INTERNATIONAL CONFERENCE
POSTGENOMICS? HISTORICAL, TECHNO-EPISTEMIC AND CULTURAL ASPECTS OF GENOME PROJECTS
JULY 8-11, 1998
BERLIN FOREWORD
The present volume brings together several documents encapsulating the presentations and discussions made on the occasion of the international conference on "Postgenomics? Historical, Techno-Epistemic and Cultural Aspects of Genome Projects," held in July 1998 at the Max Planck Institute for the History of Science in Berlin and funded by the German Human Genome Project.
Two reports have been included covering the conference material in very different ways. Whereas the first report gives a day by day account of all contributions, including panel discussions, the second deals mainly with an overview of current scientific issues and related epistemological critiques. To complement these reports, this preprint also includes the original introductory remarks by Hans-Jörg Rheinberger, as well as the program of the conference.
- 2 - CONTENTS
Hans-Jörg Rheinberger: Introduction...... 5
Program...... 11
List of Participants...... 14
Lily Kay: Report to the Human Genome Project...... 17
Denis Thieffry and Sahotra Sarkar: Report for BioScience ...... 27
- 3 - - 4 - INTRODUCTION
Hans-Jörg Rheinberger
Max Planck Institute for the History of Science
There is an inevitable dilemma to interdisciplinary conferences such as this one. Professional identities and corresponding expectations range from molecular biologists and genome researchers to historians, philosophers, sociologists, from anthropologists of science to policy makers. For humanities scholars, certain papers will appear too technical to be fully appreciated. For scientists, other papers will appear to be too esoteric and to miss the point in terms of a strictly defined scientific agenda. There is no way of avoiding this dilemma for anybody trying to engage actively in such a communicative enterprise of bridging gaps - of discourse as well as of updating knowledge. The aim of this conference is not least to contribute to the development of a discursive atmosphere allowing closer interaction and understanding between those who do the science and those who, for many different - and vital - reasons, reflect on the dynamics of contemporary genome research and try to embed and view its incentives, its conduct, and its outcomes in a broader cultural, historical, and social perspective.
As is appropriate for an institute for the history of science, many of the papers given during the conference will have a historical underpinning. I do hope that historical reflection will help to place in perspective some of the rather bold conjectures as to the genetic future of mankind that are in circulation, not only by patient interest-groups and companies, but also by scientists. I agree with Benno Müller-Hill, the molecular geneticist from Köln who said a few years ago: "Now scientists are promising a massive betterment in preventive medicine after the 'holy grail' of the human genome has been attained, and - quote - 'man will then be understood through his DNA.' I doubt all that. These promises cannot be kept. The public will become discontented when it realizes that all these expensive promises are not being fulfilled." And he adds: "Scientists should not sell hope." Looking back might give us a chance to realize how much there is to this advice.
- 5 - By way of introduction, let me summarize the questions which we, the organizers, thought should be discussed as we go through the sessions. This can probably best be done by rehearsing the elements of the - very long - title of the conference: Postgenomics? Historical, Techno-Epistemic, and Cultural Aspects of Genome Projects.
First, Postgenomics. We put a question mark after this term which might give a flavor of postmodernism. We did not invent it. Among others, it was Ernst Ludwig Winnacker, the acting president of the Deutsche Forschungsgemeinschaft who recently raised the question as to which direction research would take in a "postgenomic time." That's what he called it. Winnacker put the problem as follows: "Until now, the individual genes stood in the foreground. We will leave them behind us and ask how they contribute to the formation of individual cells, of cell communities, and of whole organisms. ... We will go for an understanding of the whole." Now, it is not for the first time in the history of biology that scientists have been proclaiming that the time has come to transcend reduction, genetic or otherwise, and to try to understand the formation of the organism as a whole. Such claims have accompanied modern biology from its inception in the 18th century. It is legitimate, then, to ask exactly what new possibilities of understanding the organism as a whole will arise once we have complete genome sequences at our disposal. What kind of questions can biologists start to ask once they have whole genome sequences to work with? Postgenomics promises to comprehend the body as a whole, in its function and development, with its epigenetic mechanisms and its outer living conditions. The problem is: Will this be a "logical" consequence of the present efforts? Or must we make a conscious effort to "rethink the organism"?
So much for postgenomics. Now to the different key-words that shall guide us through the landscape of genome research. First, historical aspects of genome research. We gave the first part of the conference the title of 'genomic re-visions.' With it, we would like to emphasize that science, like history, is a revisionist enterprise. What counts as truth today will not, as a rule, be the truth of tomorrow. Although we have been living with the notion of 'gene' for about ninety years now, we should be aware of how much its content has changed over the decades. What a distance from Johannsen's abstract entity of 1910, to the protein gene of the 1930s, to the DNA and informational gene of the golden age of molecular biology, to the hypercomplex structure of the genetic material that contemporary molecular genetics confronts us with! While there was a time when the picture of the gene could appear to be simple, we no longer live, at least scientifically, in such a time. The more molecular details become available today, the less a consensus appears to be possible at the molecular, organismic, and evolutionary level about what a gene is. Genomic organization has turned out to be terribly complex. And yet it is
- 6 - intriguing and even frightening how simplistically genes as public icons are often depicted by the media and by scientists sometimes as well. Why do even scientists talk the language of 'There is a gene for ...", although they know perfectly well that the scientific reality is infinitely more complicated? Visions, then, are subject to historical change. Is a "vision of the grail," as Walter Gilbert called it, the only way to look at DNA today? What genetic visions have we left behind us, which ones are we in the process of producing and disseminating? Is genomic research bound to intensify the present view of genetic determinism? Questions of identity and subjectivity -- are genes us? -- should be key issues to integrate into the discussions about postgenomics.
Let me move on to the second issue, techno-epistemic aspects of genome research. It will be appropriate to make some remarks on the notion of the techno-epistemic. First and foremost, the connection between the technical and the epistemological reminds one of something that appears to be characteristic of molecular biology as a whole, and of genome research in particular. Instead of being theory-driven, it appears to be eminently technology-driven. In addition, statements by many leaders of human genome projects (as well as of historians of molecular biology) amount to the conviction that these projects are not only primarily technology-driven but also technology-generating enterprises. It would be important to think about the ways in which such a strong technical imperative has been changing and will continue to change the epistemic landscape of biology, its organizational features, its disciplinary structure, its industry-university relations, its publication practices, and finally, the questions that researchers consider worth investigating. If this diagnosis is valid, then the epistemological agendas that are pursued in molecular genetics are tightly interwoven, if not generated by the instruments and experimental arrangements that go into their construction. The point is that it is useful to keep in mind that it is the representations we can generate of an object or of a process that determine how we are able to think of these objects and processes. The polymerase chain reaction (PCR) is a representation of gene replication. But does it help us to understand the intricacies of chromosome duplication? A sequence of letters is usually seen as the rendering of genomic information. What does it reveal to us, what does it prevent us from thinking? If genome research becomes more and more impossible without biocomputing, what modes of thinking does this computational transformation of biology impose on those who practice it? Classical biological representations have been, as we habitually call them, in vivo, in situ, and in vitro. What do modes of representation such as ex vivo and in silico add to our conception of the living?
