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Human Genome Project: History and Assessment
Human Genome Project: History and Assessment Hub Zwart, Radboud University of Nijmegen, Nijmegen, The Netherlands Ó 2015 Elsevier Ltd. All rights reserved.
Abstract The Human Genome Project (HGP) has been hailed as an important milestone in the history of science, in the history of humanity even, and as a project whose completion would not only transform the practice of medicine, but change forever the course of human history as well. By setting up a flanking program devoted to anticipating and addressing the ethical, legal, and social implications of genomics, the HGP has had a substantial influence on the social sciences and humanities fields involved in studying contemporary science as well. In this article, the HGP is first of all placed in a historical perspective (as a key chapter in the history of the life sciences as such). As to the history of the HGP proper (1990–2003), three stages are distinguished. Finally, the author assesses what the impact of the HGP has been, both for the life sciences as such and for the society in a broader sense. Although biomedical benefits (in the form of new treatments, etc.) have been sparse (in comparison to the stellar expectations of the early years), the HGP did change the way we think about ourselves and our own history: Its ‘cultural’ relevance has been quite significant.
Introduction The Human Genome Project (HGP) has been hailed as an important milestone in the history of science, in the history of humanity even, and as a project whose completion would not only ‘transform the practice of medicine’ but ‘change forever the course of human history’ (Davies, 2001/2002, p. xiii). It was argued that, due to the HGP, the ‘childhood of the human race is about to come to an end’ (Davies, 2001/2002, p. 10). It is biology’s version of the Manhattan Project, or, as its Director Francis Collins phrased it in 1993, the HGP is ‘more important than putting a man on the moon or splitting the atom’ (Davies, 2001/2002, p. 69). From a history of biology perspective, the HGP (whose imminent completion was announced at a Press Conference in June 2000) has been described as the completion of the ‘century of the gene’ (Fox-Keller, 2000) that began with the rediscovery of the work of Gregor Mendel in the spring of 1900, while the complete sequence became available in 2003, exactly 50 years after the discovery of the structure of DNA by James Watson and Francis Crick. Many have argued that the HGP represents a ‘paradigm shift’ in biology (Gilbert, 1991), dramatically changing the manner in which biomedical research is done (Collins, 1999). ‘Gene hunting’ gave way to a much more systematic and data-driven approach. (‘Data driven’ describes a form of research that, rather than relying on the conscious designing of experiments to test hypotheses, relies on amassing large amounts of data that can be systematically analysed, browsed, and trawled with the help of computer programs looking for patterns and associations.) Enormous amounts of sequencing data were assembled in large-scale databases, allowing for a more comprehensive analysis of living systems. Besides a series of high-impact papers in top journals such as Nature and Science (notably International Human Genome Sequencing Consortium IHGSC, 2001, 2004; Venter et al., 2001), the project has unleashed a cascade of publications of breath-taking proportions, covering various genres (research articles, books, comments, interviews, etc.), not only in the life sciences, but also in the social sciences and the
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humanities. In this article, this quickly expanding library of HGP discourse can only be analysed in brief outline. It will consist of three parts. The central part entails a concise history of the HGP in which three stages will be distinguished. Yet, as the HGP can only be properly understood against the backdrop of previous developments that evolved in the course of the twentieth century, the history of the HGP proper will be preceded by a brief ‘prehistory’ in which the main events that lead to the launching of the HGP are outlined. The third and final part will be devoted to assessing the meaning and significance of the HGP in retrospect. How do we assess its importance, both for the life sciences as such and for society at large? Seen from this perspective, the HGP no longer functions as an end point (i.e., the completion of century of the gene), but rather as a point of departure (for next generation genomics and other postgenomics developments such as systems biology and synthetic biology).
Prehistory: The Century of the Gene Michel Foucault’s inaugural lecture as Professor of the History of Systems of Thought at the Collège de France (Foucault, 1971) contains a brief but interesting reflection on Gregor Mendel. How could it be, Foucault asks his audience, that Mendel’s work, his ‘truth,’ was more or less completely ignored by the biologists of his time? For Foucault, Mendel was a kind of ‘monster’ (p. 37), someone who, in 1865, spoke of objects and relied on methods that were completely alien to the biology of his era. In short, Foucault casts him as someone who lived and worked outside established networks, outside official academic discourse: A lost voice who spoke too soon. A key aspect of Mendel’s untimely approach (of his ‘epistemic mutation’) consisted in the use of a small alphabet of symbols (Aa, Bb, Cc, etc.) to refer to pairs of (dominant or recessive) ‘factors,’ as he called them (1866/1913), that could be either present or absent in his model organism, the garden pea. What was so rigorously new, according to Foucault, was that Mendel spoke about these factors as autonomous units,
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independent of biological categories such as species or sex, as objects of study in their own right. All the rest, everything pertaining to the garden pea as a living organism, was filtered out as it were. For Mendel, Pisum sativum was simply a handy research tool for studying what later would come to be called ‘genes.’ From 1900 onward, this way of looking at the phenomena of life (studying genes with the help of a select number of model organisms that basically functioned as research contrivances, as items in the scientific tool box) came into vogue, and genetics became a core discipline of biology. In recent decades, this picture of Mendel as a garden monk living in extreme isolation has been revised. There were kindred minds to be found among his contemporaries, who were working and thinking along similar lines. One of them was Francis Galton who, like Mendel, used statistics to study life (Müller-Wille and Rheinberger, 2012). In order to articulate his views on heredity, Galton employed an interesting metaphor: Ova and their contents are, to biologists looking at them through microscopes, much what mail-bags and the heaps of letters poured out of them are to those who gaze through the glass windows of a post office . they cannot read a single word of what the letters contain (1875, p. 82).
