On Black Boxes and Storytellers: Lessons Learned in Human Genetics**Previously presented at the annual meeting of The American Society of Human Genetics, in San Diego, on October 13, 2001.
2002; Elsevier BV; Volume: 70; Issue: 2 Linguagem: Inglês
10.1086/338917
ISSN1537-6605
Autores Tópico(s)Nutrition, Genetics, and Disease
ResumoLike so many before me, I stand here expressing gratitude for the opportunity to serve as your president during the past nine months. It is a great honor, of course, but, more than that, it is also the privilege of a career for one who has never wanted anything more than to belong to the community of human genetics. I will have much to say this afternoon about the nature of this community, both for me as an individual and for us as investigators, scholars, and educators who have chosen to spend our professional lives as part of this community. I have learned many lessons from human genetics and would like to highlight several of these this afternoon, as well as to offer you a challenge for our future. Before I begin on this peaceful afternoon in San Diego, it is important to reflect on just how much our world has changed in the last month. A new view of the world and a new view of the future have been thrust upon us. We are left to wonder exactly how each of us fits into this new world and how our work can best go on. We wonder how our individual and collective efforts in research, education, and the practice of human and medical genetics can best be presented and perceived at a time of both national and international—and, for some, very personal—turmoil and tragedy. We are, at the same time, scientists—with much to contribute by way of understanding the nature of the human condition—and individuals—with much to lose because of the nature of the human condition. We are not the first generation of scientists to be asked to meet during the early stages of a war that promises—or should I say threatens—to occupy our thoughts and energy for many years to come. And we are not the first scientists to have to consider thoughtfully how science can best be served or can best contribute during a period of altered political and human priorities. There was widespread disruption to science in Europe in the late 1930s and 1940s, as Europe responded to events at that time in Germany. Not to increase the anxiety level among those of you who have flown here from overseas, but travelers to the Seventh International Congress of Genetics in Edinburgh in 1939 were torpedoed while crossing the Atlantic at the outset of World War II. Many scientists known to us, including some in this room, suffered greatly during that period and were asked to make both scientific concessions and personal sacrifice. The American Society of Human Genetics played a role in the aftermath of that war—at least vicariously through several of its members—by contributing to the discourse at that time on radiation exposure and social policy. A number of our members—Jim Neel (ASHG president in 1953–1954), Jim Crow (ASHG president in 1963), Bentley Glass (ASHG president in 1967), and H. J. Muller (the first ASHG president, in 1948–1949)—were named to the national Committee on Biological Effects of Atomic Radiation and various other committees of the National Academy of Sciences, the World Health Organization, and the United Nations that were formed to address health concerns about radiation. Out of these wartime efforts grew a new research focus: to study the effects of radiation on genes, chromosomes, and the genome. Public health concerns about the effects of ionizing radiation and chemical mutagens gave birth to a new generation of research tools to create novel mutations in model organisms. These efforts led to the emergence of the national laboratory system—at Oak Ridge, Berkeley, Livermore, and Los Alamos—each of which has played a catalytic role in the development of genetic and, more recently, genomic technologies, from which the field of human genetics has so clearly benefited. As one example that is particularly relevant to us at this meeting, it was studies on the effects of radiation that led Dan Pinkel and Joe Gray—then at the Lawrence Livermore Labs in Livermore, California—to develop fluorescence in situ hybridization methods as a cytogenetic approach to evaluate chromosome damage. It is their work that we honor, at this meeting, with the first Curt Stern Award of this Society. Stern himself would have been pleased that, in a very real sense, their work is a successor to his own Manhattan District project to study genetic effects of radiation at low doses, testing for the possible effects of exposure to fallout from nuclear weapons (Stern Stern, 1974Stern C A geneticist’s journey.in: German J Chromosomes and cancer. John Wiley & Sons, New York1974: xiii-xxxvGoogle Scholar). What new areas of science and genetics will emerge as a result of our new awareness of terrorism? Perhaps we’ve seen a glimpse of this in only the past few weeks. Public and government attention to the threats