really wanted to do exactly what you say. I wanted to try to test the water as much as I could in terms of our relationshis with the organizations. About a month ago I went to New Orleans to meet and address the Juvenile Diabetes Foundation's Board. About 50 or 100 people made up of their national leadership there and I spoke to them and we had a general discussion. I hope I was able to impart something to them, and I certainly came away with the feeling that they had a very positive feeling about what was going on and about the approach that was being taken, and a renewed sense of what they really want to achieve, which is a cure and a treatment. Some of the things that we put into motion now address some of their concerns directly. For example, the particular initiatives that we put into place, that address issues such as treatment, and trying to close the loop on insulin, therapy, which has been such a plague to the patients and their families. I came away with a very positive view of their feeling towards the research establishment, certainly of their enormous appreciation to the Administration and the Congress for what has taken place. So it was very positive. In addition, I met with the leadership of the American Diabetes Association in a slightly different format, but again I came away with the same kind of feeling. I think they are very pleased about progress on Medicare issues that has been achieved. That was one of their major objectives. They're very happy about the Type 1 initiative and they're very happy about the appropriations increases that have occurred in the area, particularly with respect to NIDDK, but also in trans-NIH research diabetes. My own sense is that these organizations that do represent patients at a national level have a very special kind of new feeling and this is really something that's happened in the last year in a very augmented way. I perhaps am just speaking from a biased point of view, but that is the sense that I got in my interactions. I've really tried, through our National Advisory Council, through this trans-NIH network, through communicating directly with scientists and speaking to as many people in the public as I can, to make the community aware of what's going on. I think it's had an enormous impact and I really again cannot express my appreciation to you and the committee enough for what has happened. I also have appreciation for Dr. Varmus for giving us a very special boost and supporting us in terms of getting the ball rolling. I think that we're moving in the right direction and I'm very encouraged.
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    Mr. PORTER. Thank you. Dr. Gorden, NIDDK supported research on kidney diseases focuses or seem to focus mainly on preventing or delaying the progression of the disease to end stage and on improving the quality of life of individuals who do have end stage renal disease. Is there also a focus on research that prevents the onset of kidney diseases in the first place?

    Dr. GORDEN. Well, certainly there are at least two or three areas that are extremely important in that regard. First is diabetes, because as I mentioned, diabetes is the most common cause of end stage renal disease or renal deterioration. The kinds of studies that I've outlined here are terribly important. That would be something that will be very important for ameliorating or interdicting the course of renal disease.

    Hypertension is another area, particularly in populations such as African Americans, as we've discussed with Mr. Stokes. Hypertension has a very specific effect in the generation of kidney disease in African Americans and the progression of that disease.

    A third area is in something we're beginning to explore, and it's something that is important for us to address. That is things like drugs, and what effect drugs might have on the kidney, particularly common analgesic drugs. A number of years ago there was a common drug that many people took called phenacetin. There were many brand names for it. It was ultimately removed from the market, but we still have a concern about people who ingest large amounts of analgesic drugs of a particular class. We're beginning to look at that. We're looking for diagnostic criteria that would give us an idea about how to diagnose drug—induced or analgesic—induced nephropathy.
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    Those are examples of areas where we would hope to interdict the kidney disease per se, and improve the treatments after they occur.

    Mr. PORTER. Phenacetin sounds familiar. Do you know the brand names?

    Dr. GORDEN. Anacin.

    Mr. PORTER. Anacin is phenacetin.

    Dr. GORDEN. And drugs like Stand Back and those kinds of things. Those analgesics were usually combinations of drugs. They contained some aspirin, but they contained phenacetin, which was one of the major ingredients.

    Mr. PORTER. Is Anacin off the market today?

    Dr. GORDEN. Yes. APC, there were a variety of these so-called drugs: aspirin/phenacetin/caffeine. Those were drugs that were proprietary drugs at the time.

    Mr. PORTER. I have to say that Anacin was the regular choice for most things when I was in the Army, APC.

    Mr. Stokes.

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    Mr. STOKES. Thank you, Mr. Chairman. Dr. Gorden, as you know, over the years, I have been involved in the development of the collaboration between the NIH, Office of Research on Minority Health and your institute. Over the past several years you've had some joint initiatives, I think, between the two Offices. Can you provide us with an update on any major joint initiatives that are currently underway?

    Dr. GORDEN. Yes, we have again with Dr. Ruffin's Office a very active collaborative program on the order of about $8.5 million. There are two different things that we do. One is that we are the administrative support for the MOTTEP, the program that's involved in trying to recruit more African Americans and other minorities to become organ donors. This is a program that's a national program that the Office funds and we actually administer for them through NIDDK.

    We also have a high school student program that we have used at each of these same sites. We bring, these students to work in laboratories in the cities in which these sites happen to be. We have a very nice meeting once a year and bring these students in,trying to interest them in biomedical research. That's been a very active program.

    We have another effort related to a program, a clinical research program, that's being inaugurated at Drew University. We have a whole variety of individual projects. One has to do with genetics of diabetes. Another has to do with support of our Diabetes Prevention Program clinical trial, and also a series of individual research grants that cut across everything from H. pylori infections to hepatitis C, to obesity, to diabetes—the diseases that are of major concern. Of course, the Office also plays a major role in our African American hypertension study. In all of the diseases that represent major disparities in minority health, the Office has been involved in collaborating with us to enhance our own resource base to build on these programs. We found it to be a very productive interaction.
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    Mr. STOKES. I'm pleased to hear that because, as you know, over the years I've seen this sort of improve and grow and the collaboration take on much more meaningful aspect in terms of not only your institute, but several of the other institutes. So, I'm glad to hear that.

    You mentioned hepatitis C a moment ago. And I notice in your formal statement you say that to combat chronic liver disease, you will launch a major natural history study on hepatitis C based on a consensus development conference response with NIAID. Can you tell us a little bit about that?

    Dr. GORDEN. This first consensus conference on Hepatitis C is another example of the real utility of these conferences. This one was extremely successful in allowing us to catalyze some major objectives and major concerns in a broad community.

    What we've done first is to bring on Dr. Leonard Seeff, who is a major national expert in hepatitis C, to work with us on this problem. We are also inaugurating a multi-center program of multiple clinical centers and a central coordinating center to begin to collect natural history data on the course of hepatitis C.

    It is a disease in which approximately 70 percent of patients who are infected with hepatitis C develop chronic liver disease. And of that 70 percent, approximately 20 percent develop cirrhosis. Once they develop cirrhosis, there is about a one to two percent per year risk of liver cancer.
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    We are developing a program that will allow us to understand the difference in the course of one patient versus another and to try to find ways to interdict the course of this disease. We think this will be a major collaborative effort. And we are further going to, in Fiscal 99, begin to augment this effort by an additional group of research grants.

    This is an area that we feel is very important and one that we, along with several other institutes, including the National Institute of Allergy and Infectious Diseases, are going to play a major role in the future.