What Mendel and Galton had in common was the intuition that the basic units of life could be represented as letters of an alphabet. Whenever biologists peered into the nucleus of an ovum through their microscope, they witnessed a process that was comparable to the processing of piles of documents containing characters, but due to the low resolution power of the instruments at their disposal, these documents were as yet unreadable for the scientists of life. Nonetheless, they were written in an alphabet (of a Mendel-like nature) and transferred as it were by ancestors to their descendants (Galton’s ovum as a kind of transgenerational communication establishment). In fact, in ancient Greek, the term ‘elements’ (stoicheia) means building blocks and may therefore refer not only to atoms as the building blocks of matter, or to Euclid’s building blocks of elementary geometrical knowledge, but also to letters of the alphabet. One could argue that genomics (the sequencing of genomes, the entirety of an organism’s hereditary information, with the help of automated high-throughput sequencing machines) from the very beginning has built on this metaphor. It constitutes an effort to dive deeper into the nuclei of cells, in order to decipher, scan and process these formerly unreadable letters, with the help of the high resolution provided by sophisticated automated sequencing technologies. Thus, the ‘century of the gene’ (Fox-Keller, 2000), which began with the rediscovery of Mendel’s effort to talk about life in terms of a small alphabet of symbols, came to a conclusion with the famous Press Conference of 26 June 2000 when Bill Clinton, Francis Collins, and Craig Venter proudly announced that the HGP was galloping toward completion, producing spates of letters: the human genome sequence, written in the A, C, G, T alphabets the ‘code of life.’ (ACGT stands for the four nucleic acid bases that make up an organism’s DNA. The ‘A’ stands for adenine, the ‘T’ for thymine, the ‘C’ for cytosine, and the
‘G’ for guanine. These four nucleic acids are the ‘letters’ of the genetic code.) The story of what happened between these two poles of the human genome narrative (i.e., the rediscovery of Mendel in the spring of 1900 and the public announcement of the upcoming completion of the human genome sequence in June 2000) is a complex one. Only a few of the major events can be highlighted here. In the 1930s and 1940s, to begin with, an important transformation took place in the landscape of science. The center of gravity shifted from Central Europe (Vienna, Berlin, and Zürich) to the United Kingdom and the United States, while the academic lingua franca shifted from German to English, and the frontier of the scientific revolution shifted from quantum physics to the molecular life sciences. This transformation was exemplified by two physicists who migrated not only from the German- to the English-speaking world, but also from quantum physics to biology. One of them was Nobel laureate Erwin Schrödinger who, in 1944, gave a series of lectures in Dublin entitled What is life? In these lectures, he voiced the idea that the ‘genom’ (as he spelled it) was basically an ‘aperiodic crystal’ containing a code comparable to the Morse code. Now that physicists had discovered the elementary building blocks of energy and matter, time had come to use the tested methods and powerful tools of physics (such as crystallography) to unravel the elementary building blocks of life. At that time, however, Max Delbrück, although younger than Schrödinger, had already put to practice what the latter advocated. He went to Cambridge and later to Caltech in California where he opted for a virus (the bacteriophage) as his model organism. For Delbrück, genes were for biology what atoms had been for physics. And therefore, he began his new career as a biologist by looking for a ‘minimal’ organism that could somehow play the role that the hydrogen atom had played in quantum physics. This search for the ‘hydrogen atom of biology’ led to the bacteriophage (literally, the bacteria eater), a virus that attacks and destroys bacteria. He settled upon the phage as his model organism because he wanted to study a living entity that came as close as possible to being ‘the gene in itself’ (‘Das Gen an sich;’ Fischer, 1985, p. 98). Thus, Schrödinger and Delbrück played a pivotal role in the emergence of a new field: molecular biology. In fact, the three scientists who in 1962 were awarded the Nobel Prize for their discovery of the structure of DNA, namely, Francis Crick (a physicist), James Watson (a biologist), and Maurice Wilkins (a physicist), had all read (and confessed to be very much inspired by) Schrödinger’s lectures, which had been published as a book in 1946, while James Watson took Delbück’s course on bacteriophage research at Cold Spring Harbor. Thus, the discovery of the structure of DNA was more or less a direct result of the broader transformation described above: the massive migration of physicists to the new biology (cf Kay, 2000). Now that the structure of DNA had been revealed, the next big objective was to read and decipher the ‘code’ embedded in it. After DNA (the double helix), the next big challenge was sequencing the whole genome (the collection of all the genes as well as the noncoding segments present in human DNA). In 1985, Robert Sinsheimer, President of the
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University of California, Santa Cruz, and Charles DeLisi from the Department of Energy, organized meetings to discuss the feasibility of sequencing the human genome. One of the first questions to be addressed was whether this would call for a large-scale, international, top–down programmatic effort (Big Science), or rather for a bottom– up, researcher-driven approach. Most participants in the debate tended toward the former and in the course of the 1980s, one of the most ambitious and controversial projects in the history of biology was designed. The final preparations coincided with the collapse of the Berlin Wall and the subsequent reunification of Germany and, to some extent, of Europe as a whole. Euphoria was in the air. On 9 November 1989, as citizens from East Berlin flooded into the Western parts of the divided city, Nature published an article on HGP scientists developing a joint database where they could deposit their sequencing materials, flanked by an article about societal issues to be addressed. The project was formally launched on 1 October 1990, with James Watson as its first Director. In 1992, Watson stepped down and was succeeded by Francis Collins while Craig Venter, partly because of his frustrations with the bureaucracy and the power structure of the official HGP, launched a nonprofit, privately funded human genome sequencing project of his own devise. He would establish The Institute of Genomics Research and later Celera Corporation to achieve this goal.
The Human Genome Project: A Concise History The history of the HGP can roughly be divided into three stages (Zwart, 2008). The first stage (1988–92) was a period of development and implementation, beginning with the appointment of James Watson at the National Institutes of Health (NIH) in 1988 and ending with the latter’s resignation (on 10 April 1992). The highlight event was the official launch of the program on 1 October 1990. Simultaneously (also in 1990) a flanking project was launched to anticipate and address the ethical, legal, and social implications (ELSIs) of the sequencing effort, also funded by NIH. In fact, 3–5% of the budget was devoted to this type of research. Thus, NIH became the biggest sponsor of bioethical and other forms of ELSI research in the United States. The second stage (1993–98) set in with the appointment of Francis Collins (1993) as Watson’s successor. The HGP now really gained momentum. For the next few years, work on the HGP came to involve a relatively large number of research groups of varying sizes and sequence capacities. The human genome was divided into 23 natural subunits (the chromosomes) and research labs competed for funding in the context of the NIH peer-review system. By 1998, only 4% of the human genome had been sequenced in this manner. That same year, however, was a turning point in many ways: the onset of the third and final stage (1998–2001). First of all, former NIH scientist Craig Venter announced that his privately funded Celera Corporation, relying on the latest automated sequencing machines, in combination with his controversial whole-genome shotgun method, would sequence the human genome much faster than the public
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consortium envisioned (Shreeve, 2004; Venter, 2007). This announcement entailed a direct challenge to the public effort headed by Collins, which was now under the threat of becoming redundant (Cook-Deegan, 1994/1995). The latter responded by formulating a more focused strategy of action. From now on, the bulk of the work would be done by a limited number of big laboratories with massive sequence capacity, such as the Sanger Centre lead by John Sulston (Cambridge, UK) and the Whitehead Institute lead by Eric Lander (Cambridge, Massachusetts): a select number of key players that came to be known as the G-5. Moreover, it was decided that publication of a finished sequence would be preceded by a working draft version, again a departure from the original plan (Davies, 2001/2002, p. 162). Due to this reorientation, the HGP was suddenly transformed into a ‘noholds-barred race to claim the human blueprint.’ A dramatic competition ensued, eagerly covered by the media, until on 26 June 2000 the ‘race’ or ‘war’ was suddenly declared over, as both sides agreed they had passed the line more or less simultaneously. Collins and Venter cordially made their appearance at the famous press conference at the White House in order to announce, in the presence of President Clinton, that the endeavor to sequence the human genome was nearing its completion . Both teams sealed a truce by publishing working draft versions in a coordinated manner in February 2001, in Science and Nature, respectively (IHGSC, 2001; Venter et al., 2001), although the fighting between representatives of both ‘armies’ over who had actually won the race, or war, would continue in various settings until today. Notably, John Sulston continued to question the role of Celera in sequencing the human genome (Sulston and Ferry, 2002/2003). After 2001, there has been a considerable aftermath. As indicated, the 2001 publication contained a draft version, and the HGP was officially declared complete on 14 April 2003, although a ‘final’ final version of the finished sequence (with 99.99% accuracy) was published in 2004 (IHGSC, 2004), while further analyses and papers on the HGP continue to occur. The human sequence is now seen as the starting point for future research. This is also visible in the images used to elucidate its meaning (Zwart, 2010). During the Press Conference of June 2000, Collins compared the HGP to the expedition of Lewis and Clark, commissioned by President Thomas Jefferson in the beginning of the nineteenth century to map the western part of North America from the Mississippi to the Pacific. This resulted in a famous map (below, Figure 1) depicting a more or less empty landscape, with a focus on its physical features, such as rivers and mountains. A few years later, when presenting a vision for the future of genomics research (Collins et al., 2003), a different picture emerged (below, Figure 2). Rather than with an open landscape, one is now faced with buildings and emerging infrastructures. The genomics future is envisioned as a three-floor building designed in the style of Frank Lloyd Wright. The basic topology, as it were, has shifted. The landscape has become inhabited. “All the initial objectives of the HGP have now been achieved,” Collins et al. argue, “and a revolution in biological research has begun” (p. 835). It will now quickly spread from the basement to biology, health, and society.