of biological and chemical warfare—heightened this week with the discovery of several cases of anthrax infection in Florida and New York—may lead to increased efforts to understand how organisms respond to exposure to such agents. As one example, different strains of mice exhibit striking differences in susceptibility to lethal toxins, including anthrax. The recent identification of the gene responsible for differences between anthrax-susceptible and -resistant strains, by Bill Dietrich and his colleagues (Watters et al. Watters et al., 2001Watters JW Dewar K Lehoczky J Boyartchuk V Dietrich WF Kif1C, a kinesin-like motor protein, mediates mouse macrophage resistance to anthrax lethal factor.Curr Biol. 2001; 11: 1503-1511Abstract Full Text Full Text PDF PubMed Scopus (75) Google Scholar), received significant attention in the lay press, perhaps more than one might have anticipated prior to September 11. Are there similar variants in the human population that might be revealed in large-scale SNP association studies? Research on model organisms, one hopes, may provide us with new insight into the nature of the anthrax response, in order to develop newer, more effective vaccines. Or will we be asked to play a more practical role in preparing us for—or safeguarding us against—future terrorist attacks? After all, each of our genomic DNAs, with its unique collection of SNPs, may be the perfect informational substrate for possible national identification cards. Even today, as revealed in a recent survey (fig. 1), while many Americans are willing to consider national ID cards, a full 50% of the American public is unwilling to have DNA information stored on such cards. This may reflect general ignorance about DNA uniqueness and what it means or, perhaps, less specific concern about privacy issues. Clearly, there is a role our Society could play, both in developing the technology and databases necessary for such ID cards and in educating and reassuring the public about the uses of genetic information. Another, more somber possibility: there may be a need for more efficient, high-throughput methods of DNA genotyping to match and identify personal remains. Our Society is already engaged in discussions with the Institute of Justice, a scientific group within the U.S. Department of Justice that is collaborating with the New York State Forensics Laboratory to develop a plan to identify personal remains in the aftermath of September 11. Many members of our Society are highly qualified and, one hopes, will be willing to contribute their expertise to this effort. These shifting priorities and the challenges of getting about business as usual aside, let me particularly welcome and acknowledge those of you who have traveled from overseas to join us at this meeting and who, no doubt, like those who traveled to the Genetics Congress in 1939, had to think hard about whether you would be able to attend this meeting at all. This week, we will hear presentations from all over the world. It may surprise many of you to know that less than three-quarters of the presentations here will be made by those from the Americas. We will hear from scientists from England, France, Germany, Japan, Italy, Finland, Belgium, Spain, the Netherlands, Sweden, China, Australia, Denmark, Austria, Switzerland, Scotland, Israel, Iceland, and Jamaica. We’re delighted to have you all with us. This annual meeting of the American Society of Human Genetics, then, is in a very real sense an international meeting of geneticists and is therefore a celebration of the unity of men and women of science from around the globe—scientists of different national origins, scientists of different personal beliefs, scientists of different religious backgrounds. Let the clearest and loudest message of this week be that, at a time when others would take away freedom of thought and action, more than 4,400 geneticists from over 20 countries came together to share new information and to speak their shared conviction that the open pursuit of knowledge is far more powerful than the fear of terror. It is a sad irony—but one worth remembering—that this is the year of one of our greatest achievements as human geneticists: the public release of the first draft sequence of the human genome (International Human Genome Sequencing Consortium International Human Genome Sequencing Consortium, 2001International Human Genome Sequencing Consortium Initial sequencing and analysis of the human genome.Nature. 2001; 409: 860-921Crossref PubMed Scopus (16384) Google Scholar, Venter et al. Venter et al., 2001Venter JC Adams MD Myers WE Li PW Mural RJ Sutton GG Smith HO et al.The sequence of the human genome.Science. 