    Mr. STOKES. Very good. Another important item, I noticed, in your formal statement. Let me refer to it. You say we are intensifying research on the biology of the prostate which includes studies of benign, prostatic, hyperplasia, prostatis and prostate cancer in collaboration with the NCI. I note this particularly because we talk about minorities, we know that African Americans have the highest rate of prostate cancer then any males in the world. Obviously this is going to be very important in terms of making some impact upon that situation. Will you please comment on this?

    Dr. GORDEN. Yes. Actually this is a very active area of collaboration with the NCI. We sponsor five George O'Brien Urology Research Centers, three of those we co-fund with the NCI with the specific objective of studying both benign and malignant prostate disease. We, along with the NCI, want to develop a very interactive program because so many of the issues, the technologies, and the influences on the prostate are similar and the kinds of approaches that one takes are similar.
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    Along those lines, we are having the second International Conference on Prostate Growth starting this weekend. Just to emphasize the importance of that, our plenary scientific speaker is Dr. Varmus. I think this illustrates his broad interest and expertise, particularly in cancer research and issues of cell growth and related issues.

    Prostate research has been an enormously important area of growth within NIDDK. We really are excited about the prospects of increased understanding. We have a multi-center clinical trial involved in the medical treatment of BPH, benign prostatic hyperplasia, that has a very substantial number of minority participants. We think that trial will also be important to the issue of cancer research, because we are collecting information—PSAs and a lot of other information—that we think is going to be very useful in understanding cancer. But the real issue here is to treat benign prostatic hyperplasia.

    We think this is an excellent example of where two NIH institutes have many common objectives. The Cancer Anatomy Genome Project is of enormous importance, and prostate is one of the major areas of concern. There will be a major importance to this particular process.

    We think that prostate research is an area in which we are making some real progress in terms of medical therapy. We bring our expertise in endocrinology to this, because some of the major treatments for cancer of the prostate have been endocrinologic treatments because the prostate is an endocrine—responsive organ. Testosterone, anti-testosterone therapies, all of these things that have been brought to bear, help us in the fight against prostate cancer.

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    Mr. STOKES. Thank you. Dr. Varmus, did you care to comment in this area, also?

    Dr. VARMUS. Well, Dr. Gorden has covered it very well, and I think that those topics will definitely come up when we have the NCI here. Those are the two institutes that are most heavily involved. There is some less minor involvement by one or two other institutes.

    But there is clearly a great deal more research and emphasis, on prostatic cancer.

    Mr. STOKES. I thank you both. I appreciate your testimony. Thank you Mr. Chairman.

    Mr. PORTER. Thank you Mr. Stokes. Mr. Dickey.


    Mr. DICKEY. Yes sir. Dr. Gorden, again let's go short questions, short answers. Where is the center of the National Obesity Task Force?

    Dr. GORDEN. It is operated within NIDDK. We are the administrator——

    Mr. DICKEY. They are in the same location?
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    Dr. GORDEN. Yes sir.

    Mr. DICKEY. Who is head of that?

    Dr. GORDEN. It is operated within the Division of Nutrition, Digestive Disease and Nutrition, by Dr. Susan Yanousky, who is an expert at eating disorders, as an executive secretary of that group. She is the person who is responsible for coordinating and for disseminating the activity of that group.

    Mr. DICKEY. Okay, now I want to go into this $45,000,000,000 a year that obesity costs our society. What are the reasons that we know of that inspire people to lose weight or to fight obesity?

    Dr. GORDEN. Well I think that is multi-faceted. I think that one important issue, and perhaps the most prevalent one that one hears about, has to do with a certain cosmetic reason. That is people have a certain desire to be——

    Mr. DICKEY. To look better.

    Dr. GORDEN [continuing]. Thin. In other words, it has to do with your looks.

    Mr. DICKEY. What else?

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    Dr. GORDEN. Well, I would hope that it is the health aspect of it. It is the realization that there is a particular set point of weight. If you exceed that set point of weight, you markedly begin to increase your risk of all those health problems that we mentioned earlier, and those things are not necessarily independent. That is, you could increase your risk of all of them, or one of them, or a subset.

    I believe that those two things are the driving force.

    Mr. DICKEY. But it seems to me that we have more peer pressure on the cosmetic look than we do on the health side. In listening to you and thinking about this problem, I see that we have more of a concern nationally than we do individually. Would you agree with that?

    Dr. GORDEN. Well, it seems to me that almost every individual you talk to wants to lose weight. And so——

    Mr. DICKEY. But they do not do it.

    Dr. GORDEN. Well, they do not do it, but they sure seem to want to do it. I think it's kind of part and parcel the same thing. It is very unusual to hear someone talking about their desire to gain weight.

    Sometimes you do because there are certain individuals that want to gain up to this normal set point, that is true. But for people of normal weight, it is very unusual to hear someone say that.
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    On the other hand, to hear someone talk about wanting to lose weight is a very common thing.

    Mr. DICKEY. But what I am really saying is that nationally, health care costs are going to consume us by increasing. Even as we bring the increase down we have the tragedy you might say of HMOs and what they are doing to us in that regard.

    But if we could ever convince our populace that health care is a national patriotic duty, then we are putting a national concern above our individual concerns, in a way. It is like if we go to war.

    Dr. GORDEN. Sure.

    Mr. DICKEY. We forget about overtime. We forget about who is working where or how many hours you have done this or that. When you are at war, it is expedient to keep moving.

    Now what I am saying is we do not have that attitude yet. I do not know what it is going to take. But I can—I didn't know it was going to come down to just to two reasons, cosmetic or the way you look and your health. But obviously those two things are not winning the battle. We have got to do something else. And that is what I am trying to bear down on.

    But let us move away from that right now because I think we have talked enough about behavioral control.
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    Is obesity related to poverty in any way?

    Dr. GORDEN. I think that there is a relationship of weight to socio-economic status. In general, there tends to be more obesity in lower socio-economic strata.

    Mr. DICKEY. Why is that? Do they have less concern about the way they look?

    Dr. GORDEN. I do not honestly know exactly what the answer is. I suppose that it would be, just coming back in a simple way to the things I said before, less concern about cosmetics. Perhaps also, cultural issues that relate to the fact that different cultures have a different view of weight and they do not have the same concern. There are a whole variety of things——

    Mr. DICKEY. How about to live for? If you feel hopelessly lost in poverty, you have less to live for, maybe.

    Dr. GORDEN. Perhaps that is certainly another element.

    Mr. DICKEY. Okay, now what I'm saying, go back to the incentives. We are now being informed by the marketplace as to how to do something about it, with all of these diets and everything else. The connection has to be some kind of incentive. Do you offer any other ideas?

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    Dr. GORDEN. Well as I say, Mr. Dickey, I think our best hope is to develop a technology that people can use in a relatively easy way. I think people want——

    Mr. DICKEY. You are thinking of drugs now.

    Dr. GORDEN. Yes. I think people really do not want to be overweight. And I think if they are overweight, they want to get back to a normal weight. But they want a way that allows them to do it. And so many people have found dieting very difficult to do. I think we need to——

    Mr. DICKEY. It is stressful.