Finally, cultural aspects of genome research. Talk about cultures is in these days. We hear speak about cultures of communication, cultures of conflict and controversy, cultures of traffic, cultures of smoking, cultures of just about everything. Is it useful to add cultures of science?
- 7 - Probably not very, unless we specify what we mean by culture. The traditional notion of culture dissociates entertainment, high and low, from the more mundane aspects of human life such as social interaction, work, politics, business. Talking about culture in the context of scientific practice means something different. First, from anthropology we have learned to look at science as a social activity with its own rules, rituals, customs, rewards, transgressions and punishments worthy of being studied in their own right. Second, contrary to what a long tradition of philosophical idealization of scientific activity would like to have, the production of science is entrenched in contexts of a larger culture, national and transnational. Science does not proceed in a social void, but is deeply embedded in the market, the media, legal system, governmental action, everyday life. Every practicing scientist will testify to this, both in the negative and in the positive (even if, individually, the positive is just owning stock shares, and the negative, feeling a social pressure to justify what he or she is doing). The production of science today is, in other words, immersed in and, at the same time, shaping an environment which it might be appropriate to term “cultural” in its entirety. With that, we could at least avoid the traditional dichotomies such as politics and economics opposed to science proper. Rethinking scientific practice as a cultural activity could help to overcome all the fallacious boundaries the sociological codification of modern society has forced on us. All these boundaries are fluid and, above all, are constantly reconstituted through the transforming powers of contemporary science itself. Although some genome projects are national and local, they are, in direct or indirect ways, linked to global genomic science, to global capital, to genomic ventures that are within the private sector, transcending national boundaries and state policies. Furthermore, it is not uncommon that knowledge generated by human and other genome projects is enmeshed with questions of "intellectual property," patents, and other aspects of commerce. These new configurations of biology and biotechnology have already had profound effects on university research and education, and on publication practices. How does this situation affect the way we might think about regulation, planning, policy, or ethics beyond the academy in the future?
Let me come to a final remark. Why historical, techno-epistemic, and cultural aspects of genome projects, in the plural? One answer is, of course, trivial. Although the genome initiative started as a human genome project almost fifteen years ago, it has proliferated and developed into a multiplicity of genome projects including bacteria such as E. coli, unicellular eukaryotes such as yeast, plants such as arabidopsis, and animals such as the nematode worm and the mouse. We cannot do justice to most of them within the restricted frame of this conference. But the reason for the plural goes deeper. On the one hand, we witness technically very different approaches to the sequencing goal, and at the same time, epistemically different goals to be reached by sequencing. On the other hand, the individual projects themselves have taken the
- 8 - form of international collaborations in which new forms of combining particular interests and sharing common data pools are tried out. Such large-scale, yet pluralistic endeavors are certainly not unprecedented in the history of the life-sciences and the biomedical sciences in particular. But they are nevertheless unique in their specific blend of transdisciplinary constitution, and in the sheer size and diversity of their networks. This is yet another of the new epistemic dimensions that need to be assessed and analyzed by those who study the life sciences of this century.
- 9 - - 10 - CONFERENCE PROGRAM
WEDNESDAY, JULY 8
Afternoon: Arrival 5:00-6:00 Reception 6:00-6:30 Welcome and Introduction 6:30-7:30 "Decoding the Book of Life" (PBS Nova 1989, Video) 8:00 Dinner
THURSDAY, JULY 9
9:00-11:30 Genomic Re-Visions (Part 1) Chair: Robert Olby (University of Pittsburgh) I. 1. The Classical Gene, Garland Allen (Washington University) I. 2. The Cultural Gene, Diane Paul (University of Massachusetts) I. 3. Molecular Gene(s), Jean-Paul Gaudillière (INSERM, Paris) Comment: Regine Kollek (University of Hamburg)
Discussion
1:00-3:30 Genomic Re-Visions (Part 2) Chair: Robert Sinsheimer (University of California, Santa Barbara) I. 4. The Informational Gene, Lily Kay (Harvard University) I. 5. The Human Genome Project: Origins, John Beatty (University of Minnesota) I. 6. Angels and Monsters, Susan Lindee (University of Pennsylvania) Comment: Mike Fortun (Hampshire College)
Discussion
4:30-6:30 Panel and Discussion Discussion Leader: Manfred Laubichler (Princeton University) Panel: Soraya de Chadarevian (Cambridge University) Michel Morange (Université de Paris VI & VII) Troy Duster (University of California, Berkeley) Sahotra Sarkar (University of Texas at Austin)
- 11 - FRIDAY, JULY 10
9:00-10:15 Whose Genome? (Part 1) Chair: Kurt Bayertz (Universität Münster) II. 1. The Human Genome Project: Present and Future, Mark Guyer (NIH) II. 2. Postgenomic Challenges, Richard Strohman (University of California, Berkeley) Comment: Steven Hilgartner (Cornell University)
Discussion
10:45-12:00 Whose Genome? (Part 2) Chair: Hans Lehrach (Max Planck Institute for Molecular Genetics, Berlin) II. 3. The Human Genome Diversity Project, Joan Fujimura (Stanford University) II. 4. Non Human Genomes, Bernard Dujon (CNRS, Paris) Comment: Svante Pääbo (University of Munich)
Discussion
1:00-3:00 Panel and Discussion Discussion Leader: Scott Gilbert (Swarthmore College) Panel: Alan Attie (Madison, Wisconsin), Günther Gassen (University of Darmstadt), Denis Thieffry (Max Planck Institute for the History of Science, Berlin), Rogier Holla (European Union, Brussels), Soraya de Chadarevian (Cambridge University)
Afternoon: Laboratory Visit (Max Planck Institute for Molecular Genetics in Berlin-Dahlem, Department of Prof. Lehrach)
- 12 - SATURDAY, JULY 11
9:00-10:30 Technologies: Material, Informational, Social (Part 1) Chair: Timothy Lenoir (Stanford University) III. 1. Laboratory Practices, Representations, Michael Lynch (Brunel University) III. 2. French DNA or the Purgatory Machine, Paul Rabinow (Univ. of CA, Berkeley) Comment: Alan Attie (Madison, Wisconsin)
Discussion
11:00-12:30 Technologies: Material, Informational, Social (Part 2) Chair: Ruth Hubbard (Harvard University) III. 3. Making Sense of "Information," Antoine Danchin (Institut Pasteur, Paris) III. 4. Gene Therapy, Alan Stockdale (Education Development Center, Newton) Comment: Christine Hine (Brunel University)
Discussion
2:00-4:00 Panel and Discussion: Social Technologies Discussion Leader (with paper): Dorothy Nelkin (New York University, New York) The Body as Commodity in the Post-Genomic Age,