2001; 291: 1304-1351Crossref PubMed Scopus (9907) Google Scholar). This is a time when scientists, philosophers, media pundits, and politicians alike, from around the world, all celebrated the single most obvious fact to emerge from the human genome sequence: that our genetic similarities are much more profound than our differences. It is a sad irony that, in this same year, we are confronted with the starkest example yet seen in modern times that there is so much more to learn about at least some of the differences that mark humankind. This week, we must attempt to place the work of human genetics into a larger and broader perspective, one both scientific and social. Part of my title for this address alludes to the “storytellers,” those who—both in science and in the lay press—contribute so much and so well to our deeper understanding of the human condition. Throughout this address, I will refer to or quote directly from some of the “stories” that were influential in determining my own path in genetics or in shaping my outlook on what is important in science. I am reminded of the writings of E. O. Wilson, the Harvard entomologist and somewhat controversial social Darwinist. Some 20 years ago, he published a book, “On Human Nature,” concerning the biological and genetic basis for human behavior and the concept of altruistic genes that are chosen for benefiting society as a whole, not just the individual (Wilson Wilson, 1978Wilson EO On human nature. Harvard University Press, Cambridge1978Google Scholar). In this book, he wrote, “No species, ours included, possesses a general purpose beyond the imperatives created by its genetic history…. To chart our destiny means that we must shift from automatic control based on our biological properties to precise steering based on biological knowledge (pp 2–6).” Whether one agrees with the basic tenets that Wilson espouses or not, we are left with our belief that only greater knowledge and understanding of genetics and its contributions to the human condition will help us truly decipher the meaning and potential of the human genome and lead us to ways of better influencing health and the state of mankind. That, after all, is our basic tenet, as stated in the bylaws of this Society (American Society of Human Genetics Web site): • to encourage and integrate research, scholarship, and education in all areas of human genetics,• to bring into close contact investigators in the many general fields of research that involve human genetics, and• to encourage discourse on the applications of human genetics as they apply to society at large. So, who are we in human genetics and where are we going? As one of the most popular storytellers of all time said, “it was the best of times, it was the worst of times.” First, the “best.” There can hardly be a better time to be in genetics. We have seen dramatic advances over the past few decades in our understanding, at a molecular and genetic level, of the role of genes in disease and in our ability to dissect genetically complex pathways and phenomena that could hardly be appreciated by generations of scientists before us. We have explored, at great depth and with great sophistication, the inner workings of our cells, chromosomes, and genes, and yet retained enough innocence and enough ignorance to be pleasantly shocked to find that we have perhaps only a third as many genes as we thought we had! By following patterns of DNA polymorphisms in both our mitochondrial and nuclear genomes, we have learned much in the last two decades about the evolution of our species and the migrations and emergence of different human populations around the globe. We have seen the dramatic beginnings—but only the beginnings—of what one might call “translational genetics,” taking fundamental discoveries from the laboratory and applying them to new advances in medicine in the diagnosis, management, and treatment of disease. We have brought genetics to medicine, from before conception to the neonatal period and, increasingly, into adulthood. Even in the aftermath of a genetic tragedy in the death of a human research subject at the University of Pennsylvania, we have witnessed the very first demonstrations of clinical efficacy in gene therapy. And, finally, in the last year, we have seen the unveiling of the human genome and the telling of some of its secrets that shape our genome and its contribution to human biology and disease. We have dared to proclaim that we have seen the future, and it is us. The “best of times,” indeed. As a group—and even as individuals—we show astonishing breadth in human genetics. What other field can boast virtuosity over such a dynamic intellectual range? It is, of course, precisely this breadth that many of us find so attractive and compelling about our field. Human genetics offers the opportunity of both medicine and basic laboratory research. It remains the best of both worlds. The challenge, however, is to find effective bridges that connect basic science to medicine. Human genetics offers a better opportunity to do this effectively than most fields, but it is still an enormous, and largely unfulfilled, challenge. It is the breadth of our field that brings many of us to this meeting year after year, and it is the breadth of our field that provides the fodder for discovery in human genetics. This breadth marks us not only collectively, but