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Figure 1
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The Lewis and Clark map. Source: http://memory.loc.gov/cgi-bin/query/r?ammem/gmd:@field(NUMBERþ@band(g4126sþct000763))
Figure 2 A vision for genomics. Source: Collins, Francis, Green, Eric D. Green, Guttmacher, Alan, Guyer, Mark S., [NHGRI], 2003. A vision for the future of genomics research, a blueprint for the genomics era. Nature 422, 835–847.
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Figure 3
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The 26 June 2000 Press Conference announcing the near completion of the HGP.
Meaning and Significance: Assessing the HGP One of the questions raised with regard to the HGP has been to what extent it can really be regarded as the advent of ‘Big Science’ in biology (Vermeulen, 2009). Both Watson and Collins on various occasions placed the HGP on an equal footing with other Big Science endeavors such as the Manhattan Project, the Apollo Program, and the European Organization for Nuclear Research (CERN). The HGP was regarded as ‘Big’ by many, first of all because of the size of the funding involved (three billion dollars as core funding) in combination with the international scale of the collaboration as well as the fact that the project was managed in a more or less centralized manner by Watson and subsequently Collins as its Director. Yet, Big Science in physics (where the concept first emerged) is typically organized around a centralized large-scale research facility, attracting hundreds of researchers (such as the Large Hadron Collider of CERN in Geneva), whereas HGP’s infrastructure remained much more distributed, while its basic technologies were not available from the outset, but were rather developed as the project evolved. Or, as Müller-Wille and Rheinberger phrase it in slightly Marxist terms, the HGP created not only a plethora of scientific products (data, papers, and the like), but also the means for their production (2012, p. 201). This may be seen as a purely ‘semantic’ question, but in the context of ongoing controversies and reflections as to what the HGP has been able to achieve, the issue proves quite relevant. Building on the widespread impression that in the end (in terms of benefits for society) the HGP did not quite live up to the stellar ambitions that were voiced in the 1990s, some may now question the viability of a Big Science approach in the life sciences domain as such, whereas others may argue that, in
view of the bewildering complexity of living systems, the HGP simply was not Big enough. This brings us to the second issue over which controversy is still raging: what has been the societal impact of the human sequence? Although it is beyond doubt that genomics has irreversibly changed the life sciences as a global research field, so far, concrete clinical benefits, for instance, in terms of treating cancer, have been sparse. During the 26 June 2000 Press Conference, great expectations were voiced in this respect. Clinton claimed that, because of the HGP, our children’s children will probably know the word cancer only as a constellation of stars. Yet, in many ways, the outcomes of the HGP were something of a disappointment. Let me go into this experience of disillusionment in somewhat more detail. The first major disappointment had to do with the number of genes on the human genome, namely, 22 500, which was an astonishingly low number compared to previous estimates that ranged from 100 000 up to 350 000 (Zwart, 2007). The human genome, moreover, appeared to be quite similar to the genomes of other species, such as the chimpanzee and the laboratory mouse. There is nothing special about our sequence. This in itself constitutes a nice example of what Sigmund Freud (1917/1947) has termed a narcissistic offense. According to Freud, all major scientific breakthroughs (and he mentions the discoveries of Copernicus and Darwin as paradigmatic examples) entail serious narcissistic offenses that challenge our basic views about ourselves. We tend to see ourselves as highly unique and central, but the truth as laid bare by science is that we are not. Yet, we are the only species on earth able and willing to think about our own evolution or about our place in the universe, and we are certainly the only species who has sequenced its own genome (or may come up with such an idea at all). An interesting paradox: food for philosophy indeed. Where does our uniqueness come from?
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As we cannot attribute it solely to our DNA, it must come from elsewhere. It must be closely interwoven with our cultural history, over and above our biological evolution. We must be, to a certain extent, manmade. We are not only the producers, but also the products of our technologies, cultures, and societies. It is precisely here that the HGP did have an impact. It has provided us with additional and valuable sources of information concerning early human history, notably by considering not only the human genome itself, but also the genome of others species (such as dogs, horses, rice, cereals, maize, etc.) as historical archives for bioarchaeological research (Zwart and Penders, 2011). In other words, the ‘cultural impact’ of genomics, by broadening our historical horizon, has been quite significant. Thus, the experience of disillusionment notably pertained to the biomedical results. While it is widely acknowledged the HGP did have an enormous impact on the way in which biological research is done, its medical applications so far have been quite limited. Although the HGP did succeed in transforming laboratory life, so far the consequences for health care, medicine, and human daily existence in general have been quite modest. This is also reflected in the societal debate triggered by the HGP. Initially, serious concerns were voiced, for instance, by Francis Fukuyama (2002) who believed that the essence of what we are is endangered by biotechnology now that the human sequence is about to be revealed. He postulated the existence of a set of typically ‘human’ genes, which he termed the Factor X, a genetic endowment that distinguished humankind in essence from other species and should be safeguarded from biotechnological interference. In France, novelist Michel Houellebecq devoted his successful novel Elementary Particles (1998) to a scientist who managed to develop an algorithm that allowed humankind to drastically ameliorate its genetic constitution, thereby altering the course of future history (an event on the scale of a ‘metaphysical mutation’). Yet, it soon became apparent that such scenarios are fairly unrealistic and that the Factor X is nowhere to be found. A related concern raised in the early days of the HGP was that of genetic discrimination: The idea that human genomics would lead to the emergence of a social underclass of carriers of ‘bad genes,’ as dramatized in the movie Gattaca (released in 1997), for example. Again, these apprehensions, grounded in rather deterministic understanding of the relationships between genes and traits, proved unwarranted. Life is too complex to be understood in such a linear and straightforward fashion. So far, the societal relevance of the HGP has been quite limited indeed. This is also reflected in ELSI research, where big concerns gradually gave way to much more everyday discussions. In 2010, the journal Nature published a retrospective. The basic question was has the proclaimed genomics revolution arrived? Collins (2010a) and Venter (2010) both contributed to the issue. Their answer and that of other contributors was, essentially, not yet. The most important outcome of the HGP resides in the acknowledgment that life is much more ‘complicated’ (Hayden, 2010) than was envisioned back in 1989, when Francis Collins wrote his very first e-mail and the HGP was about to be launched. This issue was taken up more elaborately by Francis Collins (2010b) (now Director of NIH) in his latest book The Language
of Life, written 10 years after the jubilant Press Conference of June 2000. Although he still sees the HGP as ‘one of the boldest scientific efforts that humankind has ever mounted’ (p. 299), he at the same time acknowledges that the enthusiasm that had peaked during the days of the June 2000 Press Conference has more or less evaporated: Nearly a decade has passed since that moment of celebration. Virtually all biomedical researchers would agree that their approach to understanding how life works has been profoundly and irreversibly affected by access to the complete DNA sequence of the human genome . But the effect on the public of all the hoopla in 2000 has been mixed. Most people know that the genome has been spelled out, but they have lost track of what has happened since then. They remember the ascent of the mountain, but they are unaware of the rewards that are starting to appear in the valley. (p. 3)
