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Home , David Baltimore, David Botstein, Human Genome Project, Renato Dulbecco

A t the moment of conception, the genetic blueprint At the invitation of , president of Bard ~-~ of a new life comes into being. E is an intricate College, and with the sponsorship of Los Alamos National message differing in slight but crucial ways from one , some of the leading participants in the being to another. So far molecula have Project gathered at Leon’s home on December 5, 1.990, to decoded only a tiny fraction of this set of instructions; answer questions about the goals and ethical implications of we live for the most part in ignorance of how our genetic the project. Los Alamos offers this presentation inheritance will influence the course of our lives. The goal not because the questions were all-inclusive or the answers of the Project, a fifteen-yea, international definitive but because the issues raised, both philosophical research effort, is to read the entire contents of that message and practical, will become more pressing as information and to provide the tools for deciphering the genetic differ- from the accumulates. We hope to ences among us. Are we ready as individuals and as parents stimulate discussion among you, your family, and your for the emergence of this new knowledge? Are we ready friends as we prepare to consider and act upon the resulting as a society? As a species? information with wisdom, compassion, hope, and openness. in the 2 ls’ Century

Leon Botstein: Ladies and gentlemen, special DNA sequence that makes up clinics? What positive effects might let me welcome you. The topic this the end of every human . come from the resulting technology? evening is the , Finally, Nancy Wexler, President of the Will there be a revolution in health care? and my role is to explain the format Hereditary Disease Foundation and an What could prevent us from taking full of the discussion and to introduce the Associate Professor at the Department of advantage of such benefits? What are panel. This is an unusual opportunity Neurology and Psychology at Columbia the social effects? Why might it lead to to participate in a discussion about an Presbyterian Medical College. Nancy greater social inequality, or conversely, important issue with the people who is Chairman of the Department of to greater homogeneity? Is there a valid ought to know what it’s all about. First, Energy–National Institutes of Health concern with respect to ? Can will give a somewhat joint working group on the ethical, we influence the human pool? Will brief introduction to the Project, in legal, and social issues of the Human this project affect our view of ourselves? which he will state its goals, its history, Genome Project, the group known as What myths will be challenged by this and why he thinks it’s necessary. Then, ELSI. I think there could not be a more research? What theological questions each of the panel members will be given distinguished and appropriate panel for might be invoked by this work? Is the opportunity to make an opening this discussion. there some issue of responsibility which statement. After that, the floor will be might lead us not to pursue this project? open to questions from the audience. Does the individual own the rights to I’m certain that this is not a particularly his or her own genome? What are reticent panel, so there’s no need for the legal implications? Finally, do me to moderate—but rather, perhaps, to people really want to know about their adjudicate. genetic inheritance? These questions are Now I will introduce the panelists. probably more than enough to generate is President of Rock- considerable controversy. I turn the floor efeller University. He, along with over to you, David. Howard Temin and , won the for the discovery David Botstein: One of the challenges of . I can’t refrain we have not yet fully met is explaining from mentioning that he is a graduate to people who are not directly involved of , a small liberal in the Human Genome Project what arts college like Bard College. Next, my we are doing and why we are doing brother, David Botstein, Chairman of the it. As a result, a consj derable amount Genetics Department at Stanford and a of misunderstanding has arisen. My long-time member of the faculty at MIT. purpose in this introduction is not to He invented the use of DNA markers give you a hyper-rapid education in and is one of the initiators of the Human There are many questions which were , but instead to introduce a few Genome Project. Next is James Dewey put forth by a variety of people interested of the basic terms and to present the Watson, who, together with Francis in the Human Genome Project. What are fundamental ideas around which this Crick and Maurice Wilkinson, won the the goals of the Project? What has been project is based. Nobel Prize for discovering the structure achieved and what might be achieved First, and I’m sure most of you know of DNA. Dr. Watson is Director of in twenty years? What are the main this, our are made of DNA. It the Human Genome Initiative of the scientific arguments against the Project, has been clear for about fifty years National Institutes of Health and also what are the scientific arguments for that, to the first appro~imation, all of the author of a classic book on the the Project, and how important is it a person’s inherited characteristics are character of scientific discovery—The compared with other scientific projects? specified by the DNA of the fertilized . Also here tonight is What are the obstacles to its success? egg. Therefore, to understand the entire Robert Moyzis, Director of the Center How do share the results of message encoded in a person’s DNA for Human Genome Studies at Los this project? How likely is it that the is to know everything about his or her Alamos National Laboratory and the technology coming from this project will inheritance. I did not say transcribe or discoverer of the human , a be available to physicians, hospitals, and put on optical disk. I said understand,