    Dr. GORDEN. Very stressful.

    Mr. DICKEY. And that causes overeating.

    Dr. GORDEN. That may cause it; certainly in some people it causes overeating. It is a kind of boomerang. You are absolutely right. And I think that the ease in which we can introduce things for people to do would help. If we could simply do as Dr. Varmus has suggested—through education, just have everyone simply balance their nutrition with a really active life—that would be a wonderful thing. It is probably the healthiest thing we could do.

    Mr. DICKEY. But it is not happening.
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    Dr. GORDEN. But it is not happening, and we need to keep pushing at that. Because the fact it is not happening does not mean it is not important. It is very important.

    And when you ask me which is most important, diet or exercise, I answer diet only in the sense of what we know about weight gain. About 75 percent of it relates to the intake of energy. And about 25 percent to the utilization of energy, which is exercise.

    But the interplay between these two things are enormous. And so we cannot really——

    Mr. DICKEY. Excuse me. There is something we are not talking about and that is productivity. I mean we are talking about good health and not having as many health care claims, but you know productivity on the job, is improved if the employee is in good health, I do not think this is measurable, but it has got to be one of the dividends of such an effort.

    And I wanted to say that, but that still does not have anything to do with what you are doing yet. Is that right?

    Dr. GORDEN. Well, we have to stick to what we know best. I think that is to try to do the research that is going to develop the technologies, that is going to permit weight control to be easier for people. That is where I think we have to be.

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    All these things that you mention are obviously very important. It is just that I am not quite sure I have any great insight into how to accomplish them.

    Mr. DICKEY. Well I am not—my effort comes partly because my state, I think, the latest statistic is the second highest percentage increase of obesity in the last five years, or something like that. Now this is Arkansas, a rural state.

    And I am being driven a lot by that. But there is a lot of things I am going to be doing, but they are not scientific. They are more or less what wins ball games, wins wars, wins battles and things like that. It is—I just hope you will be tolerant as we move into this area of us ground level folks, and not you ivory tower people.

    Dr. GORDEN. Mr. Dickey, I know exactly where Arkansas is and I understand the problem. I think all of these things may be important for us to do until we can really reach a kind of utopia. I think we are all on the same track there.

    Mr. DICKEY. I am looking forward to working with you and thank you for your testimony. And Dr. Varmus, you have something to say.

    Dr. VARMUS. Well, my only concern, Mr. Dickey, is I do not think we have any evidence that argues conclusively that overweight contributes to a lack of productivity. I think there would be a concern that——

    Mr. DICKEY. Absenteeism.

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    Dr. VARMUS. Well, again, I do not—if it is due to illness yes, but I think there is a concern about a prejudice against and discrimination against people because they are overweight. And concern about the further deterioration of self image. So I think one has to be cautious in that area. That is all I would argue.

    Mr. DICKEY. Okay, I do not have any more time. Thank you, Mr. Chairman.

    Mr. PORTER. Thank you Mr. Dickey. Ms. Pelosi.


    Ms. PELOSI. Thank you very much, Mr. Chairman, Dr. Gorden, & Dr. Varmus. I do thank you for your testimony today. Forgive me for coming in late here, but my responsibilities as ranking on foreign ops prevented me from being here for the entire time.

    We did at lunch have our biomedical research caucus presentation and we heard some very exciting things. And among those was that there are new breakthroughs in diagnosing vision impairments which can result from diabetes. Two doctors, a son-in-law and father-in-law, came up with this. Forgive me for not knowing their names. Is that something that has sustained the test of time?

    Dr. GORDEN. Certainly laser photocoagulation has been an extremely important therapeutic tool in treating the eye disease of diabetes. The National Eye Institute has conducted some really important clinical trials and has shown clearly that that laser treatment will markedly interdict the deteriorating course of eye disease. Laser treatment has had enormous effect in diabetic eye disease, no question about it.
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    Ms. PELOSI. That is encouraging. And then, again, a number of major newspapers reported a few weeks ago, as you know, that a major dent in the use of growth factors for the regeneration of blood vessels in the heart. How do you think this research will help persons with diabetes who are much more likely to suffer from heart problems?

    Dr. GORDEN. This technology has not been specifically applied to diabetics. There are some differences in the type of atherosclerotic or arteriosclerotic lesions that diabetics get, as opposed to non-diabetics. By and large, any technique that is going to permit the growth of new blood vessels in particular areas would be helpful. The growth of new blood vessels is a real problem in the eye. But in the leg, around arteries and the heart, there is no particular reason why this approach should not have efficacy in diabetics. But at this point, to my knowledge, it has not been tried in diabetics.

    Ms. PELOSI. In our state of California, there is a great deal of interest in the work of your institute. We are home to over 1,000,000 adults with diagnosed diabetes. Of course, it is the largest number of any state in the country.

    But we are also very concerned about the issues of juvenile diabetes and I had hoped that this breakthrough in terms of regeneration of blood vessels in the heart would give us some reason to be hopeful on the juvenile diabetes front. Dr. Varmus, did you want to add something to that?

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    Dr. VARMUS. I just think that, the result reports that I have seen have been in the limb vessels.

    Dr. GORDEN. There actually have been some very preliminary studies.


    Ms. PELOSI. I am certain that my colleague Mr. Stokes asked you about the disproportionately high rate of diabetes in the African American community, as well as in other minority populations. According to what I hear, diabetes is 70 percent higher among African Americans than among whites.

    I wondered if you could tell us what your institute is doing to ensure that the benefits of research and prevention in treatment of diabetes are shared equally and by largest number of people. If you answered this already, I will just see it in the record, Dr. Gorden. Refer to what your successes have been in making this prevention available.

    Dr. GORDEN. We have commented on it as we talked about our major Diabetes Prevention Program. That clinical trial over-represents minorities, both Hispanics, who have a higher prevalence, and African Americans and Native Americans, who have a higher prevalence of diabetes. They are over-represented in the trial and will also be a major focus for education programs. We will have a special emphasis for these populations that are disproportionately affected. These are all ongoing projects at the present time.

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    Ms. PELOSI. Thank you, Dr. Gorden. Listening to your responses to Mr. Dickey about obesity, I wondered—I always think the answer to all of these questions is the same. It is not the only answer, but it is one of the answers to all these questions, and that is access to quality and affordable health care.

    We tell people that obesity is not good for their health, but then again we do not enable them easily to have access to quality health care.

    So if that is a value, if it is something that is important that people should not engage in smoking, or use of drugs. We are saying that these things are important for their health, but at the same time, we do not place a value on every American having access to that health care. Then our message, I believe, is a mixed one.

    And so every day we hear about this issue of obesity here and now I know why, because there is something going on in Arkansas about obesity. But in any event, I would think that if those people that we were talking about, the lower end of the economic scale, had access to quality health care, they might be told more often than not about appropriate prevention and care. And also the importance of maintaining weight.