The revolution is still raging, that is the basic message of his latest book; it is ongoing and societies better prepare themselves for a massive disruptive change, but this will not come through the sequencing of the human genome as such, but rather though its subsequent stage: The era of next-generation sequencing and the $1000 genome (Davies, 2010) and, as a consequence of that, the advent of personal genomics and personalized medicine: Healthy individuals are increasingly able to discover some of their body’s inner secrets and take appropriate action. The potential for individual prediction is beginning to spill out to the general public, offering the opportunity to take more control of your fate . None of this is happening overnight, [but] without question, man’s knowledge of man is undergoing the greatest revolution since Leonardo. (p. 5)
But still, up to this point at least, the transformations brought about by next-generation sequencing are limited. In comparison to the dramatic debates of previous decades, current deliberations focus much more on everyday and perhaps even trivial examples, such as the credibility of providers of personalized genome tests such as 23andMe. One way of seeing this is to argue that, apparently, supporters of the HGP consciously created a hype in the 1990s, by willfully exaggerating its societal potential. Subsequently, after publication of the human sequence in 2001, they shifted the argument saying that life proved to be much more complex than was expected at the beginning, so that much more research (i.e., much more funding) will be needed to harvest the potential benefits. Another, less cynical, but in my view more credible, way of looking at it is by arguing that a project of the size of HGP is likely to go through a series of stages. From this perspective, Watson and Crick represent the era of childhood and playfulness, building models with toylike components without much regard for formalities, such as research projects or management structures. Subsequently, during the period of latency (the 1970s and 1980s), the focus shifted toward the development of basic tools and skills (such as the Sanger sequencing method) in preparation for a distant and still fairly abstract future. The HGP itself, then, represents the adolescence stage: the era of great expectations and fierce collisions. Finally, at present, human genome sequencing has entered the stage of adulthood and normal science. Genomics
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has become embedded in the life sciences and as such, has acquired a certain level of normalcy, so that its implications for human existence are less dramatic, more everyday, perhaps even trivial, and its promises more realistic. As was already indicated above, a significant impact of the HGP resides in its cultural relevance: The way we see ourselves and think about ourselves as humankind. First of all, genomics provides us with new sources of information, allowing us to revisit early human history in a detailed fashion, from the days of human migration out of Africa up to the emergence and spread of agriculture in the context of the so-called Neolithic revolution. Subsequently, it is clear that the HGP has prepared the ground for, and will gradually be eclipsed by, so-called postgenomic developments, such as personalized genomics (or next-generation sequencing) already mentioned above. In the early days of the HGP, the human sequence was often presented as the ‘blueprint’ of human existence or even as ‘the near-complete instructions for how to build and run a human body,’ downloadable from the Internet (Ridley, 1999, p. 1). Paradoxically, the project that started off as an exemplification of a genetic deterministic mind-set eventually undermined the credibility of precisely the genetic reductionist view of life by revealing the astonishing complexity of living systems. For example, it paved the way for the emergence of epigenetics: the awareness that the vicissitudes of an organism (nurture) may result in modifications of its genome (notably on the level of gene expression), which can be passed on to the future generations. This goes against the long-standing dogma that acquired features cannot be inherited. Another development is the shift from ‘reading’ (i.e., sequencing) DNA to ‘rewriting’ DNA on the molecular level, that is synthetic biology: the intermediary zone between genomics and nanoscience. Similar realignments can be discerned elsewhere, for instance, between genomics and brain research (cognomics). Thus, the HGP has definitely strengthened the trend, already characteristic of contemporary technoscience as such, toward the emergence of a plethora of transdisciplinary research conglomerates (molecular biology, bioinformatics, genomics, synthetic biology, epigenetics, cognomics, etc.) by which genomics itself is bound to be engulfed sooner or later.
See also: Biobanking: Ethical Issues; Bioethics in the Postgenomic Era; Bioethics: Genetics and Genomics; Direct-toConsumer Personal Genetic Testing; Ethical, Legal, and Social Implications Program at the National Human Genome Research Institute; Genetics and Society; Genetics and the Media; Genetics: The New Genetics; Genographic Project; Genomics, Ethical Issues In; Human Evolutionary Genetics; Human Genome Diversity Project: History.
Collins, Francis, 1 April 2010a. Has the revolution arrived? Nature 464, 674–675. Collins, F., 2010b. The Language of Life. DNA and the Revolution in Personalised Medicine. Harper, New York. Cook-Deegan, Robert, 1994/1995. The Gene Wars. Science, Politics and the Human Genome. Norton, New York/London. Davies, Kevin, 2001/2002. Cracking the Genome. Inside the Race to Unlock Human DNA. John Hopkins University Press, Baltimore and London. Davies, Kevin, 2010. The $1,000 Genome: The Revolution in DNA Sequencing and the New Era of Personalized Medicine. Free Press. Fischer, Peter, 1985. Licht und Leben. Ein Bericht über Max Delbrück, den Wegbereiter der Molekularbiologie. Universitätsverlag Konstanz, Konstanz. Foucault, Michel, 1971. L’ordre du discours. Gallimard, Paris. Fox-Keller, Evelyn, 2000. The Century of the Gene. Harvard University Press, Cambridge, Mass. Freud, Sigmund, 1917/1947. Eine Schwierigkeit der Psychoanalyse. In: Gesammelte Werke, XII. Imago, London. 3–12. Fukuyama, Francis, 2002. Our Posthuman Future. Consequences of the Biotechnology Revolution. Farrar, Straus & Giroux. Galton, Francis, 1875. A theory of heredity. Contemporary Review 27, 80–95. Gilbert, Walter, 1991. Towards a paradigm shift in biology. Nature 349, p. 99. Hayden, Erika, 1 April 2010. Human genome at ten: life is complicated. Nature 464, 664–667. IHGSC, 2004. Finishing the euchromatic sequence of the human genome. Nature 431, 931–945. International Human Genome Sequencing Consortium [IHGSC], 15 February 2001. Initial sequencing and analysis of the human genome. Nature 405, 860–921. Kay, Lily, 2000. Who Wrote the Book of Life? A History of the Genetic Code. Stanford University Press, Stanford. Mendel, Gregor, 1866/1913. Versuche über Pflanzenhybriden. In: Mendel, G. (Ed.), Versuche über Pflanzenhybriden: zwei Abhandlungen Hrsg. E. von Tschermak. Ostwald’s Klassiker der exakten Wissenschaften 121. Engelmann, Leipzig, pp. 3–46. Müller-Wille, Staffan, Rheinberger, Hans-Jörg, 2012. A Cultural History of Heredity. The University of Chicago Press, Chicago and London. Ridley, Matt, 1999. Genome. The Autobiography of a Species in 23 Chapters. Harper, New York, etc. Schrödinger, Erwin, 1944/1967. What Is Life? The Physical Aspect of the Living Cell/ Mind and Matter. Cambridge University Press, London. Shreeve, James, 2004. The Genome War. How Craig Venter Tries to Capture the Code of Life and Save the World. Knopf, New York. Sulston, John, Ferry, Georgina, 2002/2003. The Common Thread. Science, Politics, Ethics and the Human Genome. Bantam/Corgi. Venter, J. Craig, et al., 16 February 2001. The sequence of the human genome. Science 291 (5507), 1304–1351. Venter, J. Craig, 2007. A Life Decoded. My Genome: My Life. Viking/The Penguin Group, New York. Venter, J. Craig, 1 April 2010. Multiple personal genomes await. Nature 464, 676–677. Vermeulen, Niki, 2009. Supersizing Science; On Building Large-scale Research Projects in Biology. Maastricht University Press, Maastricht. Zwart, Hub, 2007. Genomics and self-knowledge. new genetics and society. New Genetics and Society 26 (2), 181–202. Zwart, Hub, 2008. Understanding the Human Genome Project: a biographical approach. New Genetics and Society 27 (4), 353–376. Zwart, Hub, 2010. The adoration of a map. Reflections on a genome metaphor. Genomics, Society and Policy 5 (3), 29–43. Zwart, Hub, Penders, Bart, 2011. Genomics and the Ark. An ecocentric perspective on human history. Perspectives in Biology and Medicine 54 (2), 217–231.