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— Genetics in the 21s’ Century

we have a very complicated technical -causing gene, and much of the task, first in trying to find all those genes of the oncogene has been and then in trying to understand what worked out in great detail. In fact, the they do. In the last ten years it has relationship between the two genes gave become clear that we have the technical a logical explanation as to what might means to at least begin to write down cause neurofibromatosis tumors. So to the sequence of all the base pairs in make the discovery of genes meaningful the human genome. The question is: as well as easy, we need to know the Why do it? Much of the opposition to sequences of genes in experimental the Human Genome Project is based on organisms. Yeast, for example, has the fact that just knowing the sequence genes that are very similar to those of base pairs doesn’t mean anything in of higher organisms. However, even itself. The genetic code lets you turn though the yeast genome is 250 times the base sequence of a gene into the smaller than our own, the yeast genome amino-acid sequence of a , but has been only partially sequenced. even th~t doesn’t mean anything by current technology. It’s as if you had We have the technical a row of hieroglyphics and a way of transcribing them into Urdu—but you means to at least and a complete understanding of the don’t understand or speak Urdu. That’s begin to write down message is a long way off. The big deal pretty much the situation we’re in. about a person’s DNA—aside from the The next question is: How can we the sequence of all fact that it encodes all the information for give meaning to the that are the base pairs in the making the person—is that it contains derived from the genes? Sometimes an extremely large number of paired there is a way because we’ve been human genome The bases—six billion. Simply collecting information about genes and question is: Why do it? determining the base sequence of all proteins for a long time. We know that DNA is a big technical problem. globin. It’s a protein that has been In fact, determining the base sequence studied for fifty years; it carries oxygen The first proponents of the Human of any segment of DNA is one of the in the blood. We know insulin, a protein Genome Project proposed simply to go triumphs of modern biology. that regulates the sugar in the blood. ahead and sequence the entire human For about ten years people have been We know the sequences of the genes genome with the current technology. able to sequence a little bit of DNA here, for these proteins. The functions of Many people, including me, were ap- and a little bit there. That is, they’ve these proteins have been studied in palled by this proposal because-it was been able to determine the sequence of lower organisms, such as bacteria, yeast, stupid. A framework with which to nucleotide bases for a relatively small and mice, and a huge amount of research interpret all those sequence data did number of genes. We know that the and manipulation has been done on these not exist, and the technology then sequences of most genes specify proteins organisms. So when people found the current was so slow that the job would and that the proteins do the work in the human cystic-fibrosis gene and looked at have taken somewhere between thirty . In general, however, we don’t its sequence, they said, “Aha!” because thousand and sixty thousand man-years. know how a particular gene and the the sequence looked like the sequence of The Project would have wiped out particular protein it encodes determine a gene that had been studied in a number biology in the same way that the space a visible or measurable inherited char- of other organisms. It’s called the shuttle wiped out planetary astronomy. acteristic. In this soup of six billion multidrug-resistance gene, and there is In response to this proposal, the National base pairs, the average gene, the average a substantial literature—several hundred Research Council formed a committee coding sequence for a protein, is only papers—surrounding it. When people that included opponents and proponents, one thousand base pairs long, and we found the neurofibromatosis gene, they and we drafted a set of three proposi- estimate that the human genome contains again said, “Aha!” because its sequence tions. The first was that we begin not by between 50,000 and 100,000 genes. So is related to a well-known oncogene, or blindly the human genome

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but instead by making physical maps of of which have a genetic component. If, whether we can afford not to do this it, maps similar to but on a larger scale however, just as we might visit a fortune project. Genetic diseases are like deadly than those that helped us find the cystic- teller to have our palms read, we could assassins. If you are in a family at fibrosis and neurofibromatosis genes so risk, you know the assassins are there, quickly. Included in the first proposition but you have no way of finding them were proposals to improve sequencing If. . . just as we might and no way of hiding from them. The technology so as to make it faster as visit a fortune teller Genome Project will provide ways of well as to apply current sequencing finding those assassins and methods for techniques to model organisms so that to have our palms pinning them down. It will find the lethal we might again say “Aha!” as the read, we could go out genetic killers as well as the genes for human genome is being sequenced. It life–crippling disorders such as obesity was also suggested that we make more and have our DNA and alcoholism. We’ll be learning about detailed genetic-linkage, or co-inheritance, read . . . would we the genes that are unique to and maps. Second, we proposed some the many, many genes that we share kind of oversight by scientists of this really want to know our with other species. This information new endeavor so that it would be genetic futures . . . ? will expand our understanding of our neither entirely undirected research nor genetic heritage and enable us to have your Stalinist we-tell-you-what-to-do greater control over our individual lives research. It’s somewhere in between. go out and have our DNA read and and, eventually, better diagnoses and It’s both application-oriented and goal- predictions made accordingly, would we treatments for our genetic disorders. oriented, but individual creativity is still really want to know our genetic futures applicable. And third, we proposed that and the genetic futures of our offspring? a fairly substantial portion of the money Would we want to run the risk of having be spent studying the ethical, legal, and others know? If the health-insurance social implications of the Project as a industry could predict our futures from means of preventing us from outrunning the results of , would our own thoughts and, more to the we be able to get adequate insurance point, from outrunning those of society policies? Could we be turned down for regarding the use of this information in coverage entirely? Or, if we applied for ways that will benefit humankind. a new job, could the employer evaluate and eliminate our applications on the Nancy Wexler: I have heard many basis of genetic information, saying, people ask, “Can we really afford to do “No, I’m sorry. You are predisposed to this project—not only in terms of the developing ‘certain kinds of cancer, and expense in time, energy, and money but we can’t afford to hire you because you also in terms of the costs for us as a are too likely to increase our insurance society? Can we afford the ramifications costs.” Worries such as these are not of having this genetic information made unfounded. It is a simple fact that available to the individual, to our insur- discrimination is often economically ance companies, to our employers?” driven, and people are concerned about There is, of course, the potential for The of each person here what will happen to their lives when serious misuse of genetic information contains genetic messages indicating genetic information becomes available. both in the manner in which it is that at some point you are likely to On the other hand, those of us who delivered to the individual and the way develop cancer or that you are prone to have been working in the field of genetic in which it is received by society. So, heart disease, diabetes, or some other disease for a long time and who are as we proceed with the Genome Project, disorder. No doubt several of you have engrossed in efforts toward finding we want to anticipate potential problems children with genetic disorders. Many treatments and cures, feel strongly that and concerns. Therefore, the DOE and of us know people with schizophrenia, the question is not whether we can NIH formed a joint working group on or leukemia, or Alzheimer’s disease, all afford to do this project but rather the ethical, legal, and social implications