    I am not particularly interested in the cosmetic aspects of it, but I was interested in the side effects of obesity that are so costly in terms of personal well being and the obvious loss to productivity in our country.

    Unless you wanted to comment on access to quality health care and if you thought that would help people at the low end of the scale avoid some of the problems of obesity?
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    Dr. VARMUS. That is an important issue, Ms. Pelosi, and people I think forget that a crucial part of the whole behavioral treatment of obesity is having a doctor tell you, the patient, not the entire society, that you need to lose weight to be optimally healthy.

    Ms. PELOSI. It is the same thing that we do with education. We tell children that education is the key to success in their lives and it is important to the competitiveness of our country, and yet we send them to schools in tumble down buildings, they are leaking and have environmental hazards, and are not equipped electronically with technology for the next couple of years. You say the next century, it is right around the corner.

    And I keep thinking if we would only send a consistent message, children would learn—would take us seriously about smoking in this case, and studying in the case of education which is another jurisdiction that our subcommittee has.

    If I may, Mr. Chairman, I just want to ask one quick question, but I cannot find the reference in Dr. Varmus' testimony from the other day, and it may have been in the Q&A. Dr. Varmus, you talked about interdisciplinary research and approaches to what you were doing, you presented it so eloquently, but I cannot seem to find it here now. Can you, just taking the word interdisciplinary into your computer tell me——

    Dr. VARMUS. Well we talked about that in several contexts, Ms. Pelosi. We talked about it in the context of developing new instrumentation. We talked about it with respect to developing new ways to analyze the avalanche of data that we are now generating in medical science. We talked about it in relation to developing new therapies. So I am not sure about the context because interdisciplinary work was such a broad theme in yesterday's discussion.
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    Ms. PELOSI. And the collaborative efforts being so——

    Dr. VARMUS. With other agencies, yes.

    Ms. PELOSI. Do you believe that the NIH, that you have the resources, administratively, to deal with the politics as well as the rest of the interdisciplinary approach?

    Dr. VARMUS. Well, I think that is one area in which the limits that have been placed on our support of our research management and the RMS budget has begun to pay a toll. The kind of outreach that is required by our program managers to maintain those collaborative interactions and to develop new programs that would be more interdisciplinary in nature will require, especially as our grant portfolio enlarges, some significant increase in the amount of money that we make available for research management and support.

    We are asking for a three percent increase for RMS, but then an eight and a half percent increase overall. And I am not, myself, completely confident that that is an adequate increase in RMS for optimal management of our research portfolio.

    Ms. PELOSI. Well then, I'm glad I asked.

    Mr. PORTER. Ms. Pelosi, why don't you continue with your first and second rounds combined until the next bell rings.

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    Ms. PELOSI. Thank you very much, doctors one and all. Thank you, Mr. Chairman. I thought you were serious.

    Mr. PORTER. I am serious.

    Ms. PELOSI. I thought we had to go vote.

    Mr. PORTER. We have five more minutes until the second bell, so why don't you take the remainder of the time and ask whatever questions you would like.

    Ms. PELOSI. I do not want to put our guests through some questions that they have already been through. So let me just take one, if you will bear with me for a moment, Mr. Chairman, because I think that——

    Dr. VARMUS. Mr. Chairman, could I make one brief statement while Ms. Pelosi is looking?

    Mr. PORTER. Yes.

    Dr. VARMUS. I wanted to at some point mention to you and to people who were listening, that this year we are going to make special use of our NIH web sites to make available to the scientific and advocacy communities the opening statements of our institute directors as soon as they are delivered here. So already, my presentation from yesterday, the presentations you heard this morning, are up on our web sites and we hope this will allow those that follow our activities almost instantaneous access to our opening statements.
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    Mr. PORTER. Let me ask you a question? The Speaker at today's luncheon which was focused on diabetes research, said that he wanted to ensure that the country had, in the future, a system where practicing physicians could immediately know the state-of-the-art procedures when dealing with specific diseases. Don't we already have that in place in the sense of the National Library of Medicine or am I jumping the gun?

    Dr. VARMUS. It is not in place at this point. There are two problems. One is developing the right kind of accessible database for all diseases. It is in place for some things. For example, if you wanted to ask what is the current therapy for ovarian cancer, you could get that very quickly because the NCI has developed a very sophisticated database.

    The other problem is the problem of making our physicians more computer literate and developing the habit of using the computer as a resource. Many of them have neither the expertise nor the time to do what the Speaker is asking them to do. But I am sure that when Dr. Lindberg comes here, he will tell you about efforts to do for other diseases what has already been done for some.

    Mr. PORTER. So when I saw the National Library of Medicine on the monitor in the community health center I visited in the inner city of Chicago, that system has some of the data that they would need, but not in reference to all diseases.

    Dr. VARMUS. That is correct.
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    Ms. PELOSI. I was pleased to hear that, Mr. Chairman, because of one of the efforts that we fund in our bill, the centers, which are started at the University of California, San Francisco, to get information out to the rest of the country on therapies for treating people with AIDS and HIV. I mean, this was even before the very sophisticated protease inhibitors. Because so many people did not have knowledge of this.

    Dr. VARMUS. I should make clear Mr. Porter that the entire literature database is available. The problem is making the information digestible for someone who doesn't have the time to look through all the articles.

    Mr. PORTER. Exactly. If I could say one thing to the gentlelady from California. I believe, I am not certain I am right in this, but I believe that we have just passed legislation that is now taking effect where we are collecting a special tax to hook up all libraries and all schools in the United States to the Internet. So I think we are already doing a part of what you were referring to that we should be doing.

    Ms. PELOSI. Oh yes. Well, my problem was that some of the schools do not even have the electrical wiring to accommodate.

    Mr. PORTER. Oh, okay.

    Ms. PELOSI. I think that with the technology the way it is, lots of this information will be available, as Dr. Varmus said, people have to know what is there and how to avail themselves of it.
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    Mr. PORTER. I think we are now going to have to thank Dr. Gorden and go vote.

    Ms. PELOSI. Okay, thank you.

    Mr. PORTER. The second bell has rung. Dr. Gorden thank you very much for the job you are doing at NIDDK and I think all members of the Committee appreciate your very good opening statement and your very good detail and candid answers to our questions. We thank you very much.

    Dr. GORDEN. Thank you very much, Mr. Chairman.

    Mr. PORTER. I just wish we had more than two hours because there are so many questions left unanswered. We will have to ask you to answer some for the record.

    Dr. GORDEN. Thank you, sir.

    Mr. PORTER. The Subcommittee will stand in recess until 10:00 a.m. tomorrow.

    [The following questions were submitted to be answered for the record:]
    "The Official Committee record contains additional material here."

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Wednesday, March 18, 1998.










    Mr. PORTER. The subcommittee will come to order.

    We continue our hearings this morning and are pleased to welcome Dr. Donald Lindberg, the Director of the National Library of Medicine.

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    Dr. Lindberg, it's good to see you. I understand you have a demonstration and we're going to turn the lights down for you.