Relevant Websites Bibliography Collins, F., 1999. Medical and societal consequences of the Human Genome Project. New England Journal of Medicine 341, 28–37. Collins, Francis, Green, Green, Eric D, Guttmacher, Alan, Guyer, Mark S, [NHGRI], 2003. A vision for the future of genomics research, a blueprint for the genomics era. Nature 422, 835–847.
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http://en.wikipedia.org/wiki/Human_Genome_Project – HGP. http://www.nih.gov/ – NIH. http://www.genome.gov/ELSI/ – ELSI. http://www.genome.gov/ – NHGRI. http://www.sanger.ac.uk/about/history/hgp/ – Sanger Institute. http://en.wikipedia.org/wiki/J._Craig_Venter_Institute – J. Craig Venter Institute.
Abstract The Human Genome Project (HGP) has been hailed as an important milestone in the history of science, in the history of humanity even, and as a project whose completion would not only transform the practice of medicine, but change forever the course of human history as well. By setting up a flanking program devoted to anticipating and addressing the ethical, legal, and social implications of genomics, the HGP has had a substantial influence on the social sciences and humanities fields involved in studying contemporary science as well. In this article, the HGP is first of all placed in a historical perspective (as a key chapter in the history of the life sciences as such). As to the history of the HGP proper (1990–2003), three stages are distinguished. Finally, the author assesses what the impact of the HGP has been, both for the life sciences as such and for the society in a broader sense. Although biomedical benefits (in the form of new treatments, etc.) have been sparse (in comparison to the stellar expectations of the early years), the HGP did change the way we think about ourselves and our own history: Its ‘cultural’ relevance has been quite significant.
Introduction The Human Genome Project (HGP) has been hailed as an important milestone in the history of science, in the history of humanity even, and as a project whose completion would not only ‘transform the practice of medicine’ but ‘change forever the course of human history’ (Davies, 2001/2002, p. xiii). It was argued that, due to the HGP, the ‘childhood of the human race is about to come to an end’ (Davies, 2001/2002, p. 10). It is biology’s version of the Manhattan Project, or, as its Director Francis Collins phrased it in 1993, the HGP is ‘more important than putting a man on the moon or splitting the atom’ (Davies, 2001/2002, p. 69). From a history of biology perspective, the HGP (whose imminent completion was announced at a Press Conference in June 2000) has been described as the completion of the ‘century of the gene’ (Fox-Keller, 2000) that began with the rediscovery of the work of Gregor Mendel in the spring of 1900, while the complete sequence became available in 2003, exactly 50 years after the discovery of the structure of DNA by James Watson and Francis Crick. Many have argued that the HGP represents a ‘paradigm shift’ in biology (Gilbert, 1991), dramatically changing the manner in which biomedical research is done (Collins, 1999). ‘Gene hunting’ gave way to a much more systematic and data-driven approach. (‘Data driven’ describes a form of research that, rather than relying on the conscious designing of experiments to test hypotheses, relies on amassing large amounts of data that can be systematically analysed, browsed, and trawled with the help of computer programs looking for patterns and associations.) Enormous amounts of sequencing data were assembled in large-scale databases, allowing for a more comprehensive analysis of living systems. Besides a series of high-impact papers in top journals such as Nature and Science (notably International Human Genome Sequencing Consortium IHGSC, 2001, 2004; Venter et al., 2001), the project has unleashed a cascade of publications of breath-taking proportions, covering various genres (research articles, books, comments, interviews, etc.), not only in the life sciences, but also in the social sciences and the
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humanities. In this article, this quickly expanding library of HGP discourse can only be analysed in brief outline. It will consist of three parts. The central part entails a concise history of the HGP in which three stages will be distinguished. Yet, as the HGP can only be properly understood against the backdrop of previous developments that evolved in the course of the twentieth century, the history of the HGP proper will be preceded by a brief ‘prehistory’ in which the main events that lead to the launching of the HGP are outlined. The third and final part will be devoted to assessing the meaning and significance of the HGP in retrospect. How do we assess its importance, both for the life sciences as such and for society at large? Seen from this perspective, the HGP no longer functions as an end point (i.e., the completion of century of the gene), but rather as a point of departure (for next generation genomics and other postgenomics developments such as systems biology and synthetic biology).
Prehistory: The Century of the Gene Michel Foucault’s inaugural lecture as Professor of the History of Systems of Thought at the Collège de France (Foucault, 1971) contains a brief but interesting reflection on Gregor Mendel. How could it be, Foucault asks his audience, that Mendel’s work, his ‘truth,’ was more or less completely ignored by the biologists of his time? For Foucault, Mendel was a kind of ‘monster’ (p. 37), someone who, in 1865, spoke of objects and relied on methods that were completely alien to the biology of his era. In short, Foucault casts him as someone who lived and worked outside established networks, outside official academic discourse: A lost voice who spoke too soon. A key aspect of Mendel’s untimely approach (of his ‘epistemic mutation’) consisted in the use of a small alphabet of symbols (Aa, Bb, Cc, etc.) to refer to pairs of (dominant or recessive) ‘factors,’ as he called them (1866/1913), that could be either present or absent in his model organism, the garden pea. What was so rigorously new, according to Foucault, was that Mendel spoke about these factors as autonomous units,
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independent of biological categories such as species or sex, as objects of study in their own right. All the rest, everything pertaining to the garden pea as a living organism, was filtered out as it were. For Mendel, Pisum sativum was simply a handy research tool for studying what later would come to be called ‘genes.’ From 1900 onward, this way of looking at the phenomena of life (studying genes with the help of a select number of model organisms that basically functioned as research contrivances, as items in the scientific tool box) came into vogue, and genetics became a core discipline of biology. In recent decades, this picture of Mendel as a garden monk living in extreme isolation has been revised. There were kindred minds to be found among his contemporaries, who were working and thinking along similar lines. One of them was Francis Galton who, like Mendel, used statistics to study life (Müller-Wille and Rheinberger, 2012). In order to articulate his views on heredity, Galton employed an interesting metaphor: Ova and their contents are, to biologists looking at them through microscopes, much what mail-bags and the heaps of letters poured out of them are to those who gaze through the glass windows of a post office . they cannot read a single word of what the letters contain (1875, p. 82).