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of the Project. This group, informally recommended that the Project should go known as ELSI, is working to develop ahead and proposed a sum of money that programs and legislation to ensure that would allow the work to be completed genetic information is used wisely and in a reasonable amount of time, my first to the advantage—not the detriment-of the individual and society as a whole. Unfortunately, many of the concerns Who would want and issues that ELSI hopes to anticipate to have the rest of and address are already with us. The present situation with respect to health his life predicted if it insurance is very disturbing. Thirty- can ‘t be changed? seven million people don’t have any health insurance, and fifty million are underinsured. So we need to consider task was to assure Congress that the now what will happen when the Genome scientific community wanted the Project, Project makes possible the diagnosis of believed it would work, and felt confi- more and more genetic disorders. The dent that it wouldn’t be another Hubble high visibility of the Genome Project telescope—that it was a project whose is, in effect, throwing a spotlight on success was insured if we could get biological understanding. We may existing problems of discrimination and the money. The second task was to finally understand processes as diverse social stigmatism. People are beginning spend the money wisely. SO I drafted a as the development of a human to realize that almost all of us are at group of first-class scientists as advisors from a single fertilized egg and the risk in some fashion or another, and that to the Project. I am the nominal head knowledge can give us a new impetus of the NIH component, but the real toward solving these problems. Given the benefits leadership comes from the advisors, that are going to come who meet in formal session twice a Bob Moyzis: It’s always a pleasure to year. We have also put together a staff be invited to talk about this project, one out of this project, of administrators within the National that I feel is arguably the most exciting not in two hundred Institutes of Health who are really very in the . We’re talking good. People thought our :project would about nothing less than unraveling the years but probably in be fun to administer. The third task, and complete package of genetic information our lifetimes, . . . it’s the most important, was to persuade a present in each one of your cells. In group of younger people to actually work addition to accelerating the pace of essentially unethical on the Project. We needed very bright identifying the genes responsible for not to pursue it. people to put these maps together. One known genetic diseases, the new in- initial complaint was that this project’s formation will help us to identify the lab work was for people you wouldn’t genes involved in disorders like heart mechanisms underlying complex human want to go to dinner with because they disease and cancer. The genetic compo- behaviors. To paraphrase what our next would have to be dull. On the contrary, nents of these complex yet common speaker, Jim Watson, has been quoted the Project appeals to bright people disorders are largely indecipherable as saying, given the benefits that are because, if they skillfully choose their with current technology. The Human going to come out of this project, not in region of the genome, they may get to Genome Project will change that. It will two hundred years but probably in our work on an interesting disease gene. form the basis for identifying many of lifetimes, I feel it’s essentially unethical The people working on the Project are the genes that cause the diseases that not to pursue it. as good as any other group working in afflict mankind. As well as addressing today. We ‘re giving these worthwhile pragmatic goals, this Jim Watson: I will explain my role out a number of ordinary grants, but project will provide the intellectual in leading the NIH component of the we’ve decided that a few people need to framework for the next century of Human Genome Project. After we get a lot of money if the Project is going

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a somewhat larger point of view because processes, our behavioral processes, and I’m neither a member of the Project nor a ultimately our ability or inability to part of an advisory group nor a recipient work together to form a society. In a of any grants. The Human Genome broad sense the Human Genome Project Project is now a great concern for all of represents an attempt to do all of these modern biology because the maps being things. made will help find all genes, not only There are, inevitably, ethical problems those that cause disease, but those that arising out of the works of modern do all the normal things. To a large biology, but they don’t necessarily relate extent, we are what we are because of to the Genome Project alone. We are our genes. In order to discover all the genetic blueprints that determine what we are and to understand how we came to be what we are, we need the Human Genome Project. But this project as it stands today is a very small piece of modern biology. The Genome Project is being funded at $100 million a year, whereas $8 billion a year of NIH money is spent on health research. Molecular to be done effectively. The Project is genetics, modern genetics, molecular almost in good shape from a funding biology—all of these words subsume an standpoint. We didn ‘t get all the money incredible ability, evolved over the last that was initially proposed, but I think fifteen years, to gain an understanding we’ve got enough money to fund most of the workings of all of the systems of of the good people. We’ve assembled a the body. The Genome Project will help group of highly imaginative people who to bring together disparate attempts in are committed to the Project, and I’m around the world to find out delving into ourselves. We have lived actually feeling relaxed about it. The with a myth about ourselves for a very initial objections about the Project being long time, and that myth is that we are and unnecessary science We have lived with a all equal, all the same. It’s a myth have been overcome. The next problem myth about ourselves with very potent political and social we are going to face is that of having implications and a myth we ought to developed predictive capabilities without for a very long believe as long as we-have nothing else having developed the cures. Who would time, and that myth to believe in. The Genome Project is want to have the rest of his life predicted going to teach us that we are not all the if it can’t be changed? As we find out is that we are ail same, that we are all different in ways how to predict diseases, we also have equal, all the same. we could never have unda-stood before. to find out how to do something about We are going to have to come to terms treating and curing them. That’s the with the fact that we are all born with way to make the Project worthwhile in how kidneys work, how work, different talents and tendencies. It is my the best sense. how a fertilized egg develops into a belief that knowledge brings freedom human being+r into a tree sloth. I and that knowledge of ourselves will David Baltimore: I have the reputation support the Human Genome Project in bring us freedom from potential disease, of being a critic of the Genome Project, its human focus because there are a from the potential inability to learn, a role I’m not particularly comfortable whole range of things that are partic- and from the potential inability to cope with because most of what’s going on is, ularly human, and we have to study with certain aspects of mudem society. to my mind, very appropriate and very them within our own DNA if we are We need to know not just what it is that exciting. But I can comment on it from ever going to understand our learning makes us human beings, but what makes

