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Meeting Transcript
December 12, 2002


Hotel Monaco
700 F Street, NW,
Washington, DC 20002


COUNCIL MEMBERS PRESENT

Leon R. Kass, M.D., Ph.D., Chairman
American Enterprise Institute

Elizabeth Blackburn, Ph.D., D.Sc.
University of California, San Francisco

Rebecca S. Dresser, J.D.
Washington University School of Law

Daniel W. Foster, M.D.
University of Texas, Southwestern Medical School

Francis Fukuyama, Ph.D.
Johns Hopkins University

Michael S. Gazzaniga, Ph.D.
Dartmouth College

Robert P. George, D.Phil., J.D.
Princeton University

Mary Ann Glendon, J.D., L.LM.
Harvard University

Alfonso Gómez-Lobo, Dr. phil.
Georgetown University

William B. Hurlbut, M.D.
Stanford University

Charles Krauthammer, M.D.
Syndicated Columnist

William F. May, Ph.D.
Southern Methodist University

Paul McHugh, M.D.
Johns Hopkins University School of Medicine

Gilbert C. Meilaender, Ph.D.
Valparaiso University

Janet D. Rowley, M.D., D.Sc.
The University of Chicago

Michael J. Sandel, D.Phil.
Harvard University


INDEX



WELCOME AND OPENING REMARKS

CHAIRMAN KASS: Good morning everybody. Welcome to Council Members, to guest presenters and to members of the public. I would like to recognize the presence of Dean Clancy, the designated federal officer in whose presence this meeting may officially begin.

I would also like to extend a special welcome to the members of Professor Sandel's class from Harvard University who have come down to witness how this conversation takes place inside the beltway. They've been studying with Michael this quarter, and we're delighted to have you here.

This meeting will be the third meeting on our project called either "Enhancement" or "Beyond Therapy", in which we are exploring the possible uses of new biomedical technologies beyond the treatment of individuals with known diseases and disabilities, uses either for personal enhancement, the satisfaction of client desires, or for social and behavioral control. And this meeting from beginning to end will explore technologies that might affect the native in-born capacities of human beings through the uses of genetic and genomic knowledge, that's tomorrow, that might affect human behavior above and beyond the treatment of disease through the use of stimulant drugs this afternoon, and this morning, technologies that might push the temporal boundaries and trajectory of a natural human life span through research on the biology of aging.

The first two sessions this morning devoted to aging research will explore first, the question of whether we can add years to life and exploration of the current research and future prospects, and the question of the duration of human life, whether there is such a thing as a biological warranty period.

If I might, since this is a topic dear to my heart, if you might indulge me, I would like to read a couple of pages from 20 years ago, when I knew more about this subject than I now do. But this is an introduction. Actually, by the way, when I was the Staff of NAS Committee on Life Sciences and Social Policy, which is almost 30 years ago, one of the chapters of our report was on the retardation of aging as the futuristic possibility that nevertheless raised large questions, and this is the introduction of an old essay.

"Why should we die? Why should we, the flower of the living kingdom, lose our youthful bloom and go to seed? Why should we grow old in body and in mind, losing our various powers, first gradually, then all together in death? Until now, the answer has been simple, we should because we must. Aging, decay and death have been inevitable as necessary for us as for other animals and plants from whom we are distinguished in this matter only by awareness of this necessity. We know that that we are, as the poet says, like the leaves, the leaves that the wind scatters to the ground.

Recently, this necessity seems to become something of a question thanks to research into the phenomena of aging. Senescence, decay, and even our species-specific life span are now thought to be the result of biological processes that are, at least in part, genetically controlled, open to investigation, and in principle, subject to human intervention and possible control. Slowing the processes of aging could yield powers to retard senescence, to preserve youthfulness, and to prolong life greatly, perhaps indefinitely. Should these powers become available, whether to wither and why will become questions of the utmost seriousness."

And then I make a series of arguments as to why we should take these up even now, even though these are futuristic matters, and go on to point out that the prolongation of healthy and vigorous life, and ultimately perhaps even a victory of mortality was, perhaps, the central goal and meaning of the modern scientific project as articulated by its founders, men such as Bacon and Descartes.

Bacon it was who first called humankind to the conquest of nature for the relief of man's estate, and there's ample suggestion in Bacon's writings that he regarded mortality itself as that part of man's estate from which he most needs relief. Bacon himself engaged in immortality research, and may well have been its first martyr, sacrificing his life on the altar of longevity. He apparently contracted his fatal illness while performing freezing experiments on a chicken.

Descartes in the famous passage in Part 6 of the Discourse of Method, where he rejects the speculative philosophy of his predecessors in favor of a practical philosophy that would render ourselves as masters and possessors of nature, goes on to talk about the benefits of this new power, amongst which he says that we could be free of an infinitude of maladies, both of body and mind, and even also possibly of the infirmities of age if we had sufficient knowledge of their causes, and of all the remedies with which nature has provided us.

This is an old story, and it's been a dream not just of magicians and sorcerers, but even of the great founders of modern science. The success of the past century, which increased the average life expectancy at birth from 47 to 77 is a success that cannot be repeated, since that increase was largely due to the conquest of childhood diseases, sanitation and the like. But further increases in the potential human life span, as it's been pointed out in our readings, could not come from curing the specific diseases that now afflict us even in our old age, and the debilities of old age, the weakness, the brittleness, the decline in bodily and mental powers remain. Retardation of aging through understanding of the basic processes holds the key, if there is one, both to adding life to years, and of adding years to life.

This Council takes this up, not because we've been taken in by cryopreservation or by the vast arrays of creams and elixirs that are now being sold to a gullible population of retirees and aging baby-boomers, but because of the exciting new developments in the field of aging biology itself. Aging research might turn out to be the ultimate enhancer. Who knows? But in order to separate fact from fiction and to help us understand where this field is going and what it means, we're extremely fortunate to have two of the leading researchers and scholars in this area, people whose research is not only first rate, but who have taken pains to try to bring the meaning of this work to a larger public.

For the first session, we'll hear from Steven Austad, who's Professor in the Department of Biological Sciences at the University of Idaho, and the author of a book, Why We Age: What Science Is Discovering About The Body's Journey Through Life. And in the second session, to my left, Jay Olshansky who is the Professor in the School of Public Health, in the Division of Epidemiology and Biostatistics at the University of Illinois-Chicago, also connected with the Center on Aging at the University of Chicago, and a Fellow at the London School of Hygiene and Tropical Medicine. And with his colleague, Bruce Carnes, the author of The Quest For Immortality: Science At The Frontiers of Aging.

The procedure will be as usual. We'll have presentations from Professor Austad and discussion, we'll take a break, and we'll hear from Professor Olshansky. The floor is your's, and thank you very much both for joining us this morning.

SESSION 1: ADDING YEARS TO LIFE: CURRENT KNOWLEDGE AND FUTURE PROSPECTS

DR. AUSTAD: Thanks for the invitation. The Council suggested six questions that I should try to answer in my presentation, and I'm going to march through those in a fairly straightforward way, but I'd like to start off with a little bit about what I feel is the rationale for the effort to slow human aging. And this is largely taken from the similar reasoning in the paper by Dr. Miller that is included in your briefing booklet.

The goal of I would say most of us in this field is not really the prevention of death, but the preservation of health, and I think from that perspective that goal seems consistent with all of the disease-based biomedical research efforts that we're much more familiar with, the efforts to cure heart disease, Alzheimer's disease, et cetera.

The third point is that if we continue to increase longevity by the sort of disease-based advances, which we've become so good at making over the last century, that we could be facing a major social catastrophe, and I'll just give you one example of that. Neuroscientists and my friends in the Alzheimer's Disease community tell me that approximately 50 percent of people over the age of 85 have some sort of disabling dementia. Therefore, as more and more people, as a larger fraction of the population reaches this age, we could be faced with the possibility of a vastly expanding population of people who need 24 hour a day nursing care.

And the last point is that slowing aging is really a much more effective approach to preserving health, than is the treatment of individual diseases, and I'll give you the rationale for that in this slide here, which shows that these are major causes of death. And you can see that virtually all of them increase exponentially with age. And one of the consequences of the analyses that Jay Olshansky will, no doubt, talk about later, is that curing each of these individual diseases has a surprisingly small impact on life expectancy. But more important, curing one of those diseases does not take care of all of the other disabilities that may be associated with aging, because of other disabilities, such as chronic arthritis, the decline in sensory capacity. These things also increase exponentially in aging, getting rid of one cause at a time, basically leave people who may be alive, but may be very disabled. By slowing down the aging rate, we basically delay the onset and the progression of a whole host of mortal and debilitating diseases.

Now before I get into the questions proper, I would like to talk a little bit about the history of human longevity. From many months that I spent in remote parts of Papua, New Guinea, I got very interested in how long people lived in a state of nature, because when I looked around me there and talked to the people there, the population structure was remarkably young. So I've actually spent a number of years trying to compile the best information possible on how long people lived in the ancient past, and there's really basically two kinds of data.

There is evidence from preserved human remains, and some of this evidence is actually quite compelling; that is, it's based on large samples of well preserved skeletal evidence that's subject to the sorts of forensic analysis that the police often do. And the second is the evidence from the demography of modern hunter/gatherer populations. And I think when you put these two bits of information together, you come up with a relatively persuasive case, because the trends agree so much between these two sorts of evidence. So here are the best two data sets, I believe.

The first data set, Ohio, a thousand years ago, life expectancy was just under 20 years. That's the number in parenthesis there, and you can see, and we'll see a — I'll show a number of these. These are called "survival curves", and they simply represent the fraction of the population that's still alive at any time. And you can see through this Ohio population of Native Americans, and this is a sample of over 1,300 skeletons, that not only is the mean age at death 19.8, but really there are no deaths over the age of 60.

Now in reality, there were some remains that were estimated to be around 70 years of age. Those don't show up in this analysis, simply because they didn't feel confident enough of their estimates over the age of 55, and so they just lumped all of the estimates, but I'll just tell you the oldest estimate was 70 years of age.

The second bit comes from studies of the modern Yanomami, Native Americans from Southern Venezuela, Northern Brazil, which have been studied by groups at the University of Michigan since the early 1960s, and from interrogations of those people about their ancestors, as well as current demography, we come up with a reasonably similar estimate of a life expectancy of about 17 years. But here you'll notice that the extremes go out past 80 years. Now the actual oldest age reported among these several hundred Yanomami was in the mid-70s. However, due to the demographic modeling of the data, the expectation is that in a large population, some individuals live into their early 80s, so this is basically humans in a state of nature.

And to contrast this by where we've come now, I've put the same two curves up with a curve for males in 1900, and males in the year 2000. And you can see dramatic increases in longevity, more than a tripling of life expectancy, and clearly longer longevity at the extremes. And I think the extremes may be relevant to people's thinking on this issue; that is, I noticed in the briefing booklet that it said that modern humans in the extreme basically don't live any longer than our human ancestors, and there's simply no evidence to support that case. I think that we not only live longer on average, but live dramatically longer in the extremes, and I'll present a little bit of evidence on that in a second.

Now if we look at the bottom graph in this particular — this shows the probability of dying at any specific age, and the top curve is the curve for women in 1900, and the bottom curve is the curve for women basically today. And you'll notice that the enormous changes in life expectancy are mainly due to enormous changes in the mortality rate at ages prior to the age of 50. However, there are also reductions in the mortality rate straight throughout lifetime for as long as we have data, so even though the big changes were early in life, childhood and early adult mortality, there clearly have been reductions in mortality throughout life.

Now evidence that maximum longevity has increased over what I call archeological and historical time. There are indications from a variety of studies that humans in the state of nature never lived as long as 90, probably not as long as 80 years. Certainly, there have been a handful of modern hunter-gatherer studies and a whole variety of what are known as paleodemographic studies. None suggest anyone living as long as 90.

Prior to the turn of, I guess what's now two centuries ago, there was really no well-authenticated instance of anyone living to the age of 110 years. Now part of that is very likely the consequence of just simply bad documentation, but I think it's arguable that, in fact, it's also attributable to the fact that no one lived that long.

By the turn of the last century, there are approximately 250 well documented to have lived to be 110 years old or older. About 40 of these people are known to be alive now, and this is probably the edge of the wedge, because in places like China, we simply do not have the information. And the maximum longevity now, as of 1977, was Jeanne Calment who lived to be more than 122 years old, something that is statistical outlier even today, but clearly a new phenomenon in human history.

And finally, John Wilmouth, demographer at the University of California, has done quite extensive analyses of the very good Swedish demographic record. It's about 200 years old, and has noted that at least for the last 130 years there's been a steady increase in the maximum longevity, so humans clearly are living longer on average, and at the extreme today than they ever have. I don't believe anyone thinks this is a consequence of anything except a change in the hostility of the environment, improved public health measures, improved medical care. It's not a change in human biology.

So taking that as the introduction, I'll now march through the six questions I was asked to address. The first question was how do modern biologists understand the term "aging", and I've presented a couple of examples here. The one on the top is simply the world record running speeds for the 5,000 meter run. One of the things that you'll note is that not surprisingly, the fastest running speed is among people, as it was 100 years ago, in their 20s, and there's a gradual decline until late in life. And I like to point this out because these master athletes are probably the healthiest and the best conditioned people in their ages that you can find.

The bottom panel shows basically a decline in physiological function in a plethora of traits from nerve conduction velocity, to cardiac index, to maximum breathing capacity. And that list could be multiplied endlessly. The take home message is that aging is the gradual and progressive loss of function over time, beginning in early adulthood. It leads to decreased health and well-being, and an increasing incidence of death, disability I might say, as well as disease. So I think that that definition of aging, which is one that could have easily been made 30 years ago, stands as a reasonable introduction to the topic.

The second question I was asked to address was what happens physiologically as we age, and the basic underlying theme is that there is a generalized decline in what seem to be physiological control mechanisms. Let me give you a handful of examples. Cell population dynamics, we have certain cells in our bodies that are designed to die at appropriate times when they're genetically damaged, for instance. Well-preserved cell population dynamics means that a cell dies when it should.

We also have certain cells that need to replicate on schedule, and well-behaved cell population dynamics will have cells that replicate obediently when they should. However, that control, both in the control of cell replication, the control of cell death gradually deteriorates over time, and so we're led to results of declining repair capacities because our cells may not proliferate as well as they previously did, and also the development of cancers because cells reproduce when they should not.

Certainly, on a cellular level we are beset by huge changes in protein destruction, the proteins that make up the functioning parts of our cell really are designed to turn-over at a certain rate, to die and be rebuilt, be replaced by new proteins. And that rate slows down with aging, both the rate of the destruction of damaged proteins and the rate of replacement by new proteins. There's a generalized loss of hormonal regulation, that is the production of hormones and our body's ability to respond. There is increasing damage to what are known as permanent cells, cells that do not replace themselves over most of the course of the lifetime, and increasing damage to permanent cells is permanent damage. And those are just a few of the changes. I could go on, and on, and on, but I think it makes the point, that virtually everything that can go wrong, gradually does go wrong as we age.

Now are these various phenomena connected? Twenty years ago, I think the unanimous answer would have probably been no, because there's not any obvious connection, except for the case of reduced metabolism. If we sort of take all of the biological processes, that go on in an animal's body, and you slow them down, and you might expect that just because you've slowed them down in a synchronous fashion that they would be synchronous, and I give you an example here, which is how to slow aging in fruit flies. And it's very simple, you put them in the refrigerator. So if you decrease the temperature at which you keep fruit flies from 30 degrees to 18 degrees, you can actually increase their longevity by more than six-fold. I think this is a relatively trivial result, but yet I think it's something that we need to bear in mind when I talk about some of the really spectacular modern advances in increasing longevity, which is, it's this refrigerator effect that may be responsible for part of it, in which case, it's probably got less relevance to human aging than we might otherwise hope.

However, increasing empirical evidence suggests that all of these disparate processes that we had no theoretical reason to assume would be connected, they now appear to be connected. And I'll give you just two reasons why that seems to be the case. First is that simple environmental treatment, such as reducing food intake slows aging in laboratory animals. And when I talk about slowing aging, I'm not simply talking about making them live longer. I think it's easy for us to focus on increased longevity. It's a sort of shorthand, but it often stands, or it should stand for retarded aging. Quite often, we don't know if we've simply increased longevity, or if we've actually slowed aging rate. But in the case of reducing food intake, we have slowed aging in just about every way we can measure, in the rate of memory loss, rate of activity loss, the rate of immune system decline, a whole range of things that we had no reason to think would be synchronized previously.

And finally, the most astonishing, I'd say results, scientific results of the last 25 years, that it turns out that we can alter single genes in a genetically complex organism, and by doing so, increase longevity and preserve functionality to an amazing extent. And I'll talk about what exactly the genes do, and how amazing an extent this is a little bit later, so I think these things taken together, because there's more connection between all of these various processes than we ever had reason to think before.

Now I was asked to sort of describe some of the major branches of aging research, and I've tried to outline them in this diagram here. But let me say right off, it's no longer as easy to do this as it used to be, and that's because the tools of cellular and molecular biology have made all of these disparate fields fuse together. They really now, the techniques that are used for one are used in the other, and so this is more a theoretical construct, than an actual description of various sorts of research that goes on in laboratories.

But starting at the top, the top and going clock-wise, neuroendocrine mechanisms, cellular population dynamics which includes stem cells and telomeres, I'm assuming that this Committee has heard all that they need to hear about those issues, so I'm not going to talk about that.

Then there's organ-based investigations, which are really generally associated with specific diseases, and so I'm really going to focus on the fields that start at 6:00, and go until about 10:00, which is process-based investigations, genetic manipulations and caloric restriction. So there are large fields of aging that I'm not going to mention. I'll be glad to take questions about that, but I think I've got enough to cover just with the other information, so let's start off with caloric restriction.

This is simply reducing food intake. It's not the same as malnutrition. These experiments, usually care is taken to provide plenty of essential nutrients, but simply reduce the level of food intake to about 60 percent of that that animals would eat, if left to their own devices. It's been known since 1935 that it retards aging in many domains in rats and mice, basically, and lots of invertebrates now. That is, it really does affect activity, neurological decline, immune decline, just about everything that we can measure. It's by far the best described of the age retarding treatments because it's been studied for so long.

An important point is that it's not due simply to reduced metabolism. The animals that eat less become smaller, and if you calculate their metabolic rate per cell in their body, this is not the refrigerator effect. They're actually processing energy at just the same rate as the animals that are fully fed.

One of the striking things that you don't often read about these calorically restricted animals, is they have enormously increased spontaneous levels of activity; whereas, a young mouse might run a kilometer in a night, a caloric restricted mouse might run six or seven kilometers in a night. Whereas, a normal mouse would stop running at all by the age of eight months, these animals are still running several kilometers a night at the age of two years, so they're enormously different in terms of their activity. However, it's been well-documented that the retarded aging that we see in caloric restricted animals is not simply the affect of exercise. Exercise does something, but it doesn't do this. It does something different.

The other thing is that it's been very difficult to investigate because it changes so many things physiologically. Literally hundreds of changes in the body occur, at least in mice and rats, when you simply retard their food intake. However, the new technologies that have arisen in the last decade or so promise to facilitate our future understanding of this. And I think now that the prospect is in view, that we will really understand how this simple environmental treatment slows aging as dramatically as it does.

Of the process-based areas of research, I'm going to talk about one that has the most press, which is oxidative damage, and also probably has the most unanimity of agreement among scientists about its central importance, so just a couple of words of background.

There is indirect evidence from all sorts of sources that supports the view that oxygen-free radicals which damage basically every biological molecule, and which are produced as inevitable consequence of eating and breathing, cause gradual deterioration of lots of cells and tissue. Our bodies have all sorts of anti-oxidants that are produced by our cells that destroy many, but not all of these oxygen radicals, and is probably a slight imbalance between radical production and anti-oxidant activity that may modulate the impact of longevity enhancing treatment; such as, caloric restriction. It's not always that there is an increase in the activity of anti-oxidants, but we generally either find an increase in the activity of anti-oxidants, or a decrease in the production of oxygen radicals.

So now some research findings that I think bear on the importance of this issue. Of all of the genetic mutations that enhance longevity in worms, these small nematodes that are one of the models that biomedical researchers now rely on to investigate natural processes, one specific anti-oxidant seems to be critical for the effect of all of these. If you get rid of that particular anti-oxidant, you get rid of most of the effects.

There's also a study published a few years ago which showed that a synthetic anti-oxidant made by a private company, that was to combine the activities of several naturally occurring anti-oxidants, extended the life of these worms. If we genetically enhance anti-oxidant activity in fruit flies, it's well documented now that that extends their life. And we know that caloric restriction in mammals reduces the production of oxygen radicals.

And finally, long-lived mouse mutants, these are genetically altered mice that live up to 50 percent longer than standard mice, have enhanced anti-oxidant activity, so all of that suggests that oxidant production, oxygen radical production, anti-oxidant activity are keys to understanding this. However, despite the success with invertebrates, when we make mice that were genetically engineered the same way that the fruit flies have been engineered to live longer, they don't live longer. It hasn't worked, so there hasn't been a translation from the worm and the fruit fly biology to the mouse biology at least in this one domain.

But on the other hand, I'm going to describe an unpublished experiment that I have permission from the experimenters to talk about. Recently, where they've really done something that's not at all natural. They've manipulated anti-oxidant in an extremely novel way, and really have produced a mouse that lives longer because of enhanced anti-oxidant defenses.

Now the part of aging biology that has the most excitement currently is aging biology which is retarding aging by the identification of single gene mutations, very simple changes in the genetics of complex organisms that lead to enhanced longevity, and what has been looked at, increased function.

The significance of identifying these single gene alterations is that in doing so, it allows us to relatively precisely trace the biochemical pathways that are responsible for the change in the aging rate. The huge surprise — I used to say that we'll never find a single gene that changes aging rate in any organism that's composed of more than 1,000 cells. And the chief model in this, the worm is composed of 959 cells. That was why I said that. It turns out I was dreadfully mistaken about this. In those worms we now know of mutations in more than 50 single genes that lead to increased longevity, and they're just about thoroughly done with scavenging the genome, the worm genome which has about 19,000 genes. And it looks like ultimately there's going to be about 200 genes, changes of which in any one of them lead to increased longevity, so it's a dramatic number from my perspective.

It also turns out that we now know of six genes in mice that do the same thing; that is, an alteration in any one of these six genes extends life, and in mice we know preserves function quite dramatically. Now that sort of investigation has only just begun in mice. And I'm sure as that 50 to 200 genes are basically identified in mice, and are altered, that number will grow, as well. So an enormous number of simple genetic changes have led to increased longevity. The other thing is that the effects on longevity have been astonishingly large, and in a second I'll tell you exactly how large they have been.

And the final thing is that it would be easy to make the case that these are worms, these are fruit flies, these have been evolutionarily diverged from humans for more than a billion years, so what possible reason is there to assume that these changes have any relevance to humans? And that's clearly an open question, but there's at least some suggestive evidence that they might be highly relevant to humans. I'm going to give you a little Alphabet Soup here, and I want you to ignore it, but this one pathway which makes insulin in humans and makes our body respond to insulin, and also another molecule which is an insulin-like growth factor. In that particular biochemical pathway, there's enormous preservation of that pathway between worms and fruit flies and mammals, and what those letters mean is unimportant. What the important point is, that if you'll notice the asterisks there, those are points in this biochemical cascade where alterations lead to substantial increases in life, and so have alterations in similar genes, in organisms that have been diverged for a billion years or more, that all extend life. And that suggests that there, indeed, may be highly conserved general mechanisms, and that this may ultimately have relevance for humans.

So let's focus on the worms where the dramatic developments have really taken place. So how extraordinary has been longevity extension in worms? Worms have 100 million nucleotides in their genome approximately. If you change one of those, one of the letters, one of the 100 million letters of the genetic alphabet, you get a doubling of life span. If you change two of the letters, if you change one letter in one gene, one letter in another gene, you'll get a tripling of life span. We so far have nothing of this magnitude in mammals, not caloric restriction, not genetic mutations, nothing.

Another key feature is that these mutations are effective at increasing life span if they're only activated in the nerve cells. Now one of the reasons we work on these worms is because they're so well described. And when I say they're well described, here's how well. They have 959 cells in the adult animal that are not eggs or sperm, 302 of those are nerve cells, 131 cells have died during the course of development. I mean, we know this animal really, really well. And so if you only have these mutations affect the nerve cells, you get the same life extending effects.

The other thing is there are some differences. Basically, we don't see changes in the nerve cells, unlike ourselves where some of the most dramatic changes are nerve cells, the worms usually seem to die of changes in muscle pathology, so that suggests that there may not be certainly a one-to-one correlation between what happens there. There's no obvious nerve aging.

Now I think to place this in a context, you need to understand a little bit about worm biology, because it's very different than mammal biology. These worms are about the size of a comma in your briefing booklet there, so they're very tiny. They go through four larval stages, and then become adults and live a couple of — you can see the pictures of young worm and an old worm there. They tend to get superficial wrinkling as humans do, as well.

Now a key factor is that little diagram on the right there, which shows that they really go through this sort of time-out phase, a phase that you could think of as a hibernation phase. They don't become inactive, but they stop feeding, they start moving around a lot, and they basically stop aging for up to months. And they do that when basically they run out of food, and that's a very, very different sort of biology than humans have.

The other thing is when they're adults, they basically are having no cells that continue reproducing. And sharks do get cancer, unlike the book of the popular title, but worms don't get cancer. And that, again, makes their biology dramatically different than the biology of mammals. So one of the genes that's been most studied is this gene called daf-2, which is an insulin receptor. We have a very similar gene in humans. In fact, this gene is about 50 percent conserved in its sequence of amino acids that make it up with the human one.

A single nucleotide change doubles longevity, as you can see. Now most of the worms, just another aspect of their biology, most of them are hermaphrodites. They don't have males and females. They have male and female in the same organism, except about one out of 500 is a male. If we look at that same genetic mutation in males, we get more than a six-fold increase in longevity. Something on a scale of increase that I think nobody was prepared for.

What's more, if we compare some of the simpler mutations with feeding them less, we also get about a six-fold increase. In all of the experimental animals so far, we don't seem to be able to push much beyond a six-fold increase in longevity, but we've achieved a six-fold increase by several means. And mutations in this same gene in fruit flies and laboratory mice also lead to extended longevity, although not nearly so dramatically.

In mammals, and I think here we feel safer extrapolating from one mammal species, that is mice, to another, we know that among the four — the six genetic mutations are four that are all involved in this insulin pathway. If we take those mutants which are dwarfed mice, and we furthermore calorically restrict them, we increase their longevity by about 75 percent. This is the best we can do by mammals, but if you think about increasing human longevity by 75 percent, I think you realize we're talking about something really dramatic.

Now let me make a few points about these genes, because they get reported in the press as being uniformly good. Isn't this wonderful, but there are really some things you should know. Virtually all these genes reduce normal gene function; that is, nature has produced a gene that presumably has a utility and how we mainly extend life is by disabling those genes.

A consequence of that is that all of these genes really do have substantial side effects. They don't only increase vigor and increase longevity. Some of the common ones are either sterility or reduced fertility, and that's also true of the calorically restricted animals. Some actually decrease longevity in one sex, although it may increase it in the other sex. This is particularly true of some of the genes that have been reported to extend life in fruit flies. They almost all reduce body size. They increase susceptibility to cold, which is relevant in the real world presumably. They also reduce competitive ability; that is, if you take animals of the increased longevity-type and you put them in the same arena with normal animals, and you allow them to just reproduce as they will, pretty soon the longevity genes will disappear from that arena. And none of these genes has ever been identified in natural populations. These are not things that we get out of nature. These are things we create in the laboratory. They do well in the laboratory. They would probably not do well in nature.

Let me just give one unpublished example of a gene that I think is the sort of thing that we're going to see more and more of. This is one of the few genes, like I say, they're just a handful and increased longevity comes from an enhancement of a normal gene product, so this is a mouse that's been genetically engineered to over-produce a cellular anti-oxidant. Anti-oxidant called catalase. What makes it unique is that it's been directed. It usually is active in one part of the cell, it's been redirected to another part of the cell, this part of the cell that produces most of the oxygen radicals. And when you do that, we now have the first mammal ever where increased anti-oxidant activity increases longevity. There haven't been a lot of functional studies. We don't know if it's just longevity, or if it's a generalized retardation of aging, but we do know from looking at the animals that died, that the sorts of normal mouse heart pathology has decreased in these animals.

Now very quickly, the last two questions, will average American life span significantly increase in the future? Some of you may know that Jay Olshansky and I have a wager of about a half a billion dollars on this issue, so I'll present my biased impact. First of all, being a scientist, I never say anything that I can't take back, so I'll say it depends on what you mean. You can see I've been influenced by political events here. It depends on what you mean by significant.

I think in the near term using traditional medicine, I think Dr. Olshansky and I would agree that we will get a few additional years, whether it's going to be five, whether it's going to be ten, whether it's going to be three, I think we'll find out. Longer term as the sorts of therapies that I've been talking about that work in animals actually get extended to humans, and I think that some of them will end up being relevant. Many of them will not be, I think it's easily possible that we'll get a few additional decades of human life expectancy.

The second part is, depends on what you mean by a year. And let me just give you my best guess about this. I think the time horizon for anti-aging therapies is probably something on the order of 30 to 60 years from now; that is, anti-aging therapies that really do work, and really do work in humans.

The last question, are there hard physiological barriers on the maximum human life span? I will say we don't know, but I will show some animal data that I think suggests that there are not. Let's imagine this is a hypothetical animal survival curve, and this is some sort of extrinsic physiological barrier to life span. One possible way to ask this question is to say, what if we could increase animal longevity and bring it right up against that life span? You'd basically have a more square curve, because more animals would be dying closer and closer, and closer to whatever that intrinsic limit is.

