 My colleague in the Department of Biology, Cindy Johnson-Grow. Professor Evelyn Fox Keller, a historian, philosopher, feminist, and scientist, is one of the foremost scholars on language science and the relationship between science and gender. Her interests span the sciences and the humanities. Through examinations of language, metaphor, and social history, Professor Fox Keller has eloquently demonstrated how scientists often operate from preconceived notions in seeking evidence. In the course of this lifelong work, she has transcended many borders. Indeed, she notes in her book, Refiguring Life Metaphors of the 20th Century Biology. She says, I have something of a problem with borders. Borders are meant for crossing. More, they constitute irresistible lures. Indeed, her curriculum vitae knows no borders. Trained as a theoretical physicist, she received her PhD from Harvard University. She is taught at New York University, Cornell University Medical College, SUNY, Northeastern University, MIT, and the University of California at Berkeley. She joined the MIT faculty in a permanent position in 1992, where she is currently involved in research on the history and philosophy of developmental biology. She has published on topics including theoretical physics, feminism, mathematics, as well as philosophy and history of science in a variety of journals, including the American Journal of Physics, Hepatia, Journal of History of Biology, Biology of Philosophy, Journal of Theoretical Biology, and Journal of Molecular Biology, to name a few. She has written many reviews, is editor of several books, and is member of several editorial boards. She has written several books, including Secrets of Life, Secrets of Death, Refiguring Life, Metaphors of 20th Century Biology, and Feminists and Science. Dr. Fox Keller is perhaps best known for what is now a biology classic, her book, A Feeling for the Organism, The Life and Work of Barbara McClintock. In this book, Fox Keller argues McClintock's way of doing science was in a different language from her male colleagues. In another book, Reflections on Gender and Science, Fox Keller continues to explore the many issues raised in her study of McClintock's life, and in particular the way ideologies of gender influence the practice of science. Dr. Fox Keller has received several honorary degrees and many professional honors, including the Wellick Lecture for the Critical Theory Institute at University of California Irvine, MacArthur Fellow, AAUW Achievement Award, to name a few. I would like to finish with a paragraph taken from Dr. Fox Keller's essay, Language and Science, in the book, Refiguring Life, Metaphors of 20th Century Biology. This is a concluding paragraph in an essay, and I think a fitting reminder of where we have been and where we are going. She says, acting in sync as they always do, the social, cognitive, and technical histories of 20th Century Biology have once again brought us to a dramatic and critical juncture, and if there is a moral to this story, it is this. Lest we be too quick to congratulate ourselves on our new found enlightenment, we should remember that our predilections, grounded though they must be, in our particular social and political realities, all we have to guide us. Thus, there is no guarantee that new doctrinaires will not seize the opportunity now before us. Indeed, we have every reason to expect that they will, even to suspect that they already have. How else, after all, could science possibly proceed? Please welcome Dr. Evelyn Fox Keller, whose lecture is entitled, Nature and Nurture in a Post-Genomic Age. Thank you very much, Cindy, for a wonderful introduction, and thank you everyone at Gustavus for your extraordinary hospitality over the last two days. It's really been a pleasure to be here. This is not part of my talk, but I just have to say, show you just a little anecdote about a feeling for the organism of my book about Barbara McClintock, which sat in the publishers, it was W.H. Freeman, for about eight months before they got back to me. And the problem that they had, there had been some communication back and forth, but the problem they had was with the title. Dean Hamer enacted the problem that they had with the title just yesterday. This conference that we've been at for the last two days has been a wonderful and conspicuously celebratory event. We are here to celebrate the extraordinary advances that have been made in genetics in recent decades, much of it over the last decade as a direct consequence of the project that is somewhat misleadingly called the Human Genome Project. Misleading, because the task of the genome project, as you have heard, has been to sequence not only the human genome, but those of virtually all other organisms as well. Of course, as you've also been reminded, when it was first proposed in the mid-80s, this project evoked a great deal of skepticism. But today, as it proceeds at a pace exceeding everyone's expectations, there are few skeptics to be found. As of now, the complete genomes of more than 25 microbial organisms have been sequenced, including E. coli, that illustrious bacterium on which molecular biology first cut its teeth. Genomes of more sophisticated model organisms have also been sequenced. First yeast, last year. The first higher organism, C. elegans. And now we've been told the sequence of Drosophila is already complete. The task of sequencing the human genome itself began only recently, but its progress is breathtaking. I actually started to keep track of the progress last year, writing a post script for an article I'd written on Nature and Nurture and the Human Genome Project and a book that Lee Hood co-edited. But as I rewrote that post script, I took note of the state of the progress of the human genome sequencing. And months went by and I realized I needed to update it, so I looked for another figure. And as I was preparing this talk, I looked again and I was really staggered by the way the numbers have been climbing. 