Beyond the Genome

Hallam Stevens and Sarah S. Richardson

In the celebrations surrounding the completion of the Human Genome Project (HGP), few anticipated the bewildering developments that were to come. Expectations that the follow-up work would involve routine puzzle solving gave way to a series of surprising biological revelations. Debates over fundamental problems became more controversial and unsettled. Some important questions — which in the immediate aftermath of the HGP seemed near a solution — now, a decade on, seem even more difficult and mysterious.

The genome sequencing projects promised a future in which human traits would be linked to common genomic differences. Beginning in 2005, biologists began genotyping thousands of individuals, searching for correlations between single nucleotide polymorphisms and phenotypic traits. This technique for probing the meaning and function of the genome is known as the genome-wide association study (GWAS). To study obesity, for example, GWAS sampled thousands of obese individuals and thousands of nonobese individuals. If a particular mutation at location x occurred in a high fraction of obese people and a relatively low fraction of nonobese people, this suggested that location x might have something to do with obesity. This analysis was repeated for millions of locations on the genome, building up an overall picture of locations associated with particular traits.

By 2010, over seven hundred GWAS had been published on over four hundred different diseases and traits. As more and more studies were conducted, two trends began to appear. First, many traits — even traits that biologists might have supposed to be quite straightforward — turned out to be associated with hundreds or even thousands of locations on the genome. One 2010 study associated 180 distinct locations with human height. Second, even with all these locations taken together, the numbers just did not add up. With height, for instance, studies of monozygotic twins suggested that 80–90 percent of the variation in human height is heritable. However, using GWAS to measure the contribution of each location to the overall variability in height showed that the contribution of each location to the overall variation was very small. Adding up all the contributions of the hundreds of locations only accounted for about 13 percent of the overall variation in human height.

This persistent question of "missing heritability" has continued to dog genome research. Despite the many locations on the genome responsible for influencing particular traits or diseases, there does not seem to be "enough" to actually account for what is going on. Biologists have put forward numerous suggestions to explain what might be going wrong: rare variants, copy-number variations, network effects, environmental effects, and epigenetic effects. The evolutionary biologist Leonid Kruglyak argues that the problem is conceptual: "It's a possibility that there's something we just don't understand, that is so different from what we're thinking about that we're not thinking about it yet." Attempts to solve this problem have been a major motivation for studies of epigenetics and gene-environment interactions, as well as for projects to sequence large numbers of complete genomes (such as the 1000 Genomes Project). The missing heritability problem suggested that the working of the genome was far more complex than biologists hoped or expected it to be: traits and diseases seemed to depend on a mysterious set of unknown unknowns. This indicated the need not only for new experimental tools but also for a fundamental rethinking of the working of genes and genomes.

GWAS constitute only one of the promising developments within biology over the past decade. Yet, the kinds of problems they have encountered — more data, increasing complexity, greater uncertainties — are exemplary. Today, "postgenomics" is an increasingly prevalent term within the life sciences. Dozens of recent texts in bioinformatics, genetics, and medicine promise to situate research in these fields in "the postgenomic age." Biologists invoke the term "postgenomics" to signal powerful new methods and approaches to complex biological problems. Similarly, social science analysts of the life sciences use the term "postgenomic" to refer to widespread transformations said to be sweeping these fields since the completion of the major genome projects. A recent editorial in the Economist titled "Biology 2.0" predicted that "It seems quite likely that future historians of science will divide biology into the pre- and post-genomic eras."

This book aims to reflect on the postgenomic moment by posing a set of critical questions: What are the continuities and discontinuities between the postgenomic life sciences and previous biology? Which of the hopes and ambitions of the genome projects have been realized, and which have not? How does postgenomics transform fundamental conceptual debates in the life sciences, such as those over holistic versus genetic determinist approaches, biological and socio-environmental explanations, and how to conceptualize human racial and sexual differences? And how should we characterize the relationship between new high- throughput data technologies and new modes of postgenomic investigation?

Biology has come a very long way from the iconic 1992 moment when Walter Gilbert waved around a compact disk and asserted that the As, Ts, Cs, and Gs of the DNA sequences encoded on it were us. As the essays in this book demonstrate, science studies scholars examining the life sciences, too, are reimagining their role and refreshing their theoretical toolkits in the postgenomic age.