Now over the past few years, there have been these caloric restriction experiments which, like I say, universally increase longevity, and we have actually a chance to compare curves that look like these two curves. And here are curves that are just from four of these studies, and if you look at the one in the upper left, it does sort of look like there might be a barrier; that is, the slope of that curve towards the end is really more steeply defined for the restricted animals. But if you look at some of the others, you'll see either no such trend, or you'll see that it even looks like there's a less steep slope, so I would say on the evidence of what we know about animals, we don't see hard fast barriers. And I would also suggest if we can change a single genetic letter out of 100 million and double the life span of an organism, it suggests there aren't hard barriers, as well. And that's all I have to say, and thanks for your attention, and love to discuss what I had to say.

CHAIRMAN KASS: Thank you very much. Could we get the lights so we can actually see each other. Thank you for a wonderfully clear and synoptic presentation. The floor is open for discussion. Dan Foster.

DR. FOSTER: Just one quick technical question. In the unpublished experiment on the catalase activation and the expression other than it's normal expression, was that to move it into mitochondria for the electron transport?

DR. AUSTAD: Yes.

CHAIRMAN KASS: Rebecca was it, Rebecca Dresser.

PROF. DRESSER: I was wondering if you could say a little bit more about how these animals die, animals that have had their longevity extended? At the very end, you were getting to that in your presentation and the readings. Most people say the idea is well, we don't want to just extend the life span, but we want to extend the high quality of life prior to death, so has anybody looked at — I guess the closest thing would be the mice, how they die? And I guess another concern would be something like dementia or other subtle effects of human aging that are of concern, and are things that most people dread, would be difficult to detect in animals. If we were — if our goal were to extend the human life span and make it of a high quality, and avoid the catastrophe you mentioned of dementia, how much of that could we learn from animals?

DR. AUSTAD: Well, okay. That is a very good question, so let's just focus on the calorically restricted rodents, because we know so much about those. Caloric restriction does two things. It gets rid of some diseases entirely, and it postpones others. From what we can tell — the other thing that pathologist, after pathologist, after pathologist tells me who's looked, who's done autopsies on these animals, about a third of them you find no pathology at all, so it's not clear why they died. It's not that they have lots of small things wrong with organisms, at least from what you can see at the level of the microscope. In a fair fraction of them, you see nothing whatsoever.

Given the fact that they maintain their activity to so late in life, it suggests that they're living really a highly functional life. Now in terms of dementia and whether we'd be able to see anything like that, there actually are ways of investigating this in mice. You know, and I think it's a pretty good investigation, because one of the things with Alzheimer's Disease, for instance, that's clear, is that there's a dramatic decline in spatial learning and memory, and that's very easy to kind of work out in mice. And when you do that, you do find a reduction in the rate of decline in spatial learning and memory, as well. So certainly it's not a perfect analog of what we would like to see in humans, but it does suggest that you really are pushing back neurological problems, as well.

CHAIRMAN KASS: Elizabeth Blackburn.

PROF. BLACKBURN: A related kind of question too, and perhaps either speaker could help me on this, in terms of the same question. But what do we know about it in terms of human clinical information? In other words, if we take those people who do, you know, quite naturally live longer lives versus those who have lived shorter lives, and look at the duration and intensity of their age-related diseases. Do we see that there's simply a postponement then producing the same spectrum and duration of age related diseases, in those individuals who have lived for a very long time, as opposed to those who have lived for a shorter time? Let's say, you know, 80 year old versus centenarians. Are there data about that question, which I think would answer Rebecca's question in part too.

DR. AUSTAD: Well, this is something that Jay probably has at his fingertips better than I do, but let me — my impression is that certainly people who live exceptionally long lives, let's say centenarians, really do seem to be protected from some diseases; for instance, cancer rates are much lower. Some things continue to increase as, you know, as old as people get, but some things do tend to just not occur in those people. Jay, do you want to —

DR. OLSHANSKY: Yeah. You'll see the same pathology in the extreme elderly than you will in the elderly. Everything is postponed. There's something very unusual about the centenarians and the super-centenarians. Somehow, whatever it is genetically that enables them to combat heart disease and cancer for 100 or 110 years is what makes them so unique. But in terms of pathology, you'll see pretty much the same things in the extreme elderly.

PROF. BLACKBURN: I was asking this because I think this is going to relate to the bigger question of, by postponing when life ends, is that going to change the medical burden, as one would say, to society, or simply move everything into the later stage? And I just didn't know if there's information that would suggest one way or the other. DR. AUSTAD: Yeah. That's actually been a highly controversial issue among demographers, and I'll defer to Jay to sort of answer this question.

DR. OLSHANSKY: Yeah. This issue about whether or not we are altering the expression of frailty and disability among the older population as we extend life is one that researchers have been attempting to get a handle on now for the past couple of decades. And I think initially, the belief was as we were extending life, we were making — we were increasing frailty and disability among the older population. Some of the more recent data by some researchers at Duke and elsewhere, suggests that we may be improving the health of the older population as a result of the extension of life. And I wasn't — I mean, I had a really nice figure. I wasn't going to present it, to illustrate that great caution in our effort to extend duration of life because of the very fear that Steven talked about at the beginning, if we push people out into an age window in the life span where the expression of frailty and disability is extraordinarily high, then we will face a scenario that we perhaps don't want to see, a trading off of longer life for worsening health, which is the motivation for research on aging, to postpone the frailty and disability into later ages.

DR. AUSTAD: If I could just add to that, I actually had an e-mail from some of these people at Duke last night with some of the latest information, saying you might want to present this tomorrow. So I didn't put it in my presentation, but I'll just say it's a continuation of this idea that we're actually decreasing frailty at specific ages, you know, fairly dramatically right now. And it's happening on a very small time scale; that is, the rate of decrease in frailty seems to have accelerated even since the early 1990s, so there's more stuff that's going to be coming out.

CHAIRMAN KASS: And this doesn't have to do with changing health habits and exercise?

DR. AUSTAD: Oh, it very probably does have to do with that. It probably has to do with increased medical surveillance and better treatment. Yeah, absolutely.

CHAIRMAN KASS: Janet Rowley.

PROF. BLACKBURN: Can I take advantage of my working mic to sneak in a question?

CHAIRMAN KASS: Janet, is it all right, we'll let Elizabeth go? Please.

PROF. BLACKBURN: Well, it was more a comment to enlarge on, I think your very appropriately cautionary note about saying that when you mess up longevity genes by dropping their function down a bit, and increasing longevity, one sees that there are costs to this. But I think it's interesting that some of the recent information from the worm has shown that there are clearly mutations which do increase longevity in those dramatic ways you described. And there is no measurable affect on sterility or ability to produce healthy progeny at all. So in a few cases, there is an uncoupling. Now I realize that there are many cases when there's not, but the point is that one can start to see, at least, a case where there is not an apparent cost by what's being thought to be the traditional linkage that sterility and fertility are problems that sometimes are the converse side of extension.

DR. AUSTAD: Sure. If I can just comment on that, I — that's only one of the side effects, the sterility/fertility.

PROF. BLACKBURN: Right.

DR. AUSTAD: There was another mutation that for years was known to be the cost-free mutation. And we found the cost of that as soon as we put the worms together with the normal worms, and found that they weren't — and that hasn't been done with this particular one, so we haven't found any cases where there's a cost-free addition to life yet, just because of inadequacy of the investigations to this point.

CHAIRMAN KASS: We have to take a pause for five seconds to get the system working, a moment of meditation. Janet, please. Janet Rowley.

DR. ROWLEY: I have several questions; one of which is fairly straightforward. I assume that the six genes that have been identified in the mouse are homologous to some of the genes that were found in the C. elegans?

DR. AUSTAD: Yes. Four of the genes are all part of the same pathway that was the original one that best describes C. elegans. The other two are different genes. They certainly have homologs in C.elegans, but I don't know what their effect is yet in C.elegans.

DR. ROWLEY: Well, the thing that astonished — well, the two other things that I think merit some comment, you said that the mice that were calorically restricted exercised more. Now I would have thought that that would actually increase the amount of free radicals, at least in muscle, so you think that that would be a deleterious effect. I also understand, of course, that exercise has its benefits, but overall I gather that the free radicals don't increase in calorically restricted mice.

DR. AUSTAD: No. Calorically restricted mice have been looked at in some detail in this, and originally people thought that there would be a sort of increase in all the anti-oxidants. That's turned up to be highly variable, some tissues yes, some tissues no, some anti-oxidants yes, some no. But what's universally the case is that if you look at free radical production, it's decreased in these, even though they're exercising a lot.

DR. ROWLEY: Okay. And the last question that I have relates to your statement, and I may have misunderstood it, about the mutations and you needed mutations only in nerve cells to get this increased longevity, so that all the other cells in the body either don't have this mutation, or it's not active in those cells. So what's so special about having it in nerve cells? It seems to have a generalized effect.

DR. AUSTAD: Well, this is in the worm now, C.elegans.

DR. ROWLEY: Right.

DR. AUSTAD: It's probably basically because it improves coordination of all processes throughout the bodies through hormones. I mean, the guess is that this is a so-called neuro-endocrine effect, because they've done it exactly that way, if you only allow these genes to be turned on in the nerve cells. And this was not anything that an a priori prediction. It was just an empirical and somewhat surprising finding, I would say.

DR. ROWLEY: And is it the Sir-2 gene or related to it, or is it different?

DR. AUSTAD: These were daf-2 genes.

DR. ROWLEY: Daf-2.

CHAIRMAN KASS: Michael Sandel.

PROF. SANDEL: I want to make sure I understand something you said early in your talk. In the briefing papers that frame the part of the discussion later on the ethical and social implications of this, a contrast is drawn between enabling more people to reach the natural limits of life, and pushing back those limits; that is, increasing the maximum human life span. As I understood you, over the course of human history, both of these things have dramatically changed. Is that correct?

DR. AUSTAD: Yes. Both of them have dramatically changed, but the implication is not that there's been a change in the biology of humans, but simply latent possibility for longer lives has been revealed by basically a friendlier environment.

CHAIRMAN KASS: Frank Fukuyama.

PROF. FUKUYAMA: You haven't said anything about the body of theory that comes out of evolutionary biology on aging, and I understand there — I mean, that's less well-established, and there are a lot of controversies about, you know, why you have post menopausal women and so forth, but out of that body of theory, is there, you know, a consensus, for example, about why human life spans, you know, are what they are, compared to other species, what adaptive significance that had and so forth?

DR. AUSTAD: Oh, I'm so delighted you asked. This is really my specialty, and that body of theory is actually extremely well-supported by a huge mass of empirical evidence. And the basic idea is that the less one is subject to extrinsic hazards, to environmental dangers, the greater will be the selection for maintenance of the body. And this makes a whole variety of predictions, not the least of which is that when you create a safer environment, as we have done for ourselves over the last thousand years or so, that ultimately, you're going to get the evolution of a longer life span. So even without any medical advances, all the empirical evidence suggests that over the next 25 or 30 generations, humans will biologically live longer. Our limits where they are will be increased, because of this evolutionary theory, that's its prediction, but it's also been validated by exactly those sorts of experiments in the laboratory, really dozens of times in fruit flies.

And also another thing that we predict is that there may be things that age more successfully than humans, and that's clearly the case. There are things that manage their oxygen radicals much better than humans do. And one branch of research that I didn't talk about, because it happens to be my own branch of research, has to do with understanding how those animals that do it better, do it.

PROF. FUKUYAMA: Just as a follow-up question, I mean, is there a theory about why humans live as long as they do compared to other species?

DR. AUSTAD: Yeah, the idea is that basically a combination of their social environment and their intelligence has allowed them to avoid a lot of environmental dangers that other animals — primates as a whole are a long-lived mammal, and they're a long-lived mammal it's thought because they're exceptionally intelligent, and they're exceptionally social. And those two things together will allow them to avoid a whole host of environmental dangers that let's say small things that creep around in the dark would not be able to avoid. And the best evidence for this sort of reduction of extrinsic mortality probably comes from the fact that animals that fly, whether they're birds, or whether they're bats, are exceptionally long-lived for their body size in all examples. For instance, a little brown bat that's a fraction of the size of the mouse has been reported to live over 34 years in the wild, something that is absolutely unheard of in non-flying mammals.

CHAIRMAN KASS: Gil Meilaender.

PROF. MEILAENDER: I don't know if this — I mean, my question really I think is whether what I'm about to ask makes sense. You could picture at some point farther down the road two kinds of possibilities. One, that nobody ever died from some sort of sudden pathological problem, but just wore out eventually, or alternatively, you could picture a future in which nobody ever really wore out, but there were still sort of medical crises that caused people to die.

Is it conceive — can we actually separate those two. Are the two related in such a way that it makes sense to think about those as possible futures or, in fact, however we extend longevity, do some people die? Will some people die by wearing out, and some people die because of some — even though they're not worn out, because of some sudden crisis?

DR. AUSTAD: The way I interpret your question, I think you're basically saying will we be able to slow aging, or will we will able to stop aging? And there's certainly no work in any animals that suggest that we're anywhere close to stopping aging in any organism at this point.

We've learned how to slow it dramatically, and what we're doing there is we're basically the animals are still wearing out. They're just wearing out at a slower rate.

PROF. MEILAENDER: So you wouldn't picture a future in which, however we died, we all died sort of in the pink of health.

DR. AUSTAD: That would be the ideal, certainly. And this is one of the things that the demographers have been arguing about, as we are living longer and longer, are we really compressing the period of ill-health or not, or are we simply just moving it back? And like I say, that's a controversial issue, and I bet that Jay was going to cover that in his talk anyway.

CHAIRMAN KASS: Paul McHugh, and then I'll put myself in the queue.

DR. McHUGH: I found it fascinating what you were saying, but all the things that you talked about, everything you showed was steadily declining as we grew older. And you showed that in animals, as well as in human beings. But, you know, some things get better with human beings as they get older. They get smarter. They don't run 5,000 meters any more. They walk. And they write better poetry probably, they do a number of things better when they're old than when they're young.

What is the development in your work and in your study of human beings that would begin to emphasize these healthy sides of aging, or these good sides of aging? Perhaps this is not appropriate to ask you, but this comes up a lot in psychiatry, particularly a psychiatry of meaning is always ready towards any discouragement in old people as, you know, this is what happens when you get old. I remember these discussions quite vividly when I first began in geriatric psychiatry, and I would say, you know, this person is depressed. She needs some help, and I would get back wise remarks about well, don't you understand what it's like to be old, Paul? You will understand it some day. You lose everything. You grieve, you give up your functions. And I said, well, why don't we give this person a little medicine, and then they became more like old people who are happy, and who are engaged in things, who are politically alert, and have wisdom.

Where in this research is going to come these things which fundamentally for me, anyway, if there's going to be a discussion about longevity, it's these things that are wanting to be preserved, not necessarily for me, but for the people I love, and for the people I cherish, and people whose gifts to my life I would like to preserve?

DR. AUSTAD: Yes. There is a concept called successful aging that makes biologists very uneasy, because like I say, there are dozens and dozens of things that all decline. And when I talk about aging, people often say well, that's so discouraging. Does everything decline? And I say no, everything does not decline. There are certain things like, you know, density of facial wrinkles, that goes up, but actually, one of the things that does increase, and you mentioned it, is wisdom. Sort of raw measures of mental function clearly decline, but there are things that if appropriately measured, like wisdom, the ability to see multiple solutions simultaneously that increase. And I would agree that that's incredibly important for the human condition, but it's something as basically an experimental biologist, that's very hard to assess in animals, and so I usually don't talk about it, but that's very clearly the case. And one of the things about preserving mental function is that that would be an important aspect of it.

Certainly, when I worked in New Guinea among, you know, very remote areas, the elderly people in those areas are treasured as a source of information. In fact, I went in to some areas that no one had been into for decades, only because the elderly people in the village still knew how to get there, so you're absolutely right. It's important. It's hard to talk about though in animals, which is my specialty.

PROF. SANDEL: It's probably hard to know whether those fruit flies in the refrigerator are growing wisdom.

DR. AUSTAD: Yeah, exactly.

CHAIRMAN KASS: A comment, and then a question. First of all, I would at least like to register as a question whether our immediate intuition that it would be absolutely best to go in the pink of health is, in fact, correct, and whether or not — we talked about this a bit last time, and whether death would become simply intolerable if all of us were whisked away without any kind of anticipatory decline. And one certainly couldn't comfort the survivors to say that someone was released from their decline. That's the philosophical and ethical question for reflection and discussion.

I take it that unlike Dr. Olshansky, if I understand his writings correctly, you seem to be suggesting that there is some — that there really is some kind of genetically determined species-specific life span, at least that this isn't just somehow the accumulation of post reproductive errors, but that the genetic results seem to suggest that there's some kind of switches that control something like what is the built-in possibility.

Second, you seem to say — you said that we don't find any of these mutations in nature, which would suggest that they would be disadvantageous. If these are indeed somehow connected to longevity, they're disadvantageous. An the third thing you said was there seems to be some retardation of reproductive prowess and decreased competitiveness. It's my sloppy language, you were more precise.

This question has to do with the connection between longevity and fertility, and the way in which — what the implications might be if these things were really deeply linked, that thinking about altering the genes that would produce greater longevity would not just biologically, but perhaps even also culturally, separate question, decouple these things, or at least produce a kind of premium on long-lived, non-childbearing creatures. So forget the editorializing and deal with the biology. Is there some kind of — how do you explain the fact that some of these things don't crop up? You could say that there would be no selective advantage, perhaps, but there seems to be a selective disadvantage for the appearance of these things. And does that have something to do with the fact that to make the world safe for progeny, the old ones have to die?

DR. AUSTAD: To this last point, I would say yes and no. I think clearly these things are — would be disadvantageous in the state of nature, either because of their affect on fertility or their affect on developmental rate, or their affect on competitive ability. For instance, we know in the worm that it's the ability to come out of this dauer phase that's slowed down, so I think for every one of these would be disadvantageous in nature, and that's why we don't see it. The question is, do we live in a state of nature in which something that changed, that for instance, might influence our fertility substantially. Let's just imagine that we knew how to slow it, we had a pill, that if we took the pill that would make our fertility much, much lower than it is. We could simply choose to take that pill later in life, presumably. In the calorically restricted animals you still get an effect if you start the caloric restriction later in life. Now passed a certain point, you don't, and you get a smaller effect. But this impact on reproduction seems to be important, but not critical. There do seem to be instances where you can tease them apart. For instance, if you look at a mouse that's a year old, in which case they're pretty much post reproductive, you start it on caloric restriction, you still get a small effect.

The philosophical question about whether it's best to go in the pink of health is a very interesting one. I think there's a quote from Montaigne I think in your book about that. That is something I hadn't ever thought of before, but I thought was a point worth pondering.

CHAIRMAN KASS: Thanks. Bill Hurlbut.

DR. HURLBUT: Just a tiny footnote. I mean, in addition to Paul McHugh's comment about the question of wisdom, some of the benefits of the aging process, it also seems to me that the question of the link of this to reproduction means that to take simply a medical and health-related view to this, and not to see its implications for the relation amongst the generations is also, I think, a limitation on the perspective. I'm not accusing anybody here of taking that, but I think it has to be added. Bill Hurlbut.

DR. HURLBUT: I want to ask you a little bit about some of the implicit assumptions that are going into your projection here. When I think about the models that you're studying like C.elegans or in some other cases fruit flies, I'm very struck right away by how human beings are not the equivalent of just big fruit flies or long living roundworms. And I wonder specifically in those models, for one, they may have been selected for study because they have tight genetic controls, and therefore, are more determined organisms, perhaps. And also, in the case of roundworms, the adult form, at least is a post-mitotic existence, no more cell divisions which changes the scene a lot. And so what I'm wondering is, you spoke of the conserved genes that connect human beings to fruit flies as being, what I think your statement was 50 percent conserved, which means there's a lot that's not conserved.

And I'm wondering given the — notwithstanding some of the evolutionary arguments for why species have this reproductive growth, longevity ratio and so forth, I can see reasons to suggest that human beings are, as a species and as individuals in that species have benefits to longevity, such as the wisdom you spoke of, and there's some evidence in macaque monkeys that the troops with longer-lived members survived better, so is it possible that we've actually already been selected for these mutations, if you will, of longevity. And that, in fact, human beings already represent the genetic form that will allow their maximal or some degree of maximal longevity? You see what I mean?

DR. AUSTAD: Yeah, I do, and I think they're good points. And certainly, humans are not big worms or big fruit flies. And I think we deserve to be skeptical about the translation of those results. And my guess is that most of those results, those 50 plus genes that we already know of, are going to have no relevance to the mammalian case. However, we do know these genes that do similar things in mice, and it strikes me that that offers more hope of extrapolation.

In terms of whether humans have kind of already maxed out what you can do as a mammal, that's an interesting case. And it's basically the issue under whether we can learn anything about human aging from studying animals that by definition are very unsuccessful at aging. Here we are. You know, we live decades in states of high fitness, so what can we learn from something that lives a few weeks? And I think that's again an important caveat, and it's one of the reasons that there's now movement afoot to look at animals that really are more successful at managing some of the damaging processes. And let me just give you an example from my own work.

I work on birds, and I'm looking at basically anti-oxidant capacities of birds. And the reason I'm interested in them, if you calculate the amount of oxygen they process per cell in a lifetime, birds process anywhere from three to five times more oxygen per cell per lifetime than humans do, so they do something better than we do, so it's an alternative approach. I think it's appropriate to be cautious about interpreting extending life in very short-lived things to extending life in humans. I perfectly agree.

CHAIRMAN KASS: Questions, comments? Alfonso Gomez-Lobo.

DR. GÓMEZ-LOBO: I have an information question. Are there species that have a longer longevity than human beings? I mean, how many, and what would they be? I mean, where do we stand in the scale of things? Are we at the upper end, or we in the middle.

DR. AUSTAD: Well, we're towards the top. It depends on how widely you cast your net. If you cast it into the plant kingdom, then we're not up near the top. But if you focus on animals, we are — certainly one animal that's recently come to life that's much longer-lived is bowhead whales, of all things, where recent evidence suggests that they live more than 200 years. That evidence is indirect. It's biochemical analyses, but it's supported by the fact that bowhead whales that have died recently have been found with traditional hunting implements that have not been in use among the Inuit for more than a century, so suggests that they really do live, you know, upwards of several centuries.

CHAIRMAN KASS: Tortoises.

DR. AUSTAD: Tortoises are also longer-lived, yeah. I mean, there are these things. There are mollusks that have been documented over 200 years. There's a rough-eyed rockfish, don't eat these, that's been documented 205 years, so there are other animals. Ourselves and the whales are exceptional because we're warm blooded, we have this high metabolic rate that we don't have the option of turning off when we feel like it, so that's why I focused on those.

CHAIRMAN KASS: Janet Rowley.

DR. ROWLEY: I'd like to come back to your comments about the fact that because of the complexity and going back to the caloric restriction model, though I wouldn't limit your answer to just that, that we now seem to be on the verge of either having new insights or new techniques, which in the future is going to sort out some of the reasons that caloric restriction leads to longevity, and therefore by implication may be applicable to other kinds of systems. So would you — firstly, what are the new things that you see on the horizon in your own field? And would you speculate on how some of the new discoveries might be applied in the future?

DR. AUSTAD: Sure. Let me just give you one example of how we can start to investigate this. There have been dozens and dozen of hypotheses about why caloric restrictions works. It's been virtually impossible to disentangle those, but now there are ways to do it. For instance, one of the hypotheses has had to do with the stress response, and the fact that stress is mildly elevated in these animals, and that moderate levels of stress might be good for you. You know, that's a controversial hypothesis, but yet it's been a hypothesis that's been around a while.

There are now ways to genetically engineer mice so that they cannot have that moderate elevation of stress, and so you can genetically engineer them, and you can see does that mimic the affects of caloric restriction, and find out either that hypothesis is supported or it's not. And so that's one sort of thing, is that you can start testing one hypothesis at a time.

DR. ROWLEY: And what kind of stress is being particularly implicated, I mean because there are all sorts.

DR. AUSTAD: Right. My guess would be food stress, you know, for anyone who's dieted involuntarily, but it's simply to measure it by looking at elevations in stress hormones. It hasn't been specifically identified as to what the source of the stress is, but it's hard to imagine that it's not food, especially if you deal with these animals. Because when you walk in to feed them, you know, they're doing pull-ups on the cage, you know, waiting for their food, so my guess is that that's —

DR. ROWLEY: That's specific hormones.

DR. AUSTAD: Yeah, that's — so specific hormones, you know, it's easy to test those sorts of hypotheses. Now the other thing is with the DNA microtechnology, it's going to be easier to sort of find out are there other genetic signatures for enhanced longevity. And we do the same thing when we change a gene, as when we calorically restrict animals, so I think those things are — you know, it doesn't make the problem trivial, but I think it makes the problem more tractable than it's ever been before.

CHAIRMAN KASS: Bill May.

DR. MAY: I'm not sure you want to respond to this, but as I understood the exchange between you and Leon earlier, it was a reference to Montaigne, and the whole question whether if one improves health towards the end of life, one tends to increase the sting of death, or whether the process of aging and the sense that one is moving into the twilight, and there are increased burdens right there in the body make one readier to accept one's end. I think that's the discussion that was going on. And I must say, not simply reporting personally, but I think there's a sense of readiness to accept death that doesn't relate to the sense that the twilight is here, and burdens have been increased. But also the sense of having completed one's life, and that may or may not relate to increased burdens and woe of one kind or another. But the curious things for us as human beings, what is it that produces a sense of completion? And in the setting of survival as the aim, one would say that the next generation is born and is now, as it were, on its feet, and so one has completed one's task.

But as life extends beyond the 40 and 50 years, on up to the 80 or 90 years, there's a disconnect between the event of the next generation being on its feet, and the actual life that we go on to live. And we are forced to explore different senses of what it means to have completed one's life, than simply having sustained the next generation to the point that it stands on its own feet. And it relates to the whole question whether the sense of end in human life relates simply to survival, or to other dimensions of flourishing and excellence that are different from the aim of the surviving of the fittest.

CHAIRMAN KASS: Now if I might in a way piggyback on that too, and I didn't mean to interfere with your wish to respond. If one is talking about — I mean, the main interest of this research, as I understand it, is not adding years to life, but adding life to years, and dealing with the infirmities and the debilities that afflict us. Though it looks as if the solution to the second might actually produce increments of the first, and that these two things might very well be linked.

And one of the things that's being changed in the process is one no longer thinks — one will no longer think of a life having a built-in shape somehow related to the length of a generation unless, of course, the generation now becomes 40 years because of delayed reproduction and the like. And, therefore, it's — the question of what it really means to have a complete life, when the boundary is moveable, is no longer somehow given by the life cycle, but has to be created. And that's a problem for which the increases of the life expectancy of the past century have already, I think, given us some indication. Where in Western Europe anyhow, initially would be the extreme example, where the birth rate is down to 1.2 children per women for lifetime, that means half the women in Italy are not having any children at all, and therefore, the account of what a complete life for them will be has nothing to do with producing children who reach maturity. It has nothing to do with producing children at all, so there are — these changes in the life span have profound sort of cultural changes, and the perception of one's own course of life is somehow altered.

I'm not pronouncing good, bad or indifferent, but these are — there are big changes that have nothing to do with, or that are independent really of the question of dealing with the infirmities that one would certainly welcome being relieved of. Please.

DR. AUSTAD: Yeah, I was — my original response was these are very interesting philosophical issues, and my role as a scientist gives me no special insight, and I understand that. However, in response to what you said, I was just last week in England talking with a British demographer about fertility patterns in Britain, and it turns out that during times of plague and times of economic depression over the last 1,500 years in Britain, there have been periods of time when half of the women chose not to reproduce because of external events, so I'm not sure it's necessarily just linked to disorientation from this length in life. It seems to be at least arguable, maybe not.

CHAIRMAN KASS: The time has come for a break. Let's take 15 minutes. We'll reconvene and hear from Dr. Olshansky. Thank you very much. It was wonderful.

(Off the record 10:35 - 10:51 a.m.)

SESSION 2: DURATION OF LIFE: IS THERE A BIOLOGICAL WARRANTY PERIOD?

CHAIRMAN KASS: Can we get started, please? Council Members should have at their seats now a map of where we're meeting this evening for dinner. It's just a block away from the hotel, straight north on 7the Street, and information is there. Again to repeat, warm welcome to Professor Jay Olshansky, who's going to give us the second presentation on the subject of aging research and its implications. Please.

DR. OLSHANSKY: Well, first of all, I want to thank you for inviting me. I think you're going to discover that Steve and I really don't disagree on too many things, but we'll disagree on a couple. And I'm also delighted to hear that there are students in the audience. I feel very much at home with the students in the audience, so it's wonderful that you're here, and I will be speaking to you to some extent.

Now I know the title is, "Duration of Life: Is there a Biological Warranty Period?" That's related to some work that my colleagues and I have done recently, but it will all relate to this basic issue that you have raised in this meeting.

Now these are the questions you have asked me to address, and I'm going to address them all. I'm going to address some a little bit more than others, the issue of life expectancy, first and foremost. I'll spend a bit more time on that, the hard physiological barriers. I'll spend some time on that. Demographic implications of life extension, a bit less. Breakthroughs, and then the position statement on human aging that we published during the summer, I will be discussing this.

Now let's start out with definitions first. I think it's really important that our language be correct, we use the proper language when we discuss these issues, so I'll start out with some basic definitions. Life span is defined as the verified age of death of an individual, which ranges, of course, anywhere from moments after a live birth to the world's record for longevity, in this case I'm showing you a picture of Madame Jeanne Calment, who lived for 122 and a half years. So the life span is the duration of life of an individual.

Maximum life span is the longest life span ever recorded for a species, so again Madame Jeanne Calment would be the maximum life span for humans, but it is one individual in a species, longest lived individual, and this number can only increase.