What Mendel and Galton had in common was the intuition that the basic units of life could be represented as letters of an alphabet. Whenever biologists peered into the nucleus of an ovum through their microscope, they witnessed a process that was comparable to the processing of piles of documents containing characters, but due to the low resolution power of the instruments at their disposal, these documents were as yet unreadable for the scientists of life. Nonetheless, they were written in an alphabet (of a Mendel-like nature) and transferred as it were by ancestors to their descendants (Galton’s ovum as a kind of transgenerational communication establishment). In fact, in ancient Greek, the term ‘elements’ (stoicheia) means building blocks and may therefore refer not only to atoms as the building blocks of matter, or to Euclid’s building blocks of elementary geometrical knowledge, but also to letters of the alphabet. One could argue that genomics (the sequencing of genomes, the entirety of an organism’s hereditary information, with the help of automated high-throughput sequencing machines) from the very beginning has built on this metaphor. It constitutes an effort to dive deeper into the nuclei of cells, in order to decipher, scan and process these formerly unreadable letters, with the help of the high resolution provided by sophisticated automated sequencing technologies. Thus, the ‘century of the gene’ (Fox-Keller, 2000), which began with the rediscovery of Mendel’s effort to talk about life in terms of a small alphabet of symbols, came to a conclusion with the famous Press Conference of 26 June 2000 when Bill Clinton, Francis Collins, and Craig Venter proudly announced that the HGP was galloping toward completion, producing spates of letters: the human genome sequence, written in the A, C, G, T alphabets the ‘code of life.’ (ACGT stands for the four nucleic acid bases that make up an organism’s DNA. The ‘A’ stands for adenine, the ‘T’ for thymine, the ‘C’ for cytosine, and the
‘G’ for guanine. These four nucleic acids are the ‘letters’ of the genetic code.) The story of what happened between these two poles of the human genome narrative (i.e., the rediscovery of Mendel in the spring of 1900 and the public announcement of the upcoming completion of the human genome sequence in June 2000) is a complex one. Only a few of the major events can be highlighted here. In the 1930s and 1940s, to begin with, an important transformation took place in the landscape of science. The center of gravity shifted from Central Europe (Vienna, Berlin, and Zürich) to the United Kingdom and the United States, while the academic lingua franca shifted from German to English, and the frontier of the scientific revolution shifted from quantum physics to the molecular life sciences. This transformation was exemplified by two physicists who migrated not only from the German- to the English-speaking world, but also from quantum physics to biology. One of them was Nobel laureate Erwin Schrödinger who, in 1944, gave a series of lectures in Dublin entitled What is life? In these lectures, he voiced the idea that the ‘genom’ (as he spelled it) was basically an ‘aperiodic crystal’ containing a code comparable to the Morse code. Now that physicists had discovered the elementary building blocks of energy and matter, time had come to use the tested methods and powerful tools of physics (such as crystallography) to unravel the elementary building blocks of life. At that time, however, Max Delbrück, although younger than Schrödinger, had already put to practice what the latter advocated. He went to Cambridge and later to Caltech in California where he opted for a virus (the bacteriophage) as his model organism. For Delbrück, genes were for biology what atoms had been for physics. And therefore, he began his new career as a biologist by looking for a ‘minimal’ organism that could somehow play the role that the hydrogen atom had played in quantum physics. This search for the ‘hydrogen atom of biology’ led to the bacteriophage (literally, the bacteria eater), a virus that attacks and destroys bacteria. He settled upon the phage as his model organism because he wanted to study a living entity that came as close as possible to being ‘the gene in itself’ (‘Das Gen an sich;’ Fischer, 1985, p. 98). Thus, Schrödinger and Delbrück played a pivotal role in the emergence of a new field: molecular biology. In fact, the three scientists who in 1962 were awarded the Nobel Prize for their discovery of the structure of DNA, namely, Francis Crick (a physicist), James Watson (a biologist), and Maurice Wilkins (a physicist), had all read (and confessed to be very much inspired by) Schrödinger’s lectures, which had been published as a book in 1946, while James Watson took Delbück’s course on bacteriophage research at Cold Spring Harbor. Thus, the discovery of the structure of DNA was more or less a direct result of the broader transformation described above: the massive migration of physicists to the new biology (cf Kay, 2000). Now that the structure of DNA had been revealed, the next big objective was to read and decipher the ‘code’ embedded in it. After DNA (the double helix), the next big challenge was sequencing the whole genome (the collection of all the genes as well as the noncoding segments present in human DNA). In 1985, Robert Sinsheimer, President of the
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University of California, Santa Cruz, and Charles DeLisi from the Department of Energy, organized meetings to discuss the feasibility of sequencing the human genome. One of the first questions to be addressed was whether this would call for a large-scale, international, top–down programmatic effort (Big Science), or rather for a bottom– up, researcher-driven approach. Most participants in the debate tended toward the former and in the course of the 1980s, one of the most ambitious and controversial projects in the history of biology was designed. The final preparations coincided with the collapse of the Berlin Wall and the subsequent reunification of Germany and, to some extent, of Europe as a whole. Euphoria was in the air. On 9 November 1989, as citizens from East Berlin flooded into the Western parts of the divided city, Nature published an article on HGP scientists developing a joint database where they could deposit their sequencing materials, flanked by an article about societal issues to be addressed. The project was formally launched on 1 October 1990, with James Watson as its first Director. In 1992, Watson stepped down and was succeeded by Francis Collins while Craig Venter, partly because of his frustrations with the bureaucracy and the power structure of the official HGP, launched a nonprofit, privately funded human genome sequencing project of his own devise. He would establish The Institute of Genomics Research and later Celera Corporation to achieve this goal.