Panel: Charlie Weiner (MIT), Rainer Hohlfeld (BBAW Berlin), Rogier Holla (European Union, Brussels), Enzo Russo (Max Planck Institute for Molecular Genetics, Berlin)
4:30-6:00 General Discussion Discussion Leader: Garland Allen (Washington University)
6:00-6:30 Concluding Comment
- 13 - LIST OF PARTICIPANTS
Prof. Garland E. Allen, Washington University St. Louis
Dr. Alan Attie, University of Wisconsin Madison
Prof. Dr. Kurt Bayertz, Universität Münster
Prof. John Beatty, University of Minnesota
Dr. Soraya de Chadarevian, University of Cambridge
Prof. Antoine Danchin, Institut Pasteur
Prof. Dr. Bernard Dujon, Institut Pasteur
Prof. Troy Duster, University of California at Berkeley
Prof. Mike Fischer, Massachusetts Institute of Technology
Dr. Michael Fortun, Hampshire College
Prof. Joan H. Fujimura, Stanford University
Prof. Dr. Günther Gassen, Technische Universität Darmstadt
Dr. Jean-Paul Gaudillière, INSERM Paris
Prof. Dr. Scott F. Gilbert, Swarthmore College
Dr. Mark Guyer, National Institutes of Health (NIH)
Prof. Stephen Hilgartner, Cornell University
Dr. Christine M. Hine, Brunel University
Dr. Rainer Hohlfeld, Berlin-Brandenburgische Akademie der Wissenschaften
Dr. Rogier Holla, European Commission, Brüssel
Dr. Ruth Hubbard
Prof. Dr. Lily E. Kay, Harvard University
- 14 - Prof. Dr. Regine Kollek, Universität Hamburg
Dr. Manfred Laubichler, Princeton University
Prof. Dr. Hans Lehrach, Max-Planck-Institut für molekulare Genetik
Prof. Timothy Lenoir, Stanford University
Prof. Susan Lindee, University of Pennsylvania
Prof. Michael Lynch, Brunel University
Amade M’charek, University of Amsterdam
Prof. Michel Morange, Ecole Normale Superieure, Paris
Prof. Dorothy Nelkin, New York University
Prof. Robert Olby, University of Pittsburgh
Prof. Dr. Svante Pääbo, Ludwig-Maximilians-Universität München
Prof. Diane B. Paul, University of Massachusetts at Boston
Prof. Paul Rabinow, University of California at Berkeley
Prof. Dr. Hans-Jörg Rheinberger, Max-Planck-Institut für Wissenschaftsgeschichte
Dr. Vincenzo E. A. Russo, Max-Planck-Institut für molekulare Genetik
Prof. Sahotra Sarkar, University of Texas at Austin
Prof. Robert L. Sinsheimer, University of California at Santa Barbara
Prof. Alan,Stockdale, Center for Applied Ethics and Professional Practice, Newton
Prof. Richard C. Strohman, University of California at Berkeley
Dr. Denis,Thieffry, Max-Planck-Institut für Wissenschaftsgeschichte
Prof. Charles Weiner, Massachusetts Institute of Technology
- 15 - - 16 - CONFERENCE REPORT
Lily Kay
Harvard University
To assess the efficacy of a conference, at least its immediate outcomes, it is fruitful to compare the objectives of the event with the actual experience -- presentations and discussions -- and with accounts of participants and the audience. We therefore structure the report around these features. First, we briefly outline our objectives (a more detailed version was precirculated to the participants). Next, we provide an annotated outline of the four-day deliberations, and finally we include solicited responses to the conference in a composite form and the lessons we have learned. Taken together, these three sections recount a satisfying convergence of goals and outcomes, some thematic gaps (which are worthy of follow-up), and some remarkably instructive surprises.
I. OBJECTIVES
The conference's title, “Postgenomics?” signifies our overarching question: Beyond mere repetition of historical assertions to transcend reductionism, what new possibilities of understanding the organism as a whole will arise once complete genomic sequences are available, and will this new understanding be a “logical” consequence of present efforts, or is a conscious effort needed -- in both laboratory and social realms -- in “rethinking the organism,” especially the human organism?
We therefore broached this question in its overlapping historical, technical as well a epistemological, and cultural dimensions. We aimed at tracing the gene concept from the beginning of the century to the present: from abstract unit-characters of the 1910s, to the protein gene of the 1930s, to the DNA informational gene of molecular biology's “golden age”, to today's hypercomplex structure of the genetic material. Despite the fact that genomic organization has turned out to be very complex many scientists today continue to talk the language of “the gene for.” This observation leads us to the techno-epistemic realm of genome projects, for like molecular biology in general, human genome projects are not only primarily technology-driven but also technology-generating enterprises, and these enterprises are usually
- 17 - centered on the premise and promise of “the gene for.” We sought to explore how this strong technological imperative has influenced the epistemic structure of biology -- that is, its mode of knowledge production -- its organizational features, disciplinary contours, university-industry relations, publication practices, even the choice of research questions. Since neither organisms nor even the three-dimensional structure of proteins (key to drug design) are predictable from the raw data of DNA sequences, informational technologies have become central to genome projects. We also wondered how representations generated through biocomputing have impacted on our conception of life, with their various linkages to culture. Scholars in the history and social studies of science and technology have already examined some of the cultural aspects of genomics. In light of new developments, they were now invited -- together with practicing biologists -- to further explore the scientific dynamics, as well as the social forces operating within the international scientific community and beyond: commercialization, regulation, media representations, and popular perceptions. It was an unusually large group since we sought to include, even within the various approaches, a diversity of viewpoints. Indeed the emphasis of the conference was on discussion; deliberations centered around precirculated papers, commentaries, and panels.
II. THE CONFERENCE
Showing the American television documentary “Decoding the Book of Life” (PBS, Nova, 1989) in the opening evening of the conference served as a historical document and spring- board for the conference agenda. Aired just at the launching of the American HGP, it conveys multi-faceted messages: a prospect of reading and editing the genomic “book of life”-- with an explicit promise not to rewrite it (no germline therapy); technological utopias, international economic competition, and medical-social change informed by the lessons of eugenics. This documentary also exemplified the extrapolations from monogenetic disorders (e.g. cystic fibrosis) to multi-factorial diseases (e.g. cancer), and to complex traits (e.g. musical talent) that often characterize presentations of genomics in public forums, the media, and the stock market. These issues served as a provocation for the subsequent discussions..
- 18 - DAY I
“Genomic Revisions” focused primarily on the historical trails in genetics and molecular biology which converged on the launching of the human genome project in the United States in the 1980s. Some intriguing observations about the linkages of epistemic, technical, cultural and political factors emerged during these two sessions.