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us particular, individual human beings, percentage of the genome budget for and the Genome Project is a piece of ELSI activities, we will not be able to the development of that understanding, miraculously decide all of the ethical a piece we need to support. When we issues associated with this project. contemplate the ethical challenges that We hope instead to catalyze exactly lie ahead, we need to examine not only the type of discussion we are having the Human Genome Project, which is a tonight. We all hope that society as paper tiger in many ways, but also the a whole will come to a realistic and overall capabilities of modern biology. positive consensus on the solutions long I ask you to consider whether you agree before the problems are permitted to with me that this kind of knowledge materialize. We live in a democracy. represents freedom. All of us should be involved in deciding how we want to deal with the inevitable problems.

Questions & Answers Question: You have suggested that stud- ies of DNA will ~eveal ethnic differences, personality differences, psychological Question: From a layman’s point of proclivities, and so on. Is that true? Will view, one of the most interesting things such studies reveal why two brothers, for about this massive science project, per-- The funds are being used to support example, David and Leon Botstein, have haps unlike others in the past, is that a large number of activities. The gestures that are very similar? it is taking on from the very beginning joint NIH-DOE ELSI working group, the questions of its own implications for which meets four times a year, hopes David Botstein: Frankly, we don’t human beings. How are you going to to stimulate public discussion as well know the answer to that question. examine [he legal, ethical, and social as help develop policy options that Maybe our gestures are our mother’s aspects of this project? assure that the knowledge the Project generates will be of maximum benefit Nancy Wexler: Jim Watson is respon- to individuals and to society. ELSI has Genetic facts sible for initiating the formal structure identified four high-priority areas for don’t change your within the Human Genome Project to program activities: quality and access anticipate and address those issues. in the use of genetic tests; fair use of rights. The idea that we The development of such a program genetic information by employers and are all equal means we made some people nervous. They said, insurers; privacy and confidentiality “Well, the ethical issues will take care of genetic information; and public and all have equal rights, of themselves as we go along.” But professional education. We’ve organized not equal abilities, Jim thought those issues should be conferences and workshops, and we are explored and addressed as an integral supporting a variety of research projects part of the Genome Project. So he related to this topic. We are looking gestures, and we learned them from went ahead and created a working group at existing legislation and perhaps will her, or maybe we inherited them from that is now jointly sponsored by the develop model legislation and model her—right now we can’t tell. I think, Department of Energy and the National policy. The visibility of the Genome however, that we are going to find Institutes of Health. Both organizations Project has meant that certain penchants out that in some cases our behavior is have designated a portion of their total for discrimination have been opened to inherited and in other cases it is not, budgets for the Genome Project for public scrutiny in a way they have never and we have to learn to live with that the examination of the ethical, legal, been before. fact. Common sense already tells us and social implications of the Project, that. But in my view genetic Pacts don’t thereby creating the largest biomedical- Bob Moyzis: I think it’s important change your rights. The idea that we ethics buc[get anywhere in the country. to emphasize that by setting aside a are all equal means we all have equal