The Human Genome Project: A Concise History The history of the HGP can roughly be divided into three stages (Zwart, 2008). The first stage (1988–92) was a period of development and implementation, beginning with the appointment of James Watson at the National Institutes of Health (NIH) in 1988 and ending with the latter’s resignation (on 10 April 1992). The highlight event was the official launch of the program on 1 October 1990. Simultaneously (also in 1990) a flanking project was launched to anticipate and address the ethical, legal, and social implications (ELSIs) of the sequencing effort, also funded by NIH. In fact, 3–5% of the budget was devoted to this type of research. Thus, NIH became the biggest sponsor of bioethical and other forms of ELSI research in the United States. The second stage (1993–98) set in with the appointment of Francis Collins (1993) as Watson’s successor. The HGP now really gained momentum. For the next few years, work on the HGP came to involve a relatively large number of research groups of varying sizes and sequence capacities. The human genome was divided into 23 natural subunits (the chromosomes) and research labs competed for funding in the context of the NIH peer-review system. By 1998, only 4% of the human genome had been sequenced in this manner. That same year, however, was a turning point in many ways: the onset of the third and final stage (1998–2001). First of all, former NIH scientist Craig Venter announced that his privately funded Celera Corporation, relying on the latest automated sequencing machines, in combination with his controversial whole-genome shotgun method, would sequence the human genome much faster than the public
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consortium envisioned (Shreeve, 2004; Venter, 2007). This announcement entailed a direct challenge to the public effort headed by Collins, which was now under the threat of becoming redundant (Cook-Deegan, 1994/1995). The latter responded by formulating a more focused strategy of action. From now on, the bulk of the work would be done by a limited number of big laboratories with massive sequence capacity, such as the Sanger Centre lead by John Sulston (Cambridge, UK) and the Whitehead Institute lead by Eric Lander (Cambridge, Massachusetts): a select number of key players that came to be known as the G-5. Moreover, it was decided that publication of a finished sequence would be preceded by a working draft version, again a departure from the original plan (Davies, 2001/2002, p. 162). Due to this reorientation, the HGP was suddenly transformed into a ‘noholds-barred race to claim the human blueprint.’ A dramatic competition ensued, eagerly covered by the media, until on 26 June 2000 the ‘race’ or ‘war’ was suddenly declared over, as both sides agreed they had passed the line more or less simultaneously. Collins and Venter cordially made their appearance at the famous press conference at the White House in order to announce, in the presence of President Clinton, that the endeavor to sequence the human genome was nearing its completion . Both teams sealed a truce by publishing working draft versions in a coordinated manner in February 2001, in Science and Nature, respectively (IHGSC, 2001; Venter et al., 2001), although the fighting between representatives of both ‘armies’ over who had actually won the race, or war, would continue in various settings until today. Notably, John Sulston continued to question the role of Celera in sequencing the human genome (Sulston and Ferry, 2002/2003). After 2001, there has been a considerable aftermath. As indicated, the 2001 publication contained a draft version, and the HGP was officially declared complete on 14 April 2003, although a ‘final’ final version of the finished sequence (with 99.99% accuracy) was published in 2004 (IHGSC, 2004), while further analyses and papers on the HGP continue to occur. The human sequence is now seen as the starting point for future research. This is also visible in the images used to elucidate its meaning (Zwart, 2010). During the Press Conference of June 2000, Collins compared the HGP to the expedition of Lewis and Clark, commissioned by President Thomas Jefferson in the beginning of the nineteenth century to map the western part of North America from the Mississippi to the Pacific. This resulted in a famous map (below, Figure 1) depicting a more or less empty landscape, with a focus on its physical features, such as rivers and mountains. A few years later, when presenting a vision for the future of genomics research (Collins et al., 2003), a different picture emerged (below, Figure 2). Rather than with an open landscape, one is now faced with buildings and emerging infrastructures. The genomics future is envisioned as a three-floor building designed in the style of Frank Lloyd Wright. The basic topology, as it were, has shifted. The landscape has become inhabited. “All the initial objectives of the HGP have now been achieved,” Collins et al. argue, “and a revolution in biological research has begun” (p. 835). It will now quickly spread from the basement to biology, health, and society.
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The Lewis and Clark map. Source: http://memory.loc.gov/cgi-bin/query/r?ammem/gmd:@field(NUMBERþ@band(g4126sþct000763))
Figure 2 A vision for genomics. Source: Collins, Francis, Green, Eric D. Green, Guttmacher, Alan, Guyer, Mark S., [NHGRI], 2003. A vision for the future of genomics research, a blueprint for the genomics era. Nature 422, 835–847.
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Figure 3
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The 26 June 2000 Press Conference announcing the near completion of the HGP.
Meaning and Significance: Assessing the HGP One of the questions raised with regard to the HGP has been to what extent it can really be regarded as the advent of ‘Big Science’ in biology (Vermeulen, 2009). Both Watson and Collins on various occasions placed the HGP on an equal footing with other Big Science endeavors such as the Manhattan Project, the Apollo Program, and the European Organization for Nuclear Research (CERN). The HGP was regarded as ‘Big’ by many, first of all because of the size of the funding involved (three billion dollars as core funding) in combination with the international scale of the collaboration as well as the fact that the project was managed in a more or less centralized manner by Watson and subsequently Collins as its Director. Yet, Big Science in physics (where the concept first emerged) is typically organized around a centralized large-scale research facility, attracting hundreds of researchers (such as the Large Hadron Collider of CERN in Geneva), whereas HGP’s infrastructure remained much more distributed, while its basic technologies were not available from the outset, but were rather developed as the project evolved. Or, as Müller-Wille and Rheinberger phrase it in slightly Marxist terms, the HGP created not only a plethora of scientific products (data, papers, and the like), but also the means for their production (2012, p. 201). This may be seen as a purely ‘semantic’ question, but in the context of ongoing controversies and reflections as to what the HGP has been able to achieve, the issue proves quite relevant. Building on the widespread impression that in the end (in terms of benefits for society) the HGP did not quite live up to the stellar ambitions that were voiced in the 1990s, some may now question the viability of a Big Science approach in the life sciences domain as such, whereas others may argue that, in
view of the bewildering complexity of living systems, the HGP simply was not Big enough. This brings us to the second issue over which controversy is still raging: what has been the societal impact of the human sequence? Although it is beyond doubt that genomics has irreversibly changed the life sciences as a global research field, so far, concrete clinical benefits, for instance, in terms of treating cancer, have been sparse. During the 26 June 2000 Press Conference, great expectations were voiced in this respect. Clinton claimed that, because of the HGP, our children’s children will probably know the word cancer only as a constellation of stars. Yet, in many ways, the outcomes of the HGP were something of a disappointment. Let me go into this experience of disillusionment in somewhat more detail. The first major disappointment had to do with the number of genes on the human genome, namely, 22 500, which was an astonishingly low number compared to previous estimates that ranged from 100 000 up to 350 000 (Zwart, 2007). The human genome, moreover, appeared to be quite similar to the genomes of other species, such as the chimpanzee and the laboratory mouse. There is nothing special about our sequence. This in itself constitutes a nice example of what Sigmund Freud (1917/1947) has termed a narcissistic offense. According to Freud, all major scientific breakthroughs (and he mentions the discoveries of Copernicus and Darwin as paradigmatic examples) entail serious narcissistic offenses that challenge our basic views about ourselves. We tend to see ourselves as highly unique and central, but the truth as laid bare by science is that we are not. Yet, we are the only species on earth able and willing to think about our own evolution or about our place in the universe, and we are certainly the only species who has sequenced its own genome (or may come up with such an idea at all). An interesting paradox: food for philosophy indeed. Where does our uniqueness come from?