3% by the end of 1997, by November 30th, 1998, 7.1%, by September 5th, 22%. This is obviously not from the horse's mouth, which we've gotten today. In the last two days this is from the net. And now we're told to expect a complete draft by next spring. I have to confess that I was one of the early critics of the genome project. But even for me, it is difficult not to share in the enthusiasm. Thus, I too am here to celebrate. But from what I originally thought was going to be a rather different perspective from most of the speakers in this conference. As it turns out, the difference in perspective is not quite as great as I had anticipated. What excites me is not so much the ways in which the genome project has fulfilled our expectations, but the ways in which it is transforming them. I want to celebrate the very surprising effects which the successes of the human genome project have had on biological and medical thought and the challenges these successes pose to familiar notions of genetic determinism, especially as these have acquired such a powerful grip on the popular imagination. To characterize these effects, it's useful to distinguish between biologists whose focus of research is on the genetics and development of lower organisms from those whose primary concern is on human and especially on medical genetics. Thus, I want to begin by talking about the ways in which progress in genomics has begun to change the way many students of lower organisms think about genes and genetics, and even about the meaning of the genome project itself. Then, in the second part of my talk, I'll turn to the subject that more nearly follows from my title, namely that of human genetics, the relation between nature and nurture, and the somewhat similar reevaluation of the value of genomic data, in particular of what medicine might expect from this data, reevaluations that have been prompted within the medical community. So, a decade of, I don't have slides, I come from the other side of campus, we don't do slides, but I figured, you know, I didn't realize that you would have me to fix on, so as an alternative, I made a compromise, I made one slide, so I'm going to talk about something to fix your eyes on, right? A decade ago, many biologists expected that sequence information would, by itself, suffice for the understanding of biological function. Spelling out his vision of the Grail for that very volume that I mentioned that Lee Hood and Dan Kevles had co-edited, Walter Gilbert provocatively wrote, and I quote, three billion bases of sequence can be put on a single compact disc, and one will be able to pull a disc out of one's pocket and say, here's a human being, it's me, unquote. Today, however, rather significant doubts, even among molecular biologists, are becoming extremely conspicuous, and growingly so, and largely in response to the increasing sophistication of genomic research. Instead of a rosetta stone, molecular geneticist, William Gelbart suggests that it might be more appropriate to liken the human genome sequence to the feistus disc, and as yet undeciphered set of glyphs from a Minoan palace. With regard to understanding the A's, T's, G's and C's of genomic sequence, by and large, we are functional illiterates. Now that the genomes of several lower organisms have been fully sequenced, the call for a new phase of genome analysis, functional genomics, rather than structural genomics, is heard with growing frequency. Heter and Boguski define functional genomics as the development and application of global, that is genome-wide or system-wide, experimental approaches to assess gene function by making use of the information and reagents provided by structural genomics. In their view, the sequence no longer appears as an end in itself, but rather as a tool. Quote, the recent completion of the genome sequence of the budding yeast has provided the raw material to begin exploring the potential power of functional genomics approaches. In a similar vein, anticipation of the sequence of the drosophila genome finds drosophila geneticists girding for a long haul. As Burns and Howley put it in a recent issue of Nature, for the huge, girding for the huge amount of work that will be involved in correlating the primary DNA sequence with genetic function. They write, this link is essential if we are to bring full biological relevance to the flood of raw data produced by this and other projects to sequence the genomes of model organisms. It is a rare and wonderful moment when success teaches us humility, and humility is a word that has actually surfaced three times in the last two days, and it's an appropriate word. This rare and wonderful moment is where we are today. Indeed, I suggest that of all the benefits which the successes of the genome project have given us, it is this humility that in the long run may well prove to have been its greatest contribution. For almost 50 years, we had lulled ourselves into believing that in discovering the molecular basis of genetic information, we had found the secret of life. We were confident that if we could only decode the DNA's message, we would understand the program that makes an organism what it is. That there in the sequence of nucleotides, we would find the explanation of life. And we marveled at how simple the answer seemed to be. But now, in the call for a functional genomics, we can read at least a tacit acknowledgement of the gap between genetic information and biological meaning. Of course, the existence of such a gap had long been intuitive and we were often cautioned about this gap, but it is only now that we have come to truly appreciate its magnitude and even better to begin to be able to fathom the depths of that gap. Today, we marvel not at the simplicity of life's secrets, but at their complexity. One might say that structural genomics has given us the tools we needed to confront our own hubris, tools that could show us the limits of the vision with which we began. Let me very briefly review three of the more important lessons which they have helped us to learn. The first lesson concerns the meaning of genetic stability. The second of gene function and the third of the notion of a genetic program. First, the question of genetic stability. Long before we knew what kind of a thing a gene might be, the existence of such an entity was hypothesized in order to explain the remarkable fidelity with which individual traits could be faithfully reproduced from one generation to another without change or dilution. As August Weisman wrote in 1889, quote, When we find in all species of plants and animals a thousand characteristic peculiarities of structure continue unchanged throughout whole geological periods, we very naturally ask for the causes of such a striking phenomenon. How is it, he went on to ask, How is it that a single cell can reproduce the two-zone sombla of the parent with all the faithfulness of a portrait? Weisman answered this question by proposing, hypothesizing, postulating the existence of certain units, genetic determinants, potentially immortal, particulate elements in which the capacity for faithful transmission from generation to generation was built, as it were, by