Life expectancy is - and I'll be showing you an image of this in a moment, it's the average number of years of life remaining for individuals at a given age, assuming that age-specific mortality risks from a life table remain unchanged, and what we refer to as period life expectancy is what's most commonly used. A bit more on that in a moment, because you did ask me to tell you briefly how it's calculated, and actually it's pretty important to understanding the prospective changes in life expectancy.

All right. What life expectancy is not, and this is what you will see often reported in various places. The incorrect definition is the average age at death. It is not the average age at death. Indeed, it is a number that is based on death rates observed for a population, and applied to a hypothetical cohort of 100,000 babies. And I'll show you what a life table is. How is it calculated? All right. So I know — I'm not going to go through this, of course, but I figure you should at least see a life table, and see what it looks like, because this is the basis for the measure of life expectancy.

Now what I did in the next figure — incidentally, by the way, I finally found another use for my dissertation which was published in 1984, because this figure comes out of my 1984 dissertation. It was sitting next to me when I was drafting this, so I scanned this, and here's the second use. This is a truncated version of the same table, and I just want to illustrate a couple of things here.

First of all, this column here, this M(x) represents death rates or condition of probability of death over here, and this L(x) represents this hypothetical cohort of 100,000 babies. And you basically apply the death rates to the babies. You generate a number of deaths, and then you subtract it from that to get down to the next age group. Basically, the measure of life expectancy itself is based on something known as person years of life. When an individual lives one year, that's one person. For a hypothetical cohort of 100,000, we estimate the number of person years expected to live. You divide it by 100,000, and that's your measure of life expectancy, so this cohort of 100,000 people, babies born in a given year would live this many person years. You divide it by 100,000, and that's how you arrive at this number, so it is not an average age at death. It is a hypothetical number, and the critical assumption to remember about life expectancy is the underlying premise that we assume that the death rate is observed in a given year, the year in which you're measuring life expectancy will not change for the duration of the lives of the babies born in that year. So, for example, for white female babies born in 1978, the presumption is that when they reach the age of five, that will be their observed death rate.

Well, under conditions of declining mortality, as you might imagine, this will under-estimate the observed life expectancy of these individuals. And just as a way to illustrate, we've actually been able to calculate what's known as a cohort life expectancy for the babies born in 1900 in the United States based on how long they actually lived. And when you compare the cohort life expectancy to the period life expectancy, the difference is about two and a half to three years, so it really wasn't that large in terms of — I mean it's not 20 years. It's relatively small in terms of magnitude, but there is a difference, just so you know.

Finally, aging versus senescence. When you think of — the word "aging", I know is used most often, but biologists tend to use the concept of senescence to describe what's really happening. Aging, we tend to think of, at least I tend to think of anyway, more as the passage of chronological time, so we all age at exactly the same rate. But we can senesce or grow old biologically at different rates, and this is a classic example of two genetically identical twins, who appear. This one on the left has Alzheimer's Disease, this one does not, as a way to illustrate that even among genetically identical organisms as a result of stochastic random events that occur, stochastic events that occur during the course of life, we can senesce at different rates.

All right. Why do we live as long as we do today? What led to this first longevity revolution? Why is life expectancy now up in the high 70s in humans? Well, this is — it's actually fairly straightforward to explain this. For the vast majority of human existence, birth rates and death rates were always extremely high, about 50 per thousand population. Right around 1850, death rates began to decline very rapidly. Birth rates then followed until we reach this point today, which is referred to by many as the fourth stage of the epidemiologic transition where birth rates and death rates are extremely low, about eight to ten per thousand. And this is the reason both why we have population aging, and individual aging. It's a transformation that occurred principally within the last 150 years or so.

One of the consequences of that dramatic difference in birth rates and death rates, we all know is global population growth, one of the areas, one of the reasons why I came into this field to begin with, but we also have dramatic population aging. This is referred to as an aging pyramid. It's nothing more than a snapshot picture of the number of people alive at any given age, in a given time period. This is for the entire human population in 1900. It was pyramidal. This is fairly common that you see among most forms of life, a large number of young, and a very few make it out to extreme old ages. And now in the developed world, we have created a much more tectilinear or square like age structure where it is looking — it's no longer pyramidal. You don't really see this anywhere in animals living in the wild. It's really unique only among human laboratory animals, zoo animals. That's about it.

So why did life expectancy rise so dramatically during the course of the 20th century? Well, if you remember that hypothetical cohort of 100,000 babies that I was talking about before, if you plot out the ages at which they all died based on the death rates observed in a given year, you would get something referred to as a distribution of death. It was the D(x) column of that life table. And if you plot them all out, you get something that looks like this. The area under the curve is the same. This is the distribution of death for U.S. females in 1900. This is the distribution of death for U.S. females in 1985. It is a classic illustration of a redistribution of death from the young to the old.

In other words, the vast majority of this increase in life expectancy from 47 to about 77 through 80 now for females in the United States, is a result of declines in infant, child and maternal mortality. That can only be achieved once for a population. Once it is then achieved, the only way to achieve another increase in life expectancy like that is to influence the elderly. It's a totally different ball game.

I decided to show you this figure to illustrate changes that have occurred in these various parameters. This is just based on U.S. data. Maximum life span based on U.S. data appears to have increased a little bit. I know that there was mention earlier of dramatic increases in maximum life span. I really disagree. I don't think there have been dramatic increases. There have been fairly moderate increases, and I'm not even sure if there have been increases, quite frankly, because we can't really measure the age of everyone on earth. And so it's possible that a thousand years ago we may have had people over 100. I don't know that for certain.

Modal age at death has increased from 73 to 88. Period life expectancy increased from 49 to about 80. This is just for U.S. females, just to give you an illustration of how these numbers have changed as a result of this transformation in the distribution of death.

This figure illustrates the proportion of the gain in life expectancy associated with changes in death rates at different ages. Again, it's a classic illustration, 1900 to 1910. The majority of the gain in life expectancy was associated with declines in mortality at younger ages. And now between 1990 and 2000, the majority of the gain in life expectancy is associated with the population over the age of 45.

All right. Years ago, my colleagues and I published this article estimating the upper limits to human longevity at about 85, and when we published this article, a number of people disagreed with us very openly, saying no, no, no. Things are going to go much, much higher than you anticipate. Our projected life expectancy at 85 was 88 for females and 82 for males. And it will be evident to you why we came to that conclusion, and then we followed that up with a piece ten years later. What we decided to do was to wait ten years to see whether or not the data were moving in the direction that we had predicted, or whether the data were moving in the direction as others had predicted, which was a much more rapid pace than what we had suggested. And we published our findings last year, which I'll go through very briefly in a moment.

Now previous estimates of the upper limits to human life expectancy have all relied on efforts to answer a single question, and that is, how low can death rates decline. We reversed the question. We refer to it as reversed engineering approach, and instead asked how low do death rates have to decline in order to achieve a life expectancy of anywhere from 80 to 120 years. Fundamentally different approach, and this was the conclusion that we came to. This is one of the figures from our original 1990 article.

Now it's life expectancy at birth on the (X) axis, and percentage reduction in mortality on the (Y) axis required to produce these higher life expectancies. So for example, in 1985 female life expectancy at birth was 78.3, 71.2 for males. In order to achieve a life expectancy at birth of 85, you simply go up the axis and go over. You could see it would require about a 50 percent deduction in all causes of death for females, and roughly a 70 to 75 percent reduction in all causes of death for males, just to get life expectancy up to five.

Now to provide some perspective, we calculated hypothetically what would occur with the elimination of various diseases, major fatal diseases in the population, and the vast majority of all humans die from heart disease, cancer and stroke. And we show here that if, indeed, we were to find a cure for cancer, for example, life expectancy at birth would rise by about three and a half years. Life expectancy at birth would also rise by about the same amount, three to three and a half years if systemic heart disease was hypothetically eliminated. And if we eliminated all cardiovascular diseases, Diabetes and all forms of cancer combined, life expectancy at birth in humans would rise up to about 90. So you have to believe that we will be experiencing rather dramatic reductions in mortality in order to yield these very high life expectancies. A life expectancy of 100 required about 85 percent reductions in all causes of death at every age, so when somebody says life expectancy is going to go to 100, this has to happen in order for life expectancy to go to 100. An 85 percent reduction in mortality at every age, which is the reason why we didn't believe it was possible or likely.

We then followed this up with research ten years later. We used data from three of the longest lived populations, the United States, France and Japan. Indeed, as we had anticipated, there was not a dramatic change in the probability of experiencing these much higher life expectancies, even though there were changes in life expectancies during this time period. We did experience eight-tenths of one year increase in life expectancy at birth for females. I have some other figures that illustrate this better actually.

One of the claims that was made by those who were predicting much higher life expectancies was that death rates would decline at 2 percent at every age for every year for the next 100 years. Well, that's a testable hypothesis, of course, so we took a look at the data to determine whether or not during those first ten years following that prediction, whether death rates would decline by that magnitude. And for the United States, we found if you look at the age group from zero to 99, the magnitude of the reduction was only four-tenths of one year, not — four-tenths of a percent, not 2 percent as had been predicted by those anticipating much higher life expectancy.

Interesting to point out, there were some increases in death rates in some age groups in the United States between 1985 and 1995. There have been some large reductions in death rates in France and Japan. They are not at 2 percent, but they are significant still.

Another way to illustrate this issue of difficulty in raising life expectancy, life expectancy on the X axis, percentage reduction in mortality required to raise life expectancy at birth by one year. So, for example, when life expectancy at birth is 50, it takes about a 4 percent reduction in death rates at every age to raise it to 51. When life expectancy gets up to 80, it takes about a 9 and a half percent reduction to produce the same one year increase in life expectancy. In other words, and this was really the principal message that we were trying to get across with our original article, was the higher life expectancy goes, the less sensitive it becomes to changes in death rates. The higher it goes, the less sensitive it becomes, the more difficult it becomes to raise the measure further, which is actually the reason why we were suggesting that life expectancy is, perhaps, not a very good metric, a very good measure to tell us anything certainly about the health of the population.

This will be the last figure I'll show on this, because I realize I'm beating you to death with this issue of life expectancy, but this is actually an important one, because one of the questions that came up often after this issue first arose was, well, if you were around in 1900 and you were asked the same question, how high would life expectancy rise, would you have predicted that it would go up to 80? And my answer was no. Well, then I've been told how could you make a prediction today, based on what we know today?

Now actually, as it turns out, believe it or not in a way this is a testable hypothesis. The X axis is age, on the Y axis is the proportion surviving. Remember Steve talked about this earlier. This is the same hypothetical cohort of 100,000 babies looking at the survivors now instead of those that died. This is the survival curve for the females in 1900. This is the survival curve for females in 1995, and so we asked the question. We know that life expectancy rose by about 30 years during this time period.

Well, if all of the dramatic reductions in death rates observed during the course of the 20th century were to occur again at every age, this is the survival curve that would result. This is the life expectancy that would result, about 89.1. In other words, about a ten year increase in life expectancy at birth, not the 30 years that we observed during the previous century. And if it all happened a third time, the gain would be only 6.1 years, life expectancy would be 95. It's a way to illustrate that the magnitude of the gain and the increase in life expectancy is decelerating as it goes higher. Skip that.

Now I want to present an opposing point of view. Some mathematical demographers have suggested that life expectancy will go to 100 by the year 2060. And this will happen principally by extrapolating past mortality trends into the future. And this is the figure that has been used. And there's very compelling evidence here that there have been some interesting and dramatic increases in life expectancy observed, steady increases since 1840.

This is record life expectancy observed among humans in various sub-groups of the population, increasing steadily from about 45 or so, all the way up to, the record I think now is close to 85 for Japanese females. And what they're suggesting is, is that if we have observed this increase in life expectancy for the past 160 years or so, that there is no reason why it cannot continue into the future. And so this mathematical extrapolation is the basis for the prediction that life expectancy will go to 100 by the year 2060. And if this is all you look at, if you look only at the historical trend in life expectancy, this is a very compelling argument for why you might anticipate a continuation of this historical trend.

Now this is the actual terminology that is used by the authors. They demonstrated that there's been a two and a half year increase in life expectancy per decade, and therefore, it's reasonable to anticipate that this will continue out for the next six decades. However, I used this same extrapolation method to go backward in time just to see what would happen. And if you go backward in time using the same extrapolation method, life expectancy would be zero in the year 1750. So I have argued, as have some others, that it is no more reasonable to make projections of life expectancy going forward in time using an extrapolation method, than it is to go backward in time. We basically need to understand the underlying biology of humans to make sure forecasts, rather than relying entirely on mathematical extrapolations.

So if there's going to be another quantum leap in life expectancy, we're going to have to extend the duration of life, of people like Madame Jeanne Calment and others who have already lived 70, 80, 90 or 100 years or more by 70 or 80 years, in order to achieve a comparable increase in life expectancy like that observed during the 20th Century. And here's where Steve and I are in complete agreement.

The only way this is going to happen, it's not going to happen by altering our lifestyles. It's not going to happen by ingesting anti-oxidants. It's not going to happen by injecting yourself with growth hormone. It's going to have to happen by altering the basic biological rate of aging itself, which is something we cannot currently do, but researchers are trying to do. And there's one last way to illustrate this point.

You know actually, interestingly enough, Steve, this is the first time I've ever seen you show a figure of running times. Here's mine for the world record for the one mile run, indicating that it's declined steadily, very much like life expectancy has increased steadily in the middle of the last century from about five minutes in 1850, to three minutes and 43 seconds today. So if you do a linear extrapolation of this trend, which is the same method that is being used to generate these much higher life expectancies, you would run one minute — one mile in one minute in the year 2420, and we would do it instantaneously in the year 2580.

Okay. Are there hard physiological barriers to the human life cycle? Now the answer to this question is yes and no, and I'm going to spend much less time on this than I did on the issue of life expectancy, but the yes and no answer, you know, when you say yes and no, some people will only hear the yes, and some people will only hear the no. And I will encourage you to hear both answers, and here's where I get into a bit of evolution biology, which I thought Steve was going to talk more about, but I'll touch upon this issue a bit more.

And it's the issue of why not immortality? Why aren't we immortal? And the answer is, immortality in a way already exists for DNA. And once DNA acquired the property of immortality, its carriers became mortal — you and I.

Now I use this analogy, and have used it for quite some time as a way to illustrate the fairly complex evolutionary theory of senescence. This is the Indianapolis 500 race car analogy. Now we know, of course, what the duration of this race is. It's 500 miles. If something goes wrong with these automobiles during the race, they bring them in, they fix the parts, they send them back out. What's interesting here is that when the race is over, they turn the engine off and they bring the car back into the shop, which is something we can't do in humans. The engine of life is always operating until the end.

If you were to conduct a hypothetical experiment on Indianapolis 500 race cars, where instead of turning the engine off after 500 miles, you continue to operate them, run them around the track until they all failed, you would actually see a distribution of failure times that is very much like that of living organisms, life humans, and mice, and dogs.

The key thing here is that, number one, you would get to see things go wrong with these automobiles that you would never ordinarily have an opportunity to see, because you're operating them beyond the end of their effective warranty period. And the other key point is, is that the engineers in this case did not build in a program for failure. They're simply operating beyond the time period that they were intended to be used.

Well, the same logic actually applies to sexually reproducing species, but the measure — the end of the race is not a measure of distance, it is a measure of time. And in this case, reproductive success includes not just the time period when we are producing offspring, but a time period when we can contribute to the reproductive success or fitness of our offspring as grandparents, so there's a grandparenting period as part of the end of the reproductive period. And in effect, what we are doing to ourselves and other sexually reproducing species is the very experiment that I was talking about with automobiles. We are pushing ourselves well beyond the end of our reproductive window, and we are having an opportunity to see things go wrong with our living machines that we never would ordinarily have an opportunity to see. And the further we push the envelope of survival into the post reproductive region of the life span, the more things we will see go wrong, as well.

Now this is the basic linkage that I know Dr. Kass was looking for on this linkage between reproduction and senescence. The basic evolutionary argument suggesting that natural selection is very effective at influencing gene frequencies in the pre-reproductive period, but as soon as we begin reproducing the ability of natural selection to alter gene frequencies declines very rapidly, as soon as we begin reproduction. The force of selection declines very rapidly, until we reach the post reproductive region of the life span, where the ability of selection to influence gene frequencies declines to very low or negligible levels.

Now this actually is a key figure linking reproductive and senescence. And what I will tell you is, and my colleagues and I have done work in this areas, as well, where have looked at the fundamental linkage between the timing of reproduction when puberty begins, the length of the reproductive window, and the duration of life of a species. And a number of researchers have demonstrated that the duration of life of a species is calibrated to the onset and length of the reproductive window. And we've done this in more than a dozen mouse strains from the Argonne National Laboratory database. We found something similar in humans, in dogs, that there is a fundamental linkage between these biological attributes. And if you're going to alter one, you are likely going to alter the other.

I'm going to skip over — well, actually let me show you. This actually is an important figure. You know, when we talk about death rates, this is what they actually look like. Age on the X axis. This is a semi-log scale, so when there's exponential increases in mortality, you get a straight line here. This is a way to illustrate that there have been — that the age trajectory of mortality really has not changed very much during the course of the 20th Century, even though we have lived much longer. And this actually is an important point, because many of the researchers from the biological sciences who have suggested and have argued that we have altered aging, I believe, have not actually demonstrated that aging itself has been altered, because we can't measure biological aging itself. It has been used as this, the change in the death rate, both the inflection point, the timing with — the age at which the death rate increases, and then the slope of this mortality curve, which is taken as a proxy for aging.

The biological process of aging itself cannot currently be measured, so when somebody says that aging has been altered, or aging has been delayed or postponed, I would say that we don't have definitive evidence to support this particular view. This is what is used, so much of what goes wrong with us as we grow older, as many of us have suggested is not our fault. And senescence is, indeed, an accident of surviving beyond the warranty period for living machines, which is the main point we were making earlier.

Now here's the yes and the no. There is no biological limit to life. Evolution could not have given rise to genes designed for the purpose of killing us, but nevertheless, duration of life is fundamentally influenced by biological clocks that regulate growth, development, and reproduction, and senescence is an inadvertent bi-product of these genetic programs according to evolution theory. So on the one hand no, we don't have a program designed to kill us, but on the other hand we do have programs, very tightly controlled genetic programs for growth, development and reproduction, that have as an inadvertent bi-product of their existence, senescence. And so there can be no aging or longevity genes, nor are there hard physiological barriers to extending the life span, but nevertheless, there are constraints on duration of life that are influenced by both biochemical changes that occur, biomechanical changes. This is an article we published last year of human rebuilt to last in biomechanics, then biodemographic constraints. And this is smaller, but I couldn't find a symbol for stochastic events, but it doesn't mean it's any less important, the stochastic or random nature to the aging process itself.

Now I'm going to spend much less time on this issue, Prospects for Significant Breakthroughs in Aging Research. It is important to distinguish between breakthroughs that modify the biological rate of aging, and breakthroughs that may extend the duration of life. And I think some of these animal models are really modifying the duration of life. Much as we do with humans in altering our risk of heart disease and cancer, one could make the argument that we're altering aging. I don't think we are.

Extension of life can occur without modifying the biological rate of aging. If I was asked to come up with any sort of breakthrough that I would anticipate that would modify the biological rate of aging, I would expect it would come from pharmaceutical industry that alters maintenance and repair functions. I put in slightly smaller letters caloric restriction, emetics, and genetic engineering. I'm less convinced that these will actually work on humans, and we can discuss this later.

Breakthroughs that might extend duration of life without modifying the biological rate of aging, there are plenty of these. There's a whole laundry list of ways in which we can intervene that may extend duration of life without necessarily influencing the biological rate of aging. I know you have personal interest in many of these topics.

All right. Demographic implications of life extension, I'll address very quickly. I wasn't sure which one of these — these are both the same figure, and this one is better, so I'm going to use this one. You know, this is a typical question that students of demography will ask, and so — and I'm not the first one to answer this. It was actually answered by Anthony Cole, a famous economist in the 1950s at Princeton. And so I did some basic calculations to demonstrate what would happen if we achieved immortality today. And I compared it with growth rates for the population in the middle of the 20th Century. This is an estimate of the birth rate and the death rate in the year 1000, birth rate roughly 70, death rate about 69.5. Remember when there's a growth rate of 1 percent, very much like your money, a growth rate of 1 percent leads to a doubling time at about 69 to 70 years. It's the same thing with humans. With a 1 percent growth rate, the population doubles in about 69 years. If you have the growth rate — if you double the growth rate, you have the time it takes for the population to double, so it's nothing more than the difference between the birth rate and the death rate to generate the growth rate. And here you can see in 1900, the growth rate was about 2 percent, which meant the doubling time was about five years. During the 1950s at the height of the baby boom, the growth rate was about 3 percent, which means the doubling time was about 26 years. In the year 2000, we have birth rates of about 15 per thousand, deaths of about 10 per thousand, low mortality populations, which means the growth rate is about one half of 1 percent, which means it would take about 140 years for the population to double.

Well, if we achieved immortality today, in other words, if the death rate went down to zero, then the growth rate would be defined by the birth rate. The birth rate would be about 15 per thousand, which means the doubling time would be 53 years, and more realistically, if we achieved immortality, we might anticipate a reduction in the birth rate to roughly ten per thousand, in which case the doubling time would be about 80 years. The bottom line is, is that if we achieved immortality today, the growth rate of the population would be less than what we observed during the post World War II baby boom.

We would eventually run into problems, of course, a century down the road, but just so you know the growth rates would not be nearly what they were in the post World War II era, even with immortality today. However, it would have a rather dramatic effect on age entitlement programs like Social Security and Medicare. When Social Security was created in 1935, they predicted there would be no more than about 20 million beneficiaries. This is what was actually observed, and their recent prediction, if indeed life expectancy were to go much higher, then we would run into very severe problems with the funding of age entitlement programs like Social Security and Medicare.

If there was another quantum leap in life expectancy, I don't really know how these other attributes of human life would change, marriage, retirement, work, education. I don't know any better than anyone else. What I would anticipate is, is that there would be fundamental differences in all of these attributes of society if there was another quantum leap in life expectancy.

I'm going to end with the position statement on human aging, and I'm only going to touch upon this briefly. This is something we published last year. You might imagine getting 51 scientists to agree on anything is extraordinarily difficult. In fact, as hard as I tried to get Steve to sign onto our position statement, we weren't able to get him to sign on. I will tell you that we didn't all agree on everything that we put into this position statement, but we decided to compromise on some of the language for the purpose of getting across a very important message to the public. And that is, number one, there are no anti-aging medicines in existence today. And number two, there is a great deal of very interesting, fascinating good research ongoing in the field of gerontology designed to understand and modify the biological rate of aging. And we not only support this research, but believe that it's absolutely critical to helping us deal with a much more rapidly aging population. And there was a question associated with this, do the conclusions that we came to in our position statement apply to biomedical interventions? Let me skip — well, actually, I don't want to skip by this.

A number of other publications came out associated with this question of anti-aging medicine. This one came out from International Longevity Center in New York. This is a report that was published by the GAO the week of 9/11, which is why no one saw it, suggesting that anti-aging products pose a potential for physical and economic harm. And I will end by showing you the various issues that we raised during this discussion. I mean, really this position statement grew out of a AAAS meeting that many of us attended about a year and a half ago, where we were discussing for prospects for increasing human life expectancy, and we were lamenting about the problems associated with those selling anti-aging products, so we decided to provide as definitive a statement as we could about each of these issues, about what we know and what we don't know, and whether or not we think that these influence aging itself or duration of life. And so we basically have — we tried to create as short a paragraph as we could on each one of these issues to tell you what we knew, and what we didn't know. And I'm going to end with, I know you don't want to read any of this stuff. And we have published this, but I will point out the very last sentence of our conclusion, which is, for those of you who cannot read this, "Successful efforts to slow the rate of aging would certainly have dramatic health benefits to the population by far exceeding the anticipated changes in health and length of life that would result from the complete elimination of heart disease, cancer stroke, and other age-associated diseases and disorders." So I completely agree with Steve on this point, which is one of the first points that he was making; and that is, is that research on aging is fundamental. If we can succeed in postponing many of the diseases and disorders associated with aging, the benefits would be far exceed those that would accrue, we believe, with the elimination of major fatal diseases in the population. And I think I'll end there.

CHAIRMAN KASS: Thank you very much. We'll get the lights on shortly, but if people are willing to start in semi-darkness, I think I see Robby George's hand. Please.

PROF. GEORGE: Thank you, Dr. Olshansky, for that presentation. One of the figures you had on death rates included, if I saw it correctly, a rather startling statistic on an increase in death rates for persons between the ages of 20 and 35 from the period of 1985 forward. Do you remember that figure? For the U.S., yeah.

CHAIRMAN KASS: You commented on it.

DR. OLSHANSKY: Was it this one?

PROF. GEORGE: No, I don't believe so.

CHAIRMAN KASS: It was the table that you showed with Japan and France.

DR. OLSHANSKY: Oh, this one.

PROF. GEORGE: Yeah. What's the plus one point? I mean, that jumps off the page.

DR. OLSHANSKY: Yes, it should jump off the page.

PROF. GEORGE: 20 to 39, I thought it was 35. It's 39.

DR. OLSHANSKY: 20 to 39, and it's actually — I didn't show this, but there are increases in death rates among some older age groups, individuals at older ages, as well. That's a plus 0.7 percent increase, seven-tenths of 1 percent, a 1.1 percent increase for males probably associated with HIV. But yes, it should jump off the page.

It's a way to illustrate, I think, that — you know, there's a tendency when making forecasts of life expectancy to assume that they're always going to rise. And this issue came up when I was here in Washington a couple of months ago talking to the Trustees of the Social Security Administration about this very issue, about projections of life expectancy. And it is always assumed that they are going to go up, and I have suggested, as have others, that maybe we need to be cautious about this long term projection assuming it's always going to rise. There are sub-groups of the human population that have experienced an actual decline in life expectancy in various parts of the world. Also, at some age groups that there have been increases in mortality, not always decreases in mortality, so you're correct.

DR. ROWLEY: And what's the role of guns and killing with guns in that particular age group?

DR. OLSHANSKY: Well, that's the age window where you would see the effect of extrinsic causes, like homicide and accidents. And clearly, if those are on the rise, you're going to see an increase in mortality in those age groups.

PROF. GEORGE: Do you know if they are on the rise for that period?

DR. OLSHANSKY: Well, for that period they were on the rise, absolutely. This is 1985 to 1995.

PROF. GEORGE: I'm asking whether you know if the murder rate is on the rise.

DR. OLSHANSKY: Oh, I don't know. I didn't break down the seven-tenths of a year, or the 7 percent and the 1.1 percent into the underlying causes. I'm guessing that HIV has contributed significantly to this in the United States, but I don't know about the change in homicide rate.

PROF. GEORGE: But if it were HIV, should the statistics be that out of whack with what's going on in France? I just don't know. We're talking about a rate here.

DR. OLSHANSKY: This is a percentage change in the conditional probability of death, and I just don't — I didn't break it down, so I don't know with certainty what led to the increase in mortality in that age range. But those are real numbers for the United States.

DR. ROWLEY: But isn't homicide the most common cause of death in males, particularly black males, age something like 18 to 30?

DR. OLSHANSKY: I think so, yes. Yes.

CHAIRMAN KASS: Dan Foster.

DR. FOSTER: There are certain precincts in Washington where the life expectancy of young males in certain racial groups is, you know, like Bangladesh and so forth. But in the current science, there is an estimate in regard to what was just said, that the AIDS is the leading cause of death in the world from Gallow and so forth. There are three articles there.

I think most people believe that it's Tuberculosis. And one of the things, as you may know, and particularly resistant Tuberculosis, I think one of the things that may, in fact, change things unless science is able to deal with this better, is the resistance of organisms that are going to cause a back movement into death. If I were to say, I mean other than the enemy or anarchy in the world that wars are doing and so forth, I would say that is the greatest problem that is likely to move us back, because a great deal of what that early life change and so forth has to do with the antibiotic appearance and so forth.

DR. OLSHANSKY: Yeah. There are two things that I would put my finger on that might change this trend in life expectancy. One would be the re-emergence of infectious diseases, as you were saying. And number two, the obesity epidemic which will eventually be translated into number of late onset diseases in populations. It's actually a paper that I'm just now working on.

DR. FOSTER: Yeah. This is an area I'm very interested in, but the pharmacologic approach to obesity is likely to be much more effective than the things that are going on in terms of, you know, senescence and so forth. I mean, because we already have drugs in the system that I work, you know, you worked out all the details on, that you can dramatically change obesity in experimental animals now by altering activities of one or two enzymes, which you can do with small molecules. So I'd be much more optimistic about curtailing — no, I don't know what it will do in the third world, these things will probably cost too much, but at least theoretically, the obesity problem and lipotoxicity, what we call lipotoxicity, the death of organs, heart and so forth and so on, that's an achievable thing, much more easily achievable than what we're talking about here. So that's why — I mean, if you just looked at it right now, I would absolutely agree with you.

I heard a talk this week that said obesity is the leading cause of death in the world, you know, but I think that's very different than this biological senescence that you're talking about.

CHAIRMAN KASS: Mary Ann Glendon.

PROF. GLENDON: First of all, thank you both for terrific presentations. This question is addressed to you both. We read a lot in popular literature about the implications for the welfare state, this phenomenon of relatively low birth rates and greater longevity even at present rates. And I'm wondering where — if we wanted to look into the implications for health care, for social services, for Social Security, where is that work — where is the best work done? It's an inter-disciplinary field, and I found myself wondering as I was listening to both of you, is this one of the things that demographers do, or do sociologists do it, or political theorists, or is it one of the things that falls between the cracks? I notice that one of your collaborators is from ENAD in France. I understand the French have a wonderful multi-disciplinary demography institute. If we wanted to know more, should we perhaps get somebody from over there, just on the implications for the welfare society.