    Dr. LINDBERG. I appreciate your indulging us in that respect, Mr. Porter. It's going to take another moment.

    [Pause in proceedings.]

Opening Statement

    Dr. LINDBERG. Thank you very much. I very much appreciate your kindness, and I apologize for the delay.

    I wanted to report to you, give a progress report on the work of the Library in this brief statement, particularly with respect to three areas in which the committee had inquired last year, and to some extent given us some very helpful guidance.


    Firstly, free public access to the MEDLINE data base of the scientific literature. The committee heard last year testimony from Dr. DeBakey. Dr. DeBakey drew attention to the importance of getting access to the scientific literature, both for patients and for physicians.

    The committee then told us, very helpfully and clearly, that we should continue our outreach efforts directed toward health care professionals and the public, that we should use the new technology. And specifically, the committee endorsed and supported our decision to extend free MEDLINE access. This was tremendously helpful.
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    By the late summer, we were ready to start that experiment. And Senator Specter called a press conference.

    [Video presentation.]

    Dr. LINDBERG. Happily, Senator Harkin was on hand also to encourage us.

    [Video presentation.]

    Dr. LINDBERG. The video shows the Senate, but today we are in the House. Everybody had a good time that day, it was a happy event. Mr. Gore showed up to do the first free MEDLINE search, and with the help of Dr. Varmus and Dr. Lipman, it was a successful search.

    [Video presentation.]

    Dr. LINDBERG. Of course, that event got very good press coverage, print and electronic. The Post, for example, said quite well in the headline, ''medical research is made available to all.'' That's what the Congress wants, what the committee wants, and it's what NLM wants.

    The Chicago Tribune covered it well, the Wall Street Journal gave it their own slant, but good coverage. And the Times of New York and of Los Angeles reported it.
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    Probably partly as a result of this good coverage, the use of MEDLINE searching has increased in the last six months by tenfold, a thousand percent, going from a rate of 7 million searches a year to a rate of 70 million searches a year. And more remarkable to us, the percentage of those searches that come from the general public has increased from virtually zero to 30 percent. So the experiment clearly is working, if we can keep the computers pumping along and keeping up with it, we'll be certain of it.

    Speaking of ER, here's a clip.

    [Video presentation.]

    Dr. LINDBERG. While we of course do try to make the systems understand ordinary speech such as numb chin and to make the equivalents to the Greco-Roman expressions that medical people and librarians favor, we wanted to be understood by the public, and we wanted to be easily used by the health care professionals as well.


    The next area I should report on, telemedicine, as I indicated before, is the strongest strategy for getting good biomedical applications on Internet and also the Next Generation Internet. So I wanted to show you very briefly a few examples of those applications. And I agree with Dr. Patricia Grady's high appraisal of them.

    [Video presentation.]
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    Dr. LINDBERG. This also is a home health care application in which the nurse with her back to us is making an electronic call on an old person at home. She can do six or eight home visits before noon.

    This is working quite well. The primary funding in this case was HRSA, and we're involved more in the evaluations. That used a lot of bandwidth, because you have live television both ways between the patient and the nurse.

    [Video presentation.]

    Dr. LINDBERG. This is the opposite. This is a good medical application. It's teledermatology. It's in eastern and southern Oregon, remote areas. This is a clinic, general practice clinic, probably good doctors, but they're not dermatologists. And here comes a patient with a dermatological problem. He's been almost unable to work for five years because of this eruption, for which he's seen four doctors and gotten no suitable treatment.

    The application here is to use digital cameras, which make a photograph in that clinic office, and a computer to transmit it to the expert, in this case, the Oregon Health Sciences University. You can see the pictures are quite detailed and good, even though they go over an ordinary phone line with ordinary modems.

    It took actually 20 seconds for the dermatologist to make a diagnosis, which is eczema herpeticum, and to come up with a treatment, probably Acyclovir, which can be taken by mouth, and in 48 hours, this disease that had lasted five years is cured.
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    Again, you have a computer based patient record, so that we can get evaluation of the ultimate worth and contribution and cost of these systems. There are many others in the telemedicine area.


    The third area I want to bring attention to is progress in genome infomatics. Dr. Lipman is here to take us into any details that we might wish. He and I have selected two examples, sort of at opposite ends of the spectrum, to bring to your attention.

    Firstly, there is now a new version of the gene map. About a year ago, his group, with collaborators from all over the world, produced a map of 16,000 human genes. They now have 32,000 which is perhaps half of all that will ever be known. And it's presented in these colorful codings for the gene pairs.

    But the text, which obviously I wouldn't ask you to try to read, is expressed in terms that are suitable for students and for the public, and is oriented around diseases. Nonetheless, the same data base, exactly the same, is used by and accessible by molecular biologists and physicians. One can go as far into the data base as he or she wishes simply by clicking. So that's one extreme.

    The second is a whole experiment which NCBI is doing with National Cancer Institute. It's called Cancer Genome Anatomy Project, and probably has been reviewed by NCI or perhaps will be. I know they got rescheduled.
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    What we're showing here is the traditional histology. I'm a pathologist, so I'm used to looking at thousands of these. And this is a dilemma. Patient number two will get well with treatment. Their lymphoma will respond. Patient number one will die, because the drugs won't work. And yet the histology is identical. We just can't learn any more by looking at those haemotoxylin and eosin pictures.

    A new way to look at that problem is presented by these gene matrices. This scheme allows the examination for the activation or non-activation, the state, I guess you'd say, of 10,000 genes. The representation here is that if there's a little red dot, it means that the gene is expressed strongly, and only in the patient on the left, in the case of the first one I gave you, the one that's a non-responder. If it's green, it means that the gene, which is coded by position, is strong only in the cases that do respond to the therapy.

    So this still doesn't tell you the answer to cure that patient today. But it is a clue to the persons doing basic research in oncology, which the traditional histology has simply denied us.

    So again, I thank you very much for putting up with the technology. But I did want to show you that we live by the sword and die by the sword after, lean on the computers.

    Thank you.

    [The prepared statement follows:]
    "The Official Committee record contains additional material here."
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    Mr. PORTER. Dr. Lindberg, do you have an additional statement beyond the demonstration?

    Dr. LINDBERG. No, I thought I'd just respond to your questions. I guess I should give you the President's budget request, which is, as you probably know, $171.3 million, plus an estimated contribution from AIDS to a total of $174.7 million.


    Mr. PORTER. What do you make of the 30 percent increase in, I guess you'd call them hits, on your site coming from the general public?

    Dr. LINDBERG. I think it indicates that there's been a tremendous thirst for information about health and disease on the part of the public. I'm impressed myself, every day, by the extent to which patients are educated and anxious to participate in their own health care, as contrasted with when I was a beginning student, when I think they really were neither.

    Mr. PORTER. Someone commented on the incredible amount of medical information the population gets from the show ER. [Laughter.]

    Have you heard this?