This book explores postgenomics as a live and evolving frame for discussions of changes and trends in the post-HGP life sciences. Following Richardson, we define postgenomics both temporally, as the period after the completion of the sequencing of the human genome, and technically, in reference to the advent of whole-genome technologies as a shared platform for biological research across many fields and social arenas. We characterize as "postgenomic" all of those areas of the biological and medical sciences that now use genomic information or approaches as a foundational or standard element of their research practices. "Whole-genome" technologies include human genome databases and biobanks; microarray chips for assessing the expression of hundreds of thousands of genes in human tissue; rapid, inexpensive whole-genome sequencing technologies; high-throughput screening techniques; bioinformatic and computational advances in GWAS; and low-overhead, mail-order mass sequencing and genome analysis facilities.

For many, postgenomics signals a break from the gene-centrism and genetic reductionism of the genomic age. As scientists narrate the history of the genome sequencing projects, they trace a path from a simplistic, deterministic, and atomistic understanding of the relationship between genes and human characters toward, in the postgenomic era, an emphasis on complexity, indeterminacy, and gene-environment interactions. In this sense, "epigenetics," the study of mechanisms that regulate gene expression in response to environmental signals, is an archetypal postgenomic science. A 2007 NOVA Science feature presented epigenetics as a groundbreaking paradigm shift in biology and medicine. Epigenetics, some claim, represents the new age of genomics in which nature and nurture are seen to interact in profound ways that overturn the old reductionism and determinisms of Watson and Crick's genetic code. The popular science press trumpets that epigenetics shows that "it's not all in the genes" and even that "you can change your genes." Public health activists have championed epigenetics as a mechanism for improving human health through environmental and sociostructural changes. In evolutionary biology, some have argued that epigenetics provides a framework for revisiting Lamarckian ideas, claiming that contrary to gene-centric dogma, life experience, encoded in the epigenome, can be passed on to future generations.

Yet not all are prepared to accept such pronouncements. In a widely circulated 2010 essay, Current Biology editor Florian Maderspacher offered a ringing critique of the popular and scientific frenzy over epigenetics. "What is all the fuss about?" Maderspacher asked. The idea that genes are regulated by transcription factors has been well established since Jacob and Monod's classic lac operon experiments in the 1950s. Epigenetics is not new, nor is it revolutionary. Its draw today, Maderspacher asserted, is due more to our continued search for confirmation for our social ideologies in the facts of biology. Epigenetics has become fashionable, he argued, as a result of its politically liberal "sense of empowerment. ... Much like with the idea of the vulgarizing genetic determinism ... epigenetics seems to offer solid scientific proof — DNA modification as a kind of liberation."

The critique provoked polarized responses, recorded in the comments section of Current Biology, that reveal the contested and emergent status of the young postgenomic science of epigenetics. Even as its wonders are celebrated in the popular press, many scientists, such as the evolutionary biologist Jerry Coyne, remain highly skeptical about epigenetics' novelty and about its implications for traditional models of inheritance and development. Others, such as evolutionary biologists Marion Lamb and Eva Jablonka, insist that epigenetics presents a transformative critique of the central dogma and a mechanistic framework for the study of environmental factors in development and evolution. Despite all the attention to epigenetics, its significance and even its meaning are highly contested.

The most recent exemplar of these multiplying contestations and difficulties is the Encyclopedia of DNA Elements (ENCODE) project, which announced its results in 2012. The ENCODE project began in 2003 — just as the HGP was wrapping up — with the aim of identifying all functional elements in the human genome. ENCODE was one of the largest attempts to try to understand the three billion letters of the human genome. Initial analysis of the human genome had suggested that since less than 2 percent of the nucleotides coded for proteins, the rest was "junk DNA." The project set out with the goal of building a far more comprehensive "parts list" that included non-protein-coding genes, transcriptional regulatory elements, and sequences that mediated chromosome structure and dynamics.

When the ENCODE Consortium announced their findings, they claimed that over 80 percent of human DNA had some function. Many celebrated this remarkable finding, proclaiming the death of junk DNA and predicting that textbooks would have to be rewritten. The ENCODE results were widely reported in mainstream media in glowing terms. But some biologists greeted the 80 percent figure with disbelief and outrage. Taking first to the blogosphere and then to journals, the critics argued that "ENCODE accomplishes [its] aims mainly by playing fast and loose with the term 'function,' by divorcing genomic analysis from its evolutionary context and ignoring a century of population genetics theory, and by employing methods that consistently overestimate functionality." The thrust of this objection was that comparative genomics analysis had consistently found no more than 10 percent of the human genome to be under active selection. How could, then, 80 percent of the human genome be functional? Could 70 percent of the genome be somehow immune to evolution? As the critics pointed out in scathing terms, ENCODE had chosen a definition of "function" that ignored evolution completely.