DR. OLSHANSKY: You know, this is — actually, it's not an area that I address personally, and this is not one of those things where I'd like to give you an immediate answer, but I'd like to go back and find the right people to put you in touch with. There is a lot of very good work on this topic going on in the United States. I think you're right, ENAD is a place where there's a lot of good work going on, but I'd like to think about the answer to this question, and get back to you with the right contacts. Off the top of my head, I prefer not to guess.

CHAIRMAN KASS: Rebecca Dresser. I'm sorry.

DR. AUSTAD: No, I wouldn't really — yeah, I wouldn't really have any — you know, biologists certainly don't do this. One place I think might provide a suitable guide is probably Japan, which has had a more rapid rate of increase in longevity than we have, has greater longevity now, and presumably will encounter all the same problems earlier.

PROF. DRESSER: I wanted to ask about your point that we should de-link increased life expectancy from anti-aging. Those are two different things, if that's what you meant. So I just wondered, is it — I guess two questions. One is, is it a matter of spin so that we might say that what we've achieved now is an increase in aging, rather than anti-aging in terms of success. We have successfully extended the life expectancy, however, instead of talking about this as an anti-aging measure, we could talk about it as an aging increase measure, and that the period of aging has increased.

CHAIRMAN KASS: You mean senescence. Right?

PROF. DRESSER: Yes, senescence.

DR. OLSHANSKY: Well, actually when I was talking about de-coupling, I was talking about de-coupling efforts to modify the biological rate of aging itself, and efforts to alter the manifestations of aging. And most of what we do today is an effort to modify its manifestations.

Some of the work that Steve was talking about and others, is an effort to modify the basic biological process of senescence itself, which presumably would postpone into later ages all of the manifestations of aging. So when we alter the risk of heart disease, or we alter the risk of stroke or cancer, we're not influencing the process of aging. We are actually enabling — or senescence, I should be using my own terminology. We're enabling senescence to be expressed in new ways by pushing people out into the post reproductive window of the life span, and we get to see things that we ordinarily wouldn't see. And I'm not sure if I answered your question.

The de-coupling is between, you know, efforts to go after aging, and efforts to influence its manifestations. Anti-aging, what's known to some as anti-aging medicine, and the claim is made by some that we can alter, that we can slow down, stop, or reverse aging is really nothing more than classic demonstration of the ability to become more physically fit at any age. Whether you're 60, 90, or 100, if you choose to be more physically fit tomorrow than you are today, that is a matter of choice. You can increase your muscle mass. You can reduce your rate of bone loss. You can alter mental acuity and skin elasticity. These are not alterations in the basic biological process of aging, but rather its manifestations.

PROF. DRESSER: I guess this is difficult for a non-scientist. Isn't there some overlap? I mean, for example, your last point you said in terms of research priorities, well, if we put this money into anti-aging research rather than research on various diseases, it would have a much bigger impact. But I mean, aren't some studies on cancer and so forth looking partly at aging? It's just difficult to see how those are totally distinct.

DR. OLSHANSKY: Well, I guess I don't see ongoing research in cancer as an effort to attack the fundamental biological process of aging itself, which influences virtually every cell in the body. So no, I would not see them as the same. If we were to succeed, I mean, let's say we did come up with some sort of pill that we could take that would enable us to postpone aging, then everything that we see that we associate with senescence, with growing older, with basic changes in joints and organs, and tissues and so forth, and its manifestations would be pushed to later ages.

Now we wouldn't necessarily be younger longer. We would be more physically fit longer. I don't know necessarily if we would be living longer. And I'm not sure living longer should be the goal, but living healthier should be the goal. And one of the best ways to achieve that is to go after senescence itself.

CHAIRMAN KASS: Michael Sandel.

PROF. SANDEL: This is not really a question for the presenters, both of whom really informed us in very rich ways. It's an observation, and a puzzlement about what's at stake for us in this question about longevity. We, after all, take it up under the heading of enhancement, and in other discussions of enhancement, sex selection, for example, the ethical questions have been more transparent than they are in this case of longevity.

As I — so the question I'm wondering is, why it's ethically interesting. It's clearly of great social, and economic and political importance for reasons that Mary Ann Glendon's question raised, we were to think about the implications of life expectancy for Social Security and for various other social policies. That's clear. But what hangs on this discussion for purposes of ethics?

And as I understand the ethical concerns that might be lurking here, concerns about the implications of extending life, I've only been able to glean one or two. One of them, I associate with out chairman, who worries about immortality, who wants to make the world safe for death, because immortality would raise fundamental questions about the construction of human meaning and meaningful lives. And I take that point as a powerful insight, and I certainly wouldn't quarrel with it, and perhaps no one would quarrel with it. But none of the research that we've been discussing implicates immortality. It involves longevity. To double or triple, or quadruple longevity short of immortality wouldn't raise those big questions about the meaning of life if there were no death, so this is not implicated.

A second possible ethical implication might have to do with this question of relations among the generations, would the ethical character of the relations among generations be altered if longevity were extended in some significant way. So I can see that as a possible area of ethical inquiry.

And then the third area really doesn't have to do with longevity, as such, but with alleviated infirmities and senescence, the prospect of dying at about the same age, but in the pink, as Gil was saying. And there, the question — Leon has posed this interesting question about whether that might dull our readiness to die, so I understand that question might arise. But apart from those, I don't really see what the ethical issue is, so my instinct is to say longevity, we shouldn't aim at it as a priority for research, extending life as such. I don't see any reason to do that. But neither should we worry about it. If it comes about as the side effect of research that aims at alleviating infirmities and reducing the debilitating effects of senescence. Am I missing something? And as I said, I don't mean this to be directed to — it shouldn't fall on the shoulders of our guest. The Chair can address it, if he likes.

CHAIRMAN KASS: I'll wait because —

DR. KRAUTHAMMER: Why are you assuming that we shouldn't aim at longevity? I thought you said —

CHAIRMAN KASS: He said longevity. He meant immortality.

DR. KRAUTHAMMER: No. Were you talking about longevity as a research endeavor.

PROF. SANDEL: Well, I don't see why there's any particular — given the other important things to aim at in terms of medicine, I don't know why adding numbers of years without improving the quality of life in the last part of — I don't know why that's morally compelling.

DR. KRAUTHAMMER: If we call it postponing senescence, you would say that it's not a worthy goal for research?

PROF. SANDEL: Oh, that would be.

DR. KRAUTHAMMER: All right.

PROF. SANDEL: But they've drawn our attention very well to the distinction between those two things, between enabling people to live longer, and combating the infirmities that go with senescence. I'm all for the second, but I don't think anyone has presented an argument for the first. Have they?

DR. KRAUTHAMMER: No, I'm just trying to clarify what you were saying we were against.

CHAIRMAN KASS: Mike Gazzaniga, please.

DR. GAZZANIGA: Well, just — I know if I'm silent, pretty soon Mike Sandel will ask the question I wish I could have asked, so I second his question, what is it we're doing here on the ethical dimensions of this?

CHAIRMAN KASS: I'm ready, but let other people go first. Mary Ann Glendon.

PROF. GLENDON: I don't know whether this qualifies as ethical. I'm just a lawyer so, you know, we're not famous for being strong in that department. But looking at your description of what happened to longevity over just the 20th Century in developed countries, would it be fair to say that at the beginning of the 20th Century, the dependent population was largely composed of children, rather than the elderly? And at the end of the 20th Century, the dependent population was largely composed of elderly, rather than children. Would that be right?

DR. OLSHANSKY: Well, the use of the word "dependent" is problematic, as you might imagine.

PROF. GLENDON: People needing care. I'm getting back to my interest in the welfare state, that people needing care, people who in varying degrees have to have somebody attending to basic needs.

DR. OLSHANSKY: There is clearly a shift. There's a measure called the Age of Dependency Ratio, which is the proportion of the population over 65 divided by the working age population. And that ratio has increased quite dramatically during the course of the 20th Century. I pretty much object to the word "dependency", because it implies that they're not contributing anything to society, and I would completely disagree with that.

Let me follow on on this discussion here, because the use of the word "enhancement" came up, and I think it addresses the issue that you're raising here, because there are a number of researchers who believe that a dramatic extension to the human life span would be an enhancement, however it occurs, whether it's through genetic engineering, through some biomedical technology that permits us to dramatically extend duration of life. And here's where I would throw out a caution.

I would say enhancement is a word I would only use if we knew that we were extending quality years. And the feel that I have is that we are going to rush head-on into this effort to alter aging without knowing what its consequences will be, what its manifestations will be, both in terms of the health of the population itself that's making it out to older ages, and its influence on social institutions, such as the ones that you're talking about, the contract between the older population and the — the non-working population and the working population. And there — you know, if there's just a minor difference in the projection of life expectancy, just one or two years, the size of the population, the beneficiary population increases dramatically.

When you talk about a 15 year difference in a projection of life expectancy, it's a quantum difference in an effect on entitlement programs such as Social Security and Medicare. So enhancement is a word I would use very cautiously when it comes to life expectancy.

DR. KRAUTHAMMER: But couldn't you rectify that imbalance if you have a large increase in the say non-working population by simply altering our definition of working? I mean, if you get an increase in the over 65 population, and you increase — you raise the retirement age one or two years, you've dramatically altered — you can restore that ratio, so I'm wondering why you would object to a change in what science does, and what science might achieve because of the constraints that are now set by social conventions, which can easily be changed. I mean, Bismark is the one who came up with 65 because nobody lived to be 65. It was a very reasonable way to establish a welfare state. There would be no old people, but it's a long time since Bismark, so that age is rather arbitrary.

I'm just saying if we were to make progress, if we wanted to define it as progress, we can argue about that, I'm not so concerned about the social, at least the economic implications because it depends on certain conventions which are very alterable.

CHAIRMAN KASS: Do you want to comment?

DR. OLSHANSKY: Well, in a way I agree. I think — I mean, my personal concern is more with the health implications. I think that extending the envelope of human survival, combating death by any means is going to push people into an age window where we see things that we don't want to see. And I think the modern rise of Alzheimer's Disease might be in part a classic example of a product of our success. The more successful we are at extending duration of life, the more we are going to see the diseases that are most common among the extreme elderly occurring. This was the point that Steve was making very early in his presentation, and that's the main concern that I have, is the health of the older population.

DR. KRAUTHAMMER: Can I push you on that for a second, if I may? If you were then retroactively reordering history, would you have preferred that we had not engaged in the medical efforts that reduce heart disease and others that have created the epidemic of Alzheimer's?

DR. OLSHANSKY: No. And that question, as you might imagine, I have faced many times. No, I would not ask that we stop our effort to go after the major fatal diseases. All I'm saying is we need to be aware of the consequences of our success. And if we continue to succeed in enabling people with heart disease, cancer and stroke to survive longer with their disease, we may not necessarily like what we see. I'm not saying we should be truncating that effort, we just need to be aware of the consequences of our effort.

DR. KRAUTHAMMER: But you would truncate it if it were not disease-specific, if it were just extending age for its own sake, you'd say no, let's not do that. But if it's preventing heart disease, yes, even though it'll have these consequences.

DR. OLSHANSKY: Actually, I think what I'm suggesting is that not only should we go after the major fatal diseases, and the non-fatal disabling conditions, but also in a way, perhaps more importantly, aging itself. I mean, the entire medical model is very much taking — it's a product of our effort to go after infectious diseases. It's whatever disease is in our face at the moment, and I refer to it as the hurdle approach to disease. You know, whatever is in front of us, we jump over it, only to face another one later on. And the hurdles get more frequent and higher the older we get, and I'm suggesting we push the hurdles back, and that's the effort to go after the aging process itself.

CHAIRMAN KASS: Paul McHugh.

DR. McHUGH: I also want to thank you for that wonderful discussion, and I learned a lot from it. And I'm just not sure how I'm going to phrase this, but I think you and I, and perhaps all of us are in agreement that we want to do away with the things that impair our old people, which may well include, after all, Alzheimer's Disease. Alzheimer's Disease is a specific disorder, and we may be able to postpone its onset. Instead of having a 65 year old average age, we might be able to make it 95 or 100 before it comes in, in which case it would move things along.

On the other hand, so there wouldn't be any ethical problem, it seems to me, to work on improving that. The real issue is whether we're wasting time and effort in the ultimate striving for something which is intrinsically limited, the thing that both of you spoke about at the beginning, that there is an intrinsic limit to what we are. And I would like to tell you a little point that kind of makes that clear from the opposite end; that is, how do you define a child prodigy, that is somebody who knows at 40 what he knew at 8, because you get smart but you don't — you know, there's a limit to what you can do. And similarly here, there may be a limit, after all, to what we want. We want an age period which, again, it would be nice to be as long as it could be, but during which time the health was rosy, and the people were enjoying even their limited capacities. So just as you showed us that the mile run is not going to — has a natural limit, fundamentally out of the muscles and engineering of our body, are you agreed, and is aging research now agreed that listen, fundamentally there's a limit to this longevity business, and we ought to — we've got there now. Science has told us what that is, and now we just ought to be working on correcting the things which burden us from childhood to the end.

DR. OLSHANSKY: Well, no. I would certainly not suggest that by any means. And this issue of a limit, I would be careful about. I mean, I completely agree, there are clearly constraints to the duration of life, many of which I discussed during the presentation. There are biomechanical constraints to the way in which the body is constructed. There are biochemical constraints to the way in which our cells operate. But that doesn't mean we can't intervene in these processes. And, in fact, the approach that we're taking, in a way is the one that's going to permit many more of these age-associated problems to be expressed; which is precisely the reason why aging should be the enemy, not death. Going after the aging process itself, I think is fundamental.

It was one of the primary conclusions that we came to in our position statement on human aging, is that we need to attack the aging process itself. We haven't, you know — again, this issue of how much longer we can live I think should not necessarily be an important part of our discourse. It's trying to push back the envelope of the things that we don't like to see.

As you said, using Alzheimer's as an example, if we could push it back 25 years, the time in which it expressed itself, you could say the same thing about Osteoarthritis and Osteoporosis, and vision and hearing impairments, and the major fatal diseases, if we could push them back, if we could delay them, it would have a dramatic positive impact. And I don't know if we would necessarily live longer, but it would be a huge benefit to society.

DR. McHUGH: Oh, I absolutely agree, and so then you would accept then, if we could push all those back to 100, and say well listen, 100 is where we're going to get to and that would be it, and not worry about whether we're going to get to 102.

DR. OLSHANSKY: Right. Yes.

CHAIRMAN KASS: Let me join in since I was on queue, and partly to address Michael's question. And this is not as coherent as it will be, Michael, once I listen to this discussion and realize the various things that one might have thought to say.

First of all, it seems to me if you take by what you mean by an ethical question, not is it moral or immoral, or does it violate some rule that we have before us, but is it good, then it's perfectly clear that what's under discussion here is whether it's good to proceed in the direction that this research points us to. And there's some dispute about what it is that it's pointing us to, whether it really is retardation of senescence with only modest increases of the possible life span, potential species life span if I've got it right, or whether these things are linked. And more is better, if I understand my friend Charles. I mean, life is good, and the healthier and the longer, the better.

Second, and this is one of the reasons why it's interesting to take this topic up for us, is the people who are doing the research, very exciting research, talk at most about the possible health benefits that could come from this research, but declare themselves absolutely agnostic on the larger questions of what this would mean for the broader society, whether it has to do with work, retirement, education, opportunities for relations amongst the generations, the perception of time which is very different from the gift of time. And I have a passage from a wise physician I want to introduce in the discussion. And this is one of those areas where this is kind of paradigmatic for a lot of this area.

We can agree that disease is bad and health is good, and life is good, and death is bad, and here's research which will contribute to the things known to be good. The side consequences, and they're not merely accidental consequences. They may be built-in consequences of success in this area, have — go well beyond the question of the state of health of the individuals, as has already been indicated by Mary Ann's question, by Dr. Olshansky's comments, and it seems to me that we have a circumstance, and Professor Austad — the paper he submitted for us to read was wonderfully polemical in the sense that it argued not only that this research was good, but that it was only various kinds of political obstacles that stood in the way of our doing what is really important to do. Yet, I'm not sure that if we were convening ourselves as a wise council charged with the decision as to whether to pursue this, and I'm not saying — I don't prejudge the answer, but I'm not sure that the answer that it might, in fact, retard senescence with or without dramatic increases in the maximum human life expectancy, I'm not sure we have the information to discuss that. So this is one of these areas where there's an area of research potentially profound in its importance, potentially profound in its importance, is pursued with — and let me say this with a kind of cheerful naivete about what it means.

It's not to say that it's wrong. I mean, I think there's a way in which one will be hope filled with respect, especially if you define the meaning of this in such a narrow way. Well, who wouldn't want to be rid of the need for dentures, and hearing aides, and I can't remember what the next point I was going to make, those sorts of things. But that's why I think this is — and this is a kind of window into a whole range of other things pursued for the same goal.

If you listen to the conversation, no one is interested in immortality, but everyone is interested in getting rid of the latest obstacle that stands in the way of either fitness, or of sticking around. And, therefore, that's partly why —

PROF. SANDEL: No, but that was my question. Fitness or sticking around, which is it? I'm trying to understand what the research is aiming at. That's the question.

CHAIRMAN KASS: But if I understood Dr. Austad's point, although Professor Olshansky suggests that at least with respect to the research on specific diseases, we're not doing anything with respect to senescence. But if I understood your point, that these things may very well be linked, that if you somehow retard senescence, whether you want it or not, you're getting increases in the maximum possible human life span, and you're buying the whole package.

Now you don't have to talk about immortality to think that the world would be a very different place if, in fact, there were not just centenarians around, but the centenarians were the norm. And if one talked about 120 or 150, or even 200, and I mean, there are reputable scientists who are talking this kind of language.

If I might just permit one — let me just read something which is not usually entered into this discussion. Let me mention as homework, we'll dig it out and send it around. There's a wonderful meditation on this question of the life cycle in Aristotle's Rhetoric. It's admittedly presented for the purpose of rhetorical speech, but he's got a wonderful presentation of the young, the old, and those in their prime, in which the crucial thing is not in the way the biology, but things having to do with the experience of life, and what it does to people's outlook.

Let me read one passage, if I might. This is from Eric Cassell, a physician, very wise physician. This is on "Death and the Physician", written over 30 years ago. "While the gift of life must surely be marked as a great blessing, the perception of time as stretching out endlessly before us is somewhat threatening. Many of us function best under deadlines and tend to procrastinate when time limits are not set. Thus, this unquestioned boom, the extension of life, and the renewal of the threat of premature death - sorry - and the removal of the threat of premature death carries with it an unexpected anxiety, the anxiety of an unlimited future." And here's the part that I especially like, and I'd be interested in the remarks of the young people who are with us.

"In the young, the sense of limitless time has apparently imparted not a feeling of limitless opportunity, but increased stress and anxiety, in addition to the anxiety which results from other modern freedoms, personal mobility, a wide range of occupational choice, and independence from the limitations of class and familial patterns of work. A certain aimlessness characterizes discussions about their own aspirations. The future is endless, and their inner demands seem minimal. Although it may be uncharitable say-so, they seem to be acting in a way best described as `childish', particularly in their lack of a time sense. They behave as though there were no tomorrow, or as though the time limits imposed by the biological facts of life had become so vague for them, as to be non-existent."

That's a mouthful, and it's debatable, but if you simply think about the end of life, and sort of fiddling around with what you do for the elderly, you're producing something that affects the whole perception of a life course for everybody. And since the generations are inter-linked, and since the perception of time affects how one chooses to live one's life, these are momentous things. I think not — and the study of the past century for all of its blessings, has some insights about what it would mean to continue these blessings, and add another 50 years.

I'm sorry for the sermonette, but this was intended to the two Michaels, as to why I think this is weighty and why it matters. It's not a question for immediate public policy. The research is going to go forward, but to think about it as simply an extension of more of the same without realizing that there have been hidden costs of the same for which we are now blessed, I think is to miss the opportunity that this kind of research offers for taking a look at lots of things that we've been doing, which is not to say that we shouldn't have done them, or that we shouldn't do this. But I think there is a kind of weightiness to this that is worth our attention.

DR. McHUGH: But, Leon, you say 50 years. That was my point. Is this a ridiculous idea to think that there would be 50 years added onto this?

CHAIRMAN KASS: Two-fold and three-fold increases in the worms, six of these genes in the mice, this is stuff we know for how many years? Less than ten years. And by the way, the insulin-like growth factor 1, that's the stuff that Dr. Sweeney was talking about here, and making super-mice and super-rats, in which Mike Sandel can compete favorably with his son on the baseball field at the age of 80.

DR. McHUGH: Yes. Well, if he can continue to play baseball up to age 80 but, you know, all ended at about 100, then I'm all for it. The real question here is whether we're tilting against something that has an intrinsic limit, that hence — you know, what I said about the prodigy really meant that we can all catch up with the prodigy by working hard between the ages of 8 and 40, and know what he knows then. And similarly — and we want to do that. We want to make that a possibility. But when we think about this outside limits as though they were accessible, instead of — it confronts the issue that the prodigy doesn't learn an awful lot more than what human beings can learn. We can't live longer than what human beings really can live.

CHAIRMAN KASS: Gil Meilaender, Bill, and then Mary Ann, and then I think we should probably —

PROF. MEILAENDER: Well, I'm not sure I am all for it, Paul. I want to come back to Mike and Mike's question a little bit also. I mean, although there's something a little peculiar, Michael, about you know, laying out two or three really important moral issues, and saying apart from these, what morally is at stake here? But immortality, which was one of them, isn't implicated in this research. I understand. But the question was, what are we interested in, fitness or sticking around, as you said. And I think Professor Olshansky said, and surely some others. I mean, Paul's comments have been agreeing that aging or senescence should be the enemy, and not death. And that's what I'm not sure I believe, actually.

I think that, in fact, something probably the contrary of that. I think that death is an enemy, which doesn't mean it should always be resisted. There are enemies to which one must submit on occasion, but I'm a lot less sure about aging. I love baseball. Would it really be so good if I were still playing at age 80, or would that suggest some sort of fundamental immaturity in me? I'm not sure.

PROF. SANDEL: Come on.

PROF. MEILAENDER: No, I'm serious. The notion of getting rid of all the burdens in life. I mean, you see, what we're really after here is to live perfectly fit right up until the moment of our death, and then to say okay. And say we'd really like to kind of control it and master it, and I understand that. And when my right elbow bothers me, as it's bothering me right now, I appreciate that, but I'm not sure that, you know, it's my soundest instincts that would uttered if that's what I wanted. So it seems to me that one of the moral questions that's at issue here is precisely whether certain kinds of very natural instincts that we have ought to be resisted, in a way. And one of those is that desire not see my capacities wane.

I'm not so sure that the waning of them is, in fact, in and of itself an enemy. There are aspects of it that are. I understand that, but not entirely. And so, you know, if that's — then I think there's a genuine question there about which we probably do not agree, and I wouldn't know what to call it, other than a moral question, unless, you know, a spiritual question in some ways, but it certainly is an important question.

CHAIRMAN KASS: Janet.

DR. ROWLEY: Well, I'd like to come back to your use of the term "manufactured survival time", because that bothers me, in that it implies that there really is an appropriate or biologically relevant time for death. And that what we've somehow done has been able to trick the system so the people are living longer. And then what you cite are all the negatives, kidney failure, cancer, things of that sort. And I, as somebody who's 77 years old, believe that one of the remarkable things that's happened during my lifetime is that older people are much more healthy, I suspect, than they were in previous decades and previous centuries. And I think that to the extent that we can enhance this, which again is related to somehow learning how to control or diminish senescence, is a real goal. And so I think that the positive aspects of this should be emphasized more. And I would come again to what Charles said. Fortunately, in the United States, probably almost entirely due to Claude Pepper, we don't have the mandatory retirement that faced my talented colleagues in Europe, Japan and Australia, where they have to leave their countries and go elsewhere if they want to continue an intellectually productive life, so I think that we should be looking at the positive things, not the negative.

CHAIRMAN KASS: Would you like to comment?

DR. OLSHANSKY: Well, this question of manufactured survival time, that came from one of the articles that we had published. And this actually — I'm not sure we're in any disagreement at all. I mean, this is an idea — this issue is one that I've discussed many times with my students, I'll be honest, about what would happen hypothetically if we didn't have any medicine at all? We just took a human population. We raised them in an environment where they had optimum food, they exercised every day, you know, no stress at all, and we followed this population across time, and we observed the time at which death occurred.

What would the life expectancy of this population be? Now I don't know the answer to this question definitively, but I would assume that it would be significantly lower than it is today, the life expectancy that we observe today of 80 and about 75 for males, which is a suggestion that much of time that is being lived by individuals, whether young or old, and I'm 48, and I would have died in my early 20s had it not been for time manufactured for me by medical technology, and I suspect the same can be said for many people in the room, that medical technology has saved us.

I consider the notion of manufactured time as something that is good, that is desirable, that it saves us both at younger and at older ages, and I do not object to this by any means, which relates to the question you were asking earlier, do we not support the idea of going after many of these fatal diseases. We do. I do suggest that we go after them, so I think we're really not in disagree about this issue of manufactured survival time. And if, indeed, we can push out the — we can push back senescence, then I think many of the things that you're talking about in terms of a healthy, productive, vibrant older age is something that we will see more of. It's a desirable goal.

CHAIRMAN KASS: We've got time for just two, and then we'll break. Bill Hurlbut and Mary Ann.

DR. HURLBUT: While we've been talking, I've been thinking that if that old French lady were Strom Thurman's mother, she could have been there to celebrate the — she could have restrained Trent Lott. So I've also been thinking about Michael Sandel's thoughtful little essay. I don't know if you had a chance to read that, but concerning the gift of the givenness of nature, and how interesting this is. That here we are talking about a major alteration of at least the way things play out in the environment. We've altered dramatically the curves you've showed us, and yet somehow we have this underlying impression that the goodness of the givenness of nature is achieved by opening this scenario to further life span. And I feel it too, but what worries me little bit are a couple of issues that have already been touched here better than I could phrase them, but it might be called the coordinate integration of meaningful existence. And I see several conflicting impulses going on here at once.

I agree with Gil that I don't exactly think aging is the enemy. In fact, I'd like to go a little bit on Michael's side, and say there's something about the givenness of aging that might have some good things about it, but how do we sort out what those are, and in which to intervene, if we can? I want to be used up in life. I don't want to be on reserve, or alter myself in such a way that I'm preserved but not engaged as deeply as I can, meaningfully as I can in my life.

Another thing worries me about this, is that in the initiation of the Society for Reproductive Medicine, William Hazeltine is quoted in "Science Magazine", and you probably saw that, as saying something to the effect of the real goal of medicine is to live forever. Well, if that's a little bit like worrying whether a new kind of pole is going to allow a pole vaulter to vault right over the moon, but nonetheless, there is this impulse in human nature to try to get more of life, whatever kind of life it is, or more of a better life. And I look at some of the proposals being put on the table, stem cells growing organs, which would be a wonderful possibility, but you can see how some day we might end up having a whole visceral retread, so that our basic physiological support systems were — I mean, this would be the equivalent of what you said you couldn't do, that's taking the car into the shop.

And I guess, I'm just trying to say something general here. I think a moral life is a meaningful life. And that's an integrated life, and not just an integrated personal life, but an integrated social life. And I guess it keeps coming back to Michael's interesting question here, what is there about the givenness of nature that provides meaning, and could we disrupt that? And I guess what I'm really asking for is your deepest thoughts on this. You must think about this all the time, and what do you really think is going on here? Is there a worrisome realm here, and how do you see it? You said some, but how do you see it best playing out?

DR. OLSHANSKY: Well, I don't want you to get me wrong here when I talk about efforts to go after aging. I can see how some might interpret that in a negative light, as if there's something bad or wrong with individuals growing older. I know this is the point you've raised repeatedly. I will patently admit that all the smartest people I know are over the age of 75.

When we talk about going after the aging process itself, it's a celebration of what happens as we grow older. It's a way to enhance and extend the benefits that accrue with the passage of time. It is not — it should not be interpreted in a negative light. It should be interpreted in a positive light, as something that is desirable that we want to happen, and I view aging, and I was taught about aging from Bernice Newgarden at the University of Chicago, who addressed this issue quite extensively. It's something to be celebrated. It's something to be enjoyed. That's my personal — you know, my deepest personal feeling is that I would like to see this process. I would like to live as long as I can, as healthy as I can with my mental and physical faculties operating as efficiently as possible, for as long as possible. And as a society, I see us benefitting by our aging.

I know somebody mentioned earlier that, you know, we're about to go into a radical transformation in our society. We've already gone through a radical transformation in our society in the past century in terms of population aging, and we're still here. And we're better off for it, as far as I'm concerned. And all we're saying is that I think it's something to be enhanced, but we need to be aware of our current approach to medicine.

Having said all of that, I also want to make a related point. And I know it relates to many of the issues that you've been addressing here for a while, and that is, the technologies associated with aging or efforts to influence aging process are going to happen anyway. Regardless of whether you and I want to happen, the scientific research devoted to the issue of modifying the biological rate of aging will happen. I believe efforts, and there are a number of scientists who are creating companies where they intend to sell products to the public to influence the aging process, well-known scientists are doing this. And so whether you want it to happen or not, if indeed it does happen, it's probably going to come from one of these major scientists who have created these companies. And whether or not it extends duration of life dramatically, I don't know, but much like cloning, and much like many of these other issues that you're dealing with, the battle — I mean, people are going to battle against death. They are going to fight against aging, and developing these technologies are a fundamental part of the biological sciences. And it's going to happen whether we want it to or not, so being aware of the consequences of this, understanding what it means, I think is what many of us are really devoted to working on.

CHAIRMAN KASS: Thank you. The last question from Mary Ann Glendon.

PROF. GLENDON: This is just a comment, and I'll make it very brief, but I think we shouldn't leave this subject of longevity and the diseases of old age without reminding ourselves that we're discussing it in a part of the world where people are living much longer than they are in the majority of countries in the world, where the single biggest killer is still an infectious disease, Malaria. And to my mind, it's very hard to separate the political and economic questions from the moral and ethical questions concerning what is the broader society, and what are we doing with the allocation of resources?