    Dr. LINDBERG. It's pretty popular.
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    Mr. PORTER. If you want to get something in the minds of the public, you have to get it on ER and it will get there. Obviously, you did a very good job of showing what can be done with information through the media.

    Dr. LINDBERG. I probably should say that that story they showed is a true story. That is a real search, it really was done. I don't know where they think their hospital is, but this particular hospital was in Atlanta where the search was actually done.

    Mr. PORTER. So you can now look up numb chin and get the same result that they got?

    Dr. LINDBERG. You can, unfortunately, it's not a happy sign. In the case where it was reported to us, it was actually a first sign of a malignancy. But at least they could get treated right away.

    Mr. PORTER. You mentioned Lake County in your statement, it just happened to be in Oregon. Part of my district is in Lake County, Illinois, so it was close. [Laughter.]

    I was beginning to wonder whether that was part of my district.


    Dr. LINDBERG. Well, as you know, the telemedicine works in cities just as well as it works in the remote rural areas. And there are telemedicine applications in Chicago. And in fact, there are telemedicine applications in Washington, D.C., an ambulatory renal dialysis clinic that Georgetown runs. It has an NLM telemedicine experiment.
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    The actual clinic is sort of around the corner from Union Station. But the nephrologists, of course, are all back at Georgetown, and can't be everywhere. First, we thought it was rather stretching to apply, but we now see the wisdom of it. I mean, it actually allows them to look at the status of those AV shunts, which is the major reason for renal dialysis failing and the major reason for hospitalization.

    So even in a city, telemedicine has really quite a lot to offer.

    Mr. PORTER. I may have mentioned this to you, but if I didn't I want to. I was visting a community health center in the inner city of Chicago. They were showing me the various things they do, and as I walked past a television, or a computer monitor, there was the National Library of Medicine on the screen.

    Dr. LINDBERG. Oh, good.


    Mr. PORTER. So they were hooked right into you, and were using your resources for their work very directly.

    At last year's hearing, we discussed the problem of not having enough Ph.D.'s trained in computer science information technology and genetics to help manage the overwhelming quantities of data being produced from genetic sequencing. We also discussed the possibility that private industry would lure these specialists away from academic, thus depleting the talent needed to train the next generation.
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    At this time last year, this wasn't a problem. With the Human Genome Project coming on line ahead of schedule and other technological advances happening at a rapid pace, where do we stand on all this today? Has the picture changed over the last year?

    Dr. LINDBERG. Oh, I think there will be a severe shortage of people who understand informatics and molecular biology. There's no question at all about that. I think we have foreseen it to some extent. NLM can only do what a small institute can do.

    But we support 12 training grants in medical informatics and have for some 25 years. All of those currently train people in molecular biology. Only one of them, Rice-Baylor, focuses exclusively on molecular biology. We suspect that it would probably be a good idea, if we could, to support a few additional ones.

    There are a lot of other parts of the question to support people and entice them into that field. Creation of information resources I think is part of it, to make it so that researchers can get at the information no matter where they are, and no matter where the information is. There are a number of such knowledge sources that I could mention that NLM does support.

    Beyond that, there are the medical schools. Medical schools, by and large, at the moment, don't spend—there are many things they don't teach us enough about, but one of them is computing. Probably molecular biology is in that category as well. Because all of these things are new, with respect to the old curriculum, and there's not space enough for all of them.

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    In this Next Generation Internet scheme, many people are enthusiastic about remote learning, adult learning, teaching at a distance. It may be that that will be one of the answers in recruitment of persons into that field. Dave Lipman tells me that on the NCBI home page, the one I showed you about diseases and the gene maps even, that students use it quite a lot.

    They think they are actually recruiting middle school and high school students into this field, because they actually do experiments in such classes, I think even in this city, to determine short sequences of nucleotide sequences out of gene parts, and then submit those and find out if it's a new discovery or add it to what's already there. I can hardly imagine that a student wouldn't be enormously excited by that opportunity.


    Mr. PORTER. You're requesting a study by the National Research Council at the National Academy of Sciences to look at the elements that will be required in order for the Next Generation Internet to be of maximum service to health care and medical research. Do you expect to have the Council's recommendation in time to proceed full scale with the initiative?

    Dr. LINDBERG. Yes, sir. They actually did quite a good job in other studies they've done for us, the Computer Science and Telecommunications Board did a study on medical data privacy and what would be involved in assuring such to the patients. We're quite pleased with that study.

    Now we're asking them essentially to look at the Next Generation Internet project and tell us what would it have to look like in order to be maximally useful to health care applications and to biomedical research. I'm confident they will be able to do that.
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    They'll focus, no doubt, on certain features of the Next Generation Internet that will be from an applications point of view. For example, the capacity of the Internet, the quality of the communication, the reliability and the security. Those are terms that I think are meaningful to both you and me. But in order for it all to work, that has to be translated in a kind of engineering terms, such as jitter and latency and meantime to failure, and addressing schemes and recovery schemes, the technical parts.

    So I hope that this will help us, since the Computer Science and Telecommunications Board has plenty of computer science capability and engineering. I'm hoping that that will short-circuit some of the troubles which the biomedical people would otherwise be enmeshed in, and allow us, our people, to deal from an applications point of view, to tell us what is required in order to do mammography, what is required in order to do teledermatology, what is required to do these other health care applications that we so much need.


    Mr. PORTER. This is a policy question that Dr. Varmus may want to comment on as well. The pharmaceutical industry spent about $600 million advertising prescription drugs directly to patients on the Internet last year. FDA regulates prescription drugs, but what about advertising on the Internet? Who's monitoring what's being advertised there, and do you think this is a problem?

    Dr. LINDBERG. Are you asking Dr. Varmus?

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    Mr. PORTER. I was asking both of you, so whoever would like to comment.

    Dr. VARMUS. Actually, I think I would have to consult on that. We don't have any oversight of what they're doing. And I was unaware of the number, or that the cost was that large. I'd rather consult on that.

    Mr. PORTER. I think they also advertise prescription drugs on television, if I'm not mistaken.

    Dr. VARMUS. Yes.

    Mr. PORTER. That puts a certain amount of pressure on professionals. But I don't know whether that's——

    Dr. VARMUS. They're advertising in the newspaper as well. They are obviously free to do that. I would rather reserve judgment.

    Mr. PORTER. So we haven't studied the implications of this?

    Dr. VARMUS. No, we certainly haven't, and I'd rather consult with my colleagues at the FDA and get their views before I comment publicly.

    Mr. PORTER. I assume, Dr. Lindberg, you want to do the same.

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    Dr. LINDBERG. Sounds right.

    Dr. VARMUS. Very wise. [Laughter.]

    Mr. PORTER. Mr. Stokes?

    Mr. STOKES. Thank you very much, Mr. Chairman.

    Dr. Lindberg, nice to see you again.

    Dr. LINDBERG. Thank you, sir.


    Mr. STOKES. Dr. Lindberg, to what extent has the Library of Medicine been able to conduct effective outreach efforts with respect to environmental hazards and pollutants, and particularly as it relates to disadvantaged and minority populations?