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rights, not equal abilities. The fact is predict with certainty whether a person individual we can help that individual I could never have been a professional will be smart or be a fast runner without develop his or her maximum potential. basketball player—I simply wasn’t tall regard to factors such as education and This may mean tailoring the individual’s enough. training. education both to take advantage of strengths and to compensate for weak- Leon Botstein: That’s not the reason. Question: In his opening statement nesses. It may mean counseling an David Baltimore said the knowledge individual to take directions in life that resulting from the Genome Project will build on inborn capabilities. bring freedom, but knowledge also brings responsibility and choice. Sup- Jim Watson: I would prefer to trust pose prenatal testing reveals a genetic the individual rather than the state in propensity toward alcoholism or low IQ that sort of decision. Some people or something else that the parents may feel very strongly that sex selection simply not want to settle for even though shouldn’t be allowed, but I would have it is not a disease. Will the parents be compassion for parents who already allowed to say, “We do not want this had eight boys and wanted a girl. I being ever to come into existence”? Can would personally be very frightened society eventually determine that certain by any political control that took the qualities disappear? We can already do power away from parents. I shudder that to some extent, but if it’s a question at the thought of state control over this of IQ, what will happen? issue. The laws would necessarily be imperfect. David Baltimore: There is no question that along with knowledge and the David Botstein: I would like to point freedom of choice will come very out the following simple-minded nu- David Botstein: That was among the difficult social and political questions merical facts about designing the make- very many reasons. On the other hand, that have major moral aspects and that up of future generations. When you certain skills or abilities are easily don’t have a right or wrong answer. pass on traits, you pass them on in a improved by training. Take running, As our knowledge of human genetic binary way. The father’s sperm decides for example. Even unselected people variability deepens, the opportunity whether an offspring will be a boy or can run. They may run much more to avoid more and more traits in our a girl. That means half the fertilized slowly than their potential, but if they offspring will present itself. It is very eggs will be boys, so if you choose train hard, eat the right stuff, and learn boys you already have only half of the how to get down on the blocks and fertilized eggs to choose from. If you anticipate the starter’s gun, they will run By understanding make another binary choice, you have faster. It will be extremely difficult to the inheritance of an a quarter of the eggs to choose from. sort out the genetic component of such If you have yet another binary choice, skills even if we are able to follow all individual, we can help it’s an eighth. If the array of basketball- of the genes involved. Some people will that individual playing genes is thirt~y, then only one be very smart or very athletic because out of over a billion of the they study or train, and others will be up develop his or her has them all, and that’s a prohibitively at the same level due to natural talent. maximum potential. low fraction. So choosing a genotype Separating the two components is not a for anything complicated is, in principle, matter of genetic technology alone. It’s extremely impractical. It’s just not likely difficult, and for some abilities it’s never doubtful that we will see the disappear- to happen. The moral problem is there going to happen. So while we will be ance of specific traits, but individuals whenever you choose one embryo over able to figure out the genetic component will have a wider range of choices. another, but this business of specifically for a lot of these personal traits, it’s To me, it is much more important that designing your offspring in one fashion very unlikely that we will be able to by understanding the inheritance of an or another—forget it!

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Leon Botstein: David, the popular myth Question: David Baltimore pointed is not so much being able to choose out the myth of equality. But we’re among embryos but being able to make fortunate that in our political system, changes in a given embryo. in our culture, in our institutional ar- rangements, we try to assure equality David Botstein: Genetic information of opportunity in a wide variety of will permit you to identify, in part, ways. But there is another kind of what’s going to happen to an individual. myth deep in our Western culture, and That’s a prerequisite to manipulation, that is the notion that we are volitional but it’s not nearly sufficient, and ma- , that we have a capability to nipulaticm, at least manipulation of egg choose how we act, appropriately or and sperm cells, is very, very far away. inappropriately. I do not object to the What you can do is choose from among Genome Project on this ground, but the available embryos and, as I said, it’s it seems that we are heading toward unlikely that there will be much of that. challenging a fundamental precept of In fact, [ expect there will be none. our society as we unfold the dynamics of behavior by means of our growing Jim Watson: I’d like to make a point. understanding of genetic inheritance. [ Eugenics is supposed to be a bad word wonder whether some of the opposition that we sort of equate with Hitler. It says lute agony upon your descendants. If to the Genome Project might stem fi’om we are trying to determine or change you have the option of having children a fear that the results of the Project will the of the human germ plasm. without that gene, you might certainly show that we are not in fact volitional The most repulsive aspect about the want to choose that option. That’s my animals and do not really have free will, eugenic efforts both in this country and, opinion. Likewise, if you know you are in particular, in is that eugenic a member of a cancer-prone family, and Jim Watson: I have not met anyone choices were made by the state, often on there are means by which you can have who does not believe he has free will, the basis of very incomplete knowledge. children who would not possess this the ability to make choices. But we will In this country we had a sterilization trait, I think you as parents should have not really know what that means until program that involved about twenty the opportunity to make that choice. I we understand how our brains function, thousand women who were judged to think it would be absolutely dangerous and that is a long way off. Nevertheless, be feeble-minded solely on the basis of for anyone else, especially the state, to if we eventually do understand how their being prostitutes. This program make such decisions. To say that parents they function, I will be very surprised was carried out in the 1920s and 1930s, must perpetuate things that bring only if we feel any differently. If you are and the people who were sterilized had born into a given political or cultural no choice in the matter. The matter went No one should be tradition, there are pressures to stay in to the Supreme Court, where a decision that tradition. My political views are was made in favor of the sterilization allowed to prevent us pretty similar to my parents’ political program. The jurist most responsible for from improving our own views, and so traditions are passed on. the decision was Oliver Wendell Holmes, We might say that I don’t really have the who said that the state had the right to individual lives and the freedom to be a Republican, but actually improve its future citizens. Then when lives of our children. I do. So I don’t think the Genome we saw what happened in Germany, we Project is going to touch the free-will decided that eugenics was extremely bad. issue. On the other hand, to say that you can’t agony upon themselves and their off- really make choices to eliminate a gene spring appears. to me to be terribly Question: When you say that the gene for Duchenne’s muscular dystrophy, to immoral. No one should be allowed that causes cystic jibrosis is somehow say that you want to perpetuate that to prevent us from improving our own abnormal, I think we are all with you. gene for your descendants, is to be individual lives and the lives of our But in the case of behavioral or learning mad. Tlhat gene brings total and abso- children. processes, how do you decide what the