In Part I, recounting the consolidation of the Mendelian paradigm -- the notions of the gene as the “atom of life,” which developed during the classical era (1900s-1930s) -- historian of biology, Garland Allen (Washington University, St. Lewis), exposed a key dilemma: The Mendelian paradigm has been challenged from the very beginning at both the structural and functional levels. Genes have been recognized to be much more complex and less discrete entities (both structurally and functionally) than postulated by the classical Mendelian experimental model (in fact, calling the whole gene concept into question). Yet simplistic notions of the gene have persisted in a variety of ways in both the scientific, and especially the popular, literature about heredity. Nowhere is this more prominent and perhaps more dangerous, Allen underscores, than in research on the genetics of human behavioral and personality traits that have again increased in frequency and boldness of assertion on the coattails of human genome projects. Historian of biology, Diane Paul (University of Massachusetts) revealed similar incongruities about eugenics. Her contribution highlights a dilemma about the persistence of eugenic visions (visions of selective human breeding through genetic knowledge and technology). From the critiques of Mendelian inheritance by biometricians, from conclusions of the Hardy-Weinberg analytics of population genetics, and from the prevalence of polygenic traits and pleiotropic effects (known since the 1920s) it had been persistently demonstrated that eugenic measures (such as sterilization) were unrealistic as population/social control, yet the same old arguments about eradicating the “gene for” or breeding genius have kept resurfacing (e.g. the Nova documentary); and have become prominent again in the discourse of genomic medicine. Then why this persistent scientific and cultural appeal of genetic reductionism? In his historical reconstruction of the molecularization of the gene, historian of life science, Jean-Paul Gaudillière (INSERM, Paris) offered some novel insights into the issue. He argued for a history of molecular biology that combines studies of “science, technology, and medicine,” since molecular genes first appeared in the 1940s at the crossroads of heredity, biochemistry, and medicine. Thus in the fifty years which followed, the molecularized gene participated in the history of a technological century, as part of a biomedicine dominated by large-scale industrial systems and health crusades, notably war on cancer. As the session commentator, biologist and historian, Regine Kollek (University of Hamburg), observed: While the first two papers serve to historically problematize too simple a
- 19 - view of the relation between genotype and phenotype, all three presentations conveyed how structures, within which genetics has been embedded, have shaped research commitments. The discussion further underscored these points, raising the question of whether genomics has continuing links to eugenics, and what exactly we do mean by “genomics” (in contradistinction to genetics).
How did the powerful vision of the human genome project as “decoding the book of life” become so pervasive among molecular biologists and the public? In Part II, historian of science, Lily Kay (Harvard University) argued that the interlocking informational and linguistic representations of DNA were historically and culturally contingent. Though epistemologically problematic, they caught on in the 1950s through the impact of communication sciences -- information theory, cybernetics, and computer science -- in nearly every discipline; and they were instantiated in the work on the genetic “code” (1953-1967). The genomic “book of life” thus dates to the mid-1960s and, as such, according to Kay, has constituted a new form of bio- power: Beyond material control of bodies and populations there is now the problematic vision of controlling life's logos, the Word, or DNA sequence. Historian of life science, John Beatty (University of Minnesota) traced some of these power relations (also presented in the Nova documentary): the political and economic interests of national security behind the congressional promotions of the human genome project in the 1980s, specifically the competition with Japan and the consolidation of the roles of the national laboratories at the twilight of the cold war. The political dynamics behind NIH's sponsorship remains to be explored. The social dimension of the human genome project was further examined by historian of science, Susan Lindee (University of Pennsylvania) through the images of genomic angles and monsters -- the promise of transcending human limitations (disease, intelligence, even accessing Christ's DNA) and the threat of producing aberrations in the human condition -- Frankensteinian forms, threat to human rights, and dangers to creative biological research. All three presentations underscored, as did the commentary of historian of science, Mike Fortun (Hampshire College), that the epistemology is not homogenous, and that it is inseparable from an open-ended cultural and political history of the human genome project.
The subsequent panel discussion was intended to tie together the different genetic re-visions of the first day together: deliberations on the historical development of gene concepts and the challenges of new knowledge of epigenetic networks, juxtaposed with elaborations on the centrality of institutions and politics in the consolidation of molecular genetics. Though the linkage between these two themes was evident, it was not properly exploited. The closing discussion opened up a topic which would remain on the table throughout the conference: Are practitioners of genomics being unfairly portrayed as naive reductionists and are not the critiques addressing an outdated simplistic picture of the human genome project, now being
- 20 - replaced by more nuanced understanding? And if so, how can the public (e.g. Congress, stock markets, the media, insurance companies, and medical consumers) be informed of the contingencies and complexities implicit in genomic knowledge?
DAY II
“Whose Genome?” focused on two issues. One issue emerges from the acknowledged non- uniformity of genetic endowments: genetic variabilities among individuals, among various native populations, and, of course, among species. The other issue is raised by the present commodification trends (property rights, patenting, stock options), with its additional questions of ownership of genomic products and processes.
In Part I, molecular biologist, Mark Guyer, as representative of the human genome office, NIH, emphasized the necessity of a concerted analysis of human sequence variation (“the human genome” is currently based on a genomic composite of 14 individuals); the sequence data is widely available through electronic data bases. Well ahead of its 2005 target date, the Project's goals now consist largely in reassessing the objectives in terms of sequencing capacity, quality control, and accessibility. Clearly, such large-scale sequencing initiatives are based on faith in the predictive powers of genomic sequences, a view presupposing a straight forward correspondence between genes, structures, and functions, a “genetic program” in short-hand terminology. “But where is the program?” provocatively asked the cell biologist, Richard Strohman (University of California, Berkeley). His answer was that the notion of a genetic “program” is biased and that a new phase (postgenomics?) is now upon us. Moving beyond the four phases of genomics -- monogenetic and polygenetic determinism; shift in emphasis from DNA to proteins; and functional genomics -- he predicts that human genome projects are now approaching the fifth phase, concerned with non-linear, adaptive, properties of complex dynamic systems (he stresses that only 2% of human disorders are monogenetic). At this phase the limited vision of linear genetic causality would be replaced by analyses of networks interacting with the environment and operating across four levels of regulation: genetic (sole concern of current HGPs), epigenetic, morphogenetic, and organismal. As planned, and as the commentator, sociologist Steve Hilgartner (Cornell University), stressed, we witness here diametrically opposed presentations: NIH's official institutional position vs. a consciously unorthodox critique based on studies frequently ignored by genomicists.
In “Whose Genome?” (Part II) sociologist Joan Fujimura (Stanford University) addressed the complexities and controversies surrounding the Human Genome Diversity Project, developed as a corrective to the HGP and as a means of tracing the origins and divergences of human
- 21 - populations. In its attempts to gather DNA samples from native cultures (or populations) around the world, the HGDP has met with great resistance and criticisms, especially from native advocates who have viewed it as a form of biologically-based racism. At stake is the issue of what are the criteria of and who defines “culture,” anthropologists or biologists. As the subsequent discussion showed, much of the controversy is grounded in the confusion/conflation of cultures and populations. However, as the commentator, biologist Svante Pääbo (University of Munich), pointed out, the biological and anthropological definitions of culture need not be dichotomous, rather both can be creatively combined toward a more nuanced understanding of culture. Understandably, far less controversial is the place of non-human genome projects in the public arena. Molecular biologist, Bernard Dujon (CNRS, Paris) contributed an up-to-date review of such work, ranging from bacteria to mouse. The findings from microbial genetics were particularly striking, revealing, among other things, that all sequenced genomes include a large portion of ORFs (Open Reading Frames) lacking any significant homology with characterized genes, thus suggesting biases in classical genetic studies and potentially masking a wide range of genetic functions. From an organizational perspective, the remarkably successful yeast genome program provides a major lesson for genomics as a large-scale science. It represents the common achievement of a community, rather than an individual initiative; it was based on coordination of effort rather than short- minded competition, and helped improve laboratory expertise and efficiency, including their commercial off-shoots.