definition. Weisman's determinants were direct precursors to what later came to be called genes. Genes, too, were at the beginning hypothetical entities, and again, with their potential immortality, their capacity for faithful reproduction and transmission assumed as an inherent property and accepted as part of their very definition. Yet, despite the many remarkable successes of classical genetics over the half-century that followed Weisman, the question remained, what kind of an object might a gene be that it can reproduce itself with such remarkable fidelity, generation after generation? Indeed, it was this very property of the gene, the manifestation of what he called a durability or permanence that borders on the miraculous that so mystified the physicist Erwin Schrodinger in the early 1940s as to inspire him to take on that grandest of all questions, his very famous little book called What Is Life? Schrodinger's answer came in the form of a structure he proposed for the gene. He suggested the gene might be an aperiodic crystal or solid that was protected from the ravages of entropy by the laws of quantum mechanics. And after 1953, after Watson and Crick, Schrodinger's model, though conspicuously wrong in details, acquired something of the air of retrospective prophecy. With Watson and Crick's dramatic discovery of the structure of DNA and the rapid acceptance of DNA as the genetic material, an extraordinarily simple explanation of genetic stability was immediately apparent. Complimentary base pairing A to T and C to G could do all the work of conservation that was required. To the extent that the DNA might be seen as an aperiodic crystal, one could even say that Schrodinger had been vindicated. But the history of science is replete with irony, and the aftermath of Watson and Crick's great discovery offers no exception. To be sure, DNA is copied in living cells with the fidelity that does indeed border on the miraculous. But contrary to expectations, what we have now learned is that the source of this high fidelity does not adhere in the structure of the DNA. In fact, left to its own devices, DNA cannot copy itself at all. DNA replication will simply not proceed in the absence of the enzymes required to carry out the process, and without an elaborate system of proofreading and repair, it will proceed sloppily, accumulating far too many errors to account for the observed stability of hereditary and developmental phenomena. The first indications that cellular processes were involved in the maintenance of genetic stability already began to emerge in the early 1960s. But against the background of so long a history in which stability had been assumed to adhere in the gene itself, the implications of these findings were slow to dawn. But with the tools that have become available in more recent years, the field of DNA repair has exploded, and the picture of the complexity of the mechanisms involved in proofreading, editing, and repairing damaged or miscopied DNA that has now emerged is truly mind-boggling. Genetic stability is not caused by the structure of genes, but is itself the product of a highly orchestrated dynamic process that involves the interaction of scores of enzymes organized into complex metabolic networks that regulate and ensure both the stability of the DNA molecule itself and its fidelity in replication. Moreover, we have begun to read about other enzymes organized into other repair pathways that work to monitor and correct errors in transcription, translation, and even protein structure, thereby ensuring a degree of stability of biological organization going well beyond that of merely genetic stability. I just, I wanted to mention, I just was at a conference in Pavia just last weekend before I came here celebrating the 200th anniversary of Spallanzani, a conference on reproductive biology, which was all about the recent interest and attempts at cloning. The hot topic for all of these biologists involved in nuclear transfer and cloning was the following. This was the experiment that everybody was talking about. What happens if you transfer a nucleus into an egg that is missing the repair mechanisms? And the answer is, I mean, everyone expects that the nucleus of an ordinary cell cannot survive without the repair mechanisms that are provided by the cytoplasm. The implications of these findings have yet to be fully explored, but this much is clear. Responsibility for the stability of biological traits across generations is to be found not in the molecular structure of the genes, but in the mechanisms which are themselves the guarantors of the stability of that structure. Furthermore, these mechanisms are not static but dynamic, and an explanation of how they do their job will need to be sought in the complex systems of cellular dynamics that are at one and the same time the products of and the safeguard of genetic information. Of course, the stability of that information is an absolute prerequisite for natural selection, but the system, and this is the important point, the system of biological organization upon which that stability depends was also an achievement of evolution. Indeed, as it now appears, an achievement that would have needed to be in place before natural selection could begin to work its magic. The second lesson concerns the meaning of gene function. What is the relation between a gene structure and its function? Much of contemporary research is devoted to this question, and it is yielding dramatic and often surprising results. Results that raise as many questions as they answer. Indeed, we find ourselves obliged to ask that most elementary question of all, what, in fact, is a gene? And here, too, I start with a brief historical overview. Ever since the early days of genetics, it has been assumed that the function of a gene, like its stability, adhered in its structure. But how does structure translate into function? For a long time, this question was effectively bracketed by a very simple way of talking, by the simple expression gene action, a way of talking that granted to genes the power to act, even if we could not say how. Indeed, the great achievement of the mid-century was to put teeth into this notion of gene action. First, in the early 1940s, with Betel and Tatum's one gene, one enzyme hypothesis. And then, in the mid-50s, with Seymour Benzer's demonstration of the structural coloniarity of genes and proteins. And finally, just a few years later, with the discovery of the actual code by which nucleotide sequence is translated into amino acid sequence. Finally, we could answer the question of