CHAIRMAN KASS: Thank you very much. Our deep thanks to both of our visitors this morning for wonderful presentations, very engaging and open and illuminating discussion. We will adjourn and meet back here promptly at 2:00, where Dr. Lawrence Diller will be with us for an afternoon presentation. Thank you.

(Off the record 12:27 p.m.)


SESSION 3: PRESCRIPTION STIMULANT USE IN AMERICAN CHILDREN: ETHICAL ISSUES

CHAIRMAN KASS: Since this Council has taken a fair amount of flak for believing that great literature actually has something to offer the consideration of some of the large bioethical themes, I hope that you will appreciate this selection from literature. This is thanks to Josh Kleinfeld of our staff, who, in connection with this particular part of the meeting, put together for the staff a large collection of selections from literature — meant to illuminate, in a way, the nature of childhood — which included selections from "Secret Garden," and from "The Adventures of Tom Sawyer" and the like.

And if I read just one paragraph, maybe our colleagues will arrive. I see that my willingness to do so is producing them in droves. I don't have a Tinker Bell. Just one paragraph.

"Mrs. Darling first heard of Peter when she was tidying up her children's minds. It is the nightly custom of every good mother after her children are asleep to rummage in their minds and put things straight for the next morning, repacking into their proper places the many articles that have wandered during the day."

"If you could keep awake, but of course you can't, you would see your own mother doing this, and you would find it very interesting to watch her. It is quite like tidying up drawers. You would see her on her knees, I expect, lingering humorously over some of your contents, wondering where on earth you had picked this thing up, making discoveries sweet and not so sweet."

"And pressing this to her cheek as if it were as nice as a kitten, and hurriedly stowing that out of sight. When you awake in the morning, the naughtiness and evil passions with which you went to bed have been folded up small and placed at the bottom of your mind, and on the top beautifully aired are spread out your prettier thoughts, ready for you to put on."

I see that that little soft shoe has produced a quorum, and that we can move ahead.

AUDIENCE MEMBER:

Could I ask, are the briefing book materials available outside?

CHAIRMAN KASS: It should be in the package that you have.

This afternoon's session is on prescription stimulant use in America's children.

We have moved from the thoughts about the future to the present; from old age to things especially connected with childhood; from life span and genetic alterations, to brains, behavior, and drugs.

This for some people is already a topic already well worked over. It is old-hat arguments about Ritalin that have bubbled over several times in the last 15 years, including with Congressional hearings.

Yet, I would point out that this is not been the subject of any discussion as far as I know in any previous national bioethics council. Ritalin is a stimulant, useful in the treatment of attention deficit and hyperactivity disorders. It is according to the report, and not just in the briefing book, available and widely used off-prescription by snorting on college campuses.

And if one member of this council can be trusted to report accurately, is used on campuses not only by students, but by faculty members in lieu of afternoon naps.

That this, in addition to being used as treatment for clear disorders, has been used widely and in fact independent of any disorders, and is available for the enhancement of attention and performance. But also according to at least some critics, to produce compliance and pacification, with a sex ratio of use, some places numbering from 8 or 9, to 1 boys to girls.

In any case, we are going to concentrate primarily on this drug in its use in children, where the questions of the nature of childhood and the medication of our children is of some special interest.

And it is a special pleasure and privilege to welcome Dr. Lawrence Diller to the council this afternoon. In an area in which there have been zealots and radicals on all sides, this is a man who has occupied the sober middle voice of moderation, and of care, and of proper concern.

He is a practicing behavioral and developmental pediatrician for nearly 25 years in Walnut Creek, California, and he is also an Assistant Clinical Professor at the University of California at San Francisco, and the author of two very important books in this area, "Running on Ritalin" and "Should I Medicate My Child."

Dr. Diller, it is a great pleasure to haver you here and we are looking forward to the presentation.

DR. DILLER: I am delighted and honored to be here. I have been reading up on you, Dr. Kass. I got your book, and I am also very, very impressed with you and this panel.

But in particular what maybe distinguishes me from some other presenters here is that I am a clinician and on the front lines, and in here I think your essay on what is wrong with bioethics today, or something along that line, you were somewhat dissatisfied with the blah-blah nature of bioethics these days. And you were suggesting perhaps a more activist bioethics position. And I would say that I have no choice since I am there making decisions, clinical decisions, every day, in terms of who should or shouldn't get medication, and what are the treatments.

And that the ethical questions that I am facing have forced me to consider my role, and really my sitting here is just a very wonderful culmination of this personal attempt to address my own professional qualms in what I am doing.

And you will see at the end I think that it leads to a very activist position in bioethics. I am starting 10 minutes late, and I may have rip through some of this since I also noticed that —

CHAIRMAN KASS: You can take your time.

DR. DILLER: Okay. I have got 18 questions where otherwise everybody else got 12 or less, and I am not going to even try to do that. So here we go.

Overhead picture appears

If it was only this easy, (speaking in response to slide on screen) and in fact the demands on children and adults don't even allow for this kind of choice in the real world, especially school.

And on the other end the article in JAMA in 2000, which let the world know that 2, 3, and 4 year olds were taking Ritalin, provoke political cartoons like this one.

And what are we talking about here? (More slides shown.) We are talking primarily about two drugs. They are both classified as stimulants. Amphetamine, which is better known as dexadrine or adderall, and methylphenidate, which has many different names at this point.

And the most famous or infamous one is Ritalin, but actually Ritalin has been surpassed relatively by — the Ritalin trade has been surpassed by Adderall, which is an amphetamine, and Concerti, which is a methylphenidate-based product.

You can see by this schematic that their structures are very similar and in large group studies, their actions and side effects are very similar. So if I say Ritalin from here on, I am referring pretty much to the whole class of stimulant drugs, unless I specifically say a trade name otherwise.

And here are the current ever-expanding list of stimulants available, and I say that with a little bit of synergism, since while this boom did not begin with the pharmaceutical industry, it has really been supplanted and taken over by what is seen as an ever-expanding world-wide market in the production and use of stimulants.

And there is a graph in your book that is a little bit more up to date, but I took the 10 years between 1990 and 2000 to show you what the DEA keeps track of here, since it is a controlled substance. On the left is amphetamine, and on the right is methylphenidate, a 2,500 percent increase in production and use in this count.

Granted, not all directed to children. This is important. The biggest growing market for stimulant use in America is not in children, ages 5 to 13. It is actually in the teens and adult market, and the adult market over 18 is the most rapidly growing use of stimulants.

And again this is a change. Again, you will see here the much greater increase in amphetamine has to do primarily with the introduction of Adderall and the marketing of Adderall to physicians.

I am trying to guess at how many kids are taking stimulants. This is guess-work. I am not going to go into the details of how these were arranged. The problem with most published samples is they are based on small districts collected nationwide at best, usually in just some localities.

And you will see in a moment the huge variability in the use of stimulants preclude being able to expand a national guesstimate on how many children and people are taking stimulants.

And I am not going to go into why my figure is different from, say, from et cetera. But the general guess is about — at this point would be about 4 million children taking stimulants perhaps right now.

So the question that comes up, or the first question that comes up on NBC, or CNN, is, "Is Ritalin over-prescribed?" But then the adjoining question is Ritalin under-prescribed, and the answer is probably yes, depending on the locality. Meaning under-prescribed and over-prescribed, depending on the locality that you check, but I have changed my answer over the years to say is Ritalin over-prescribed? No longer, it is both, and it is basically, yes, even though there are pockets of under-use.

And what we are talking about here, the indication for stimulants in our country, narcolepsy is one of them. It is used occasionally as an augmenter for depression and Altzheimers, et cetera.

But by far and away, 99 percent of these drugs are used for the symptoms of attention-deficit and hyperactivity disorders. I am not going to spend a lot of time on the description and the problematic nature of the ADHD diagnosis today. I didn't feel that was really my mandate.

But just to remind you that the core symptoms are inattention, and hyperactivity, and impulsivity. However, a change in 1980 in the diagnostic criteria said that you could have ADHD without being hyperactive.

Just again, like all psychiatric diagnoses, there are no biological or psychological tests for ADHD, and more interesting to me is looking at the use of stimulants in America, and in the wide variation which points — you don't know how many people have ADHD for sure, but you can be much more certain of who is using Ritalin, and we will find out in a short time why.

And there are wide variations based primarily on social, cultural, and economic factors in Ritalin use in our country and the world. And this is a DEA map of several years ago.

It does not show up all that well here, but green is under-use, and red is over-use, and it is interesting that Hawaii perennially has been the lowest per capita stimulant-using state in the country, generally using one-fifth per capita of what the highest using state does.

More recently you will see this cluster in New England. It used to be that Michigan and Indiana, and New England now has, you know, 4 or the top 5 States clustered over there. And one sees that it is in proximity to Boston.

Massachusetts is also now — this is a map from 1998. It is how far away you are from Boston that determines the likelihood of how much Ritalin that you are going to get. And no specific institution is mentioned.

What we see documented is a half-to-one-quarter-eighth use in African-Americans with comparable socio-economic status compared to white Americans in the use of Ritalin.

Similarly, Asian-American children are conspicuously absent from this "epidemic," you might say, probably for other reasons. And then Hispanic-Americans fall somewhere between white American use and African-American use.

Just an example of how two localities contiguous to a body of water have very different Ritalin use rates. The reason why we use Canada here is that it is said that culturally when American sneezes, Canada catches pneumonia.

So there is a very similar phenomenon and controversy going on in Canada. The difference is that they have national public health. So every single Ritalin prescription is documented.

You can do this in Canada, and you can't do this in the United States. So what we have is then Victoria, a very homogenous, white, basically suburban community on the other side of Vancouver Bay or whatever from Vancouver, which is a polyglot, very Asian city, and you see the difference in — and again we have National Health in Canada. And so access is not the issue here for the difference in Ritalin-use rates between those two communities. And so one concludes that in Canada and in the United States, while there are pockets of under-use, ADHD diagnosis and stimulant use is primarily a white middle and upper-middle class phenomenon.

Whether that is good or bad would remain to be seen. For example, African-American women had many fewer hysterectomies in the 1980s. That turned out ultimately to be a good thing. African-American men get very few or very much less coronary artery bypass surgery.

It remains to be seen whether that is a good thing or not, and we are still not sure about the Ritalin issue. What is the reason for this wide disparity?

Well, the diagnosis is part of it. There is no test, and ADHD, except in extreme situations, can be a diagnosis in the eye of the beholder. Just to complicate things, a psychiatric diagnosis may be challenged in adults, but it is a very challenging and questionable procedure in children to witness here the number of additional diagnoses basically as a way of describing children.

And it is not unusual in certain tertiary clinics for children to have 3 and 4 diagnoses, along with the ADHD. What does all this mean? I think the nomenclature in the neurological system has a lot to be desired.

I want to highlight learning disabilities and opposition defiant disorder. And I leave bipolar out because bipolar is the most controversial diagnosis in children these days, but in the Harvard Clinic, 23 percent of their ADHD kids had a bipolar disorder.

This is a very important study, because this is a study that tells you what is actually happening in the real world, and not in the university center where the children are highly screened and categorized perhaps appropriately.

Basically you are looking at a population of 4,500 community kids, and those are the ages. It turns out that the prevalence is about what people feel, 3 to 5 percent maybe is what is out there in the population.

They found that 7 percent of the children overall were receiving stimulants. Of those with diagnosed ADHD, about three-quarters were getting Ritalin. What that meant was that over half of the children getting Ritalin had no ADHD.

They may have had other problems, but they were — the medicine in the real world is being used for a variety of problems, including those of impulsivity, and inattention, and hyperactivity.

They also found like I have told you before that within their study that the more affluent the family, the more likely the child was to get stimulants.

And just again to highlight here, there is a huge difference between university-screened children and what is happening in the real community. The response from organized medicine, academia, has been for diagnostic guidelines and to push diagnostic guidelines on to the community.

But if history is any guide, that previous guidelines have never, never changed doctors, and practicing behaviors, which are much more influenced by economics and threats of legal suits. And we will see in the short time why economics might push doctors towards using stimulants.

So there has been a thousand percent increase basically between methylphenidate and amphetamine in those years. Why? Well, guess what. I am not going to tell you.

It is in this book and it is 340 pages long, and it goes beyond what I can do in a 40 minute presentation. And again that is not my mandate. I may touch on it briefly at the end. Okay. But this is important. The United States uses 80 percent of the world's Ritalin.

Now, it used to be 90 percent, and so it is changing in other countries. Canada uses almost as much as we do per capita. Australia is catching up. The U.K. — it is Western Europe where it is very different, of course. The under-developed countries don't have or don't use any stimulants at all.

But even though Western Europe is maybe catching up, physicians in the U.K. are still using one-tenth rates of Ritalin use than we are. In France and in Italy, it is practically not used at all. And in Germany, it is somewhere in between.

So that doesn't mean that they could be using a little bit more Ritalin. It could be why are we using so much Ritalin.

Now, a little bit on the drugs themselves. The way that these stimulants work, is that they block dopamine receptor sites, and therefore increase the neurotransmitter at the synapse, and tagged dopamine seems to show up more at the pre-frontal cortex and the local cerruleus in the brain.

However, there still is no coherent theory to entirely explain Ritalin's action in ADHD. In other words, dopaminergic theories have been thoroughly explored by attempts at getting dopamine levels in the brain, and trying to get PET scans.

You read about these things, and they are very tantalizing, and very interesting, and no doubt they are biological correlates. However, at this point — you know, like the PET scans, and the MRI scans, and any biochemical testing, none of them are ready for prime time, except on television, in terms of clinical use.

Why? Because there are way too many false positives and way too many false negatives. Ritalin is — this is basically what we know about Ritalin's effects. (Excuse me for the sound effects. This was for another, and it will get either louder or softer and we will find out in a moment.)

Well, it does increase concentration efforts, and effort compliance, and peer relations. It decreases motor activity and impulsivity, and defiance, and aggression.

It increases strength, and endurance, and speed, and we may have a chance to talk about Ritalin in sports in a moment or towards the end. And academic grades do improve in the short term.

We will talk about — there is no paradoxical effect. Ritalin works the same on children, adults, ADHD or not. There is no change with complex skills.

Okay. The long term studies were done, and there were decent long term studies done in the 1960s and '70s. They have been criticized for non-randomization.

The children who were treated with Ritalin, let's say, just 6 to 13, there was no long term changes when looking at them post-adolescence. Neither good nor bad being treated with Ritalin, or not being treated with Ritalin.

The rejoinder is that these children should be treated through adolescence, and then we would see a difference, but at least childhood treatment of Ritalin resulted in no long term changes.

In these studies, they were broken up where also they received either family counseling or special education. Curiously, the families that did receive family counseling, and special education did show reductions in arrest rates and substance abuse at 18.

And Ritalin tended to be augmenting to that. The studies have been criticized for non-randomization. A way of interpreting those studies would be that those families that choose to get involved in counseling, and/or special education, or have access to it, may be a different kind of family than one that doesn't.

And overall only small effects on learning and achievement long term. So there is a disappointment long term even though short term results are very, very impressive.

Just quickly here on Bradley's initial report, he said "appears to become hyperactive kids." Well, that's not how it got understood. and for decades, and still this notion that somehow a response to Ritalin means that if you calm down, it means that you are hyperactive and ADHD. It happens to everyone.

And indeed stimulants were studied extensively by the military in the 1950s, and I like to say that people don't know this, but Rommel used amphetamine with the German Afrika Corps in World War II, and the GIs were given amphetamine in return, and many GIs came back addicted to amphetamine after the war.

The military ultimately decided not to use stimulants as routinely. Why? Because of episodes of erratic behavior, and the idea of giving someone a gun who acts erratically was not thought to be prudent.

Finally, this was nailed finally with Rapaport studies of normal boys and men, and again showed equal amounts of improvement, and this is important for people considering enhancement versus treatment.

Equal amounts of improvement in performance tests between ADHD boys and non-ADHD boys on continuous performance tests when given stimulants. What happens here is that if this is ADHD, and this is normal children, when you give them Ritalin, this is what happens. The normal children act super normal.

And I already made the point, the last one there. Side effects. What doctors would generally feel tolerable side effects, sometimes families feel differently.

Temporary appetite suppression, insomnia, more seen with the amphetamine class. And this phenomenon called rebound, where the behavior deteriorates after the child or the medication wears off, is reported to be a very common phenomenon, and is never studied yet in any formal study, and I find that pretty interesting.

Tics have been brought up, and it is controversial, and I would say that currently if someone has moderate to severe ADHD, you ought to give them stimulants in the face of tics, because the ADHD is generally a more disabling condition.

Euphoria will occur. It doesn't occur in children. I would say the only clear biological difference that I can see, and this is important when it comes to abuse, is children don't get euphoric when you give them — and I am talking pre-teens here.

That something is happening, and I think it is partly physiological, and I think it is partly sociological, because in the Army studies more euphoria was reported when the GIs took the medication in groups than when they took it individually. Isn't that interesting?

I find that very interesting. Anyway, kids don't like higher doses. They complain. They say they feel wired. They feel weird. And teens and adults will say they feel grand. They feel powerful.

Long term growth was an issue raised in the 1960s and 1970s, and studies from the '80s and '90s seem to squash that concern. What remains? The notion that Ritalin is in your system and out of your system is something that we have always held to be able to tell parents.

Well, in fact, animal studies show single or two doses of Ritalin permanently affect receptor sites. They increase the number of receptor sites in the synopsis, okay?

DR. McHUGH: Can you tell us what it means?

DR. DILLER: I don't know what it means.

DR. McHUGH: Can you explain what that means to the audience?

DR. DILLER: Well, one stance is that giving one or two doses of Ritalin to rats — and you have rats who are unexposed to Ritalin, and then you expose rats to Ritalin, because you have to kill them and section their brains.

And you label the dopaminergic sites, and that the dopaminergic sites increase in the exposed Ritalin rats after one or two treatments. What does that mean clinically? I don't have a clue.

I am talking fast, and I am going through things very quickly. If there are questions, please, I don't mind being interrupted. The use in toddlers as I already mentioned is highly controversial and touched a national nerve as you saw, and that resulted in two conferences on the subject, and there is a study going on at Columbia right now.

We will talk about this in a moment, and this is the big fear that parents have. The increase of subsequent drug use in pre-exposed children to Ritalin. And then the notion is that Ritalin actually is superior to non-drug treatments in the treatment of ADHD. And we will touch on illegal use in a moment.

Okay. And the presensitization effects in animals and humans: single doses of Ritalin to both animals and humans presensitize them to subsequent addiction.

I am not going to go into the details of the clinical studies. One says that Ritalin does sensitize children to cocaine and cigarette abuse as adolescents, and one study says it doesn't, especially if you give it to them as teens and adolescents.

In other words, if you take Ritalin from a doctor, you won't abuse the drug yourself. My opinions on this as a physician who continues to prescribe Ritalin to children is I think both the presensitization effects, and whatever effects clinically, treatment as a child has on subsequent adult or teenage substance abuse is small compared to effects of family and neighborhood. That allows me to continue to prescribe at this time.

It is a little bit beyond our — I am doing pretty good in terms of time actually here, but I want to get to some of the moral-ethical issues, and that may take some time.

We will probably touch on this. I guess this is the hottest one here. I already said that the greatest expanding market is in the adult market for adult ADHD. There is also an illegal market going on here, and you can read what it says.

Now, the bottom bullet there, I already mentioned the GIs. Since World War II, in the United States, we have had three waves of doctor-prescribed stimulant abuse epidemics.

In 1945 to 1950 was the GIs. In the early '60s, it was the period of the Dr. Feelgoods, and that just came up again recently, where the Hollywood stars were being treated, and so was President Kennedy being treated with IV amphetamine, and in the late 1970s and early '80s was dexadrine for diet control, weight control.

In all those situations, there were indications, support indications, for doctor-prescribed stimulants, and in all those situations a core group of patients became addicted through their physicians. There is no doubt in my mind that we are going to have another wave of doctor-prescribed stimulant abuse. Again, the paradoxical thing here is that it is actually safer in children than it is in adults.

And the adult situation has only really just started in the last 3 or 4 years. And when you see family physicians in particular prescribing stimulants, you know that they just won't be able to follow their patients as closely.

I want to get into the issue here of ethics and values. Okay. First of all, the issue of ADHD as a neurobiological diagnosis, and what that means is that either when a child or an adult has this, and what it means politically very often is that it could be used in the service of saying— "Well, we can't really do anything about this kid environmentally. He is really pretty much determined to have this problem. The only thing is to contain him and to give him drugs." It also again raises issues on a moral level that if indeed they are so determined this way, then in fact if they make wrong choices, they can't be held morally culpable.

I actually like what Russell Barkley says about this. He is the intellectual guru you might say of ADHD, and he says that ADHD might be considered an explanation, but not an excuse for behavior.

Here we see maladaptive behavior as disease, versus accountability and responsibility. This is a big issue in the schools, particularly over discipline. And that the disability movement has held schools accountable in the sense that unless they make adaptations to their children's diagnosis, the child can't be held responsible for acting out behavior. This whole issue really pits the rights of the individual versus the rights of the community in probably some of the most provocative ways.

Indeed, you know, 3 children out of 4 were expelled for I think bringing a weapon to school, and this was before Columbine, and the fourth one was not because he had an ADHD diagnosis, and the schools had not made an adaptation, in terms of a behavior plan.

I am not saying that there shouldn't be behavior plans for children. And don't get me wrong. Buthis can be used again politically in very interesting ways.

Similarly the ADHD defense has been raised repeatedly in criminal law. It has never gotten a criminal off because those are based more on the McNaghten Rule of knowing right from wrong, but it has mitigated sentences, and I would suspect that you will see wealthy clients using that defense more than poorer clients in criminal cases.

This notion here as more and more people use Ritalin with their children, will it cause parents who aren't ready to use Ritalin, to feel like they must? And this has happened absolutely, and especially in the arena of special education.

But it happens daily in the classroom. Probably the most famous or infamous case of this is Patricia Weathers' child in Upstate New York, who actually was reported — she and another family were reported to their local Children's Protective Services because they decided to stop giving their children psychiatric drugs.

The school reported the parents to CPS for medical neglect. In both cases the cases were thrown out, and they were adjudicated in favor of the parents, but it does show the extent to which schools at least have come to believe that acting out children is a biological problem that needs to be addressed with a drug.

Parents repeatedly have come to me and their legislators complaining about pressure from the school to get a medical evaluation and medication. The response has been in 11 States, and in essence gag laws preventing teachers or school psychologists from mentioning ADHD or Ritalin to the families.

They can still talk in terms of a medical evaluation, but they must exhaust — the general language of these laws is saying that they must exhaust educational and disciplinary techniques before they request a medical evaluation.

The impairment question is an interesting one. The notion of having a psychiatric disorder implies that you are impaired in some kind of way, but Ritalin is very — ADHD is very interesting in here, in that the standard has been not necessarily impaired compared to others, but impaired in terms of your potential.

So therefore if your Wexler Intelligence Scale comes out at 120 or 130, and you are only getting B's and C's at school, and you are not attending, and meaning not paying attention, and maybe you are disinterested, or maybe you have ADHD inattentive type, this is a common reason for parents and/or teachers bringing children to my attention.

This notion of impairment was brought to the forefront socially in a case of medical students versus The National Board of Medical Examiners, where these medical students had twice failed the national credentialing exam, and claimed that they wanted unlimited time on the basis of their ADHD disability. The courts adjudicated against the medical students, and indeed, Russell Barkley, cited a — a witness for the National Board of Medical Examiners, in that the court ruled that while the students may be impaired within their own potential, they certainly are not impaired compared to the rest of the population, in that they finished medical school.

And indeed that on the individual clinical level many — I see very few — I see very few felons in my practice. I see very many lawyers, doctors, accountants, coming in wondering whether they have adult ADHD.

And whether that anxiety or setting the bar too high for them, but certainly the degree of achievement that they have made that allows them to come to my office strongly suggests that they are not severely impaired.

And yet, "Driven To Distraction," the book by Edward Hallowell, opened the gates for the use, I think, of stimulant medication in the adult population, primarily for enhancement purposes. That's my personal opinion.

I will get flak from that in certain self-help group organizations. Again, that goes very nicely into the last two points, treatment versus enhancement, and where is the line. Where is the line? There is no line. There is no line.

Cosmetic Ritalin. You have Peter Kramer here, and so the notion of better than good. Well, in Prozac it is mood, but in Ritalin, it is much more so clearly performance, and it has been known for a hundred years.

And so the issues of Prozac are kind of still speculative. And Ritalin? We have known that for a century. Interestingly, Ritalin and amphetamines are banned in sports. Why? Because in sports, we consider not just the achievement itself, but the effort involved in the achievement.

And it is felt — and Dr. Sandel raises this somewhat later on in enhancement, I believe, versus treatment, or the problems of enhancement. We take not just the achievement, but the effort involved.

And it is felt that somehow taking a stimulant drug cheapens that effort. But there is another important reason that Dr. Sandel doesn't mention, I believe, in his paper, and that is free will under pressure.

If one athlete is permitted to take a stimulant drug, a performance enhancer, it puts pressure on all the other athletes to take the drug just to stay even.

For that reason, stimulants are banned in most professional sports, and they are banned in the U.S. Olympic Committee Sports. Interestingly, under legal pressure from self-help groups, the NCAA allows the use of stimulants in athletes who have a doctor's note that says that they have ADHD.

Now, the question is, isn't academics different from sports, you know? Sports is competitive, and sports is extracurricular. Well, I am not so sure how extracurricular it is to an inner-city child trying to get out of the ghetto. I would say that is a pretty life-meaning thing that he is engaged in.

But certainly things like the SAT test are competitive. That's why it is partly there. And reports are increasing of children — and you will be hearing about this more, but children taking stimulants specifically for exams. It is already done on the college level, but being given stimulants by their doctors is something that we are facing. Will we be soon seeing drug urine testing for SAT exams?

And I think I am going to move quickly on this. This is the building I feel of anti-affirmative action swell that is going to occur in the disability rights movement. And the Bakke decision marked the line between the retreat from affirmative action.

And these kinds of things driven by the disability rights — and I am not — I mean, I think there are some very disabled people, and this is not my axe to grind. I am only saying that as disability becomes more and more nebulous, that these kinds of things are going to cause problems for the general community.

I am going to move quickly. Basically the MTA studies are the best government studies, and the headline that you saw earlier was "Drugs Work. Psycho-Social Treatments Add Nothing." Well, it turns out that it is not so cut and dry as that, and it turns out that the families preferred combining treatment with drugs.

But this is the important issue here. I am not worried that Ritalin doesn't work. I am worried that Ritalin works. It works quickly, and relatively cost effectively. But I don't see Ritalin as a moral equivalent to helping parents parent better, and helping teachers teach better.

And Joseph Biederman at Harvard said, "Well, we simply don't have enough money to provide all the psycho-social interventions." So with that I counter my own modest proposal.

With classroom size averaging 29 kids per class, and 4 million or so children taking Ritalin, I propose that we increase the number of children taking Ritalin to 7.5 million, and we could probably increase classroom size to 40 kids per class and save a lot of money.

Is anybody interested? Does the President potentially want to float that one? All right. There are those who said in fact that this is a conspiracy between academia and the pharmaceutical industry, and to some of the self-help groups that are funded by the pharmaceutical industry.

And I say that you don't need any conspiracy. You have the invisible hands of Adam Smith at work here. Market forces. But I do want to touch briefly on the pharmaceutical industry's influence.

There are market forces working on the physicians, too. Psychiatrists are paid much more for psycho-pharm follow-up visits than they are for one 45 minute visit with the child's family. Much more, three times more.

But with the drug industry here, this is how they influence what is going on in our thinking about children. There is money for the drug research, and there is absolutely as you know an incestuous relationship right now between researchers and the drug industry.

They claim a lack of conflict of interest. I don't see how that is possible long term. There is some talk about these studies published only promoting positive findings.

And advertising the doctor's work, and I am paid $500 to attend a dinner supposedly as a consultant for Atomoxetine, the new Strattera drug, and it was just a promotional event.

Okay. No stock dividends or equity to special education and family treatment here. And this is a picture of an ad in a women's magazine. I couldn't get in the title below in that. It says, "Homework is no longer a problem at the Williams' family because they have learned about ADHD. Call this 800 number."

What is my problem with this picture and that message? Well, to me, it reduces a fairly complex social developmental undertaking, homework, to one thing, the brain, to be solved by taking a pill.

Now, I may tell that to you, and occasionally I get on t.v. when they need a responsible dissenting voice in this otherwise media blitz, let's say, on Strattera, the new atomoxetine drug.

But relatively speaking, where is my voice compared to the power a million dollar corporation can bring to the introduction to a new drug? So the way that we think about children being so influenced by profit-making institutions deeply concerns me.

And ultimately what we have here, and I am almost done, is an intolerance in our country of temperamental and talent diversity. We have a great fear that our children will not make it, and this fear is passed on to the teachers, who put a lot of pressure on the kids.

Would Tom Sawyer and Huck Finn be on Ritalin today? No doubt in my mind that they would be if they lived in my community. I see Tom Sawyers weekly.

What have we got here? It's not going to change very fast. Basically, we have a culture whose state religion is corporate consumer fundamentalism, which says seeking emotional and spiritual satisfaction comes from material acquisition.

And so I have a lot of round peg and octagonal peg kids who aren't fitting into square educational holes, because the message there is if you don't get into college, buddy, you are sunk. Ritalin will lubricate that hole for that child.

I am not against Ritalin. I use it after we fully explore what we can do with the family and the school, and if the child is still struggling, it can make sense. I am against Ritalin as a first and only choice.

One guy said, "Well, Dr. Diller, would you withhold treatment for diarrhea until you were absolutely sure of the cause, or would you treat the diarrhea?" Well, no, I would treat the diarrhea.