Led by cell biologist and historian of biology, Scott Gilbert (Swarthmore College), the panel discussion picked up some key themes from the sessions: lessons about context-sensitive regulation sites learned from the E. Coli genome project; that current data bases are unprepared to handle such complex information; globalization of genomics and the impending reorganization of European research under biotechnology industrial imperatives; and the status (and contradiction within) patent laws with respect to genomics, as laid out by the European Union. But by far, Hans Lehrach's (director of the Max-Planck Institute for Molecular Genetics, Berlin and head of its human genome project) statement was the most provocative, for he sees the driving force of genomic projects as the search for maximal efficiency in the production of molecular databases, and scaling up of sequencing and functional analysis, correlated with efforts to automate experimental routines. Lehrach's vision of a futuristic laboratory was concretized by an afternoon visit to the Institute. Juxtaposed with Strohman's critique, Lehrach's aspirations (including commercial ones) sparked heated discussions until the end of the conference.
- 22 - DAY III
“Technologies: Material, Informational, Social,” addressed the various dimensions of human genome projects as sites of emergence or consolidation of new research practices; clinical promises; and reconfigurations of social attitudes and practices.
In Part I Michael Lynch, as a laboratory ethnologist (Brunel University) exposed the multifaceted nature of laboratory representations by examining PCR (Polymerized Chain Reaction) as an exemplar of a technology that reoriented the practices of genomic research. Analyzing the blackboxing, packaging, and marketing of such “tool kits” (e.g. cDNA probes, cloning and sequencing kits, software), he observed that the distinctions between commercial advertising, journalism, research practices, patenting, and technical publications tend to become blurred. These practices have had an impact well beyond the laboratory bench. Commercial services are often sold at higher administrative levels, from which vantage point “science” -- and DNA -- is viewed as a mode of production to be managed. The anthropologist, Paul Rabinow (University of California, Berkeley) recounted a somewhat different kind of DNA management: the French case. Based on his participant-observer experience (Centre d'Etude du Polymorphisme Humain, CEPH, and their collaboration with the Boston-based Millennium Pharmaceuticals, Inc.), he observes a disjunction between the push for scientific competitiveness and national, as well as, social values. He registers a profound uneasiness about the consequences of recent DNA technoscientific developments within the French cultural milieu. The new form of biopower challenges human dignity, he observes, since new technologies that give life its form are producing results that escape the philosophical self- understanding provided by both the classical world and Christian tradition. Mainly addressing Lynch's paper, biochemist Alan Attie (University of Wisconsin, Madison), commented on the adverse impact of the new “tool kits” on biology education: how the blackboxing of procedures has been pedagogically limiting the biochemical training of a new generation of molecular biologists.
In Part II, molecular biologist, Antoine Danchin (Pasteur Institute), addressed problems of genomic complexities through novel approaches. Since the study of life should never be restricted to the study of objects, but to their relationships, genomes cannot be considered simply as collections of genes, he argued. Using models organisms, such as E. coli and Bacillus subtilis, he has sought to understand genome organization by exploring the distribution of genes along the chromosomes, via the concept of neighborhood and by using special algorithms. He concludes that the order of genes is far from random but is linked to the function of genes in relation to the cell's architecture, thus arguing against exclusive molecular
- 23 - explanations of upward causation: evolution creates functions and functions “capture” structure. This sophisticated picture of genomic functions -- even in bacteria -- contrasted dramatically with the facile promises of human gene therapy, as examined by anthropologist Alan Stockdale. (Education Development Center, Newton, MA). Taking the cystic fibrosis (CF) experience in the U.S. as a problematic case study, and having interviewed the relevant constituencies -- researchers, clinicians, administrators, and patients -- he presented the many problems related to gene therapy, even in the simple monogenetic case of CF: confusion between gene replacement and reversal of the disease, overstatement of prospects, neglect of adult patients in favor of children, cost-ineffectiveness, deficiencies of legal frameworks, lack of patient and physician education, and faulty communications. Gene therapy (replacement), even if it succeeds, is a technology that appears to be very far in the future. As commentator, sociologist, Christine Hine (Brunel University), underscored, the complexities emerging from studies of genome projects (even in bacteria) need to be communicated to patients, without assuming the public's inability to cope with such ambiguities.
The conference concluded with a panel deliberation on human genomes and social technologies, discussions loosely structured around Dorothy Nelkin's (New York University) presentation on the commodification of the body in the genomic age. She has described how, along with other body tissues and parts, genomics is having profound implications not only for medical practice and social policy, but for the meaning of the human body. The lively discussion which followed spilled from critiques of somatic gene therapy to those of germline therapy -- not only the ethical violations but also the problems with the science itself. Despite explicit promises to never temper with the human germ line (e.g. the Nova documentary), despite failures of human somatic gene therapy, and disregarding the ban on experimentation with human embryos in some European countries, some leaders of genomics have begun to push for germline therapy, seeking to bypass the regulatory procedures that would inevitably have to be established. Perhaps, if regulatory and social structures remain largely subordinate to global market forces, the postgenomic era would include also germline manipulations as its legacy.
TO SUM UP:
While the conference was organized according to a particular logic, the sessions‘ themes began to overlap after the first day, demonstrating, as we had hoped, that all these issues -- historical, techno-epistemic, cultural, political, are strongly intertwined in genome projects. We have not achieved all our goals: Too much discussion was devoted to an ultimately unrewarding global
- 24 - critique of genetic reductionism; there never emerged a satisfactory definition of “genomics,” let alone “postgenomics”; the roles of informational technologies received only minor coverage; and, as the commercial and industrial dimensions came into sharp relief, it became plain that the conference would have benefited a great deal from the presence of biotechnology representatives. On the other hand, the strength of the conference lay in the unusual sustained dialogue among scientists and scholars in “Science Studies.” As one participant put it: on the first day there were two camps, the scientists and humanists; on the second day fissures began to develop within the two groups, differentiating and refining their views and showing no clear consensus on either side; on the third day, some real cross-overs took place. Perhaps, the lessons and even the unanswered questions from this conference can serve as a guide for moving beyond celebration and encourage sustained communications between science and the public, and between scientists and scholars in the humanities.
PROSPECTS
From the deliberations of the conference it has become clear that -- ethical, social, and legal issues notwithstanding -- closer attention should be paid to the very epistemological aspects of the new, genomic mode of practicing biology. This includes an assessment of the new ways of data processing and data delivery, of new forms of cooperative projects, of relations of knowledge production to application, of the lessons gleaned from developmental biology, of epigenetics, of the reintroduction of morphology, and of whole animal representation in conjunction with genomics; in short, inclusion of the complete dynamics of the organism promises to reconfigure what it means to do biology in the coming decades. If there is something to Lehrach's postulate that the very epistemological core of biological experimentation is about to change -- from hypothesis-driven, single experiment to systematic, large-scale data production, followed by modeling -- then this vision should indeed provide an appropriate theme for comparative and historical case studies that evaluate these changes against the broader contours of life science in the twentieth century.