how genes act, and the answer had a stunning simplicity. What does a gene do? It makes an enzyme. Not only did this answer have the elegance of a mathematical equation, but also, and more importantly, it fulfilled the long-standing expectation that it would be possible to discern or to read the function of a gene in its structure if only we knew how to decipher that structure. Now, what has happened to this wonderfully simple idea in the years since? Needless to say, things have turned out to be a little bit more complicated. Alongside the phenomenal progress that has been made in the identification, the mapping, and the sequencing of particular genes, we have also learned a great deal about both the structure and function of genetic material that does not fit into our original picture and that even threatens to throw the very concept of the gene either as a unit of structure or as a unit of function into disarray. Techniques and data from sequence analysis have led to the identification of repeated genes or repeated sequences, split genes, overlapping genes, cryptic DNA, antisense transcription, nested genes, genes within genes, transposition, multiple promoters that allow for alternative sites of and variable criteria for the initiation of transcription, all of which have tremendously confounded the task of defining the gene as a structural unit. Which piece of DNA is going to count as a gene? Similarly, the discovery of the extensive editorial process to which the primary transcript is subject, the process of alternative slicing, of regulatory mechanisms operating on the level of protein synthesis, and of also widespread genetic redundancy. All of these have confounded attempts at a clear-cut functional definition of the gene. Indeed, quoting William Gelbart again, Gelbart suggests that the gene might well be, quote, a concept past its time. Unlike chromosomes, he writes, genes are not physical objects but are merely concepts that have acquired a great deal of historic baggage over the past decades. Close quote. To be sure, and no one is arguing with this, and least of all me, the concept of the gene played an unbelievably important role, an essential role in leading us to our present understanding of biological phenomena. But today, Gelbart suggests, we may well have come to the point where the use of the term gene might in fact be a hindrance to our understanding. Historically, the self-identity of gene structure and gene function had always been taken as a given. But now I am saying that current research has put a clear and demonstrable wedge between structure and function. We have learned that the function of a gene depends not only on its sequence, but as well on its genetic context, on the chromosomal structure in which it is embedded, and which is itself subject to developmental regulation, and on its developmentally specific cytoplasmic and nuclear context. Let me give you just one example of the kind of difficulty that has arisen. In many organisms, as Bruce Baker mentioned today, the RNA transcript of a particular stretch of DNA is routinely used as a resource for the construction, not of one protein, but a number of quite different proteins. Bruce said the number can be as large as 50 to 100. Depending on the context and the stage of development in which it finds itself, different pieces of the transcript are cut and pasted together to form a variety of new templates for the construction of a corresponding variety of proteins. Which of these different transcripts corresponds to what we can call the gene? If it is to be the original stretch of the DNA, which provides the resource for all of these proteins, then we can no longer say that a gene makes an enzyme or a protein, for it can be employed to make a number of different proteins depending on the state of the cell. But if we choose the messenger RNA transcript after it has been edited and spliced, then the problem is that that gene, if we call that structure the gene, that gene has no permanence at all. It is cold into being only as needed, nor does it at any point reside on the chromosome. One way to resolve this dilemma would be to think of the gene as two very different kinds of entities. One, a structural entity that is maintained by the molecular machinery of the cell so that it can be faithfully transmitted from generation to generation. And the other, a functional entity that emerges only out of the dynamic interaction between the structural gene and the many other active components of the living cell. Okay, third lesson. Third lesson I promised to talk about also bears on the question of function, but now it is the function of the genome as a whole rather than that of individual genes that is the issue. In other words, the question here is not so much the making of an enzyme, but one might say the making of an organism. For even if we could still hold to a simple equation between one gene and one protein, we would still have to ask, how can an organism be made out of the mere accumulation of different proteins? And once again, I go back to the early days of genetics and to the notion of gene action. The tacit implication of that early notion was that the development of an organism could be envisaged as a kind of summation of the action of many different genes. If the direct activity of one gene led to one trait or character, then presumably a complete set of genes ought to lead to a whole organism. But even the geneticist, the father, one might say of modern genetics, T.H. Morgan, could see that such a system of gene action would not be able to explain development unless, that is, it was coupled with an additional assumption, namely that genes act variably, cold into action at different times of development by other non-genetic factors. As it happened, it was not until the 1950s that Morgan's proposal of differential gene activation began to take root among geneticists. And when it did, it had a slightly subversive effect. For, after all, does not the suggestion that genes must rely on non-genetic factors for instructions as to when and where to act, threaten their autonomy, and even their causal primacy? Certainly, many arguments to that effect could be heard at the time. But in just a few years, yet another triumph of early molecular biology succeeded in putting traditional expectations of genetic control safely back on track. In 1961, Francois Jacopes and Jacques Manot presented the compelling evidence they had found for a gene-based mechanism of genetic regulation in E. coli. And as they argued in their concluding sentence, quote, the discovery of