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As we cannot attribute it solely to our DNA, it must come from elsewhere. It must be closely interwoven with our cultural history, over and above our biological evolution. We must be, to a certain extent, manmade. We are not only the producers, but also the products of our technologies, cultures, and societies. It is precisely here that the HGP did have an impact. It has provided us with additional and valuable sources of information concerning early human history, notably by considering not only the human genome itself, but also the genome of others species (such as dogs, horses, rice, cereals, maize, etc.) as historical archives for bioarchaeological research (Zwart and Penders, 2011). In other words, the ‘cultural impact’ of genomics, by broadening our historical horizon, has been quite significant. Thus, the experience of disillusionment notably pertained to the biomedical results. While it is widely acknowledged the HGP did have an enormous impact on the way in which biological research is done, its medical applications so far have been quite limited. Although the HGP did succeed in transforming laboratory life, so far the consequences for health care, medicine, and human daily existence in general have been quite modest. This is also reflected in the societal debate triggered by the HGP. Initially, serious concerns were voiced, for instance, by Francis Fukuyama (2002) who believed that the essence of what we are is endangered by biotechnology now that the human sequence is about to be revealed. He postulated the existence of a set of typically ‘human’ genes, which he termed the Factor X, a genetic endowment that distinguished humankind in essence from other species and should be safeguarded from biotechnological interference. In France, novelist Michel Houellebecq devoted his successful novel Elementary Particles (1998) to a scientist who managed to develop an algorithm that allowed humankind to drastically ameliorate its genetic constitution, thereby altering the course of future history (an event on the scale of a ‘metaphysical mutation’). Yet, it soon became apparent that such scenarios are fairly unrealistic and that the Factor X is nowhere to be found. A related concern raised in the early days of the HGP was that of genetic discrimination: The idea that human genomics would lead to the emergence of a social underclass of carriers of ‘bad genes,’ as dramatized in the movie Gattaca (released in 1997), for example. Again, these apprehensions, grounded in rather deterministic understanding of the relationships between genes and traits, proved unwarranted. Life is too complex to be understood in such a linear and straightforward fashion. So far, the societal relevance of the HGP has been quite limited indeed. This is also reflected in ELSI research, where big concerns gradually gave way to much more everyday discussions. In 2010, the journal Nature published a retrospective. The basic question was has the proclaimed genomics revolution arrived? Collins (2010a) and Venter (2010) both contributed to the issue. Their answer and that of other contributors was, essentially, not yet. The most important outcome of the HGP resides in the acknowledgment that life is much more ‘complicated’ (Hayden, 2010) than was envisioned back in 1989, when Francis Collins wrote his very first e-mail and the HGP was about to be launched. This issue was taken up more elaborately by Francis Collins (2010b) (now Director of NIH) in his latest book The Language
of Life, written 10 years after the jubilant Press Conference of June 2000. Although he still sees the HGP as ‘one of the boldest scientific efforts that humankind has ever mounted’ (p. 299), he at the same time acknowledges that the enthusiasm that had peaked during the days of the June 2000 Press Conference has more or less evaporated: Nearly a decade has passed since that moment of celebration. Virtually all biomedical researchers would agree that their approach to understanding how life works has been profoundly and irreversibly affected by access to the complete DNA sequence of the human genome . But the effect on the public of all the hoopla in 2000 has been mixed. Most people know that the genome has been spelled out, but they have lost track of what has happened since then. They remember the ascent of the mountain, but they are unaware of the rewards that are starting to appear in the valley. (p. 3)
The revolution is still raging, that is the basic message of his latest book; it is ongoing and societies better prepare themselves for a massive disruptive change, but this will not come through the sequencing of the human genome as such, but rather though its subsequent stage: The era of next-generation sequencing and the $1000 genome (Davies, 2010) and, as a consequence of that, the advent of personal genomics and personalized medicine: Healthy individuals are increasingly able to discover some of their body’s inner secrets and take appropriate action. The potential for individual prediction is beginning to spill out to the general public, offering the opportunity to take more control of your fate . None of this is happening overnight, [but] without question, man’s knowledge of man is undergoing the greatest revolution since Leonardo. (p. 5)
But still, up to this point at least, the transformations brought about by next-generation sequencing are limited. In comparison to the dramatic debates of previous decades, current deliberations focus much more on everyday and perhaps even trivial examples, such as the credibility of providers of personalized genome tests such as 23andMe. One way of seeing this is to argue that, apparently, supporters of the HGP consciously created a hype in the 1990s, by willfully exaggerating its societal potential. Subsequently, after publication of the human sequence in 2001, they shifted the argument saying that life proved to be much more complex than was expected at the beginning, so that much more research (i.e., much more funding) will be needed to harvest the potential benefits. Another, less cynical, but in my view more credible, way of looking at it is by arguing that a project of the size of HGP is likely to go through a series of stages. From this perspective, Watson and Crick represent the era of childhood and playfulness, building models with toylike components without much regard for formalities, such as research projects or management structures. Subsequently, during the period of latency (the 1970s and 1980s), the focus shifted toward the development of basic tools and skills (such as the Sanger sequencing method) in preparation for a distant and still fairly abstract future. The HGP itself, then, represents the adolescence stage: the era of great expectations and fierce collisions. Finally, at present, human genome sequencing has entered the stage of adulthood and normal science. Genomics
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has become embedded in the life sciences and as such, has acquired a certain level of normalcy, so that its implications for human existence are less dramatic, more everyday, perhaps even trivial, and its promises more realistic. As was already indicated above, a significant impact of the HGP resides in its cultural relevance: The way we see ourselves and think about ourselves as humankind. First of all, genomics provides us with new sources of information, allowing us to revisit early human history in a detailed fashion, from the days of human migration out of Africa up to the emergence and spread of agriculture in the context of the so-called Neolithic revolution. Subsequently, it is clear that the HGP has prepared the ground for, and will gradually be eclipsed by, so-called postgenomic developments, such as personalized genomics (or next-generation sequencing) already mentioned above. In the early days of the HGP, the human sequence was often presented as the ‘blueprint’ of human existence or even as ‘the near-complete instructions for how to build and run a human body,’ downloadable from the Internet (Ridley, 1999, p. 1). Paradoxically, the project that started off as an exemplification of a genetic deterministic mind-set eventually undermined the credibility of precisely the genetic reductionist view of life by revealing the astonishing complexity of living systems. For example, it paved the way for the emergence of epigenetics: the awareness that the vicissitudes of an organism (nurture) may result in modifications of its genome (notably on the level of gene expression), which can be passed on to the future generations. This goes against the long-standing dogma that acquired features cannot be inherited. Another development is the shift from ‘reading’ (i.e., sequencing) DNA to ‘rewriting’ DNA on the molecular level, that is synthetic biology: the intermediary zone between genomics and nanoscience. Similar realignments can be discerned elsewhere, for instance, between genomics and brain research (cognomics). Thus, the HGP has definitely strengthened the trend, already characteristic of contemporary technoscience as such, toward the emergence of a plethora of transdisciplinary research conglomerates (molecular biology, bioinformatics, genomics, synthetic biology, epigenetics, cognomics, etc.) by which genomics itself is bound to be engulfed sooner or later.
See also: Biobanking: Ethical Issues; Bioethics in the Postgenomic Era; Bioethics: Genetics and Genomics; Direct-toConsumer Personal Genetic Testing; Ethical, Legal, and Social Implications Program at the National Human Genome Research Institute; Genetics and Society; Genetics and the Media; Genetics: The New Genetics; Genographic Project; Genomics, Ethical Issues In; Human Evolutionary Genetics; Human Genome Diversity Project: History.
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Relevant Websites Bibliography Collins, F., 1999. Medical and societal consequences of the Human Genome Project. New England Journal of Medicine 341, 28–37. Collins, Francis, Green, Green, Eric D, Guttmacher, Alan, Guyer, Mark S, [NHGRI], 2003. A vision for the future of genomics research, a blueprint for the genomics era. Nature 422, 835–847.
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http://en.wikipedia.org/wiki/Human_Genome_Project – HGP. http://www.nih.gov/ – NIH. http://www.genome.gov/ELSI/ – ELSI. http://www.genome.gov/ – NHGRI. http://www.sanger.ac.uk/about/history/hgp/ – Sanger Institute. http://en.wikipedia.org/wiki/J._Craig_Venter_Institute – J. Craig Venter Institute.