But if I even suspected that a factory upstream was polluting a river that was causing the diarrhea, and if I just treated the river, or just treat the child without addressing the larger issue of the factory, then I am complicitious.

And this is a term that I have picked up as a physician, with values and factors that I think are bad for children. So my role as a doctor, yes, is to relieve suffering, and if we have explored the alternatives, and we have tried them, then I will give Ritalin.

But my role as a citizen compels me to speak out about the larger issues. So I think that this thousand percent rise is a canary in the mine shaft, and we should be looking at the demands on children, and think of Peter Pan stories and things like that.

And look at how we distribute resources to children, and their families, and to schools. Real quickly, I think our diagnostic system is a mess, and that one of the reasons why we diagnose someone with ADHD and give Ritalin is because it allows for services.

The doctors make more money also if they come up with a diagnosis. We should consider a needs- based system that they use in mental retardation already.

Early learning is great. The Sesame Street and Headstart works very well to make a difference for the inner-city poor, but it has repeatedly shown to make no difference for the middle and upper-middle class.

What it does create is a sense of inadequacy, and everyone involved in education will tell you what we are expecting from four year olds is what we expected from five year olds a mere 20 years ago.

Well, there is just too large a segment, especially of boys, who aren't getting it. And when they look distracted, and parents of 4 and 5 year olds are coming, and referred by the school teachers, saying, "Does this kid have a chemical imbalance?"

I think we need to reintroduce round and octagonal holes in school for round and octagonal pegs, who will do quite well, thank you, in a maybe non-high-tech, non-professional position.

I think it would be very boring by the way if everyone became either — it used to be doctors or lawyers, or Bill Gates. What makes our culture rich is diversity. And yet we are training all the kids to do the same, and if they don't do it, we are giving them Ritalin.

I am just going to — I can't read this, and I am just going to let you see it. This is more communication between doctors and teachers, a very big problem. This would be very helpful in reducing the amount of ADHD or Ritalin if we could get more powers to provide immediacy of reward and punishment in the classroom, which works very fine.

A similar thing. Parental counseling does work, especially for the younger kids, but getting access to it is difficult.

So this is the final thing, ADHD and Ritalin use in America, and I think it is a message not just for children with ADHD, but all the families with children in America.

It is time that we paid attention and that is the website where you can get a lot more information. Thank you.

(Applause.)

CHAIRMAN KASS: Thank you very much for covering a lot of ground and raising a lot of terrific questions, and for the spirit of concern that animates this and all your work on this subject to date.

We are going to get the lights on so that you can see the whites of their eyes as the conversation starts. I wonder if — well, other people volunteer, but I would certainly like to ask two of our colleagues who work either in neuroscience or in psychiatry to offer their thoughts on the phenomena.

I mean, I take it that this is — that while this is a large matter with us now, what we know about — we included in the briefing book this long review article out of Johns Hopkins by Riddle on pediatric psychopharmacology, and it is perfectly clear from the spirit of that, that the biological understanding of psychopathology has won and has emerged victorious.

DR. DILLER: In the medical model?

CHAIRMAN KASS: Yes, in the medical model, and that there are lots of opportunities for all kinds of disorders, some of them clearly defined, and some of them squishy.

And also lots of opportunities, and never mind the diagnosis, where there will be a considerable demand for the aid of pharmacology to produce either compliance or better attention, or other sorts of desirable things that parents with perfectly understandable reasons may want for their children.

So I would be interested to know either from the side of the neuroscience or from the side of psychiatric practice — well, there is a question raised about how we are taking this subject up, not only for itself, but what it might be a token for a whole area of similar things.

And whether I could ask Mike Gazzaniga and Paul McHugh to start in the conversation if you wouldn't mind.

DR. GAZZANIGA: Sure. Thank you. We are in a situation where the National Institutes of Mental Health, I think, endorses the use of Ritalin and says it is safe. It is the most studied of all the drugs administered to children.

And so we do have one of our major health/government agencies saying that this is an effective way to treat. And I am neutral on it. I am just reporting that is the fact of the case.

But I would be interested in knowing that given your conservatism on it and caution for it, when you actually get into the clinic and you see the next hundred kids that are referred to you, where does it land? How many of them do wind up having Ritalin prescribed?

DR. DILLER: I think on the ones who are — well, first of all, I am in private practice, which is different, and I do see a relatively middle-affluent population, and I think that is to be considered.

But to answer your question, I would guess relatively about a third of the children who come in to see me, about a third to about a half wind up ultimately taking Ritalin. It is often a step-wise procedure in my situation.

I actually don't get to see the most flagrant cases of ADHD, because they are generally referred, or they are being addressed by the pediatrician and primary care doctor, okay? I am seeing the complicated cases of ADHD, or I am seeing lots of borderline stuff, the Tom Sawyers and the Huck Finns.

The case is made by the pro-medication side of the morbidity involved in untreated ADHD. The notion that many of these children do very poorly in school and ultimately become prey to both the juvenile justice system and in substance abuse.

And there is no doubt that impulsivity is an important factor as a temperament trait to those kinds of problems. The question is whether ADHD is the best marker of that, or are there other better markers, temperament markers, of intensity or adaptability especially being one of them.

In any case, they said there is usually morbidity of not treating, not treating children with Ritalin, and I don't know — again, no one has long term data to say if Ritalin really is effective long term.

But I don't feel that we can just wait until we get finally, quote, "a good study," and in fact that good study will never happen in the United States anymore, because it is standard medical practice to give Ritalin.

But again that doesn't deny the issue that I am raising, which is that there is a core group of disabled children who wouldn't need a physician to say that there is something terribly wrong.

But that I suspect is along the lines of one-eighth — and I am guessing — of who gets Ritalin now. But there is a much larger group of a gray zone as you saw in that Rocky Mountain study, and that is a demonstration of real life practice there.

And there the notion of morbidity and using Ritalin to address morbidity raises for me serious ethical questions. Again, for me, the idea that Ritalin works is not at issue. The question is as a substitute or as an equivalent for helping parents, and/or teachers, simply because it either works faster or costs less money.

Now, studies again that say it works better than helping parents, or helping teachers, I think they are looking at a very narrow definition of what the problem is.

And I think that these studies look at the ADHD symptom list, and in that sense you could say that Ritalin is very specific. It is almost as if the disorder has become tailored to meet the effects of the drug.

At least ADHD has evolved over the last 30 years, and I have that feeling very much so. And by the way that is not unique to ADHD diagnosis. The rates of depression soared after the introduction of Prozac.

So the way that we conceptualize things very often are influenced by what treatments or how they are promoted. Anyway, I have got a little meandering there. I want to be clear here again that the answer to your question is, I would say, one-third of the kids.

But it usually is a step-wise process, particularly for the younger ones and the borderline ones, where we give behavioral interventions and make sure that the learning issues are addressed for a good 2 to 3 month period. It isn't very long.

But really — and you can see what the family is capable of, and what the school system is possibly able to mobilize. But that is with a physician who acts as a strong advocate for those other things happening.

And typically the way that the economic system has worked out, and ideologically also, but it is very much driven by economics, again the notion that the child psychiatrist or the behavioral developmental pediatrician, is much more rewarded by a 15 minute psychopharmacology follow-up visit than a 45 minute visit.

So if your only tool is a hammer, all solutions are nails, and what has happened to our profession, I'm afraid, is that the person potentially with the most experience, and the most social clout, in terms of getting things to happen and change, has been relegated to giving one pill or another, and I think that is a damn shame for the sake of the children and the families.

CHAIRMAN KASS: Dr. McHugh, Paul McHugh.

DR. McHUGH: Yes. Well, that was a wonderful presentation, and for my colleagues, I would like to only underline a few things that you said that I think that they need to know in order to judge how this situation came about.

We have talked before, but I want to talk further about the present diagnostic system in American psychiatry, the DSM measure. It is a very peculiar classificatory system because it fundamentally is a symptom checklist for almost everything.

It doesn't organize things according to their natures, and even according to their causes and their development. So it has encouraged psychiatrists to use a top down approach to diagnosis. Instead of taking a history from the beginning of the developing person, and seeing aspects of that person's life played out in the themes that all of us face, such as schooling, family, occupations, marriage, and the like.

And it goes in and it says do you satisfy these five criteria here, and three of the other criteria. The result of that is that since there aren't a whole huge number of symptoms that anyone can show mentally, is that there is a huge expansion in the people who satisfy checklists.

You mentioned ADHD and that is our subject, but depression, and PTSD, social phobia. People say 1 in 8 people suffer from social phobia. All of this is top-down, and encouraged by both the classificatory system and by the fact that drugs seem to make a difference.

What happens as you have said in this approach is that drugs do make a difference, but no one thinks about the consequences in the social network of the person. No one thinks about the character of the child, and no one thinks about the character of the family.

No one gives advice on parenting and to a person about how they might overcome certain matters. And they do expose them to, after all, drugs that have serious consequences, including addiction.

DR. DILLER: But I don't want to leave on the record, let's say, this notion that children are becoming addicted by being treated through Ritalin. There is no evidence of that. The drug is misused.

DR. McHUGH: I was saying that some of the drugs — for example, adults now, with adult ADHD, they have become addicted.

DR. DILLER: Yes, that is an issue.

DR. McHUGH: And they get a checklist, and they get a pill, and they get addicted. So the younger child does not become addicted presumably for the reasons that you said. That he doesn't like the drug because of his neurobiology. But your point about this issue is a general issue, and is a specific example of a general issue in American psychiatry today.

DR. DILLER: You know, we had lunch, and we agreed a lot about problems with the DSM, but being entirely realistic, the DSM is not only an ideological document, but it is a legal and financial document.

And it is particularly in its accessing services and money that the DSM is powerful, and the DSM for nature will not change until we are able to offer services and/or rights to people in another way.

Again, the drive towards disability, and the drive towards pathologization comes, and people are in genuine need much of the time, and they are looking for help and the way that they can access that help either in terms of services or money is by obtaining a diagnosis.

This economic push, and then there is a service industry built around that, in terms of the physicians and the mental health industry. Until that changes, and again I think that more and more people are asking about that, but there is a very entrenched bureaucracy here that sees it working well.

DR. McHUGH: A bureaucracy built by the psychiatric choice of a DSM-based approach, and the linkage that they could have with powerful drug companies.

It took only a few years to build that bureaucracy, and a coherent attack on it could I think bring it down, especially if you could show — and we can show — that an approach to patients — that it takes a little more time, but it is bottom up rather than top down — will not only do better for the patients, but do better for research. Ultimately right now our research on depression is incoherent.

DR. DILLER: It is delightful to have this kind of conversation, but you tend to have these at bioethics meetings, and not at industry-sponsored technical meetings.

DR. McHUGH: Well, that's because I don't take any money from drug companies, Dr. Diller.

CHAIRMAN KASS: He is also not afraid of anybody.

DR. McHUGH: Yes, right. But to just press on a little bit further in what you are saying. I do think that the other point that I wanted to emphasize that you made very good is this pressure to choose this, and you mentioned that athletic endeavors have struggled to fit that out.

You and I mentioned that at lunch, but my colleagues might well remember that a very distinguished American psychiatrist, Arnold Mandel, a person that I know, and a delightful man, was the psychiatric consultant to the San Diego Chargers, who were all on amphetamines, and he went down to try to stop them, and the defensemen said, "Now, listen, Dr. Mandel, can you imagine what it is going to be like for me to get out there with these other 300 pound guards dripping with amphetamine? I have got to do it." And in the process of trying to help them with this, Arnold Mandel got into a considerable amount of trouble with the FDA over it.

So that pressure which we saw in the sports is not present for families for all kinds of things.

And what is missing fundamentally is an understanding of the person and the distinctions amongst disorders that could express themselves in similar ways, but would take quite different treatments.

And that is both a technical, professional, and deeply moral problem right now in our field.

CHAIRMAN KASS: Michael Sandel.

PROF. SANDEL: This is a question that I would like to direct initially to you, Paul, and then to Dr. Diller. Taking the critique of the DSM and the overuse and so on that you have educated us about really over a number of these sessions, and hearing the stories about Huck Finn and Tom Sawyer, which you often hear in the popular discussion — and, well, they would have had if only ADHD had been around, they would have been diagnosed and so on.

DR. DILLER: Or worse.

PROF. SANDEL: Here is the thing that as a non-medical expert that one is led to wonder, and I wondered what your answer would be. Is ADHD really a disorder or a disease?

DR. McHUGH: In my opinion, when I first was introduced to ADHD in my training, it existed, but it existed in a very few children, and it was associated with the most remarkable forms of hyperactivity, in which — and usually with a touch of brain damage and mental retardation.

These were children that would run around and tear up the household, fall asleep in the laundry basket, and then wake up and buzz around further. Those were the cases that Bradley was talking about back in 1937 when he introduced the idea that amphetamine might seem to improve.

It was these kids, and there has been an insidious spread of that to the point where a sizeable proportion of people temperamentally on the active side are encompassed by the term, since the drug will slow all people down who are, let's say, 10 years old. It will slow — and if you can imagine a dimension in which kids with a Bell-shaped curve related to their activity, you can see that there would be a group out here on the right, and there might be a disease group that was also pushed further out to the right.

If you could move them all to the left, you would if you were strict in your criteria get few of the temperament and all of the people with the disease.

But if you were loose in your criteria, you would move down close to the mean, so that anybody that spoke back to Mrs. Murphy in the third grade like I did would be on it, you know, right off the bat. And those are serious issues that should be of concern to us.

DR. DILLER: Well, when you asked the question, I kind of like internally moaned because it is a fighting words kind of question, especially to those families that have made a commitment towards treating their children with medication, because the implication then is, well, you know, you are just making all of this up, mom and dad, and it is used in that kind of rhetorical kind of way. I know that you didn't mean it that way.

DR. McHUGH: Nor did I by the way.

DR. DILLER: I know. I know. And so my answer is similar to Dr. McHugh's, and maybe a little bit different, in that there are — well, first of all, the construct has lots of problems to it.

The construct meaning as defined in the DSM-3< "often fidgets — you know, often acts up," — well, what is often? You know, the construct, even though two psychiatrists can agree — and we will get to in a moment about this Bell-shaped curve that he was talking about — is very different in the community.

So that study, and how it is willy-nilly diagnosed, and prescribed in the community. There is a core group of children, and I don't care what environment they are in, or how they were raised, or whatever, who would be troubled by problems of inattention and impulsivity, and hyperactivity.

And again if Dr. McHugh is referring to that group, this whole panel would probably agree on that. Again, I was guesstimating one-eighth to one-tenth of what we treat.

In fact, WHO criteria in Europe tend toward that criteria, and that is what you get, one-eighth to one-tenth. That Bell-shaped curve that Dr. McHugh mentioned, attention and the ability to focus, let's say, is dimensional.

It is not categorical. You suddenly don't have ADHD if you have 5 of 11 symptoms, and if you have 6, then you do. I mean, that's crazy. Pardon the pun.

But let's say you have — or I have to make a graph like this, and you have a Bell-shaped curve, and over here is really good attention, and that can be a problem, too. Sometimes that is called obsessive-compulsive type stuff.

And here is really poor attention, and unlike intelligence, for example, trisomy, and Downs syndrome, where you have that Bell-shaped curve, and then you have a space, and then you have another curve, clearly identifiable. That's not true with these symptoms, okay?

The real interesting thing is where that line — let's say that if this is bad, where that line of deviance is decided, and that is clearly culturally, socially, family, economically determined. So, you know, Hawaiians are way over here. African-Americans are over here, and it looks like Victoria is almost like in the middle, where they start to worry about it.

And the diagnosis has become broader and broader, and again, speaking of — and I am laughing at Dr. McHugh, and his feistiness, okay, which might have been construed as a non-compliant ADHD.

Very often the weaknesses that we have as children are the very things that we learn to work off of and develop our strengths on. And again I think it would be a very — and you have got to remind parents about that, because they are so afraid that their kids are going to get hurt and fall behind.

But in terms of how we become full people is often working off of our weaknesses. And Dr. Kass' kind of work and in looking at enhancements, and the thing is that as we choose to focus on things that are good, and attention. And what is the Wexler Intelligence Scale anyway?

It just checks out how good you are going to do in school. It says nothing about creativity, or other important things, such as how well you relate to people. It says nothing about that, because I would tell you that emotional intelligence is the best predictor of how happy you are going to be as a person, rather than anything that you do on the Wexler Intelligence Scale.

My point is that by over-valuing certain characteristics that we can do something about, we wind up diminishing other important characteristics, and how often will I have to tell a family of a very sweet — you know, a 10 or 11 year old girl. You know, she does have a learning problem, and she isn't going to do as well in school, but she has a great heart, you know what I mean? And that is going to serve her so well. How can we protect her through this educational process that will otherwise diminish her because it is a square educational hole?

DR. McHUGH: If I could just finish off then. I did want to ask you a question, Dr. Diller, that you would know and I don't. But I remember that about a decade and a half or so ago that Dr. Stevenson looked at the schooling systems in mainland China, where they apparently had this understanding that boys were wrestlers.

And that they organized the school day where instead of having a kid come in at eight o'clock and sit at a desk until noon, that they had frequent recess breaks, especially for the boys, for some 25 minutes after every 45 minutes, and brought them back in for courses.

Now, do you know anything more about how other cultures and other places that don't have access to drugs, have approached the issue of hyperactive boys, and the tendency of boys all would be a bit more of that sort.

DR. DILLER: Well, my quip was that they are probably beaten more regularly, you know.

DR. McHUGH: It didn't do me any harm.

DR. DILLER: And that is a concern again. I mean, there is a legitimate concern that in the past that these children were simply labeled as bad, lazy, or whatever. Again, the line here between emotional moral things like motivation and caring — you know, Barkley at one point considered ADHD a neurological disorder of motivation, but he realized that he was moving into such a philosophical mine field that he quickly focused more on impulsivity being the core feature of ADHD.

And to answer your question, in every culture, and in every society, and again the pro-medication biological camp will trot this out, there are kids who meet criteria for ADHD. It is a — and as you would expect, in any Bell-shaped curve.

If you are tight enough in your criteria, you will select the group that has this problem. How different cultures handle it I think is of interest. I would say in general, if I can make a comment there, we have looked at the notion of the presto-tempo, or the notion of why America and that question there.

One of them is the presto-tempo theory of ADHD that are fast-paced; you know, computers, video games, t.v., cell phones, pagers, et cetera, which lead to an over-stimulation of children, and therefore they have more ADHD.

I have trouble with that, because I think that children in Milan, and Tokyo, and London, are pretty well exposed to similar things, and yet their use of Ritalin is non-existent in Tokyo, and actually non-existent in Rome, because the Italians have not legalized Ritalin yet. They are going to shortly.

More compelling to me is this notion of consistent and inconsistent cultures, and a consistent culture is one that demands group conformity and making the self secondary to the group in general, okay?

An inconsistent culture prides its independence, spontaneity of expression, and ideas of self, but then demands conformity at school. The best examples of a consistent culture are the Westernized Asian cultures, where again Ritalin use is virtually non-existent.

There is probably this core group of children who are being beaten. The best example of an inconsistent culture is ours, where again all these notions of self-expression are valued, but then we demand conformity at school, and Western Europe is somewhere in between.

So I am not answering your question there, but I think parenting and discipline is a very important aspect. You know, 50 years ago or 60 years ago when there was more authoritarian type families, we were seeing a different kind of problem in children. We were seeing much more psychosomatic disorders in children. Now with the liberalization of parenting, whether it is to the authoritative model, or permissive model, or just our confusions about discipline in raising children, parents are very mixed.

They get this mixed message, and teachers do, too, about what is the right thing to do. We are seeing a different kind of problem, and a much more acting out kind of problem.

DR. McHUGH: I agree that the parent problem is a major issue in the culture. I just wanted us to also remember that there are different schooling patterns that produce a different environment for a young child, and as I said, I thought that Stevenson had reported these quite distinct classroom periods for boys, young boys, in mainland China.

DR. DILLER: The model in our country is really Pelham's work out of the University of Buffalo, where they do use token reinforcement and time out in the classroom.

And they operate with that and can generally operate without medication with very hyperactive children, and/or in a more generalized classroom, reducing the frequency and total amount of medication for the day in these kinds of classrooms.

CHAIRMAN KASS: Gil Meilaender and then Frank.

PROF. MEILAENDER: This is a different kind of question from what we have been talking about. One of the sort of trickier difficult things about the kind of questions that you are dealing with is that you have got a drug that might have any number of uses that most everybody would regard as legitimate and appropriate.

But then would also have uses that might seem at least questionable, and there might be many cases when you would say, "Well, I don't know if that was so wise, or maybe even a virtuous judgment about the use of it."

You might be reluctant to just say it is wrong. What I am interested to know though is whether you can give me some examples where you would say it is wrong.

Physicians, after all, hold one another accountable for their practice. So, for instance, if I see my doctor and I say, you know, I lag mid-afternoon every day, and my doctor gives me one of these drugs to help, is that unwise, or is that wrong, and if it is not wrong, then what would be wrong? I am looking for — I would like a few examples of a place where you would want to hold another physician accountable.

DR. DILLER: Well, it is not an easy question. I can think of situations where —

PROF. MEILAENDER: I would not have asked it if I thought that it was.

DR. DILLER: Well, I can give you situations on the extreme, where I think the doctor is wrong, not just morally, but legally, okay? But I think the notion of being wrong morally is so much more interesting and problematic than the extreme examples that I am about to give you that I know have happened.

For example, it was reported to me that in a managed care health care system that a mother went to the doctor for an initial interview about her child and problems at school and ADHD.

And the child psychiatrist gave the mom the checklists that are used typically to get or to define the diagnosis as best as possible, either symptom checklists that Dr. McHugh was referring to. You know, how much does he fidget, and how inattentive is he, et cetera.

She had the forms filled out by her, and her husband, and the teacher, and she mailed them in and received a Ritalin prescription in the mail for her son without the doctor ever seeing the child.

I would say that that is wrong, and I think that the doctor would be morally or legally culpable because he never saw the child. Mind you that our leading researchers say that really seeing and interviewing the child for the diagnosis of ADHD is rather not an important part of the diagnosis.

Why? Because children really can't report accurately what they do, and they can sit there very nicely like this in our office and still have problems outside.

So leading researchers in fact do not see children under 11 or 12. It is very interesting. They simply conduct an interview with the mothers over the telephone, and are being able to extrapolate statistically what they have done in the past, and that is how they conclude that the child is ADHD at home.

I have gone a little bit off, I know, but this is just an example.

PROF. MEILAENDER: If I may, the example that you gave, it sounded sort of like a bad practice.

DR. DILLER: Yes.

PROF. MEILAENDER: But if the child had met with the doctor, and the doctor determined that the child really met these symptoms, it would not have been bad to prescribe it.

What I am looking for is an instance where it would just be wrong to prescribe it. I mean, for instance, if you don't like my example that I gave about lagging in the afternoon, occasionally where somebody might do all the right steps, in terms of meeting, that you would just think that it was a mistaken idea?

DR. DILLER: Well, it is really tricky. Again, it really depends on the doctor, and the doctor involved, and the patient involved. It is really tricky because the medicine has ubiquitous performance enhancing effects.

Who is to sit in judgment and say that this is not a bad enough problem? I would be more concerned, let's say, with an adult who has a history of alcohol or stimulant abuse, or is currently abusing alcohol. I think that would be a very bad idea to give them stimulants.

You have to be a pretty responsible person, and you have to be a pretty responsible person or have a pretty responsible family to use stimulants appropriately and safely.

So one of those factors would be how responsible is that person, and I think alcohol abuse makes me think very likely that he is a bad candidate and could get into trouble.

The example that I think of is a 28 month old who I never saw, but I saw the mother. This is for me very — the kind of example that comes up to a lesser extreme. I saw the mother, who called me up and said would you be willing to medicate my 28 month old with psychiatric medication.

And I thought — and this was before the Zito study in 2000. This was about 4 years ago. I thought, well, that's interesting. What could a 28 month old possibly be doing that the mother would want me to medicate that child with psychiatric drugs. So I met the mother.

The mother to me was a health professional. She clearly had problems herself and was under a great deal of stress. I subsequently — and so I said, "Well, I would like to meet your child one time." She didn't come back because of the insurance that didn't pay for subsequent visits.

But I did have to call her about something about 3 or 4 months later, and she told me that she had gone to see a very big name in the Bay Area in child psychiatry, and this 28 month old was taking Zoloft, Adderall, and Neurontin.

I called the physician up. I knew him once, and I said, "Joe, what was this kid doing that he could be on three psychiatric drugs?" The mom had a lot of problems, and he said, "Well, Larry, we have the best diagnostic facility in the Bay Area, and this kid had depression, a bipolar disorder, and ADHD."

Now, I was telling Dr. McHugh back in the bad old days, some 35 years ago, I used to talk to psychoanalysts and have the same kind of disconnect. Actually, some psychoanalysts are now my best friends.

I said — and the mom was ready to jump off the Golden Gate Bridge — she told me. So I said, "Well, why didn't you treat the mom, you know?" Did I think that doctor did wrong? Yes. I actually wrote an article about it. I never mentioned his name.

But on a lesser level that is happening across this country, you know. Smaller degrees of wrong, and I gave you that one as one that I feel was clearly wrong, you know. That is the best that I can answer that one.

CHAIRMAN KASS: Could I follow on this, because I am looking for certain generic things out of this conversation as well. Frank, would you forgive me for butting in on this? You yourself indicated that the line between therapy and enhancement is fuzzy.

In a way it doesn't — it may not finally matter whether there really is a disease or not if there are conceivable benefits to be had from a medication. But I will stipulate that the medication is relatively safe, and as these things go, this one is at least as far as we know, at least in children.

So if one wanted to say what really is the problem here, part of the problem seems to be that this is an easy way around getting to the heart of much more difficult problems, and that would take a lot more time, and maybe do a lot more good, and that this is a kind of cheap and quick way to avoid really grappling with difficulties that are there.

But when Gil pressed you — and the problem is then complicated because the decisions are now made by parents with the collusion and collaboration of some physicians for children who have no say in this, and so that is the special case.

But if one would move for the moment to the adults, and ask, yes, you might not give stimulants to someone who is an alcoholic or other sorts of things, but are there uses — assuming that someone would say, look, this will help me.

It will help me be less drowsy. And it will help me be more alert. It is not actually cheating as Charles would say, and it is not like having steroids in body building to make me simply more alert, because when I am more alert, I can actually work harder and accomplish the things that I really want to do.

So the question is, is some sort of skeptic sitting here and saying, well, why should we be worried about these things in their extra medical use, assuming that we stipulate their safety?

DR. DILLER: They are not safe in adults. That is an important factor. You are talking about a hypothetical — well, first of all, I think the hypothetical is worth considering, because the search for the Holy Grail is on.

You know. Lilly just introduced Strattera, and it is not Ritalin. The Holy Grail in ADHD pharmaseuticals is finding something that works as well as Ritalin, and doesn't have abuse potential.

Why? The implications as you say are major. If there was a substance that could do that, it would be a universal market potentially. The thing that was interesting to me, and I had not considered it until I did that Hastings Center conference 6 years ago is this notion of the idea of valuing certain attributes and qualities over other attributes and qualities.

And you have got to remember that if there ever was a substance like this, there would be a corporate entity strongly, strongly, selling that, in terms of making money. And I think it is a — in the hypothetical it is an interesting question, of what would be bad about it.

And I think there is potentially something bad about it, in that it devalues other human qualities that are actually rather important, simply because we can improve one.

So that is how I would answer it in the hypothetical, but I want to be very clear that — well, I feel like Cassandra in America here. You know, this thing that is going on in the adult side in my opinion is doomed to bite us again.

And it will take probably the deaths of certain individuals, and probably celebrities, traced back to doctor-prescribed stimulants that will once again get the country — well, and the threat of legal suits to the doctors.

As I said, that is what changes doctors' opinions. So there is no medicine like that yet for adults.

CHAIRMAN KASS: Frank, and then we should probably move forward to the break. We are running — we started late, and we will run a little over. So, Frank, Bill, and Charles.

DR. FUKUYAMA: Well, you began the question that I was going to raise. I mean, I think that Jim Wilson in the discussion on Prozac said, well, why is this interesting or important. And actually I think that Dr. Diller answered it in a couple of ways.

I mean, the last one, I take that answer to be that it is an agent of social control, and it is a way of forcing or making people conform to certain models of behavior that may not be the ones that the child naturally chooses, or they may actually be the way by which society does a certain kind of social engineering, which we may not like.

But the other one I think was implicit in what you said, which is that it reduces our understanding of moral agency. That it biologizes or medicalizies a whole range of behaviors that traditionally were thought of as moral behavior that somehow came from within each individual, and had to be socialized, and taught, and so forth.

And now because we understand that there is a biological basis for some of this behavior, you then take the next step and say that it is all biological, and it is simply the result of not having taken the pill.

So I think that is kind of a key to why this is a problem, and I think that it is not a hypothetical problem. It is a problem in the present. It is part of a much larger phenomenon of denying individual responsibility for a whole range of activities that we thought of as under individual control.

Now, my question is if we agree that ADHD is over-diagnosed, and Ritalin is over-prescribed, what is the public policy measure that would fix that problem. I mean, you suggested — I mean, you kind of stated that you didn't think there was much you could do short of celebrity deaths.

But there are a couple of ways that you could imagine. I mean, there is a demand side, and there is a supply side. On the demand side, I would imagine that that is probably the case; that there is so much interest on the part of the self-help groups and the parents, and the school systems, that it is hard to imagine a cultural revolution occurring short of the celebrity death to change that.

On the supply side, however, it is already the case that the fact that this is a Schedule II drug dramatically limits. I mean, if the movement to get it reclassified —

DR. DILLER: To get it decontrolled.

DR. FUKUYAMA: To get it decontrolled a few years ago had succeeded, I presume that the numbers of people taking this would be in the 10s of millions.