regulator and operator genes reveals that the genome contains not only a series of blueprints, but a coordinated program of protein synthesis and the means of controlling its execution, unquote. With these words, Jacopes and Manot introduced a new metaphor for thinking about biological development far more sophisticated than the earlier notion of gene action, and it soon became the dominant paradigm for the explanation of biological development. This notion, this metaphor, was the genetic program. A few years later, Jacopes described the organism as the realization of a program prescribed by its heredity, claiming that, quote, when heredity is described as a coded program in a sequence of chemical radicals, the paradox of development disappears. For Jacopes, the genetic program, written in the alphabet of nucleotides, is the source of the apparent purposiveness of biological development. Referring, he refers to the often quoted characterization of teleology as a mistress whom biologists could not do without, who did not care to be seen with in public, and writes, the concept of program has made an honest woman of teleology. Although Jacopes did not exactly define the term, he noted that the program is a model, is a metaphor borrowed from electronic computers. It equates the genetic material of an egg with the magnetic tape of a computer. Once again, a great deal has happened since those early years, not only in molecular biology, but also in computer science. Although we still speak of programs, the meaning of that notion, both in biology and in computer science, has changed considerably. In both arenas, programs have come to be understood as multi-layered and distributed. To be sure, the informational content of the DNA is essential. Without a development, one could say life itself cannot proceed. But current research obliges us to reconceptualize the developmental program, what Lee Hood earlier called the software program. Not simply as a set of instructions written in the alphabet of nucleotides, but rather as distributed throughout the fertilized egg. Today, if we were to ask of what does the developmental program consist and where does it live, we would have to say that it consists of and lives in the interactive complex made up of genomic structures and the vast network of cellular machinery in which it is embedded. As Garcia Bolida writes, development results from local effects. There is no brain or mysterious entity governing the whole. There are local computations and they explain the specificity of something that is historically defined. In other words, if we wish to keep the computer metaphor, we would now describe, we could now describe the fertilized egg as a massively parallel, a multi-layered processor in which programs or networks and data are distributed throughout the cell. Here, in this new understanding, the roles of data and program are relative. For what counts as data for one program is often the output of a second program, and the output of the first is data for yet another program or even for the very program that provided its own initial data. For some developmental stages, the DNA might be seen as encoding programs or switches which process the data provided by gradients of transcription, activators, or alternatively, one might say that the DNA sequences provide data for the machinery of transcription activation, some of which is acquired directly from the cytoplasm of the unvertilized egg. In later developmental stages, the products of transcription serve as data for splicing machines, translation machines, et cetera, et cetera, et cetera. In turn, the output of all of these processes make up the very machinery or programs needed to process the data in the first place. Okay. Now for my second theme, signs of change in medical genetics that, in a certain sense, can be seen as paralleling the changes I've been talking about in developmental genetics. Here, too, a shift calling for increased attention to context can be detected, but now the context at issue includes not only that of the organism, the cellular environment, but also the environment in which the organism finds itself. In a recent article in the TLS, Times Literary Supplement, DJ Weatherall, director of the Institute of Molecular Medicine at the University of Oxford, raised the question, how much, in fact, has genetics helped? And he directly confronts the issue of what he called the disappointing medical benefits so far from the DNA revolution. Where others have expressed concern over the continuing therapeutic gap in the treatment of all genetic diseases, the more serious problem for Weatherall is to be found in the leap of gene diseases such as thalassemia, for which the benefits of genetic analysis and subsequent screening have been undeniable, to more common conditions involving complex, polygenic systems, for example, heart disease, stroke, psychosis, diabetes, and even to such diseases as cancer, which are only very rarely genetics in the usual sense of the term, that is, in the sense of the term as a hereditary state. For none of these conditions, much less behavior, has it yet proven possible to translate scientific advance into significant medical advance. A decade ago, the prospects of effective genetic intervention appeared imminent, but such early optimism has given way to a widespread appreciation of the enormous difficulties involved. As Weatherall writes, transferring genes into a new environment and enticing them to do their jobs with all the sophisticated regulatory mechanisms that are involved has so far proved too difficult to task for molecular geneticists. The moral, which some leaders in the field now draw, would almost surely not have been anticipated in the early days of the Human Genome Project. It points not only to the complexity of genetic organization, but also, and really surprisingly, to the importance of environmental factors in disease. Thus, from the spectacular, what he calls the spectacular advances in our understanding of the molecular mechanisms of cancer, Weatherall concludes that, quote, for the first time, we can begin to understand how our genes can be damaged by the environment that we have created. Similarly, he infers from our new capabilities for identifying genetic risk factors in polygenic diseases the possibility of a more efficient focus on preventative public health resources. Rather surprising shift in focus. Other developments seem also to be prompting shifts toward a more global perspective, in particular with a steady increase in the number of genes identified as causal factors of disease, the