marks even as individuals many of the best scientists and scholars in our field. Our breadth spans pure basic scientific inquiry into the formal genetics, as well as molecular genetics, of both Homo sapiens and a variety of versatile model organisms, disease-oriented and patient-oriented research into the basis for human disease, and translational and clinical research at the doorstep of medical practice. It is a tapestry wide enough to cover both the most fundamental advances in basic science and the most potentially meaningful applications in medicine. It is this breadth that invites and enriches the conceptual leaps that any field needs to make real progress. I refer not to progress of the sort as one travels down a well-marked path, with reasonably predicable outcomes and advances. Rather, it is the discovery of what I’ve called in my title “black boxes.” These are the totally unforeseen and unpredictable discoveries that come only from a willingness to wander—at least intellectually—well off the path in search of explanations for the unexplained; in search of broader implications for what may, at first, seem like an incidental observation; or in search of new tools needed to chip away at or peer into the black box of uncertainty that surrounds so much of genetics. It is these conceptual and technical leaps that not only open doors but point to the existence of doors where there were none. Let's look at some examples of what I mean. We could go back to Sir Archibald Garrod, the father of inborn errors of metabolism, who nearly 100 years ago first articulated the significance of those rare individuals whose, in his words, “alternative course of metabolism…must be looked upon as somewhat inferior to the ordinary plan” (Garrod Garrod, 1902Garrod AE The incidence of alkaptonuria: a study in chemical individuality.Lancet. 1902; 2: 1616-1620Abstract Scopus (419) Google Scholar). His notion of “chemical individuality” provided a conceptual understanding in humans—for the first time in any organism—of the metabolic and biochemical consequences of genetic deficiency in individual genes, a lasting concept with profound implications for both biology and medicine. Or we could look to Al Knudson's statistical evaluation of epidemiological data in the rare childhood tumor retinoblastoma and his careful articulation of the two-hit hypothesis of cancer that has served the fields of human genetics and cancer molecular biology so well for the past 30 years (Knudson Knudson, 1971Knudson AG Mutation and cancer: statistical study of retinoblastoma.Proc Natl Acad Sci USA. 1971; 68: 820-823Crossref PubMed Scopus (5176) Google Scholar). Or to the theoretical enunciation of the power of restriction fragment length polymorphisms and linkage maps by Botstein, Skolnick, White, and Davis, published in The American Journal of Human Genetics in 1980 (Botstein et al. Botstein et al., 1980Botstein D White RL Skolnick M Davis RW Construction of a genetic linkage map in man using restriction fragment length polymorphisms.Am J Hum Genet. 1980; 32: 314-331PubMed Google Scholar). Or the demonstration by Kan and Dozy of the practical value of such RFLPs for studying the evolution and diagnosis of sickle-cell anemia (Kan and Dozy Kan and Dozy, 1978Kan YW Dozy AM Polymorphism of DNA sequence adjacent to human β-globin structural gene: relationship to sickle mutation.Proc Natl Acad Sci USA. 1978; 75: 5631-5635Crossref PubMed Scopus (536) Google Scholar). This is a particularly good example to explore, because it not only underscores the dizzying speed of converting basic discovery in human genetics to clinical benefit but also proves the old maxim that chance favors the prepared or, in this case, the broadly educated mind. First recognizing and then cracking this particular black box required mindful physician-scientists, driven by a clinical need and aware of the theoretical value of polymorphisms in prenatal diagnosis. This concept wasn’t new; after all, it was proposed initially by Haldane in the context of protein polymorphisms (Haldane and Smith Haldane and Smith, 1947Haldane JB Smith CAB A new estimate of the linkage between the genes for colour blindness and hemophilia in man.Ann Eugen. 1947; 14: 10-31Crossref PubMed Google Scholar). But it took another 30 years to develop the theory more formally and generally in the context of DNA polymorphisms, building upon the discovery of human DNA polymorphisms in 1978 by two groups. One was the chance observation of a single nucleotide difference between independent genomic clones by Lawn and Maniatis when they first cloned the human β-globin gene (Lawn et al. Lawn et al., 1978Lawn RM Fritsch EF Parker RC Blake G Maniatis T The isolation and characterization of linked δ and β-globin genes from a cloned library of human DNA.Cell. 1978; 15: 1157-1174Abstract Full Text PDF PubMed Scopus (594) Google Scholar); little was made of this observation or of its potential human genetic implications. The second discovery, however, was Kan and Dozy's careful