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healthy or normal gene is? Is there and make choices when the effects of p~obably because for complex things like a way of dejining normal by more valid the disease are so unpredictable. heart disease, it is doubtful that we will means than merely by accepting society’s ever be able to say with real certainty viewpoint? Bob Moyzis: That’s an important point. that if you do this or that you’ll be free One of the more immediate impacts of of the disease. David Botstein: That’s a good question. this project that we all hope to see is a I don’t know what’s normal. In dealing more individualized approach to health Question: You said you have received with species other than ourselves, we care. Complex human diseases like a g~eat deal of funding for this ve~y have an operational definition of normal. heart disease, for example, are likely to dijjicult technical project, but I think Normal is what you find out in the wild. the ethical aspects are even more It’s called wild type. If you catch a dijjicult. I’ m interested in knowing how fly and it has certain characteristics, they will be addressed, How will they that’s wild type, that’s normal. Any be funded and how is that money going differences are not called or to be spent? diseases, they’re called polymorphisms, a neutral term, right? The point is that Nancy WexIer: The efforts to evaluate when people die horrible deaths due to the ethical, legal, and social implications their genetic content, we say disease, but of the Genome Project are as much a part we might simply view it as a variation of of the Project as the effofis to construct what you would call wild-type human. the maps. ELSI’s activities go hand in hand with the development of the basic David Baltimore: You say there are science because it’s critical that our normal and polymorphic variants, but discussions, workshops, research and that’s not really correct. There is no conference grants, and efforts toward normal. They are all polymorphic variants. It’s unlikely that we’ll David Botstein: That’s right. I stand see many people going corrected. into their obstetrician’s David Baltimore: I learned it from be the result of a combination of many or gynecologist’s you so I know it’s right. There is a genes. Nevertheless, you are treated offices to sort through range of variations we consider normal like the generic human being, and the and there are those outside that range doctor tells you the fifteen things that embryos ~!nd pick that we consider abnormal. Things like you should do to lower your cholesterol. out their favorites. are clearly diseases, but The new information will free us from we have to be very conscious of the fact this idea that we’re all the same, and that in any gene we will see a very wide you’ll get much more individualized policy development be grounded in range of variation and that most of that medical treatment. In five or ten years the capabilities and limitations of both variation is normal. you will be able to walk into your current and future technology. David’s doctor’s office and the doctor will take calculations show that it’s unlikely that Nancy Wexler: Even in terms of a a little bit of blood, get an analysis we’ll see many people going into their single disease the variation can be very of a variety of genes, and be able to obstetrician’s or gynecologist’s offices great, and variations in the symptoms personalize your treatment. Maybe you to sort through embryos and pick out and progression of the disease make will be able to eat all the eggs that you their favorites. People talk about these counseling very difficult. For example, want because it’s probably not going to kinds of horror stories,, but technically one child with cystic fibrosis will die at matter whatsoever, bul you better avoid, and practically, I doubt it will be our age four and another will still be living say, jogging ten miles per day because top problem. At this point we are trying at age fifty. It’s hard to consider options it’s probably going to kill you. I say to clarify the issues and assess the most

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salient ones through discussions of the employment. Funding also goes toward when boy meets girl and there’s an kind we’re having right here. What individual research grants, conference added dimension, the genetic cost. The are people really concerned about? grants, and post-doctoral fellowships two might be a perfect match until What do people see as the issues for designed to address the entire range of they check to see if they have matching them? Are there issues of which ethical, social, and legal implications of cystic -fibrosis cards. Is that where we’ re we are unaware? A group of seven the Project. The ELSI Working Group headed, everybody carrying around their research teams around the country, has carefully evaluated the Americans own genetic ID card? Third, Dr. Watson, managed by ELSI, has undertaken a With Disabilities Act and outlined you said everyone has free will, but three-year study to evaluate the benefits suggestions for the improvement of does everyone have the same capacitj of making a test for the cystic-fibrosis the Act relative to genetic issues such as to exert their will? And is that capaci~ gene available to the public. The study discrimination and privacy. ELSI also detectable through genetic testing? IS will also develop and assess methods for sponsors public outreach meetings in it associated with a gene? And if it is educating and counseling people who order to encourage community discus- associated with a gene, lhen what does want to be tested for this gene. We sions. We hope to educate the public that mean for those who don’ t have the hope the findings will supply health- and stimulate community interest and capacity to exert their will? care professionals with strategies that involvement in the process of shaping maximize a person’s understanding future policies. Jim Watson: You have cited several of genetic testing as well as record- ethical problems that need to be ad- keeping and disclosure policies that Question: You have a lot of big names dressed, but the most critical of them— will best protect the individual against working on this project, and they have and you referred to it indirectly—is what breaches of confidentiality, stigmatism, drawn an enormous amount of funding, I call genetic injustice. DNA replication and discrimination. ELSI has also cong~essional and otherwise. How will established an Insurance Task Force this project affect other areas of science working toward developing guidelines where funding might be somewhat re- NO matter how duced? it may upset the