prospect of a genetic demarcation between health and disease becomes ever more problematic. And it does so on two different levels. What I might call the population level and the organismic level, the individual level. First, as genetic risk factors rise in number, so too do they proliferate throughout the population. And the difficulty such proliferation raises for a genetic demarcation between healthy and diseased individuals is obvious. Francis Collins put the point with admirable succinctness, we are all at risk for something. The potential for a similar problem can be seen on the individual level as well. Thus far, the number of disease-causing genes, so-called disease-causing genes, is still only a small fraction of the total number of human genes. But it is a considerably larger fraction of the number of genes which have actually been identified and mapped, and it is growing rapidly. A comprehensive database has now been put on the web by the Weizmann Institute in Israel called Gene Card, and that database lists a total number of we have many more I know, but lists only 8,532 genes. Of these, 1,359 are characterized as disease-causing, that is a little over 16% of the total. Now, here's a question. How high might that fraction go? Well, obviously, not past one. But in principle, mutations predisposing us to some kind of misfunction or abnormality could be found in every single gene necessary for normal human functioning. However, one construes the notion of normal function. The very possibility of misfunction is, in fact, implicit in the notion of function. We might thus paraphrase Collins and observe that all genes are at risk for something, that is, all genes are, at least potentially, causal factors in disease. To be sure, we could restrict the notion of a disease-causing gene to its mutant form, but even then, we would have a problem. For once the function of a gene is seen to depend on the genetic, chromosomal, and cytoplasmic context of that gene, so too must the prospects for a misfunction arising from a mutation in that gene. There is more than a little irony in these developments, particularly when viewed in the context of current discussions of genetic disease. Even a cursory view of the literature makes it abundantly clear that that concept has lost none of its earlier force, not in the biomedical community, and certainly not in the popular imagination. As I've already indicated, the number of genetic diseases has continued to grow, and so too has the range of conditions described under that category. Today it includes not only a large number of heritable conditions that had earlier been regarded as normal variants, but also conditions such as cancer that may be genetic, but are not, at least not usually, heritable, or that may be genetic in the sense of involving genes, and even conditions which are not themselves genetic, but which might nonetheless be susceptible to genetic intervention. David Magnus, for example, observes that the concept of genetic disease has now expanded to be virtually all-encompassing, and like many other, including myself, Magnus worries primarily upon the negative effects of such an expansion. He writes, the result of the increasing focus on reductionist measures is the neglect of the social factors which studies show are the key determinants of the health of populations. Consideration of the main causes of death, including cancer, leave open the possibility that emphasis on gene therapies may not be the best allocation of resources. But in this talk, my main concern has been with the conceptual frameworks rather than with policy questions per se, and especially with the ways in which the Human Genome Project itself has helped erode the very reductionism on which it was originally premised. In the recent calls for a functional genomics, I read an either tacit or explicit acknowledgment of the limitations of the most extreme forms of reductionism that had earlier held sway. And in new expressions of interest in preventative public health policies, I read a similar message. I even suggest that the open-ended expansion of the concept of genetic disease may have itself to help point the way back to concerns about organismic, environmental, and social context. But I admit, my reading of the current literature is selective. I argue that the writings that I have discussed, even if they are unrepresentative, do clearly indicate an alternative route for post-genomic, biological, and medical science to take. Of course, whether or not it will remains an open question, and the answer to this question may well prove to depend less on the views of biological or medical scientists than on the dividends to be realized by rapidly expanding pharmaceutical industry. And on this note, I want to add another point that has come up in the course of discussions in the last two days. As I said, a number of speakers have made reference either explicitly or implicitly to the surprises that the genome initiative has given rise to, and to the humility, to the recognition of how much there is that we don't know. So a final word on humility and what the implications of humility are. I take it as axiomatic that the response, the proper response to the recognition of how little we understand is to try harder and to look for other richer frameworks for understanding. But there is another route that is available, and it seems to me one needs to, and you call attention to the possibility of an alternative route, which is to give up on explanation altogether and to say it's too complicated, our explanations have failed, our theories have failed, maybe we should just content ourselves with what we can make do, what we can manage to, what changes we can affect, what products we can create, what we can do in the lab. And in view of the convergence between science and commerce, it seems to me to be an increasingly likely or increasingly dangerous possibility however you look at it, whichever way you want to look at it. So thank you very much. Ladies and gentlemen, we will take three or four questions. If you would stand up and speak very clearly. And here I thought I got to have the last word without any recourse, but I'd be delighted to take questions. Since so many of my closing remarks were aimed directly at you, I think it's only appropriate. Right? Very big. This question is, with regard to my last comment, how does that differ from the last 2,000 years of medicine? Well, you know, a philosopher Collingwood wrote in 1939, he argued that that biomedicine, it wasn't his word biomedicine, medical research was a