elucidation in the same year of a different RFLP downstream of the sickle-cell mutation (Kan and Dozy Kan and Dozy, 1978Kan YW Dozy AM Polymorphism of DNA sequence adjacent to human β-globin structural gene: relationship to sickle mutation.Proc Natl Acad Sci USA. 1978; 75: 5631-5635Crossref PubMed Scopus (536) Google Scholar). This paper was a model of prescient thinking and provided a clear outline for much of molecular genetic analysis in our field during the 1980’s. It took the breadth of the field—encompassing medicine, formal genetics, and molecular genetics—to capture the true significance and promise of this particular conceptual breakthrough. For those of you students whose eyes are rolling up because you’ve never heard of some of these people and can’t believe I’m prattling on about events way back in the 1970s (much less the 1940s), let me assure you that there are more-recent examples too. There was Sir Alec Jeffreys, who discovered, in 1985, the existence of highly polymorphic minisatellite DNA loci in the human genome and gave birth to an entire new industry based on DNA fingerprinting (Jeffreys et al. Jeffreys et al., 1985Jeffreys AJ Wilson V Thein SL Hypervariable “minisatellite” regions in human DNA.Nature. 1985; 314: 67-73Crossref PubMed Scopus (2609) Google Scholar). There are any number of clinical geneticists who demonstrate repeatedly the value of the rare, and sometimes unique, patient for illuminating black boxes. One of my favorite examples of this involves Bonnie Pagon and Uta Francke (ASHG president in 1999), who understood implicitly the significance of an unusual patient, B.B., who presented with four normally distinct X-linked diseases simultaneously (Francke et al. Francke et al., 1985Francke U Ochs HD de Martinville B Giacalone J Lindgren V Disteche C Pagon RA et al.Minor Xp21 chromosome deletion in a male associated with expression of Duchenne muscular dystrophy, chronic granulomatous disease, retinitis pigmentosa, and McLeod syndrome.Am J Hum Genet. 1985; 37: 250-267PubMed Google Scholar). It was this patient's deleted X chromosome and DNA that led to the elucidation and eventual positional cloning of genes for all four of these disorders (chronic granulomatous disease, retinitis pigmentosum, McLeod syndrome, and Duchenne muscular dystrophy). There were the cytogenetics and clinical genetics communities, starting with David Ledbetter, whose careful persistence to follow-up on chromosome 15s that looked just a little bit shorter under the microscope revealed the cytogenetically tiny deletion that marks Prader-Willi syndrome. It was this finding, followed by Merlin Butler's insight that virtually all of the deletions were paternally derived, that laid the groundwork for the eventual documentation by Rob Nicholls of imprinting as a black box concept in human genetics (Nicholls et al. Nicholls et al., 1989Nicholls RD Knoll JHM Butler MG Karam S Lalande M Genetic imprinting suggested by maternal heterodisomy in non-deletion Prader-Willi syndrome.Nature. 1989; 342: 281-285Crossref PubMed Scopus (600) Google Scholar). There was Art Beaudet (ASHG president in 1998), who recognized an unusual female patient with cystic fibrosis whose father appeared not to be a carrier. Rather than assume nonpaternity, which, no doubt, many would have done, his group demonstrated that the girl had inherited two full copies of her mother's chromosome 7 and no copies of her father's chromosome 7 (Spence et al. Spence et al., 1988Spence JE Perciaccante RG Greig GM Willard HF Ledbetter DH Hejtmancik JF Pollack MS O’Brien WE Beaudet AL Uniparental disomy as a mechanism for human genetic disease.Am J Hum Genet. 1988; 42: 217-226PubMed Google Scholar). This was the first fully documented case of uniparental disomy in humans—a black box, at the time, if ever there was one! There was Haig Kazazian, whose discovery of an L1 repeat element inserted into the factor VIII gene in two cases of hemophilia A (Kazazian et al. Kazazian et al., 1988Kazazian HH Wong C Youssoufian H Scott AF Phillips DG Antonarakis SE Hemophilia A resulting from de novo insertion of L1 sequences represents a novel mechanism for mutation in man.Nature. 1988; 332: 164-166Crossref PubMed Scopus (593) Google Scholar) established the relevance of this class of repeats in medical genetics and uncovered the surprising degree of dynamic movement of L1 elements in our genome. There was Carolyn Brown, then a postdoctoral fellow in my lab, who persisted in trying to explain an observation that had no obvious explanation: an X-linked gene that seemed to be expressed only in females, not in males (Brown et al. Brown et al., 1991Brown CJ Ballabio A Rupert JL Lafreniere RG Grompe M Tonlorenzi R Willard HF A gene from the region of the human X inactivation centre is expressed exclusively from the inactive X chromosome.Nature. 