Jim Watson: The money spent on the insurance companies Genome Project is going to make other and the employers, aspects of biological science more effi- cient by bringing them out from under an confidentiality has to umbrella of complete ignorance, similar be a guaranteed right. to the one that shrouded before the discovery of oncogenes. A lot of money is now being spent on trying isn’t perfect, so some people are born to alleviate terrible medical conditions. with genes that do not work properly. People go to Congress, and Congress People are either slightly disabled or votes money in an attempt to help. For greatly disabled depending on what gene example, one of the best things we can function is impaired and the extent of do to address the problem of aging is that impairment. Everyone knows that to try to find the genes that predispose people are different from one another, one to Alzheimer’s or other forms of and it’s been convenient to ascribe those abnormal aging. By doing that we’ll differences to our environments, to gain real scientific clues as to what is the fact that we didn’t have certain going on and what we can do to help. opportunities in our childhood, or we didn’t have a good education, or we for insurance policy by 1993, and we Question: First, could you share with us didn’t see a doctor when we should have commissioned a White Paper to the three or four most dificult confiden- have, and so on. delineate policy options in the area of tiality questions related to the Genome In our rational society we think we genetic testing relative to insurance and Project? Second, I can imagine a time can pass laws to correct the inequalities

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resulting from man’s environment. We genes, and what we have to do is try to disclosure policies vary from one healtl- can do away with poverty. We can do find cures and treatments so that we can care provider to another. away with all the things that clearly circumvent the inequalities. Another complication arises from make people unequal. But now we Our knowledge of some diseases is the fact that our are inherited know that certain kinds of inequality improving so quickly that such hopes from our parents and passed on to come from our genes. A paper on early- are not completely unrealistic. In other our children. That simple fact means onset identifies a gene on cases, science won’t be able to come that personal information about one the short arm of that to the rescue. In those cases genetic individual’s genome will often yield predisposes women to breast cancer. information must be confidential. We information about that individual’s shouldn’t be stamped as unequal due parents, siblings, or children. It’s like to our genetic heritage. No matter how pulling a thread on a sweater—one tug it may upset the insurance companies and a whole string of aunts, uncles, and the employers, confidentiality has to and cousins begins to unravel. We be a guaranteed right. For example, want the use of genetic testing to be a no presidential candidate should be positive development in a health-care able to say, “1 will let my genes be environment where privacy is assured, seen by everyone,” thereby forcing but there may be situations where his opponent to come out with what absolute respect for an individual’s might be construed as damaging genetic genetic privacy could be detrimental to information. The need for confidentiality their relatives’ health. ELSI is working is paramount. We must try to treat and to develop policies that will help satisfy cure as much genetic inequality as we questions about the ownership and can, but it exists and we’ve got to live control of genetic information as well with it. as matters of consent to disclosure and use of such information. It’s a complex David Botstein: Jim proposes to make issue, but we need to keep in mind genetic information so confidential that the fact that the real attraction of the nobody but the individual can know Genome Project lies in the hope that anything. The better solution would by understanding disease genes we can be to have health insurance guaranteed develop treatments. Before we had the Women who inherit that gene are going for everyone. Then the injustice of to have a much greater probability of having the wrong genes would not be It’s like pulling a thread having breast cancer than other women. compounded by the injustice of not That’s terribly unjust, there’s nothing having any health care, which is where on a sweater—one nice about it, but it’s true. How do we we seem to be heading in this country. tug and a whole cope with that inequality? Do we tell If we solve the insurance problem, then people to have tests so they can find out I believe there will be no pressure for string of aunts, if they have that gene? Do people really genetic testing. Usually health insurance uncles, and cousins want to know? Would it be better if is the issue. everyone thought they were equal, that begins to unravel. it’s God’s will if they get cancer? Nancy Wexler: We as Americans feel Some call New Jersey the Cancer that we are legally entitled to greater ability to detect disease genes, the only State because of all the chemical com- confidentiality than is actually granted way a couple could find out whether panies there, but in fact, the major factor us by law. We’re now looking at the they had the matching cards mentioned is probably your genetic constitution. If extent to which existing laws protect earlier was to have an affected child, you were lucky enough to have both against violations of confidentiality. The and then they had that agony to face. your parents live to be one hundred, genetic privacy issue is complicated One of the benefits of having a genetic you’re probably going to live a long life. because laws vary from state to state test for breast cancer, for example, is Basically the inequality comes from our just as record-keeping methods and that it allows for early detection and