radically different kind of science from physics, that physics sought causes where medical science sought handles, handles to effect change. That medical science was not interested in causes, so he called medical science a practical science rather and contrasted this with physics as a theoretical science. I think that Collingwood very dramatically overdrew the difference. I think that physics has always been a mixture of practical and theoretical, as has biology. Medical science may much less so. But it does seem to me that the course of biological research, as I observe it over the last, certainly over the last 50 years, has moved quite conspicuously and dramatically toward pragmatism, toward what you can make happen in the lab. And I do, so there may not have been a change in medical research, but I think there's a quite noticeable shift in biological research that counts as an explanation or the extent to which even explanation is pursued. And I think this has a lot to do with the convergence between science and commerce. Sir, please speak up. That may be, but I'm completely out of my depth knowing nothing about discussions involved in the preservation of sacred texts. I'm sorry. Well, yes, of course. I was a very selective reading of the text of the literature, and it's not the dominance you by any means. But yes, of course it's ironic. It's kind of wonderful, yes. But I don't think it was a waste of money at all. I think the investment in the genome project has been crucial for expanding our horizons, and I think we've gotten a lot of very valuable concrete information and tools and products out of it. And we have also gotten to expand our horizons. That's amazing, and I think that's well worth the price tag. Thank you very much. Ladies and gentlemen, the president of our college, Dr. Axel Steyer. You'll note that on the agenda for this conference, I'm listed as giving the opening greeting and the closing remarks. I think that gives you some sense of the good political sense that Chaplain Elvie has in having outlasted six presidents here at Gustavus, making me think that I'm the orphan omega of this particular conference. Let me just, for those of you who did not hear all these presentations, begin by giving you just a few famous and perhaps even infamous quotes or paraphrases from presenters, and I will leave Dr. Keller out of this since we had her here just a second ago. These will be comparable in exhaustion and in exhaustive nature. It will be just as exhaustive and as deep as Cliff notes. But Dr. Venter, we will remember that you have promised us a mapping or sequencing of the human genome project to be completed certainly by this time next year but perhaps by next spring. We'll remember that Darwin was not quite correct in seeing evolution as totally random, rather programmed into each gene as a mechanism for change. Understanding individual variations is the key to medicine of the future. We might well have a U.S. department of genetic identity one of these days, and it is very easy to look back at science and see its foolishness, but very difficult to look forward and see it. Dean Hamer. Behavioral genetics deals with individuals and not with groups we learned. Genes predispose the behavior they do not determine it. Genetics gives us one more way of knowing ourselves. Genes plus environment plus development equal behavior. And then I think I may have this wrong as I might take notes about this while as some undergraduates, but it's at least it'll be part of the legend because I'm going to repeat it and write down people think that you said this. And that is that studies of serotonin connector genes suggest that in this short form it leads to more anxiety and more sex, and in its long form is more commonly found in happy people who have less sex. Is that fairly close? Lynn Eves. Scientists are not ideologically neutral. Spirituality equals human interaction with this world. Like Paul Tillich I'm more interested in the questions asked than the answers. And if science and religion are going to talk both need to listen. Lee Hood is back home by now in Washington but I will just again summarize what I take to be some of his memorable statements. Whenever you look at another individual almost everything you see is protein. Discovery-driven science needs to complement hypothesis-driven science. Perhaps displace it, I'm not quite sure. The way to look at biology is to view it as an information science. Biology and biotechnology drive each other and the human genome project has catalyzed paradigm changes in biology and medicine. Elizabeth Blackburn. See if you recognize yourself in this. The job of chromosomes is to see that genetic material is passed on over the generations and telomeres make this happen. Telomeres serve as a reservoir for replenishable DNA. Lose a telomere, lose a chromosome. Cells just hate broken DNA. Could telomere capping slow down aging or cancer? Bruce Baker. You and I are much closer to fruit flies than any of you ever thought. The revolution genetics makes biology the science of the next century. Genetics is now central to every branch of biology and model organisms are key for understanding basic development. The fruitless gene controls all aspects of male courtship behavior in fruit flies and some eun behaviors echo this information in fly genes. I did have a thought here about barflies and if there was any connection what is your sign, yes? That presumably is the singing of the barfly. As some of you know in my office I have a fading photograph of 26 Nobel laureates. Wrigley robed and looking somewhat stern, austere. They participated in the dedication of the Alfred Nobel Hall of Science in 1963. The last of these, the physicist Glen Seabourg our good friend and the originator as was noted yesterday by Chaplain Elvie of the idea of an American memorial to Alfred Nobel died last year 44 years after winning the Nobel Prize he was always very proud of being the person in the United States or in the world where the Nobel Prize for the most number of years 44 years he lived after receiving the Nobel Prize. The plans when annual symposium was born out of the conversation among the Nobel laureates present on that dedication day and a group of them constituted the planning committee for the first Nobel conference on genetics in the future of man held in January of 1965. Now I don't know whether this is a function of nature or nurture but among the most obvious improvements from that first conference are the move from January to October meetings and a much better venue. Now we're about to bring the 35th