DR. DILLER: The use of triplicate forms in various States, for example, greatly diminish the — New York and California are being low on that thing, they both use triplicate forms.

You know, when you are writing the prescription, it is like for a narcotic, and that also very much decreases it. But go on with your question.

DR. FUKUYAMA: Okay. So, for example, it seems to me that one of the powerful economic incentives since the designation of something as a disorder is such a squishy matter, it seems to me that the drug companies are actually inventing their own disorders for which their drugs are used.

DR. DILLER: Yes.

DR. FUKUYAMA: And that this is all fed now by the ability of them to market directly to consumers. So I had noticed after Prozac went off patent, all of a sudden you saw it reappearing as treatment for menstrual — I mean, there was a new menstrual disorder that no one had ever heard of and so forth.

DR. DILLER: Right.

DR. FUKUYAMA: I mean, would it be possible to — I mean, one way of getting at the supply side is simply to ban this kind of advertising, which a lot of other developed countries do not permit, because that would kill — I mean, that would get at some of the economic self-interests on the part of the pharmaceutical companies to create new diseases for which their drugs are solutions.

DR. DILLER: Well, I attended a litigation conference on Ritalin and class actions, and I became very respectful of how corporate bodies are incorporated, or have the rights of individuals, and how there is an obscure law, or where the Supreme Court ruled in 1884 that gave them this right.

And unlike individuals, they live forever, and have enormous ability to exploit free speech. So I think in fact the trend is still in the opposite direction.

For example, it had been illegal to — because the U.S. is a signatory to a 1972 U.N. treaty on narcotics that prohibits the direct advertising of potential substance abuse drugs to patients. The reasons seem obvious. You get hooked on this stuff.

And until about a year or two ago, that was either respected or not challenged by the pharmaceutical industry, and now under free speech, they are actually pushing that agenda, and they have been successful on the State Court level.

I am much more pessimistic that those things will make that big a difference. If my wish list would begin with a serious reconsideration of the — and it is going to tie into so many things, that the disability diagnosis, or the diagnosis as the key to accessing services and dollars.

And again this is such a strong drive to get this diagnosis. The pressure is not just on the parents. The pressure is on me. I want to help this kid. How many principals or teachers have come to me and said can't you find some diagnosis to give this kid so we can give him some help.

It is hypocritical. There is a model, and I already mentioned it, and the mental retardation wing of mental health, or service for the mentally retarded, has long ago given up trying to classify all the things that they do, and it is called a needs-based system of providing services.

I think that when I was in medical school that there was a lot of crazy things going on then, too. They used to — because of the insurance system, we used to hospitalize someone to remove a hang nail because the insurance system would pay for it as an in-patient, and they wouldn't pay for it as an out-patient.

And that was a legacy of 40 years ago when surgery was the main reason for insurance. Well, it took a while, but about 20 or 30 years later, they finally said, you know, this is cheaper to do as an in-patient.

I think — and I don't know how long it is going to take, but this disability-driven diagnostic driven system, everyone on the outside is pretty much agreeing that it is crazy, but no one seems to be able to stop it.

I would like if we can reach some impressionable Congressional or Executive minds with that kind of solution, and begin to work on it, because DSM-V is coming, and it is not going to be very different.

It's can we subvert — you know, the DSM-V may have some value, but there is some real pernicious aspects to the DSM-V, which is mostly driven by service and dollar values.

If we can alter the need for that kind of diagnosis, then let them have their DSM-V for research purposes. It may be a useful document on some level for those purposes, but not for clinical decision making.

CHAIRMAN KASS: Let's do the last two briefly if we could. Bill and Charles, and then we will break.

DR. HURLBUT: Obviously we all are sensitive to the meaning of putting chemical compounds into the neurologic system, the whole systems of young children, and especially troubling is these early cases of very early use of these drugs.

But if you think of this as the equivalent of replacement therapy for a real deficit, you can kind of justify it maybe, and hoping that something like dextroamphetamine spansule won't be lingering out there in the future horizon.

But you referred quite a few times to the meaning of human diversity, and of course a profound fundamental question is does diversity include medical deficits. Do you know what I mean?

Just like it no doubt includes genetic differences that some of which have a downside to them. So here is my question. We have had really just a few generations of standardized education. It is kind of an experiment long term, but it is still there.

But it seems clear in our society that heading on through the educational track is your ticket to success, and you have brought this out. So prescending for the moment from the medical concerns, go back to Leon's question about what do you say to somebody who says, look, it is perfectly obvious that education is the way to the future.

And I want my kids to have a good future, and they say — and back to you — that it is not about materialism. But just a basic standing in the society and open opportunities.

And you said that there is a canary in the mine shaft from this. How many other things are going to be like this, where you might be able to make a real difference in the outcome using a drug. Isn't that just looming out there?

DR. DILLER: I think that in our — well, I would just say it as our performance obsessed society. I don't see it as benignly. I think what has been trotted out over and over again is the difference between what you can earn with a high school diploma versus a college diploma.

And this is waved at parents and such, and I think it is going to be a tremendous cost to our culture and society if we insist that everyone go through 4-year college.

That doesn't mean that children on an individual basis shouldn't get help and even take drugs. But I think it would be helpful — well, first of all, because there is lots of successful people who didn't go to college.

Yes, statistically, you know, this is the best guarantor of financial success. As I told you, emotional intelligence seems to be a better predictor of happiness.

So I do think the issues of Ritalin go to the core of values here, and whether values are such that — and again, is everyone hitting or in the square peg. Is everyone in the square peg. We can maybe alter them to be pretty square, and we may get better at it.

But I would still question that, and I guess it is a fundamental values question there, and that is good for this group to take on.

CHAIRMAN KASS: Charles.

DR. KRAUTHAMMER: It's late and I will pass. I have been — my issue has been covered. Thank you.

CHAIRMAN KASS: Well, Dr. Diller, thank you very much for a very stimulating and very forthcoming, and thoughtful, and serious presentation. Council Members, we have a session to discuss Michael Sandel's working paper.

If you didn't get it beforehand, it was provided at your places. Let's make the break a little shorter so that we have a little time between the end of the day and dinner. Why don't we take 10 minutes and return in 10 minutes for Michael's session.

(Whereupon, at 3:41 p.m., the meeting was recessed and was resumed at 3:58 p.m.)


SESSION 4: WHAT'S WRONG WITH ENHANCEMENT: DISCUSSION OF PAPER PREPARED BY MICHAEL J. SANDEL, D. PHIL.

CHAIRMAN KASS: While we are coming back to order, let me simply make a comment to the council members, both with respect to the session that we have just finished, and the sessions this morning.

There are I know some of you, because you have spoken to me privately about this before, who are concerned about the connection between the kinds of conversations that we have had here as illuminating and interesting as they may be, to the charge to this council, and the to the questions of public policy, though I remind you that part of our task is to articulate the human and moral significance of these advances even before we say good, bad, or indifferent, or recommend things for the President or other people to do.

I was — and as often the case, although I am interested in the conversation, I am trying to take the temperature of the room, and especially when the lights are down, it is not always easy to see what is behind these genial facades.

This last topic, where — and especially the way that Dr. Diller presented it, it is perfectly clear that this is not a matter for which some simple government regulation has got some kind of answer.

The most that you are going to do is either do something about advertising or something about production. On the other hand, it does seem to be a topic of very rich — or at least at the center of some of the things about which we have been concerned at least in this part of our work.

And I will follow up with you after this meeting, but I would be interested to know what members think is the value of perhaps pursuing this topic in somewhat greater depth, and maybe to invite some additional conversations on it.

Partly because there has been some public attention to it, and partly because it is a way of calling attention to the kinds of dimensions of the uses of these technologies that are not simple — this is right or this is wrong, or pass a law, or set up a regulation.

And the question is whether this is something that we are equipped to do or equipped to do well, or whether you think that what we had this morning or this afternoon on this topic was somehow sufficient.

So please be thinking about it, and if you have opinions about that now, or during the course of this meeting, pass them on to me or to Dean. But this is an area where, as Bill made a comment to me at the break, that there is at least a large and influential constituency, namely the middle and upper-middle class, who have a horse in this race, and who have some kind of concern, and who have some kind of voice, which is not the case with respect to some of the other things that we have talked about.

So be thinking about it, and let us hear from you. The second announcement before we turn to the discussion of Michael Sandel's discussion paper is to say that a request has been made that council members, or at least some council members would like to have some feedback and reaction to our special visitors from the Center of Ritalin Prescription.

And I would like to invite any members of the council who would be free to simply, when we adjourn today, which will be about 5:30, to simply spend 15 or 20 minutes with these young people if you would like.

Those of us who want to sit around with them, we will do so, and the rest can move and prepare for our dinner. But we will do that in this room, and we will break briefly so that anybody who would like to leave can do so unobtrusively and without embarrassment.

But if you are — and again if some of you are willing to say, and we would be glad to hear — and not to be interrogated, but to hear your own thoughts about these matters. Thank you.

And with that, I would like to open the discussion of Michael Sandel's paper, entitled, "What is Wrong With Enhancement." As it indicates itself, it is an attempt to give voice to some of the disquiets that have been uttered in this room on several occasions as we have moved from the blood doping of athletics, to various mood, memory, and behavior altering drugs, to choosing sex of children tomorrow.

And we will hear from Francis Collins on the possibilities of genetic enhancement, and this is Michael's attempt to set aside on one hand the questions of safety and unfairness, and to try to talk some about the thing itself.

It is brief, and it is concise, and I think it should provoke an interesting discussion. And Michael has indicated that he has had his say, and would like the conversation to proceed.

There will be a return to this topic at the next meeting, wherein we hope to bring before you some of the staff prepared working chapters on the particular topics. And I have at least volunteered something on this topic myself.

So that we will have at least one more go on the general topic, but Michael has done us all a service by trying to focus at least his own thoughts and clarify some of the issues before us in this paper. And I simply would just open the meeting for its discussion.

Charles, you were neglected at the end, and you are one of the less than silent characters in the presentation of this. I don't know or don't want to put you on the spot, but if you have something to open with, that could get the ball rolling.

DR. KRAUTHAMMER: Let me just say that the last session I think was — we had been talking about enhancement in the abstract and often wondering why we are talking about it, and whether this is highly theoretical, abstract, and future oriented.

And I was struck by how the last session illustrated that we have a massive huge current case of mass enhancement, if you like, happening before our eyes. And this is as concrete a case as we could have.

And it seems to me that it might turn out to be the fulcrum of whatever general report or discussion that we have. I would certainly like to start with that, because it is such a striking case. And let me digress for a second from Michael's paper and refer to the last session. It seems to me that what we have heard from Dr. Diller and what I think is fairly clear is that there might be a very small number of cases of a real disorder or a disease, a very small number.

And that the rest is classic enhancement, and these are kids whose performance is enhanced by a drug that we know can do specific things, and happening on a mass scale, with the interesting good twist that it is being imposed on children.

So that it is a form of social control and sort of pedagogical pharmacology, or pharmacological pedagogy is more accurate. And it troubles me, and I think we ought to really maybe focus, at least if the staff is going to be preparing a paper on this, as to what is troubling about it, and whether or not apart from the question of regulating it, whether or not we can articulate what is wrong with it.

And I think that there is a lot wrong with it, and it might be the starting point in any discussion of enhancement. Now, that is just sort of to take off from what I had intended to say at the end of the last session.

I think that Michael's paper is really a wonderful summary of this question, and I think that he gets right to the basic issue. Safety is too easy a way to dismiss enhancement. It is a distraction.

Fairness is also not the real issue, because if you let everybody have the enhancing agent, then you have overcome the fairness issue. The real question is why does this disturb us or why does it bother us.

And I think that he has sort of given us the two basic answers. Agency and — well, diminished agency and hyper-agency. I tend to the first view because I think it is so simple and easy to understand, and intuitive, and then I will defer to Michael to try to convince us on the second, which I think is more subtle, and which is harder to grasp.

But I think the reason that we are disturbed about enhancing drugs or enhancing surgeries or enhancing genetic manipulations in the future is that it is the Rosie Ruiz of achievement.

It gets you there by a way that does not require your own effort, and is a way around effort, and application, and demonstrations of excellence. And it is simply — it is both cheating and cheap as I said at our discussion at lunch.

And it diminishes our humanity to do things that way. As I understand Michael's argument, that is one way to look at it, but there is a more subtle thing that is diminished by the use of enhancing agents, and that is — well, it is not diminished. Our humanity is diminished by the fact that we are sort of acting as super humans.

And creating where we shouldn't be creating, and determining where we shouldn't be determining. And that it is fundamentally an issue of hubris. I find that harder to grasp, and because it is less intuitive, if I could, I would defer to Michael to try to explain to us how that ought to be our chief concern about enhancement.

CHAIRMAN KASS: Janet.

DR. ROWLEY: Well, this is an area where I am totally out of my depth, and I did comment to Michael on what a marvelous piece of — of trying to describe the problem, and to actually point out its subtleties.

But let me take a totally different point of view, and if what one wants for global society is an enhancement of life overall in that society, then why is it wrong to help individuals, or let individuals help themselves to achieve greater things for that society.

CHAIRMAN KASS: Michael, do you want to collect or do you want to respond? Maybe it would be better to respond, rather than to treat this as a press conference and we will discuss issues. So why don't you — well, did you want to piggyback on that or go somewhere else perhaps?

PROF. BLACKBURN: I think this is a piggyback, and stop me if it is not, but it got me thinking about hubris, and I sort of see two kinds of aspects to hubris, and I wondered if you could clarify that.

One is the hubris where something is done and then because we didn't know enough about it, that we arrogantly thought that we did, and then we come to some catastrophe unintended, because we basically thought we knew more than we did.

And then the other is I think or what I sense as being the other meaning of hubris, which is just the arrogant period. You know, even if there were no unintended sequela that just the act of doing that.

And so perhaps you could in the course of you discussing these questions clarify how you feel about those two in your discussions. I liked your piece very much indeed, and that was a strong test of me having to read it, and having gotten off the plane, I read it last night, and I enjoyed it very much. So I enjoyed it under tough conditions.

DR. KRAUTHAMMER: If I could piggyback on the piggyback, and just sharpen the question. This is sort of a double-jump. It is just to say to Michael that if I understand your argument, it seems to be very broad and very sweeping, as a way of saying that by not accepting nature's gifts as is, and trying to either imitate or surpass them by some mechanism, we are acting in a hubristic way, and exercising a mastery that is somehow morally or humanly illegitimate.

And it would seem to me that the logical extension of that argument is that — and you sort of hint this in your last line — is to return to a 17th century vision, and a reenactment of nature that is sort of a questioning and undermining of the entire scientific enterprise, if not the whole biomedical enterprise, which is precisely to deny nature, and to overcome it, and to master it.

It seems to be a fairly radically conservative position, which I find rather in principle coming from you delightful. But I am not even sure that I would embrace it. So let me pose it that way.

CHAIRMAN KASS: I think rather than put more pigs on this back, let's let Michael respond, because he has got —

PROF. MEILAENDER: That is quite a metaphor, Leon.

PROF. SANDEL: Well, these are terrific questions, and I am not sure what the answers are, but let me try. To begin with, Charles' last question, first, and then to work back.

My suggestion is not the thoroughgoing quietistic conservative acceptance of nature that you suggest. I don't think that we should accept nature's givens or gifts as is.

That would be too quietistic. I am not one of those, though there are some who think that creation is complete, and that the work of creation should simply be an object of reverence and awe, but I don't accept that view.

And I think modern science, any science, would be wholly disabled by that view. I think that the view that I want to try to work out here is one that allows room for, and even imperatives for, human beings participating in repairing the given world.

So the given can't go without interrogation or question. The suggestion though by emphasizing the giftedness is a counter-weight to the willfulness that predominates in our culture, is really just an argument to accord weight to the given.

And to accord some respect to the given as we go about exercising our will and participating in repairing the given. And so to go to — and to try and develop this by working my way back across the questions that Elizabeth and Janet have raised, the hubris, it can't be hubristic to try to make things better, and this is also to Janet's question.

That would be too heavy a notion of hubris. It would be entirely disabling, not only of science, but of all sorts of human projects of moral and political, as well as scientific improvement.

What I am trying to — I am trying to develop some considerations that can combat our tendency, which is the opposite tendency, to ride roughshod over the given without interrogating it or appreciating it.

And so to the two senses of hubris that Elizabeth raised, I think I am for some version of the first, where the hubris consists in thinking we know what we are doing, but not fully understanding the consequences of what we are doing.

But it can be tricky to distinguish the first kind of hubris from the second, and one way of getting at this is to go back to the earlier discussion that we had, the Ritalin discussion, because in one way the knowledge is true knowledge. That if we give the child the Ritalin that it will have this effect on the child's behavior. So it is true knowledge, but when we get into the larger unintended consequences, not even putting aside some unintended consequences about incurring addiction down the road.

But let's say that it were not addictive and that there was no harm to this child. Still what we might miss would be precisely by riding roughshod over the given, by making this a widespread practice, we would diagnose it in cases where we would actually have, let's say, an accurate diagnosis that the kid was, or had, attention deficit disorder, or couldn't fit in that well, or was a nuisance in the classroom.

But — and here is where this goes back to Charles' first question. Here is where the mistake is not just that we are cheating and we are giving the kid an edge that doesn't come from the kid's own effort, and this also addresses Frank's construal of that position.

The real wrong it seems to me here is by not appreciating the given, we miss human qualities that at first glance may appear to be just a form of nuisance.

And here there are two cases that I would like to bring us back to; the Huck Finn case, and the young Paul McHugh case, where at first glance what we now appreciate as Paul's feistiness, then, looking quickly anyhow, was just a nuisance in the classroom let's say. I am imagining.

And so we wouldn't say when we prescribe Huck Finn or the young Paul McHugh the Ritalin, we wouldn't say what was quietistic and in what ways does mastery run wild, failing to appreciate the given.

Well, you might say the given is the scourge. It is this kid running around making trouble, and that might actually be true. But by not running roughshod over the given, and by interrogating it, and by inquiring into it, and by enlarging our moral imagination about the way this trait might if properly understood fit into a larger narrative of human possibilities, we might say, yes, we could cure the squirminess now and the misbehavior, but at a cost.

And not at a cost that later that he will become addicted. So here, Elizabeth, is where it is or we are getting it right in the narrow sense. The knowledge isn't false. It will cure the squirminess, but by attending to the given, we come ultimately to see the feistiness under another description as a gift, and not just a nuisance.

And so here is how it is not just quietistic. Here is where there is an interrogation of the given, and the interrogation, and how successful it is, will depend on the reach of our moral imagination may be competing narratives and descriptions of how this terribly troublesome kid might actually — that there might implicitly be some implicit human qualities that are worth apprising.

So it is not purely quietistic. We wouldn't always defer. We might do our best to figure out what is going on here and say, well, better that he should have the Ritalin.

There are some gifts that aren't transparent as gifts. That we might have to learn to love Paul's feistiness, but having learned, then we do see it as a gift; whereas, at first it really wasn't.

So the appreciation that I am arguing for here can very well be an acquired taste, but the moral project, the task of the moral imagination here, is to be open to the acquisition of acquired taste of that kind.

CHAIRMAN KASS: Did you want to comment to Janet, or just the comment —

PROF. SANDEL: Well, I thought I sort of had, and Janet will tell me if I hadn't. So this is not against improvement. This is not against improvement, but because I meant the example to show how by interrogating the given that we may appreciate it, but we may also decide that in some cases — well, still, we have to fix this.

And I am not saying that we should never fix things. Often we will come to the conclusion that what has been given is something that is in need of fixing it, of repairing. But maybe I didn't address fully what you were worried about.

DR. ROWLEY: Well, just the comment that your examples in the discussion really related to individuals and comparing individuals who — one has given a great deal of effort to achieve a very high level of performance, and another just does it effortlessly because they are very fortunate to have been born with it.

And then if you by giving a drug help one, compared to the other, doesn't that somehow taint what appears to be success on the part of the person, because it is not the person's achievement. It is the drug's achievement.

And I fully accept that, but I was just thinking that we have discussed it, and I would have to say that I was surprised, though we had this conversation some months ago, and again at the extent to which people are using various stimulants in the broader population, that looking at the other side of it, if you — if these help people to achieve more — and I think that this is a big if, because Dr. Diller said that in the long run the children taking Ritalin didn't do any better in performance than the children who didn't.

And so that says in the long run that it doesn't make any difference. But the contrary point that I was trying to say is if in fact some of these help people to achieve more or to be more creative in ways that advances societal goals, then should we look and not be quite so judgmental as we may appear to be?

CHAIRMAN KASS: Frank, go ahead, and then we have to go to Professor Sandel's presentation.

DR. FUKUYAMA: Well, I would like to answer exactly that point. I mean, I think that you have to have an unambiguous understanding of what it means to — you know, what is unambiguously an enhancement or an achievement, and I think that most people that say, well, why not, think that that is an unambiguous — you know, it is pretty unambiguous what makes a better human being.

You know, if it is somebody that achieves higher test scores, or has an higher IQ. But I think that a lot of the things that are possible now, and may be possible in the future, are very ambiguous.

For example, would it enhance a person to cure a child of any genetic predisposition for homosexuality. Is that an enhancement? Is the world better off — you know, is society better off if parents had that choice of preventing that particular disposition.

Is it better — you know, I have been involved in a variety of these kind of hypothetical things, but supposing that you could eliminate proclivities for hatred.

I mean, people would say, well, wouldn't the world be better off without hatred. Well, yes and no. If there are no hateful things in the world, then maybe the world would be better off if you didn't have this emotional response.

But if there are really hateful things, then maybe that is not such a good thing. The same thing with proclivities for violence and aggression. I mean, these are commonly thought of as targets of enhancement.

Wouldn't the world be better off if we had less of this, and I think in just the examples that we have had that I was astounded that there is this thing in the DSM called oppositional disorder, which I assume is something that Martin Luther and Rosa Parks had in spades, you know.

And if you have this drug that allows you to get over oppositional disorder, have you enhanced society, and are the goals of that enhancement so obvious.

And I just don't think they are. I mean, I think that is the fundamental problem. And I guess that is in a way what you are talking about with the — I mean, I guess trashing the given, I don't like that language, because it just sounds too conservative.

I just think that the problem is that what is given and what is an alternative to the given are morally laden terms, where people act as if it is obvious in which direction improvement lies.

And I think that is the fundamental issue here, and that in many cases it really is not. I mean I will stop there.

CHAIRMAN KASS: Bill May, and then Gil, and then Alfonso.

DR. MAY: I have a cluster of points. Your paper contrasts —

CHAIRMAN KASS: Bill, could you get closer to the mike, please.

DR. MAY: Your paper contrasts openness to nature's gift, and then on the other side willful control. There is a complication that part of the gift is the ability to control.

So part of the honoring of the gift, it might be slothful, inadequately to respond to challenges for control. So it would not be an active impiety to engage in controlling. It would be acting upon a portion of the gift.

Nevertheless, at the same time, all of our discussion of enhancement today is related to the issue of control, and I suggest that there are two sides of science, the beholding and molding, and there are two sides to parenting, accepting love and transforming love.

And by the way, there are two sides to the human body; a means of controlling the world, and a means of savoring the world. And most of the discussion of enhancement today has related to enhancements that increase control in a humanitarian culture that is pathologically driven towards this one-sided development.

And there may be no discriminal reforms to control it. It may require a revolution in consciousness, which of course the late '60s talked about. And they used drugs not for the sake of control, but for the sake of savoring.

And that is another reason there is a complication in the word enhancement, too. Enhancement is a means of control, but enhancement has a way of enlarging savoring. So it is an interesting issue.

And, of course, worried conservatives and worried liberals alike amongst parents worried about the use of drug enhancement in that culture, which was checking out of the world, rather than this intense slavery to the world.

I mean, I have a kid in Trinity School in Manhattan, a grandchild I should say, and another one in St. Albans. And I see it take over and shadow family life from 2, and 3, and 4 years of age on. It is really quite appalling what is going on.

But if one would talk about the two sides of science, which are really there. It is not just a question of collapsing science, because after all there is ancient science, which was concerned with beholding.

And it is modern science that has emphasized the other side of molding, and have we developed it one-sidedly, and it is an interesting issue.

But this is also reflected in the human body. On the one hand, we are identified with our bodies as a means of control — feet for walking, and hands for manipulating, tongue for talking, and so forth.

But the body on the other side is through the senses and is a way of being open to the world unbidden. And it is very interesting that disease attacks us at both points. It not only undercuts control — the guy with the heart attack suddenly used to control his world, and now he is controlled by others — but it also impoverishes the senses.

And then part of the controlling efforts of medicine can relate to both of these sides through disease, both disease as it assaults control, and disease as it impoverishes our ability to be open to, and savor the world as a gift.

The sleeping pill also clouds the mind. The tranquilizer may get rid of some agitation, but can leave the individual feeling like a fish out of water, gaffed and stunned at the bottom of a boat.

And so there are various ways in which the very effort to get at the problem imposes some ranges of the problem. That is a cluster of points, and I am not sure which you want to respond to.

CHAIRMAN KASS: Did you want to add something to this, Michael, or —

PROF. SANDEL: Well, no, I think that is magnificent. I agree with — I take that as an elaboration more than as a challenge. I think it is an eloquent elaboration of these themes, and I would say that it is really the one-sidedness, and this is really a reading of where we are in the moral culture.

It is the one-sidedness that leads to the — that makes it important to try to rearticulate the side that has been eclipsed or diminished by the impulse of mastery and control.

And which isn't to say that we should give it up. We need to try to find a way to hold the two as human powers, and capacities, and stances toward the world simultaneously.

So insofar as this is a polemic against the first pole, the one of mastery and control, it is for the sake of reversing what is a powerful one-sidedness in the culture, but I accept entirely and agree with everything that Bill has said.

CHAIRMAN KASS: Gil Meilaender.

PROF. MEILAENDER: This will in some ways follow up on Bill's points. In fact, I often learn from Bill, and it makes me wonder why he doesn't always vote the right way. I can't understand that.

But I actually have four points. I think they are all interrelated, and certainly the last three are. So I am going to do my own piggybacking here, Michael.

The first is a little different, but I would just like to hear you say a word or two about the word gifted in your paper. Is it a metaphor or not?

Iris Murdoch once said that your consciousness, your hyperagent if there ever was one, or will, had a glorious incarnation a century earlier in Milton, and his name was Lucifer.

And if we are to recapture the sense of giftedness, do we have to know ourselves as creatures, which means in relation to a creator, or is there — I mean, I don't know exactly what giftedness means there. And I would be interested in hearing you say something about that.

Now, point two is that in relation to the — in connection to the relation between parents and children, and I think, although I had to read your paper quickly, that you are really thinking mainly of the — and especially as you take the beholding and molding stuff, and so forth — you are thinking of the relation between the generations in some ways.

But we need help in making certain distinctions. For instance, parents are supposed to inculcate, and they are supposed to civilize, and they are even supposed to transform in some ways, though transforming love insofar as it gets placed over against accepting love in your paper, you know, is problematic.

And so we are supposed to accept, but accepting doesn't mean failing to inculcate. It doesn't mean failing to civilize. But somehow it means backing off from certain kinds of transformation. How do I know?

I mean, I certainly agree with the general point, but how far does that get me unless I have some criteria for distinguishing. The third point is if we think not about somebody molding someone else, but just about living our own lives, and not about self-other, but about one's own life, isn't there some sense in which a person is supposed to think of his life as a project that he undertakes?

And is that ruled out by your critique of hyperagency, or if not, sort of what is the right way to think about one's own life as a project. And then, fourth, and I think it certainly relates to what Bill said related to all of these points, is that it is true — or at least I am prepared to agree that part of being human is to understand our giftedness, and to appreciate the givenness of our life in certain ways.

But part of our nature is our freedom to reshape life as well. Every time I go to the dentist and have novocaine, I am very pleased that someone did not just rest content in what was given.

And so to be human is to be two-sided in this way; to be finite and limited by certain givens, but also to be free to reshape them. Okay. It's good that you want to nudge us back in a certain direction, and I actually agree with that.

I don't mind the tenor of that at all, but how do we know when the given exercise of our freedom is creative or is going to be destructive. I mean, that is really the question.

Even if we buy what you say, that is the question that we have to get at. How do we decide on any given occasion whether this is the exercise of freedom that transgresses and steps across a boundary, a given boundary that ought not be stepped across.

Or whether it is the exercise of freedom that makes us human, you know, and fulfills us. So I accept the kind of fundamental move, and these questions are all about kind of how far it will take us without the ability to make certain kinds of discernments and distinctions.

CHAIRMAN KASS: Michael, go ahead.

PROF. SANDEL: I will try to answer as many of the four briefly. First, on the idea of the gifted. Does that mean that we need to understand ourselves in relation to a creator as the giver of the gift?

I would say that this is a difficult question. My answer would be that one important source of this understanding and this orientation to one's self and to the world is or does come from various religious traditions.

So I think that broadly speaking to view life as a gift or to appreciate the giftedness of life is — and of nature, and of creatures within nature, one powerful source of that understanding is the source of religion, and various religious traditions.

And it is I would say a religious sensibility. I wouldn't say that though it is a religious sensibility, I wouldn't say that it requires necessarily religion or a belief in a giver of the gift.

I think that is an open question. But there may be multiple roots to this mode of understanding, and while many of the roots — and the most powerful and influential roots are religious, I wouldn't want to say — and I couldn't be confident in saying that that is the only available root.

As for parents and children, parents inculcating, civilizing, transforming, as well as accepting, how do we know, and how do we know when the exercise of our freedom is creative and when destructive?

I don't think that question admits to a general answer. I think that we have to confront ourselves with particular cases, particular instances, of the tension between molding and beholding, accepting and transforming, in the case of parents and children, and also in other domains.