1991; 349: 38-44Crossref PubMed Scopus (1074) Google Scholar). Her persistence (very much in the face of my initial skepticism, I must confess) led to the description of the XIST gene, now known to play a pivotal role in X chromosome inactivation. And, as a final example, there was Stephanie Sherman—also still a trainee at the time—who outlined what became widely known as the “Sherman paradox” (the observation that the penetrance of fragile X mental retardation differed in different carriers within the same pedigree and appeared to depend on one's position in the pedigree [Sherman et al. Sherman et al., 1985Sherman SL Jacobs PA Morton NE Froster-Iskenius U Howard-Peebles PN Nielsen KB Partington MW Sutherland GR Turner G Watson M Further segregation analysis of the fragile X syndrome with special reference to transmitting males.Hum Genet. 1985; 69: 289-299Crossref PubMed Scopus (305) Google Scholar]). This concept, derived (it should be stressed) only from formal genetic considerations, defied explanation until the gene was cloned a few years later and one of the most famous of the black boxes to emerge from human genetics was uncovered—namely, trinucleotide repeat expansion. Who in the next generation of trainees, in this age of genomic reductionism—where everything, it seems, has to have an explanation embedded in our genome sequence—who will propose the next new genetic concept with no obvious precedent or molecular explanation? What marks each of these discoveries is the imagination and intellectual courage that it takes to stray off the path and look for black boxes. Real progress—in this or any field—requires that we don’t just walk through open doors; we must be open to the possibility that there are doors we haven’t even seen yet and be open to the data that first hint at the existence of those doors. I like black boxes, because they challenge one's thinking to the extreme and invite us to muse about what mind-boggling, possibly crazy, probably even wrong in detail, explanations could conceivably explain the data. I like black boxes, because you can draw sometimes wildly speculative models, and no one can look up the answer in the back of the book and tell you are wrong. No one can look to other systems or precedents and tell you that you must be crazy. You might be crazy, of course, but, then again, you just might be right. My delight with black boxes probably shouldn’t come as a surprise. After all, I’ve spent much of the last 20 years ignoring proteins and instead chasing after repetitive, so-called “junk” DNA and noncoding transcripts in our genome. Those were—and to a large extent still are—black boxes. The early decades of human genetics were full of such musings. After all, today's younger scientists might hasten to point out, there wasn’t much else to do! There were no cloned genes and databases of genome sequence. There weren’t transgenic mice or yeast models to test critical predictions of hypotheses. There weren’t fancy confocal microscopes or deconvolution software to provide high-resolution images in three dimensions or in living cells. Without a catalogue of enzymes and genes, one had the freedom to infer the existence of new activities and the role they might play in metabolism or development. Often, of course, as I’ve just illustrated, such insights came from a collection of patients or even that one unique patient whose phenotype begged for an explanation. Absent complete data, one had to rely on one's cunning and, well, just plain thinking, to milk all that one could out of limiting amounts of clinical or laboratory data. How different the challenge is now, when we are, at times, inundated with mountains of data, and the task is to sort through them to find the most cogent and the most meaningful. It takes great intellectual discipline to put your pipette down and just think about the data. The best and most impactful scientists do this regularly. In those premolecular and pregenome years in human genetics, there were often just the hypotheses. Some of them were truly creative and mind-stretching exercises, free from the confining scaffold of well-understood molecular, cellular, and genomic principles that now enlighten us all but tend to constrict our freedom of movement intellectually. In the 1960s and 1970s especially, the literature was full of wonderful genetic models to explain how things might work. They greatly advanced our thinking and prepared the field to accept the notion of a totally novel and unanticipated mechanism once the data were advanced enough to demonstrate it convincingly. Many of the black boxes that I’ve discussed are now well known (and, in some cases, even well understood), and it may be difficult for some trainees in the audience to consider a day when these concepts were not a fully established part of human genetics. It is a sign of their significance, however, that each of these formerly-black boxes is now so firmly rooted in our field. These discoveries, and so many others like them, opened new doors where there were none before and where there is now an open passage for exploration and further discovery. The impact of such discoveries goes well
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