    Dr. LINDBERG. I understand the question. We've been interested in and concerned about the problem for quite a long while. Again, as a small agency, we do what we can.

    But our basic job is to acquire, organize and disseminate information for the benefit of the public health. We do this through a couple of dozen data bases that relate to toxicology and environmental health. Very often, data comes from other agencies, NIOSH, CDC, ATSDR, etc., and sometimes funding comes along with those as well.
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    There are two persistent problems in this field. One, the data bases have on several occasions been examined by experts, let me just say, including the National Academy. They're always given very high grades for quality. And yet I think they're under-used by the health care fraternity in general.

    And we actually started eight years ago to look into the question what could be done to improve and increase the use of it. We paid particular attention to minority populations, because we had heard that in fact, such populations are more at risk for environmental hazards at home and work.

    So we thought we would look in on the HBCU group of schools, particularly those that had health components, medicine and dentistry or pharmacy. And it turned out that they were under-users also. So we started a program aimed at that group of schools that's been really very, very helpful. A lot of guidance has been given by the deans and chairmen of those schools. We started with them, and then we started with faculty, and then we've worked with students and graduate students and equipment, connections to Internet as that came along, that whole business.

    There was enough enthusiasm from ATSDR that they actually contributed money such that we could go from our original set of 9 schools to 42 schools. I think a lot of headway has been made in that respect.

    In the end, there was a great difficulty in understanding chemical problems if one isn't trained in chemistry. So we found that it has been helpful to provide special training to groups that might take an interest in environmental health. That's been done both at the community level and also at the level of medical librarians and the toxicology meetings and the pharmacy departments.
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    So I would say in general we're doing a reasonable job with it. Now, there are several uncompleted pieces we haven't had time or money to get to. We started one recent one that I think you might find encouraging. There's a project called SPRY, which I have to always look up what it means, oh, yes, Setting Priorities for Retirement Years. I mean, actually they put a high priority on having a cute name. [Laughter.]

    Mr. STOKES. I'd be interested in that.

    Dr. LINDBERG. Essentially, that group wishes to get older people, senior citizens and also particularly minority, and particularly urban groups, informed about how to use Internet for their own purposes, basically. But in our case, we're particularly interested in this environmental health issue.

    So we've started a train the trainers program. And this is operating now in 20 cities, 20 cities and 14 States. That seems to be encouraging. My colleague, Mr. Smith, points out that Cleveland, Ohio, happens to be one of those. And that's not a surprise.

    Mr. STOKES. I'm pleased to hear that.

    Dr. LINDBERG. They're on the ball.

    So that's going to put sort of power to the people, I suppose, is the principle behind this. This will give the people, in this case the elderly, the ability to make their own searches, find out how their own communities are doing.
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    Mr. STOKES. Your answer sort of leads me into my next question, and that's with reference to the fact, as you know, this past June, Vice President Al Gore came to Capitol Hill and introduced Congresspersons and staff to the new free Web-based access to MEDLINE. This approach, of course, offers the public wider access to up-to-date information on state of the art treatment, diagnoses and prevention health information.

    Such information is of course becoming more and more critical in our ever-changing health care system, especially in this managed care era. Today, a patient has to play a more direct and active role in his or her treatment.


    What major efforts do you have in mind for extending the availability of health information?

    Dr. LINDBERG. We have big plans. I don't know how fast we'll get them all achieved. But we agree with exactly what you indicated, particularly the new health care reform, that the best protection that a patient and a family have is direct access to the best information, which is of course in the peer reviewed public literature.

    We're really taking three approaches to this. Firstly, we think that we probably can and should enhance the content of the library data bases, if they're going to be aimed at the public. So we have already added a string of consumer newsletters and journals about consumer health, and taken the pains to be sure that the index and terminology is something that we think is suitable. We hope it's suitable.
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    I think I indicated that the genome map frankly caters to the public. I mean, it's got a tremendously good readership of students and the public, and we want to do more of that. Actually, Dr. Varmus has spoken about that to Dr. Lipman. We were originally afraid we would talk down to people. When we found that someone with the background of the Director could take an interest in it, it's encouraged us to go further.

    Clinical practice guidelines is another area that I know the committee has had an interest in as well as we. We have arrangements with the Agency for Health Care Policy and Research to, let's just say for the moment, integrate our efforts, so that the patient would benefit.

    I think, Mr. Stokes, I should also say, in a way it's repeating the obvious, but the last 10 or 15 years have brought a whole lot of new areas, therefore a whole lot of new data and a whole lot of new collections for us. Women's health is one of the areas, AIDS is one of the areas that didn't exist before. And we've added those.

    Now the Congress has taken an interest, and this committee, even, in complementary and alternative medicine. That is an intellectual area that is represented by journals and terminology. We've addressed that as well, and we think we know that that's of interest to consumers.

    So those are the steps that we're taking. And we have a long way to go. But the one last step that needs to be taken, I would say, for not only this question but for the whole country, is to be sure that everybody, to the extent we're capable of that, certainly every town and every school, every hospital, has access to the Internet. That isn't the case in this country yet. And where there is access, it often isn't wonderful.
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    So we are participating in Next Generation Internet. We're also ourselves doing a string of surveys to try to make sure that things continue to improve in that respect, to monitor, to push it, to give connection grants to those that are having trouble getting connected. I think that's the general domain that we have to work in.


    Mr. STOKES. I was very impressed by the presentation that you gave us here this morning with reference to telemedicine and technology. When we talk about telemedicine in terms of being user friendly, how is this reflected in access by inner cities and, remote, rural areas of the country?

    Dr. LINDBERG. Yes, I think the main thing, I do understand your question, and I think the answer clearly is, yes, it's important. But I think we can't lose sight of effectiveness. I mean, the doctors that saw one of the patients I showed you had this terrible eruption for five years. Well, he probably saw lots of nice people and they smeared stuff on or wiped stuff off or gave him antibiotics and were kind to him. But it was all the wrong thing. It wasn't the right diagnosis. I mean, isn't it so much better if you just take the time and, all right, it takes 15 minutes for the things to be transmitted. But you waited five years, so 15 minutes doesn't matter.

    I mean, the technology has to be effective. It has to be high quality. It has to work. And I think in rural areas or urban areas or anywhere, we all appreciate that most.

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    Mr. STOKES. Thank you very much, Doctor, my time has expired.


    Mr. PORTER. Mr. Stokes, we'll have a quick second round here.

    Let me ask you Dr. Lindberg, about the volume of published or available information that is growing hugely. It's already huge and it's getting larger all the time. I think people who look on the Internet often find too much information. Is there any way to give qualitative direction through what you've put on the web to direct people to the best information and what they might want more easily?

    Dr. LINDBERG. Yes, it's a very, very important question. And I can't say that we know exactly what to do about it. We worry about it a lot.

    We definitely are very, very careful to whom NLM links. Because it is a heavily-used page; it may be one of the most heavily used. And legalisms aside, we don't want it to be an implied endorsement when we switch somebody to a source that isn't really good.