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treatment and the ability to save many, fibrosis is a recessive disease, so only many lives. people with two CF genes, we call them homozygotes, are affected with David Baltimore: The questions about the disease. But most CF genes are in confidentiality and testing may be the heterozygotes, people with one normal most difficult issues facing us at this gene and one CF gene. These people time. In the long run, however, I expect are carriers, but they exhibit no adverse this concern will probably dissipate symptoms and therefore are not selected and eventually disappear. As we learn against. Since they are not selected more, we will discover that all of us against—and why should they be?—the have some deleterious aspects in our CF gene will always remain within the inheritance, and the only means of population. having a work force at all will be to dismiss the concept of the perfect person Question: Would that be true for domi- for the perfect job. However, I hope that nant genes as well? long before we come to that conclusion, we will have put the responsibility not David Botstein: No, it is not true for on the individual but on the insurance dominant genes. But there are very few companies and the employer. We have prevalent dominant genes for serious health insurance so as to share health Nancy Wexler: Yes! It’s definitely diseases except those that are new risks, and one of the rights an individual self-correcting. Most never mutations, Dominant disease genes tend has is the right to work in the profession intended their scientific work to be used to fall by the wayside because of their of his or her choice. I’m uncomfortable for anything other than the detection of dominance. People who are afflicted about psychological testing, and I am serious diseases. In certain situations, with the worst dominant diseases usually very much opposed to genetic testing as however, it is necessary to institute laws don’t live long enough, or they’re simply a basis for gramting or denying employ- or use social policy to prevent other unable, to bear offspring. ment or insurance. people from using scientific knowledge for purposes beyond those which the Question: Who will take care of the geneticists had envisioned. confidentiality of the genes of an embryo? Is it possible to protect it? If it’s possible Question: If we use genetic information in the , is it also possible to select against certain disease genes, in India or Argentina? such as cystic jibrosis, by choosing the good eggs and avoiding the bad ones, David Botstein: The problems in India will our gene pool be depleted? and Argentina are very serious, and I doubt that any massive amount of genetic screening will be done. Many The question is: Can countries still have trouble getting vaccinations done. you eliminate genes from the population ? Nancy Wexler: Nevertheless, let’s rec- ognize the fact that they had to pass a law The answer is: No. in India against sex selection because parents were using genetic screening to avoid having female offspring. David Botstein: The question is: Can you eliminate genes from the popula- Bob Moyzis: The question concerning David Botstein: That sort of problem tion? The answer is: No. There is the gene pool raises a very critical is self-comecting. a simple numerical argument. Cystic point, namely, that all species, humans

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included, benefit from great genetic Nancy Wexler: The room would be Question: I am not really completely diversity. It is essential for our sur- empty ! comfortable with the scientific aspects vival and future adaptability. Although of what we have discussed, but it seems some have imagined that genetically Jim Watson: It is a disease which can to me that there are really two issues. homogeneous societies would have bring great suffering, but it can also One we would all vote for, namely, the advantages, true homogeneity would bring great fortunes. Manic-depressives issue of diseases; and one we would be a death sentence. Environments can do things that others say cannot all vote against, that is, the issue of change, including social environments, be done. So it’s a case where it’s not personality traits, such as IQ. We’re and a species that cannot adapt will be obvious that we’re dealing with a bad spending this coun~ry’s fo~tunes so as eliminated. No matter how much we gene. to make learning about our genes a lot learn about the human genome over the easier. Are we going to learn more about next hundred years, there will always these somewhat vague personality traits remain many things that we do not or more about these lethal diseases? understand or cannot predict, such as who will be a great artist. It’s not clear we will ever figure out the genetic It seems . . . that there components of complex human traits are really two issues. such as creativity. If you select against a particular gene, you may be eliminating One we would all vote something else that we deem valuable for, namely, the issue but the origins of which we don’t yet understand. of diseases; and one we would all vote No matter how much against, that is, the we learn about the issue of personality human genome over traits, such as K). the next hundred years, there wili always be many things that we Leon Botstein: We would almost David Botstein: I believe we will do not understand or certainly lose our great poets. understand diseases much earlier than personality traits because diseases are cannot predict. Question: Suppose you jind a genetic much better defined. We haven ‘t re- propensity for something like aggression, ally defined personality traits precisely Jim Watson: A case in point might which affects other people as well as the enough to correlate them with genetic be the genes which predispose people individual. How would you cope with information. So diseases will probably to manic-depressive psychosis—finding that? Do you leave all of society naked come first. those genes is an objective of the Project. and exposed to a pei-son who might be We want to find a treatment that will be dangerous? Question: Do you suspect the ethical better than lithium since some cases considerations will have to broaden in don’t respond to it, nor to any known Jim Watson: I think that’s the sort of order to be relevant to other cultures and drug. We’re thinking the Project may be ethical question that you can’t really other societies? Tonight, the answers the best way of finding out what goes deal with until you’ve shown that such about confidentiality seem to relate back wrong. On the other hand, we might a genetic propensity exists. Even if to our society, which values individual want to pause and wonder what our you could, how would you use the rights and has insurance. But the trans- society would be like without manic- information? Most good scientists, for fer of this technology to cultures that de]?ressives— example, are terribly aggressive. don’ t have notions of individual rights,

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much les,s insurance for individuals, The human-genome sequence itself is, might have very serious repercussions. essentially, not one of the five-year goals. The expectation is that it will Nancy Wexler: That is an important be completed in approximately fifteen issue. People are concerned about years. giving diagnostic probes to , for example. Should we give diagnostic Jim Watson: Within the next five to ten testing capabilities to countries where years we want to get all the tools needed counseling is not likely to accompany by the disease-gene hunter, the person the tests and where confidentiality who wants to find, say, the Alzheimer’s rights are not guaranteed? Through gene. We are in a hurry to get them. an international organization called the That’s our impatience. We say in five Human Genome Organization, which years, maybe ten, the last bits of that has an ethics working group, we try resource will be put together. We are to collabc~rate with other countries in in a hurry. ❑ order to emphasize the importance of providing those services and protections. Photos by G. Steve Jordan, New York

Question: What is the time frame in which you hope to accomplish the Genome Project?

David Botstein: The high-resolution genetic-linkage map and the sequences of some of the model organisms are both parts of our five-year goal, as is a great majority c,f the physical map.

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