annual Nobel conference not by sheer coincidence also in genetics to a close. For me, and I suspect for many of you this closing session especially was such a provocative, fine and profound presentation as that by Evelyn Fox Keller is a sweet bittersweet moment at these annual Nobel conferences. It is a time when we savor and relish all that we have experienced these past two days all that we have learned and in many ways our intellectual horizons have been expanded. In Albert Einstein's physics and reality one of my favorite observations and I've used this before is that the whole of science is he says the whole of science is nothing more than a refinement of everyday thinking. But refined thinking of the sort we strive to inspire in Augusteva students requires precise observation, careful experiments oftentimes counter-intuitive approaches, deep reflection and especially in contemporary genetics research a mastery of technology. It required the hard work of science and distinguished teachers, our speakers here have carried out on our behalf. I know from conversations with a number of people on campus, campus visitors, young and old alike this has been a stimulating conference for them as well. I know that many college and career decisions have been made these last couple of days and I'm conscious of the public service the Nobel conferences perform. It will be obvious to all why again we stop classes for two days each year in order to have a conference that provides intellectual stimulation for our students and faculty alike as well as for thousands of campus visitors. This is one of the high points of the academic year at Gustavus. We owe a large debt of gratitude this evening to our special guests our superb speakers and panelists for assisting us in coming to a better understanding of the genetic, the molecular and perhaps even the sub-molecular basis of life in the search for variety and abundance. Craig Venter, Dean Hamer, Lyndon Eves in absentia, Leroy Hood, Elizabeth Blackburn, Bruce Baker, pardon me and Evelyn Fox Keller, I know it yesterday that we, your audience and students had high expectations of you and for this particular Nobel conference and you have not disappointed us. Indeed you have exceeded these high expectations not only because of the inherently interesting nature of your Nobel conference topic not only because of the promise that your research and reflection have for the betterment of the human condition not only because we have a greater understanding of the achievements and possible perils of the rapid advances in genetics but also because you are teachers of the highest order. Persons committed to helping us appreciate the wonders of scientific discovery to sharing with us a joy that comes from learning how life works at its most fundamental level. We've been privileged to encounter in you a graciousness and eloquence an uncommon generosity of spirit an inspiring passion for your fields of inquiry a willingness to share some of your life's work with a deeply interested and appreciative audience. This has been an intellectual feast, friends and friends you are indeed. You have not shied away from the ethical and theological questions that have always been a landmark of these annual gatherings and I'm happy to say that or say once again that these Nobel conferences individually and collectively give fine expression and some reform to our college's educational vision and mission. There are many people who have worked long and hard some of them for more than two years to make the 35th annual Nobel conference a reality. The 1999 Nobel conference adviser committee chaired by Professor Colleen Jax to serve special thanks. Dean Wallin and his hard-working staff in public affairs and new services. Pat Franczek and the good people in the media services, Steve Chulgren and the dedicated folks in our dining service student and faculty mentors and hosts and the many people in the physical plant department among those who we especially thank. We had also to express deep appreciation to the director of these Nobel conferences for the past 20 years and the sort of shaper of them adviser for the last 35 years Chaplain Richard Elvie, the consummate campus intellectual and the omniferous, if that's the right word collector and disseminator of knowledge and wisdom at Gustavus. Although he is a key facilitator for our next year's Nobel conference word is that he plans to retire as director and his chaplain at the end of May presumably to serve as a personal consultant or at least to have conversation, to be a conversation partner with God from the new home base that he and his lovely bride have established in the Mexican Riviera. Dick, your magic hand and vision have helped to form and guide these Nobel conferences for decades. You will surely be missed, but just as surely your legacy at this college will live on in the high stands you've helped us accept for these Nobel conferences. Dick, I believe that Dean Wallant would like you to come forward. I would like you to come forward. Please, for his brief presentation here. I believe they do this in Sweden. You present with flowers. Dick, 35 years. Thank you, people, thank you. Four words. People I've worked with these years, some of them in the back, some in the front. About you I have four words. One is high competence, what a run we've had at every part of this conference, and we've gotten it done and we've learned how and we do it well. And then I've experienced the genuine goodwill of a community, Gustavus Adolphus College, for these years. And then I, I don't know if this is one of Bill Bennett's virtues or not, but the word for me is loyalty. Loyalty to this program, to this, to this Nobel conference and then loyalty to myself and then finally affection. We've always talked about the Nobel family because somehow I've felt your love and we love you too. Thank you. Now once again to our distinguished speakers, we've called upon your knowledge and wisdom, your energy and goodwill, your stamina, and even your patience. In good Nobel conference tradition you have responded generously on all counts. We thank you and wish you Godspeed until we meet again. To all the guests from off campus, we wish you a safe journey home and invite you to mark your calendar for next year's 36th Annual Nobel Conference on Globalization 2000 Economic Prospects and Challenges scheduled for October 3rd and 4th in the year 2000. With that wish and with that reminder, we formally bring this 35th Annual Nobel Conference Genetics in the New Millennium to a close. Dear friends, I bid you a good night.