Inevitably, "postgenomics" has different meanings for biologists in various disciplines and research settings, and in the dispersed and fast-paced world of genomic science the meaning of the term has the potential to evolve rapidly. Biologists also seek to do different things — including carve out aspirational futures and seek funding and investment — with the concept of postgenomics. Conceptions of postgenomics serve to mobilize new agendas in the open play of the twenty-first-century biological frontier. "Postgenomics" has taken root in a competitive research environment in which private and governmental funders are wondering whether to continue to invest in genomic sciences, technologies, and knowledge despite their well-advertised failures to deliver cost-effective and novel advancements with direct clinical applications. Postgenomics, it might be argued, is, among other things, a mode of extending the project of genomics in the face of a restricted resource environment and increasing skepticism about genomics' prospects to provide concrete benefits for society and for human health.

Some of ENCODE's critics have suggested that the 80 percent figure was a publicity-grabbing stunt designed to generate greater excitement about genomic approaches and procure more investment in this particular mode of high-throughput research. This is what Mike Fortun has termed the "promissory mode" of genomics: a reliance on continuously renewed and hyped, but rarely fulfilled, promises of providing therapeutic and technological breakthroughs. Indeed, some of the discomfort about the ENCODE project was its "big science" flavor: a centrally coordinated project, involving over four hundred scientists, critics argued, was the wrong approach to answering the kinds of questions that ENCODE was asking. Postgenomics has provoked increasingly sharp disagreements about how to share (often diminishing) money and rewards among institutions, projects, and individuals.

But the ENCODE controversy is not just about hype, methodology, and organization — it also shows how far biologists are from an agreement on an account of genomic action. It is not merely that the definitions of fundamental terms — such as "functionality" — are still open to contestation. The debate points to significant uncertainty about the overlapping roles (and relative importance) of evolution, DNA structure, transcription, and regulation in the human genome. Genes, the New York Times reported in 2008, are having an "identity crisis": acknowledgement of the importance of epigenetic marks, alternative splicing, post-transcriptional modification, and noncoding RNA have rendered the concept almost meaningless. Nature's "Genome at Ten" issue ran with the headline "Life Is Complicated": "The genome promised to lay bare the blueprint of human biology. That hasn't happened. ... Instead, as sequencing and other new technologies spew forth data, the complexity of biology has seemed to grow by orders of magnitude." The notion of the gene as "master molecule" is gone, but the disagreements exposed uncertainties about how else to talk about the proliferating objects, relationships, and levels involved between DNA and phenotypes. Rather than settling debates, ENCODE has muddied the waters; rather than answering older questions, it has raised new ones.

In contrast to the confident announcements that accompanied the HGP a decade ago, prominent biologists now caution against overoptimism. "The consequences for clinical medicine," Francis Collins said of genomics in 2011, "have thus far been modest." Likewise, genomic entrepreneur Craig Venter suggests that there is still a long way to go to transform human genomes into medical knowledge: "The challenges facing researchers today are at least as daunting as those my colleagues and I faced a decade ago."

More than a decade after the completion of the HGP, we stand at a moment of transition and contestation. During this "postgenomic era," genomes have become a shared platform for biological research across many fields. But as the examples given here suggest, fundamental tenets of the genomic research agenda have been challenged from all directions. Amid the deep controversies and disagreements within biology, what role exists for humanities and social science analysis?

Since the HGP was first proposed in the 1980s, science studies scholars have held a critical — and at times oppositional — posture toward genomics. They led the way in exposing the genetic reductionism and bald biological determinism of many genome sequencing boosters. They insisted on the need for social and ethical reflection on the potential harms of DNA technologies. This produced a vibrant decade of engaged and highly influential science studies scholarship on human genetics. Historians, philosophers, sociologists, and anthropologists worked intensively to understand the social, cultural, economic, and political consequences of genomics, examining the cultural transformations wrought by genomics around notions of identity, nation, affiliation, privacy, and personal health. Despite their critical bent, social science scholars earned the respect of practicing scientists, finding allies and interested audiences among geneticists seeking to place their work in a wider context.