- 25 - - 26 - POSTGENOMICS ?1
AN INTERDISCIPLINARY CONFERENCE AT THE MAX-PLANCK-INSTITUTE FOR THE HISTORY OF SCIENCE IN BERLIN
Denis Thieffry, Max Planck Institute for the History of Science and Sahotra Sarkar, University of Texas at Austin
In 1997 Ernst-Ludwig Winnacker, Acting President of the Deutsche Forschungsgemeinshaft, posed the question: "In which direction will research go in a postgenomic era?" (Die Zeit, 2 May 1997) As the human and other genome projects begin to churn out massive sequences, the functional significance of which is at present poorly understood, that question is apposite. Winnacker elaborated on the problems faced by genome workers and the direction in which research must go: "Until now, the individual genes stood in the foreground. We will leave them behind us and ask how they contribute to the formation of individual cells, of cell communities, and of whole organisms. ... We will go for an understanding of the whole." Winnacker's question--and the beguiling word "postgenomic"--formed the background for a conference (8 -11 July 1998), "Postgenomics? Historical, Techno-Epistemic and Cultural Aspects of Genome Projects," organized by Hans-Jörg Rheinberger (Max Planck Institute for the History of Science in Berlin) and Lily Kay (Harvard University), and funded by the German Human Genome Project.
While conferences on genomics and the Human Genome Project (HGP) have become commonplace, this one was unique in three ways: (i) significant attention was paid to the sequencing of non-human genomes; (ii) a successful effort was made to engage scientists, social scientists, and humanists in active discussion, not only of the usual ethical, legal and socio-political questions raised by genomics, but also of basic epistemological questions about the conceptual framework and research strategies of molecular biology; and (iii) the conference brought together US scholars with those from several European countries (besides Germany) encouraging wide-ranging cross-cultural comparative discussions. The conference included sessions based on pre-circulated papers and formal responses as well as daily panel
1 This report will be published in Bioscience, possibly with some minor modifications.
- 27 - discussions. Besides molecular biologists, active participants included developmental biologists, anthropologists, ethnologists, historians, lawyers, philosophers, and sociologists.
FROM GENETICS TO GENOMICS
The conference began with a reassessment of the history of genetics and historical issues emerged repeatedly throughout the three days. Some of the historical questions raised were of well-known relevance to genomics (see Kevles and Hood, 1992; Cook-Deegan, 1994). In general, however, the historians tried to extend and contextualize received histories of genetics and to use that understanding to probe the scientific and human contexts of contemporary genome projects.
Garland Allen (Washington University, St. Louis) discussed the dichotomy between technical and popular understanding of the gene in the early decades of this century. This dichotomy resulted in popular misapprehensions about the assumed power of the gene. Though the limitations of genes as sole causal agents of phenotypes were scientifically recognized from the beginnings of genetics, that recognition rarely filtered through to the popular level. Using "feeble-mindedness" as an example, Diane Paul (University of Massachusetts at Boston) discussed eugenic measures that were proposed--and sometimes implemented--in the 1920s and 1930s. What is striking was that negative scientific findings--for instance, that "feeble- mindedness" did not show a Mendelian pattern of inheritance--had negligible influence on social policy. This surprising story confirms Allen's dichotomy between technical and popular conceptions of the gene. Regine Kollek (University of Hamburg) noted that the gene was a polysemous concept, that is, it has many meanings, and emphasized that the epistemic status of the gene (i.e., what it really can explain) requires specification in each context.
Turning to more recent history, Jean-Paul Gaudilière (INSERM, Paris) challenged the conventional story that genomics constitutes a radical departure from genetics because it involves technological innovation (especially the introduction of large-scale computation) and has an applied orientation. He noted that much of classical biochemical genetics research was conducted in an applied medical context after 1940. Similarly, cancer research played a significant role in the development of molecular biology in the 1960s. Genomics should consequently be regarded as being in a continuum with these developments. The fact that medical expectations drove funding for molecular biology in the UK was further emphasized by Soraya de Chadarevian (University of Cambridge).
- 28 - Perhaps the most popular technique in molecular genetics today, the Polymerase Chain Reaction (PCR) found its way in most biological laboratories within a decade. Adopting an anthropological stance, Michael Lynch (Brunel University) analyzed various modes of representation of a single laboratory technique, PCR, from the laboratory bench to the advertizing media.
John Beatty (University of Minnesota) discussed the origins of the US HGP, in which the Department of Energy, itself a successor to the Atomic Energy Commission (part of whose mandate was to study the mutational effects of radiation released at Hiroshima and Nagasaki) played a major role. Beatty attributed the decision to initiate the HGP partly to a perceived economic war between the US and Japan that replaced the defunct Cold War in the minds of US policy makers in the late 1980s. Beatty's story complements received accounts of the origins of the HGP (such as Cook-Deegan, 1994), which emphasize scientific, medical, and technological factors.
LESSONS FROM MICROBIAL GENOMICS
Much of the conference was devoted to the accomplishments and the present state of genome projects. Bernard Dujon (CNRS, Paris) reviewed the status of the numerous 'non-human' genome projects, ranging from bacteria to mouse. Most striking in his account was the preponderance of microbial genome projects. Not only are all completed genomic sequences those of microbes (16 bacteria, with genomes ranging from 0.58 to 4.60 Mb, and one unicellular eukaryote, Saccharomycescerevisiae , about 12.07 Mb), but a wealth of additional microbial genomes are being sequenced. Dujon listed 46 bacteria, 8 archae, and 7 unicellular eukaryotes. Genomics has thus been concerned primarily with unicellular organisms, many of which are of medical importance (e.g., Mycoplasma genitalium and Mycoplasma pneumoniae, Mycobacterium tuberculosis and Mycobacterium leprae, Neisseria meningitidis, Plasmodium falciparum, Trypanosoma rhodense). Others are of economic (e.g., S. cerevisiae) or environmental importance (e.g., Archaeoglobus fulgidus). Some are model organisms for fundamental research (e.g., Escherichia coli, S. cerevisiae).
Although medical and economic interests play a crucial role in organism selection for genome projects, they do not preclude important benefits for basic science (see Dujon, 1996, for the lessons from the yeast genome project). Indeed, though at first mainly considered as platforms for technological development, microbial genome projects have already produced several surprises. One of the most striking was the discovery that all sequenced microbial genomes
- 29 - include a large proportion (typically about a third) of open reading frames (ORFs) lacking any significant homology with already characterized genes. The proportion of unknown genes further increases when the focus is on "single genes" (i.e., genes that are not members of multigene families). This result suggests that there were significant biases in gene identification using classical genetic analyses. Because classical methods have failed to identify so many genes, they have potentially failed to uncover a wide range of genetic functions.