    So we in general don't do that. We switch to other parts of our institution, of NIH, sometimes within HHS. Or labeling the nature of the link, we will switch to universities that have been given grants by us and then the connection is very obvious. So all those telemedicine projects, for instance, have home pages.

    But I don't think that's a good ultimate answer to you. There is another level of implication, of course, in the literature that we embrace, if you will. We subscribe to something like 25,000 journals of one sort or another. We index, in round numbers, 4,000. So we've already sort of skimmed the cream off the top. And this is done by a peer review process: NIH and HHS actually chartered committees, and with great care. But still, that is the cream.
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    Beyond that, everyone is a bit confused, to be frank. There are a number of places that purport to give you a list of URLs, as they say, the addresses of what's cool and what's new and what's fun. That doesn't seem relevant to any of the questions that this committee would ask, because you want to ask what's medically important and relevant.

    Our answer is that we switch to institutions we know to be good. We switch to research grants that we know got a very high priority and are done by sincere and hard-working people. As I say, we now are bringing into the main MEDLINE materials that are created by consumer groups. So for instance, some of the new additions that we've just made this month are FDA Consumer, then of course, Harvard Health Letter and Men's Healthwatch. The Harvard and the Hopkins ones are well known.

    There are other journals such as the Mayo Clinic Health Letter and Health News from the New England Journal of Medicine. There's one we put in on breast feeding review which actually comes from Australia. That was picked by the biomedical library reviews, by our own reviewers; our chartered group. And MedScape Women's Health also that went through a peer review.

    So we're bringing different voices, I suppose, more than any orchestration, but selected voices carefully. I don't know how to go further, I truly don't.

    Mr. PORTER. Is there a need, and maybe Dr. Varmus wants to comment on this, is there a need to look at this even more broadly and pull together some others, even outside the Institute, that might have thoughts on all this?

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    Dr. VARMUS. There is a cohort of computer-savvy people, not necessarily within the NIH, that happen to know something about this. One of my former post-doctoral fellows is heavily involved in evaluating Internet sites for information on health and information on science. The average scientist going to get more information about technology or about allied fields, there is a plethora of available sites, but not all of them are up to date or highly reliable.

    Some of the journals—Science, the Journal of the American Medical Association and others—now have technology and web-oriented sections of their journals that allow their readers to be guided to particularly effective web sites after someone who is knowledgeable has reviewed a large number of sites.

    Mr. PORTER. Mr. Stokes.


    Mr. STOKES. Thank you.

    You mentioned earlier that on the MEDLINE services there's a category known as Women's Health. Is that correct?

    Dr. LINDBERG. Yes. Well, it's an intellectual domain, anyway, that's represented.

    Mr. STOKES. Can I also go on MEDLINE and find a category in terms of minority health?
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    Dr. LINDBERG. Oh, sure, absolutely.

    Mr. STOKES. Tell us what we'll find there.

    Dr. LINDBERG. You'll probably find a great deal written about it. Now, it has that same issue. In this case, what you'll find is all peer reviewed articles in the traditional journals. And no doubt, there will be many different aspects. I'm sure that you'd get so many that you'd want to say narrow your search to say, tuberculosis and hypertension and whatever. There would be many, many such articles.


    Mr. STOKES. I'm pleased to hear that.

    You mentioned earlier Historically Black Colleges and Universities. If I understood you correctly, they are not quite up to par in terms of the new technology, is that correct?

    Dr. LINDBERG. Well, I hope they are now. I think they weren't at the time we started our study. But I mean, the nine HBCUs that we worked with initially are Drew, Florida A&M, Howard, Meharry, Morehouse, Texas Southern, Tuskeegee, University of Arkansas (Pine Bluff) and Xavier.

    So you know, that covers quite a big range. Obviously Howard is looked upon by the others as being rather fortunate and in rather good shape. But I think in the confidence of the group that formed, they essentially said, well, look, it isn't a matter of equipment alone. Some of us need to get better equipment. But we all need to get a better understanding. And they joined hands to start a program which, as I said, has lasted eight years now, to be certain that the leadership of the school and the senior faculty had a good understanding of what we at NLM have and others had in the way of data bases and support, and also a way to keep current.
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    So I think we've plugged the holes as far as those schools being behind. I'm not sure they aren't ahead right now, to be truthful. They certainly had a very sincere, good effort.


    Mr. STOKES. I'm also very pleased to hear that. The fact that you have been so sensitive and responsive to that area is commendable.

    Recently, the media has been reporting on a possible shortage of highly skilled, highly technical personnel, especially in the computer field. Is the Library experiencing this type of thing in recruiting or in being able to retain persons in this area?

    Dr. LINDBERG. I think what you say is true generally, particularly in cities like Washington, where the unemployment rate for those kind of people is very close to zero. They're greatly sought after.

    I think we're doing okay in the Library and at NIH. But I think we are concerned about the role that we and NIH need to play in, first of all, recruiting new people to science, to recruiting minorities to science, and making sure that there is technical training made available. We have only 12 programs, but those are quite good. They deal by and large with pre-doc and post-doc education, I shouldn't say training, really, it's education.

    We've had a little bit of contact with the high school level, Coolidge High School. At NIH, each of the institutes has a kind of a little brother school, if you will. So ours has helped us a great deal to understand what it would take to inspire boys and girls at that age to science.
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    As I say, I think NCBI is doing a very, very fine job with the Entrez and the home page that draws high school students into science. Maybe you'd want to ask Dr. Lipman to comment on that.

    Mr. STOKES. Dr. Lipman, would you like to comment?

    Dr. LIPMAN. Thank you. I agree with everything Dr. Lindberg has said.

    Dr. LINDBERG. That's good. [Laughter.]

    Dr. LIPMAN. I would point out that since we're an intramural group, one of the best things we can do beyond the outreach that we're doing with the web site to intrigue high school and college students in the area and educate them is that we obviously train post-docs and graduate students ourselves. We also have high school students coming through and so forth.

    And although that's just a drop in the bucket in terms of the number of people, sometimes these individuals can make a big impact. So that's a great opportunity that we have to work with young students and we would look forward to increasing that.

    Mr. STOKES. Thank you, Dr. Lipman. Thank you, Dr. Lindberg.

    Thank you, Mr. Chairman.
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    Mr. PORTER. Mr. Stokes, thank you.

    Dr. Lindberg, thank you so much. You're doing a wonderful job there and we appreciate your coming to testify today. It's always fascinating to listen to all the developments that are occurring and thank you for the fine job you are doing.

    Dr. LINDBERG. Thank you.

    Mr. PORTER. We have two votes on at this time and I must be at a meeting with the Speaker at noon. I'm going to attempt to find another person to chair in my absence. We may be able to get started, at least, and see how we go. If not, we're going to have to reschedule, because we're going to run up against a time limit, but let's see what we can do.

    We'll stand in recess for the votes.


    [The following questions were submitted to be answered for the record:]

    "The Official Committee record contains additional material here."