And I don't think this admits of criteria that can be specified that would be very interesting or helpful in advance. As far as shaping one's own life, the idea of life as a project isn't as bound up with the idea of hyperagency, or is there a way of making sense of one's life as a project that still or that departs from the hyperagency.

I think that there is, and the way it would — the account one would give would be to view one's life as a project in the sense of a narrative, with a certain characteristic form, or point, or telos.

And what it means to live life as a project on this view would be to struggle, and to deliberate, and to wonder, and inquire as we went along the course of our life and faced important life decisions, and whether we are realizing the point or the purpose of the broader life story or narrative in which we find ourselves.

So I don't think the idea of life as a project commits us to willfulness, to the idea of willful choice or a hyperagency, if you incorporate in the idea of a project a certain story, with a point or a telos that we may only glimpse. But that we work out as the project unfolds.

CHAIRMAN KASS: A quick response.

PROF. MEILAENDER: Yes, just real quick on the last point. Does that require that rather than understanding one's self, does that require that one understand one's self as a character in this story, and not as its author?

PROF. SANDEL: Both. I don't think that those are mutually exclusive descriptions.

DR. KRAUTHAMMER: Can it be written by anonymous rather than be a signed author, and that I think is the distinction. Could I interject here, or would it be unwise, or —

CHAIRMAN KASS: I am torn. I mean, this is — the form of the discussion is in a way going to produce or make something very episodic as different people have different points to make, and they sort of go back and forth.

On the other hand, I have got a cue of about seven people who I think — well, let's see if we can collect some of these things and keep them on one topic.

DR. KRAUTHAMMER: I won't jump. I will wait.

CHAIRMAN KASS: Okay. What I have is Alfonso, and I have Robby, George, Mary, Rebecca, Dan Foster, Bill Hurlbut, myself, and Charles. But we can perhaps collect some of these. And, Alfonso, please. I try to be a policeman of topics.

DR. GÓMEZ-LOBO: I think I am going to be a collector. I don't think I am going to stray away from Gil's remarks, and some of the stuff that Frank said.

The first thing is that I was very grateful for this paper. I greatly enjoyed reading it, but it seemed to me that when I read it two nights ago that there was a certain incommensurability between the paper and the discussions as I expected them to take place, and as they did take place this morning.

And the reason is this, is that we are moving within the assumptions of contemporary technology. Now, I think — well, Heidegger, for instance, has tried to characterize contemporary technology, and just to point out a few things.

I think that the spirit of modern technology is that if you can do it, then do it. And if you can't do it, find a way to do it. And that is why it is this primacy of acting in our desires that gives us a very special view of nature. Now, I am of course aware that the concept of nature which underlies our discussions is the 17th century one as Leon mentioned.

But I think it is fair to say that human beings have tried to think about nature in different ways, and the mechanistic views of the 17th century is not the only way.

In fact, I would say that there is something that strikes me in everything that I have learned in this council, is that there has to be some concept of nature which is valid today, which is not reducible to that concept.

And by that I mean the following. I have seen that nature seems to be a very fine-tuned system of causes, which has room for imperfections. And that is why there is this urge to improve it.

But I think that we would be blind to say that there is no valuable, for instance, in certain natural occurrences, and certain natural events, and certain natural timings. Let me just give you an example of what I have in mind.

I was reading about these attempts to have — I think it was a 60 year old woman to have a baby, and I said to myself, well, there is something really odd here, and I thought about this lady fighting teenagers who is almost 80.

Now, all of us have had experience fighting teenagers I assume, and you need a lot of energy. So I said to myself, well, shouldn't one think that there is a certain wisdom, and that wisdom can be interpreted in evolutionary terms to say, well, there is a moment when child bearing stops and perhaps other human activities can of course continue to be practiced.

Now, my last comment is this. Even if we emphasize the technological view, the view that if it can be done, let's do it, and there are two things. One is something that Frank was calling our attention to, and it is that we are not sure what the good is in the operations of enhancement for the most part.

Nature is much too complicated a set of causes so that we can really think that we have a hold on it to say, oh, this enhancement, great. Let's go for it.

We have seen many times in these discussions that there are very serious questions concerning what would happen if this enhancement is attempted.

Well, there may be downsides which are really very worrisome. And the last point is this, is that even today technology relies on nature. Cloning, for instance, is a way of harnessing a natural power.

It is this business about cloning for — I'm sorry to go back to this stuff, but to stem cells, without admitting that we let nature form an embryo, and then the embryo develops by natural causality, and then comes the stem cells.

That is just forgetting the role that underlying given, if I may use your term, is there, even in an extreme of technological endeavor.

CHAIRMAN KASS: Thank you. Robby George.

PROF. GEORGE: Michael, I was struck as Charles was, and evidently Alfonso as well, by that point that you make at the conclusion of the paper about the ethics of — sorting out the ethics of enhancement, requiring us to reopen some questions that had really been closed off by the adoption of a certain mechanistic view of nature in the 17th century.

Now, when Charles challenged you as to whether that implied on your part a rejection of modern science, I thought that your answer was entirely correct and effective.

But I want to ask not so much about that as about whether a view that is closely associated with mechanism, the mechanistic view of nature in the field of ethics would have to be thrown over.

I do note in answering Charles that you didn't say that you want to hold on, and I am suspecting that it would have to be, no, you don't want to hold on to the mechanistic picture of nature.

That is really different from the answer. You were saying modern science doesn't depend on. We can affirm what is good in modern science without adopting an underlying view that perhaps many modern scientists hold that isn't essential to affirming modern science.

So I would distinguish the question of whether we ought to be mechanistics about nature from the question of modern science, and I take it that you do as well.

Now, it seems to me that if we accept the conception of giftedness that you have laid before us, and on the terms that you suggested, and without supposing that you are arguing for anything more than overcoming a one-sidedness that has been introduced by an obsession with control and so forth. So just on your own terms.

But if we accept if, and are prepared to act on it, whether individually, or as a community, and whether informally, or formally through our public institutions and through public policy, it seems to me that it follows from that — and I wonder if you agree — that we are prepared to suppose that there are times when it is necessary from an ethical viewpoint to forego the satisfaction of our wants or our desires for the sake of ends, for the sake of goods, that are understood as intelligentibity valuable and worth acting for the sake of, and worth practicing restraint for the sake of, and worth foregoing advantage for the sake of.

But which have their value quite independently of their capacity to satisfy wants and desires. And if that is right, then what has to be rejected is —

PROF. SANDEL: Well, I can give a short answer to that. Yes, sure.

PROF. GEORGE: Okay. But if that is right, then what has to be rejected it seems to me is the philosophy of non-cognitivism in ethics, which is in fact closely associated historically and philosophically with the mechanistic picture of nature.

And with that I think we would have to reject materialism, and determinism, and any reductionist view of judgments of value, and reductionist in the sense that it would reduce them to the material, or even to the merely emotional. And then the question would be —

PROF. SANDEL: Well, can I answer those? Yes, fine. I am all for that.

PROF. GEORGE: So, so far so good. Okay. Then just a quick question on Gil's point. In responding to Gil's question about the creator, and whether the gift implies the giver, you answered by saying that religion is a root to the understanding of giftedness, but perhaps not the only one, and that certainly seems right to me.

But what I wonder is whether it was responsive to Gil's question as he framed it. It seemed to me that the question wasn't about the root to grasping the point about giftedness, and then everything else follows that you and I agree on.

But rather it was does it follow from the reality of giftedness. If it is a true judgment, if it is an accurate judgment that there is a giftedness that we need to understand in order to act up rightly, does it follow from our grasp of that true proposition that there is a giver?

Is there an inference that is invited from the understanding of giftedness to the reality of a giver, and would it be less than fully reasonable to stop short of drawing that inference?

CHAIRMAN KASS: The President's council on Bioethics is now going to ask Michael Sandel about whether there is something like this psychological that basis is proof of the existence of god, and let the record show —

PROF. GEORGE: Well, it relates to something that Michael has written about I think very, very well, and ultimately it goes to the question of religion and public policy, and the place of religion in Michael's now famous critique of Rawls raises these questions.

DR. KRAUTHAMMER: Is it constitutional to offer an answer to that question?

PROF. GEORGE: In fact, you don't have to answer it. I do want to simply insert that I think what is really — that that is really what Gil's question boils down to.

CHAIRMAN KASS: It is all yours.

PROF. SANDEL: I would say that whether — if you accept all of what you have described, this rejection of mechanism, and therefore of non-cognitivism, and materialistic, and ethics, and all of that stuff, and if you are lead to be persuaded by the idea of the importance of this idea of gift or giftedness, does that commit you to a particular theology or religious view.

I don't know the answer to that question, but I think that is an important question that is suggested by this line of reflection, and the way that we would go about exploring the answer to that question would be to look at the different accounts that people might offer who accepted the views that you just summarized.

And to see which accounts of this idea of giftedness, or of certain limits on the project of mastery and control, made the best overall sense of these views.

And we are not in a position to do that here, but I don't take that to mean that it is not a good question, or a question that doesn't naturally arise out of this line of reflection.

So that is how that would be the next stage in this kind of investigation. We would have to have different people give various accounts, theological or otherwise, of how you might explain this orientation to nature, and to the world, and so on, and then we would have to see which ones among those made the most sense, and seemed the most plausible, all things considered.

PROF. GEORGE: I agree.

CHAIRMAN KASS: Mary Ann.

PROF. GLENDON: I am wondering how you would react to an interpretation of your paper. When I read it a couple of times, the sentence that really jumped out at me was the one on page 3, the beginning of the first full paragraph.

"The moral problem with enhancement lies less in the perfection it seeks than in the human disposition it expresses and promotes."

That seemed to me to be the heart of what you were saying, and as I thought about it, I thought, well, you know, teachers want to edit things. So, I was thinking if I were editing this, I would say that the moral problem with some forms of enhancement, because as Janet said, we all agree that there are some that are wonderful improvements.

And I would put an "s" on the end of disposition, and then it seemed to me that the heart of the problem is what dispositions exactly are we talking about. What is it that is worrying us about the dispositions that are expressed and promoted by some forms of enhancement.

And then I was thinking about some garden variety, non-dramatic forms of enhancement, the kinds of enhancement that in an affluent society we all engage in to some extent.

And it seemed to me that when this disposition — and here is a little elaboration of your paper that I wonder if you would agree with, but one disposition would be this kind of endless desires that I think we have to thank Dr. Diller for having called our attention to the idea that we may be establishing a State religion of consumerism.

This kind of desire after desire without reflecting on what kind of people are we being individually and as a society. And is that really the kind of people that we want to be.

We may have gotten into this without reflecting much on it, but then we are constituting ourselves in a certain way, and it might be time to think about it.

Another disposition, and maybe it is just another way of saying the same thing, we talk about enhancement as though there were infinite resources for all kinds of enhancement. But every choice that we make is a choice not to do something else.

So that you get into this situation where we spend a lot of money on diet aids, and Dan is right. Obesity is a horrible threat to human health, but we spend more money on diet aids than people in other countries spend on food, and they are starving.

So there is something wrong with that. Does that fit with your —

PROF. SANDEL: Yes to everything that you said. Both the editorial enhancements, and the elaborations of the human dispositions that are at stake here. Yes, I think in both respects that is not only in the spirit of what I was trying to say, but I think it is an improvement.

CHAIRMAN KASS: Rebecca.

PROF. DRESSER: I guess my comments are similar to a lot of those that have been made. This issue of line drawing and distinctions, and trying to decide when graceful acceptance and adjustment is appropriate, and when some sort of active intervention is appropriate.

So you said that repairing the given world is all right, but we should accord some weight to the given, and one of the problems is that we tend not to appreciate certain characteristics that might appear to be nuisance characteristics.

So I wondered if — and this is an inappropriate abbreviation of your very elegant analysis, but take — the argument is to take a broader view of the harms, costs, and I think somebody said downsize, of intervening in these ways. And that is really what our discussion should focus on, as well as perhaps the benefits of not intervening.

That it is just a richer understanding of what is at stake here. Is that really what you are arguing for, and I guess I would have two further questions.

One is did you or do you have any ideas about how this discussion, public discussion, should be orchestrated, and how do we go about encouraging parents, and doctors, and everybody to have this richer thinking about these interventions.

And then I wondered — you know, with genetically modified foods now, there is this precautionary principle; that if we don't have the wisdom to understand what the full consequences, negative consequences could be, we shouldn't go forward.

That is, in the absence of sufficient information, we should not go forward. Whereas, it seems to me that the tendency that we have today is that we think we should get some information, sort of basic safety information, but then if it looks okay, then let's try it. Our presumption is in the other direction.

PROF. SANDEL: Just briefly on how to orchestrate public discussion of these wider considerations. I don't have — I am not terribly optimistic that there is a good prospect of doing this.

If you look at the work of this council, and the tenure of the deliberations, it is rare even among groups who are taking up questions of bioethics and medical ethics, even before you get to the problem of how any such discussions are given later importance in the public arena.

So I think it is very difficult, and one of the reasons it is difficult was also touched on in the earlier session, and goes to Mary Ann's point about consumerism. So much of the public discourse has been inhospitable to this kind of discussion because we are swamped by ads, not to say campaign contributions from the pharmaceutical industry.

So if you look at the actual shape of how the public discourse is actually structured, I think there are powerful obstacles of that kind. So it is going to be very difficult, I think, which is why we are so far I think down the road in one direction of these two components of science, and of modes of understanding of parenting.

CHAIRMAN KASS: Dan Foster, please.

DR. FOSTER: I am not sure this is not going to be interpreted as sort of a dumb statement, but I do want to say before I make this point that I want to make that one of the things that concerned me today about the Ritalin and so forth is the whole thing looks fake to me.

It is an enhancement that is fake, because long term achievement doesn't occur. It is a fak if what he said is true. I mean, if you look at it two years out, there is something, and there is no difference.

And I think that is sort of a worrisome thing. The second thing that I would say is — and I am going to exempt medical care and medical research from enhancement in the usual sense, because I am absolutely committed to what medicine does.

We are involved in preventing premature death. We are involved in the relief of symptoms when a cure is not possible, and we are in the business of comforting during the walk through. That we are committed to, and that includes the research activity. But cosmetic surgery, and all of these other things seems to be trivial. And what I was really worried about follows from what Mary Ann said, is that — and it is not — well, what kind of message are we giving to our country, or to the society, or to the world, by the emphasis of let's say on education and four years of college.

I mean, the statement is made that the main thing that it will enhance is one's ability to earn money relative to somebody with a high school education. And money would be involved, I suppose, with pleasure, and power, and influence.

And so in one sense one could say that we are trying to reproduce in some sense the elite of the country, and you are successful if you can drive a BMW, or you spend all your life seeking for this. I am tremendously worried about the leaders and about greed, about greed.

And I am not talking just about Enron, and I am worried about this idea of go to school, and make more money, and get more consumerism, or whatever, because of greed.

There is going to be an issue of academic medicines coming out next week, and it has to do with the whole issue that we talked about, the patenting of genes.

We see the best that we have of people trying to get power and money out of knowledge that should be involved with the whole society. I just heard from David Korn from AAMC who we were talking with this week about somebody who is patenting the idea of a diagnostic work-up for Alzheimers.

That is to say, that if you measure APOE-e4, or E-4, you have to pay them, because they have put a thing together. I think we ought to look at this issue that is coming out there. There are 11 chapters on patenting and so forth.

I am worried about the message that comes out, because it is both trivial and may enhance the things that Mary Ann points out that are not the best of our society at all.

When I was a trustee of the Dallas Independent School District, and this was before the big city school districts were destroyed by the desegregation situations, we did something very interesting.

We had a very interesting Board of Trustees. We were the seventh largest district in the country, and we were not harmed by — we had plenty of tax base, and we didn't have militant teacher unions, and we had a perfectly workable ratio community.

We dealt a magnet school, for example, amongst other magnet schools, which was very interesting. It was a place that you had to go if you wanted to spend four years studying Russian. But it was also the only place that you could teach a kid to become an airplane mechanic.

Because our school board felt that we ought not to try to reproduce ourselves. There were four of us who were doctoral on there and so forth. It is a terrible mistake to try to reproduce yourselves.

I mean, sometimes some of my residents say that because you are a physician scientist, you will be disappointed if I want to practice internal medicine in a small town, and I said that's crazy. I just want you to be the best internist that you can be.

So I think this idea of a stereotyped achievement in school, or something else, gives a terrible view about values. I will tell you that I — well, our medical school takes care of the poor, and I also take care of a lot of really rich and powerful people.

You know, people like the President of GTE, and so forth, and I find that human values are much more often to be admirable in the poor, who have no resources, and who are sick and dying, than I see in the people who have all these attributes that might be called enhancements, with their facelifts, and their cars, and so forth.

I just don't want to give this sort of message about that, and it is one of the reasons that I resonated to what you put in here, and that Mary Ann talked about. We don't need to reproduce ourselves.

And as a matter of fact, if you wanted to enhance things better for the world, the best enhancer is money. And the best thing that you could do in the world is to get clean water.

It is not anything fancy, and I would like us to be a country that is at least equally concerned with whether our kids are going to get into a pre-school at two years of age, as I would be about the people who are dying throughout the world because they don't have any water.

And so I don't know whether — and as I said, it may sound dumb, but I just don't resonate to much of what we are talking about with enhancement here.

CHAIRMAN KASS: Let's see. Unless someone wants to speak to that, what I have next actually is Bill, and then Paul.

DR. HURLBUT: I actually just want to second that. I think we have a widening number of people, and I don't know how to say that correctly, but a growing trend in our society who view nature, or to revise our view of nature off of our traditional ideas, and see nature in a kind of evolutionary model.

And usually it is simplistic evolutionary theories, too, and one that emphasizes the arbitrary nature of the whole thing, like we are some kind of a chance-driven coincidence within a chaos, but that competition is very central to the whole matter.

And that morality doesn't necessarily flow forth within the — or to put it this way, that the material and the moral don't flow forth from a single source, but the moral is actually an agency in the service of social cohesion, and not something intrinsically rooted in a transcendent referent, or some deeper purpose woven into nature.

So that what you see is — and I see this in my students. I see a sense that really this is about competition on another level, and slowly but surely you get that drift back return to the guiltlessness of a predatory conscience basically.

You see a sense that if you can use something to transcend the genetic lottery, why not if you can use something to a personal advantage. You weren't made that way by any overall benevolent force, but you are just the product of a certain shuffling of genes or circumstances.

And then you face the odd kind of question that is implicit in the indeterminacy of human nature; that Simone du Buvoir once said that human beings are that species which by nature has no nature.

And so you add the post-modernist flavor to this notion of evolution, and the emphasis on power, and you get this kind of arbitrary drift of where you should go with all of this new power over nature.

I found something in Michael's write-up that struck me as worth asking you to elaborate further on, and that is that if you think about Buvoir's statement, the problem is that we do have an open indeterminacy, but it is built on a very complex and beautiful structure that allows this kind of freedom that we actually have.

And that is fragile, and that if we go fooling around with it too much that we will walk ourselves right out of the arena. That we will actually damage the very structure which gives us the possibilities of who we are.

The phrase that I liked in your statement was that you referred to disfiguring fundamental relationships. So I ask you to elaborate on that a little bit. Could it be that there is what you might call a series of concentric circles, at which there is human prerogative to intervene without disfiguring things, normal cautions.

But that there comes a level at which, or another level at which biomedical interventions are violating the very infrastructure of being, the very social cohesion that makes possible the kind of meaningful lives that we have? Do you see what I am getting at?

CHAIRMAN KASS: Michael, do you want to comment? Do you want to take it later, or —

PROF. SANDEL: Well, I don't have a good general answer. but I agree with the general point. But to specify it more fully, I think that we have to look, as we have been doing in earlier sessions, case by case, of the interventions to see whether there are instances of the impulse to mastery and control run wild, and disfiguring some important goods.

Or whether they are repairs of the given that are consistent with an appreciation of the goods, and so the reason that I hesitate to specify in general is that I think here we do have to take up the instances as they come along, whether it is Ritalin, or whether it is sex selection, or whether it is cloning, or whether it is longevity, or whatever the case may be, and have those discussions each time in the fullness and richness of the cases.

Because the goods at stake will differ, and these are discussions and deliberations that have to attend to the actual goods that are at stake, and how to articulate them, and see how they may be threatened by an intervention, and how they may survive and so on.

So this is really a framework for making sense of the particular discussions that we have about those goods when the particular enhancements or interventions arise.

CHAIRMAN KASS: I have Paul McHugh, Michael Gazzaniga, Charles, and myself, and then I think we will have exhausted ourselves. Who did I say first? Paul.

DR. McHUGH: First of all, I very much enjoyed this essay of yours, Michael. I enjoyed it for its content, and I also enjoyed it for its style. You are the person who I appreciate most who was able to write exactly the way he speaks.

And I can read this and say that this is Michael talking, and I enjoyed it for that reason. But there were several things that came up that I wanted to address, and not only your personal attention you drew to me, but also what Gil said about the issue of searching for criteria that would help us, and make us concerned about certain forms of enhancement.

Now, in certain ways of transforming human beings, the criteria that we have are very clear, and we can see certain agencies that do it extremely well, and bring on virtues that we wish to support.

For example, we have a very clear idea of what we want out of a United States Marine, and the United States Marine Corps is wonderful, it being able to produce these virtues in these young men, and women now, with great advantage by the way to the young men that it is a co-ed group.

I can expand on that and tell you more about that, and what it has done, for example, to reduce the alcoholism that the Marine Corps had previously ignored.

But the Marine Corps is very, very good at developing certain virtues, but not complete virtues. Some of the virtues of life are left out, and I thought that the criterion for which people bring children along are the criteria that they see as the kind of outcome that they really want in their children in character development, that every person ultimately in my opinion should become a self-conscious pilgrim.

And that parenting has the responsibility to bring that self-consciousness along, subduing some traits that might be excessive, and at the same time bringing on others, and appreciating them.

Now, I was extremely fortunate in that I was brought up by two very loving and very intelligent parents.

PROF. GLENDON: Patient parents.

DR. McHUGH: it was interesting, Mary Ann, some of them were — my mother was more patient in everything than my father, and yet both of them combined together to both affirm and to transform.

And there may be a question really when I was reading your article as to whether — and it comes back to what Bill was saying, whether there may well in most parental — and if we are lucky enough to have two parents, that it might be easier to have the feminine affirming and the paternal transforming.

And I don't want to get into that as to whether they have to have Y-chromosomes or two X-chromosomes, but the issue for me seems to be that many people require in fact these two kinds of people, or two kinds of elements, to work together in transforming character.

And one of the problems of the consumerist world here today is that the chance of having the kind of two parents that I had is much less often possible for other people.

And this is a tremendous loss in forming a self-conscious person who thinks about his or her traits, and tries to minimize his vulnerabilities and maximize his strengths, which parents help.

The problem that Ritalin exists for me is that so often in the process it short-circuits the character formation role of the parental pair. The parental pair in my case that could be patient enough for my restlessness, and at the same time committed enough to accept some aspects of the energy that was there to bring me directiveness.

And Ritalin has — Ritalin just takes that out of the formula to some extent. Now, if you have a disease, ADHD, there is no question that it is just want Dr. Diller said. If you have one of those children that we want to give Ritalin to in the middle there, we would all say help him, because we won't even be able to have a conversation.

But with the others who have unfocused energy, and that Ritalin controls, it may well interfere with the parental role of enhancing self-consciousness in the person about what will do better, and what will do less well.

And so I am very interested in what you are saying. I think we could expand it certainly in this idea of what should be better familial situations for people to ultimately bring themselves on, and what are the issues that enhancing may well disallow, and finally I would like to remind you that poor Huckleberry Finn didn't, like Paul McHugh, have two loving and intelligent parents. He had to learn it on his own.

DR. KRAUTHAMMER: He had Jim.

CHAIRMAN KASS: Indeed, and that is a serious point. Mike Gazzaniga.

DR. GAZZANIGA: Mike, let's see if we can cash this in here. You basically don't want yuppies to shuffle the genes. You want Mother Nature to. And let's say you really are against Ritalin, and let's just use it as a metaphor for enhancement.

So what you are sort of arguing for, and I think that a lot of people would come to those views, whether they come from a strict biologic position, a scientific position, or a religious position. There are all kinds of ways to get to those conclusionary points of view.

But the basic idea is that we want to get this issue before the public someone said. How do we get people thinking about this. So let's now imagine that you become President of Harvard.

And let's imagine that you are going to have a new doctrine, and the new doctrine is that no applicant to Harvard can be enhanced in any way. And we are going to check your Ritalin records, and we are going to check your pre-implantation genetic record.

We are going to see whether you took the Kaplan. Whatever it is, you can't do that, and we want breezy, natural intelligence at Harvard. Let's say that you put that as a — let's say the President of Harvard came out and said that is a pre-condition for applying to Harvard.

Now, that would get national attention, and they would all go to Dartmouth. But the specific question is imagine that before the President announced that he actually put that question before the faculty at Harvard, what would the argument and the discourse be amongst the faculty at Harvard to that proposition?

PROF. SANDEL: Does this also apply to the faculty?

DR. GAZZANIGA: No, that's too late.

PROF. SANDEL: I think it is an intriguing suggestion. I had not thought about it before. I don't know.

DR. GAZZANIGA: Well, we have your class here, and we expect them to answer this.

PROF. SANDEL: Maybe this is one of those questions where I would be wiser to defer to the students afterwards, and we will put that on their agenda.

CHAIRMAN KASS: Provided that they turn in their pills first, right? Charles Krauthammer, and then I will take a word, and then we will close it up.

DR. KRAUTHAMMER: Rebecca mentioned a little earlier about genetically engineered fruit, and it occurred to me that you would get an enormous public uproar both here and abroad when you mention enhanced tomatoes, but you don't get very much when you talk about enhanced children.

And perhaps that is why we are having this discussion, and I think it is reasonable and important for us to talk about enhancement, because it has been looked at up until now in a very narrow way.

I want to return to, which I think is the central and sort of original point in Michael's paper, and that is the one that Mary Ann focused on; that the moral problem lies less in the perfection that it seeks than in the disposition that it promotes in that hubristic disposition.

And that disposition is mastery, and I think, Michael, that overstates the case, because we appreciate and we want mastery when we are going after disease.

That same disposition to master nature is what has powered all of medicine, and has brought us to this fantastic position of relieving misery and suffering through the conquest of disease.

I think where we want to draw the line is to say that we want that mastery to go up until that point, but not until then, and invade the land of the normal.

And that I think is — we may from what I heard this afternoon, I think we may actually have something of a consensus for all of the differing points of view expressed. And that is that there is something troubling about that mastery when we are mastering what is otherwise the normal.

And I think the best example came this morning, and in the discussions this afternoon in the discussion of Ritalin. The notion that we have — I mean, Paul McHugh had pointed out that if we — there is a very small number of kids who need it, and we would all agree with that, and like obscenity, we would all recognize it and there would be no discussion. That is disease if you like.

And we would want to cure it, and there wouldn't be a question of the illegitimacy of the mastery in doing that. The problem is that we all know that under a charade of medicine that there is a huge number, millions of kids, being treated as if it were a disease, but what we are doing is altering the normal.

I love the image of the little Paul McHugh, running around and sticking pigtails in inkwells, and I am sure that he got the strap, but he didn't get Ritalin, and that is the way to do it.

And it is very disturbing that there are millions of kids who are getting now a drug which is — I mean, it may not have a long range effect that we can measure, but it sure is having a short range effect, and it is changing their character or personality and performance.

And that I think is disturbing, and that is where I think we really ought to draw the line, and for two reasons. One is the one that Michael talked about earlier, and I think that Elizabeth had raised it, is that the problem is that it is our own ignorance.

We are changing parts of nature, human nature, and that we really don't understand the things that we are actually doing. I think that as Dr. Diller had indicated, when you take a kid who may not be performing that well, you alter that performance, and there could be all kinds of other human characteristics in her or him that we are altering, taking the round peg and changing it so it fits.

In that sense, we are subtlely altering a person in a way that we may not even be aware of, and the hubris is thinking that we know exactly what we are doing, and that we are focusing on one measure of performance, and that is it.

And I think that in and of itself is problem number one. The second is a problem that Frank had talked about. There is something totalitarian about this alteration of the normal, and I also was struck by that slide, where it said oppositional disorder, because that is out of the Soviet lexicon.

That is what they did when they threw people into psychiatric prisons. Now, obviously this is not comparable, but the mind-set which allows you to treat oppositional disorders is truly disturbing, and when you unleash it on millions of kids backed by a huge industry, which is making money off of this, and as the drugs of enhancement are universal in their potential markets, as opposed to drugs for disease, there will be huge commercial pressures behind the enhancing drugs.

I think that it is truly disturbing. This is in Ritalin, and it is clearly a form of social control. It is a way in which a modern society, which has less toleration for what used to be called the masculine or male characteristics of obstreperous if you like, is suppressing it by the use of drugs. That's disturbing.

Now, it is not the most — it is not rampant totalitarianism, and it is not Soviet psychiatry, but it is a hint of what is to come, and the reason why we ought to be disturbed about enhancement in general.

I think Ritalin is the perfect example, and it illustrates the two problems with the kind of the mastery of the normal. One is that we have limited knowledge, and we think that we have more than we do; and second, we are exerting a form of social control over the normal, which in the end could be truly frightening.

CHAIRMAN KASS: Charles, I think you graciously stepped aside at the end of the last session, and I will pass since I will put some of my own remarks in writing for the next time.

Let me thank Michael especially, but the whole group for a very stimulating discussion. Would you like a last word, Michael? You are entitled if you would like.

Okay. If not, we are adjourned until tomorrow morning, and I remind council members that we will start at 8:30. Francis Collins will be here, and could I exhort you to be prompt.

And I would remind those that would like to stay and talk with the students will do so. We will take a 30 second break for the people who would like to leave, and then the rest of us can stay.

(Whereupon, at 5:30 p.m., the meeting was adjourned, to reconvene at 8:30 a.m., on Friday, December 13th, 2002.)


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