Microbial genomics has also taken the lead in functional analysis. For example, libraries of mutants have been produced for all S. cerevisiae "orphan genes" (those with no known function) and systematic functional assays are under development. Hybridization membranes and microchips now allow the characterization of transcription patterns of all genes in different growth conditions. Finally, new methods also allow the study of intracellular localization and interactions of proteins in situ. Such snapshots of mRNA and protein concentrations at the level of whole cells constitute an invaluable resource for deciphering the corresponding complex networks of interactions.
Microbial genomics has also been innovative from a theoretical perspective. Deploying a single concept, that of a "neighborhood," Antoine Danchin (Institut Pasteur, Paris) introduced a potentially ground-breaking perspective linking genome organization to cellular structure and function. A "neighborhood" can be defined wherever there is a precise concept of "distance." In biology, distances can be defined in terms of recombination frequency, DNA or amino acid sequence similarity, codon frequency, and many other ways. Sequence similarity is routinely used to assign functions to new genes, whereas physical proximity on chromosomes is used to predict transcriptional units (operons) in bacteria. Comparison of codon frequencies in E. coli and Baccilus subtilis hints at a possible regulatory role of codon usage. The concept of neighborhood can also be applied to metabolic charts to derive families of functionally related enzymes or to identify functional complexes of cellular constituents (e.g., protein complexes such as the "degradosome"). Finally, the concept of neighborhood is already routinely used in the exploration of bibliographical databases; neighboring articles are then defined in terms of the number of shared keywords (e.g., in the use of the NCBI Entrez software to explore MedLine).
Danchin‘s view of the bacterial cytoplasm is that of a gel traversed by a ribosome lattice which undergoes relatively slow movements. In such a viscous medium, the diffusion of large molecules (e.g., tRNAs, mRNAs, proteins) is very limited; this significantly constrains gene transcription and translation (Danchin and Hénaut, 1997). For instance, long mRNA threads are unlikely to move freely in the cytoplasm, but are guided by the ribosomes during transcription, leading to further channeling of the resulting products towards specific cellular
- 30 - locations. In consequence, Danchin argues that translation (not transcription) has to be the driving force in gene expression, thus inverting the usual representation which starts with DNA and gives priority to the process of transcription. Similarly, he suggests that the map of the cell must be in some way in the chromosome. Combining an analysis of the position of genes in the chromosome with an analysis of their codon usage and an analysis of the location of their products in the cell, Danchin provides preliminary support to his claims in the case of components of the outer membrane of E. coli.
Finally, statistical analyses of genome sequences are proving to be powerful in revealing functional features including, for example, the identification of regulatory loci. But statistical analyses of both yeast and bacterial genomes also point to some limits. For instance, important regulatory sites sometimes escape statistical screening. Also, a single polynucleotide stretch may have different regulatory effects, depending on its position on the chromosome or on the presence of other regulatory sites in its vicinity.
OF MICE AND MEN
Turning to multicellular eukaryotes, Hans Lehrach introduced the German Human Genome Project (launched in 1995) and research being conducted at the Max Planck Institute for Molecular Genetics in Berlin. These projects encompass various chordate genomes, including Amphioxus, zebrafish, mouse, along with human. The main ideas driving Lehrach's projects is the search for maximal efficiency in the production of molecular data, the scaling up of sequencing and functional analysis, and correlative efforts to automate experimental protocols. For instance, in the case of the zebrafish, the production of libraries of cDNA clones, specific probes, and embryo labeling at various developmental stages, are processed in parallel by an array of robots (Maier et al. 1997). Among prospective targets is the automation of the production of specific antibodies for the corresponding proteins. In this futuristic laboratory, the main tasks of a biologist might well consist of adjusting control parameters, selecting interesting data, and making them available to the scientific community through the World Wide Web.
For the human genome, Mark Guyer (NIH) reviewed the history of the US project, assessed its achievements, and presented a set of goals for the next five years (Guyer and Collins, 1995). The HGP is well on track and perhaps even ahead of the original schedule. Mapping efforts have already led to the localization of tens of thousands of markers, and the 2005 target date for the completion of the entire sequence now seems easily achievable. Concerns such as sequence
- 31 - accuracy, continuity, assembly, and rapid public release are being addressed. In this context, it is not surprising that the 1998 goals consist largely of reassessing the general objectives of the HGP in terms of sequencing capacity, quality, and accessibility. Bioinformatics, but also studies of the ethical, legal, and social implications (ELSI) of the HGP, are due for further financial support. Finally, and perhaps most important, the new goals explicitly emphasize the necessity of a concerted analysis of natural human sequence variation, as well as the need for further development of functional genomics. The decision to recognize and analyze natural human DNA sequence variation addresses one of the most important scientific criticisms of the original program of the HGP (Sarkar and Tauber, 1991).
Related to the last issue is that of sequence diversity among human populations. It was addressed by Joan Fujimura's (Stanford University) discussion of the Human Genome Diversity Project (HGDP), which was partly proposed as a corrective to a perceived bias in the HGP because the DNA being sequenced was primarily collected from populations of European origin (Cavalli-Sforza, 1997). Though the genome under sequencing is in fact made of bits taken from cell lines of various origins, most of these were ultimately derived from "Western" individuals. However, HGDP, which attempts to collect DNA samples and trace human diversity around the world, often from isolated populations, has met much resistance and criticism. Understandably, representatives of indigenous groups generally consider the collection and transferred ownership of bodily materials objectionable, resist the potential economic exploitation of their DNA, and fear new pseudoscientific justifications of racism. These disputes are yet to be resolved.
At the basis of large-scale sequencing initiatives always lies some faith in the predictive power of genomic sequences. In the human case, the availability of a good genetic map together with the complete genomic sequence is presumed to constitute a powerful tool for tracking genetic diseases and ultimately for designing appropriate therapies. The prospects of somatic gene therapy are often used to convince funding agencies to support basic research in genetics. Already advanced as an idea in the 1960s, the promise of gene therapy embraces a wide variety of diseases. However, on the basis of an extensive anthropological study of the recent clinical experience with cystic fibriosis in the US, Alan Stockdale (Education Development Center, Newton, MA) reviewed problems related to gene therapy in general: frequent conflation of gene replacement with a full cure; exaggeration of medical benefits; deficiencies of the legal framework; lack of education of both patients and physicians, as well as of a failure of communication between them.
Despite much publicity and promises, few clear examples of successful applications of somatic gene therapy can be found to this day. Technically, the obstacle most regularly encountered is
- 32 - the poor efficiency of available gene delivery systems, which has led some scientists and physicians to promote germline gene therapy, a supposedly technically much simpler way to achieve gene replacement than somatic gene therapy. This possibility was discussed at a recent symposium, "Engineering the Human Germline," held at the University of California at Los Angeles (20 March 1998). That discussion violated a virtual taboo that has been in place throughout the history of the HGP. Manipulating the human germline was held to be too troubling a prospect to entertain in public and, in Berlin, in a meeting held in a building almost adjacent to former Nazi torture chambers, eugenic fears were inescapable.
Nevertheless, several participants at the Berlin conference, especially Charlie Weiner (MIT), initiated a discussion of the Summary Report of the UCLA symposium. The discussion that ensued was among the most searching at the conference. There was general consensus that there are strong prudential arguments against human germline therapy. As Rheinberger and Scott Gilbert (Swarthmore College) argued, at the present level of technical know-how, germline interventions in any species have a high probability of disrupting patterns of development. Sahotra Sarkar pointed out that these technical problems would almost certainly be solved eventually. The real issue is whether there are deeper ethical reasons to object to human germline therapy. A more systematic inquiry into the nature of these reasons is badly needed. Fujimura and Sarkar both argued that a public discussion of these issues was desirable before any decision is made to develop or not to develop human germline therapy.
Whether or not human germline therapy becomes technically feasible and socially acceptable, many participants at the conference agreed that the promise of genetic medicine had been exaggerated to the general public. Rheinberger quoted the German molecular geneticist, Benno Müller-Hill (who is also one of the best-known critics of the Nazi abuse of genetics): "Now scientists are promising a massive betterment in preventive medicine after the 'holy grail' of the human genome has been attained, and 'man will be understood through his DNA.' I doubt all that. These promises cannot be kept. The public will become discontented when it realizes that all these expensive promises are not being fulfilled. Scientists should not sell hope" (Müller- Hill, 1991). M. Susan Lindee (University of Pennsylvania) and Dorothy Nelkin (New York University) carefully documented the rise of the gene as a cultural icon which partly explains the exaggerated power of the gene that is found in public discourse (Nelkin and Lindee, 1995). Nelkin also provided a troubling analysis of the emergence of the body and body parts as commodities in the marketplace. A recent attempt to regulate this market was discussed by Rogier Holla (European Union, Brussels), who introduced the new directive of the European Commission for legalizing and restricting the patenting of biological materials and processes.
- 33 - EPISTEMOLOGICAL CRITIQUES AND RECONSTRUCTIONS
Turning to the conceptual development of molecular biology, Kay argued that historically contingent interlocking informational and linguistic representations of DNA, which emerged because of the impact of communication sciences in the 1950s (Judson, 1979; Keller, 1995; Sarkar, 1996), have led to a reification of a genetic "code." She questioned the existence of a "Book of Life" encoded by DNA sequences. Sarkar argued that classical genetics had consistently failed to explicate how nature-nurture interactions caused phenogenesis and wondered whether genomics could do any better. It is possible that, by providing a powerful alternative, genomics will finally displace discredited classical techniques such as heritability analysis that were used to navigate the nature-nurture problem. Lehrach defended the gene- centered point of view arguing for the centrality of genetics and genomics for all biological research.
At the theoretical level, talk of genetic information and codes leads to the idea of a "genetic program" driving phenotypic expression. But Richard Strohman (UC-Berkeley) asked: "Where is the program?" His answer was that the notion of a genetic program, at least in the usual sense of a set of sequentially activated routines, is illusory (see also Strohman, 1993). He distinguishes five overlapping phases of genomics which he suggests evolved partly from technological developments and discoveries emerging from the HGP. The first and second phases correspond to monogenic and polygenic determinisms; the third consists of a shift of emphasis from DNA to protein (e.g., Alberts, 1998); the fourth focuses on the functional role of genes in model organisms, for example, transgenic or knockout mice (also discussed by Michel Morange, Université de Paris) (see also Miklos and Rubin, 1996); and the fifth consists of an awareness of nonlinear, adaptive properties of complex dynamical systems. At this stage (postgenomics?), unjustified recourse to linear genetic causality will be replaced by the analysis of rules governing environmentally open networks of agents including, but not limited to, genes.
Strohman also distinguishes four levels of regulation of biological activity: genetic, epigenetic, morphogenetic, and organismal. The mainstream genome projects are mainly restricted to the first level, for which agents (DNA sequences), processes (replication, transcription, and translation) and rules (base pairing and the genetic code) are well characterized. Though agents (gene-protein networks, morphogenetic fields) and processes (DNA modifications, epigenetic regulation) can be identified at the three other levels, specific rules have not been thoroughly characterized yet. These gaps in our biological knowledge might explain the ubiquity and hegemony of epistemological reductionism in contemporary molecular biology.
- 34 - TOWARD POSTGENOMICS?
One of the most striking characteristics of genomic projects consists of the development of new modes of production, exchange, and organization of biological data. The conference brought together the experiences of scientists involved in genomic projects in France, Germany and the US. There also was some discussion of genomic projects in which the scientists were not personally involved. It became clear that important differences exist between the various projects. For example, Dujon discussed the differences between the centralized single- laboratory strategy of The Institute for Genomic Research (TIGR, Rockville, MD) for bacterial genome sequencing, which emphasizes increasing technological sophistication, and the network-based approach of the initial European S. cerevisiae genome project, which relied on using locally existing expertise and technologies.
The general tendency has been towards improving and scaling up sequencing performance. The rapid adoption of "shotgun" sequencing testifies to the precedence of rapid and efficient sequencing over functional analysis. At the same time, genome projects rely increasingly on sophisticated informatics, both hardware and software, to drive automated sequencers and to assemble, store, and analyze DNA sequences. Many software packages for sequence analysis are already available, for example, to localize putative genes, to predict their structure and function, and to look for promoters and putative regulatory sites. However, the main public DNA databases (GenBank in the US, EMBL in Europe) are not yet prepared to deal with basic functional information (for a recent review of molecular databases, see Ashburner and Goodman, 1997).
Functional analysis of the putative genes uncovered by the genome projects is still largely in its infancy. This is attested to by the fact that attempts to anticipate the results of gene mutations in metazoans (e.g., knockout mice) usually fail. Similarly, many of the so-called "genetic diseases" have turned out to be far more complex than initially expected. Redundancy, functional complementation, and complex epigenetic regulation seem to be the rule rather than exceptions. Many regulatory mechanisms have proved to be context sensitive, and the dynamics of gene expression often depend on both the past history and the environment of organisms. As a result, genomes are being increasingly conceptualized as complex dynamical systems, even able to engineer themselves to some extent. There is thus an increasing need for formal techniques to deal with these open dynamic gene-metabolism networks. This need goes beyond efficient sequencing and even beyond the mere identification of functions of individual sequenced loci. Without the development of such formal techniques, "postgenomics" will remain little more than a beguiling name.
- 35 - What was most interesting during the meeting was a confrontation of a broad variety of opinions, with respect to both social and epistemological issues, including those such as the estimation of the predictive power of DNA sequences. Strikingly, as the conference progressed, it became clear that disagreement on such fundamental issues was as broad among the scientists themselves as between them and historians, philosophers, and other social scientists and humanists. These discussions underscored the extent to which scientific issues about genomics remain unresolved. Unfortunately little of these debates reaches the general public even though, in the case of so human a science as genomics, these disputes concern issues of immediate and general public interest. As scientists, we are left to wonder how to address this problem.
ACKNOWLEDGEMENTS
Thanks are due to Judy Johns Schloegel for comments on earlier drafts. The opinions expressed in this report are the sole responsibility of the authors and should not be taken to reflect the positions either of the Max-Planck-Gesellschaft or the Deutsches Humangenomprojekt.
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- 37 -