An Unexpected, Submicroscopic Journey
Stephen L. Talbott
From In Context #24 (Fall, 2010)
It was in the fall of 2008 that Nature Institute director Craig Holdrege suggested I might like to look into what was happening in epigenetics. The term “epigenetics” was of course familiar to me — I had written a fair amount about genetics and genetic engineering. But my focus had always been very broad: what sort of view of the organism was driving geneticists; how was their work affecting our thinking and our public policy, for example, in agriculture and medicine; and what of the organisms themselves who were suffering this tinkering with the foundations of their existence? Diving into the immense technical literature so as to engage the issues at the level where molecular biologists were posing their precise and narrow experimental questions was not something I would ever have thought of doing on my own.
“Epigenetics” can be taken in the widest sense as referring to our understanding of how the organism makes use of its genes. It’s a matter of putting genes in their context — an effort that has gained tremendous momentum world-wide since Craig wrote his prescient 1996 book, Genetics and the Manipulation of Life: The Forgotten Factor of Context. So it was this context — which means, I eventually reminded myself, just about everything — that Craig so casually suggested I look into!
Fortunately, I didn’t fully consider the scope of the task at the time — the thought probably would have paralyzed me — and in January, 2009 I dug into my first pile of technical literature. Sensibly, given a vivid awareness of my own limitations, I focused initially upon those cellular processes most directly involved in gene regulation. And immediately the surprises began.
In the first place, it needs saying that I am no molecular biologist. In fact, I am not a biologist at all. Yet in some ways — and this was my initial surprise — I found the literature, for all its challenging technical aspects, oddly familiar and accessible. It didn’t take me long to figure out why: the researchers whose reports I was reading were treating DNA and genetic processes with the mindset of computer engineers. The mechanistic logic they were trying to elucidate was not at all unlike the kind of logic I had had to deal with for many years when I worked for computer manufacturers. DNA, as everyone knows today, is commonly regarded as the bearer of a digital “code” or “program.” The way researchers were explaining its role in the cell was scarcely different from the way I often had explained how software and hardware works.
Another surprise had to do with how slow the media outlets were to pick up on what was happening. My familiarity with computer engineering enabled me quickly to recognize how remote from computation were the actual phenomena the molecular biologists were trying to describe. Their language may have been engineerese, but the reality obviously had little to do with any logic of engineering. And, at some level, the researchers themselves have seemed to realize during the past decade that they are engaged in a revolutionary transformation of their field, even if their language and many of their working concepts remain “old-school.” No one reading the literature today with a receptive mind can fail to see that a great deal of our understanding of genes and organisms is being turned inside out and upside down.
Puzzlingly, however, almost none of this extraordinary significance of the research was making it into the popular media. Encountering one remarkable finding after another, I began wondering why I had previously heard almost nothing of the drama taking place in the molecular biological laboratories. The emerging picture of the organism had little to do with the tired, same-as-always images conveyed in the press — images of genes mechanistically orchestrating the life of the cell and organism. I was daily reading dense technical reports suggesting the need for a much more vivid and living understanding of the organism — reports in which the researchers themselves often expressed a sense of excitement about the almost over- whelming pace of their new discoveries and about the changes required in their ways of thinking. Wouldn’t the science reporters for, say, the New York Times, want to play a leading role in exploring the implications of all this — and in keeping the general public informed?
In the end, I was fully sucked into the research and decided I could at least do my own part in presenting the ongoing discoveries to a wider audience. This led to four rather lengthy and technical essays in The Nature Institute’s online newsletter, NetFuture. These in turn have helped produce opportunities I could scarcely have imagined before my research began:
— I was asked to give a presentation to a gathering of molecular biologists, ethicists, philosophers, and social scientists at the Hastings Institute in the lower Hudson Valley of New York. The conference was focused on synthetic biology, the discipline where researchers try to attack the problem of synthesizing simple organisms from scratch. I spoke to a very attentive and engaged audience about the picture of the organism emerging from molecular biology today, which is a picture far removed from the one in the minds of those who are currently imagining they can craft an organism by assembling a collection of parts.
— A book containing articles offered as a festschrift to Harvard biologist emerita Ruth Hubbard (author of the classic Exploding the Gene Myth) is currently in preparation, edited by Sheldon Krimsky of Tufts University. Hubbard herself, along with her Harvard colleague, Richard Lewontin, are advisers for the project. Quite unexpectedly, I was invited to submit a chapter for the book — a chapter that survived the initial review process and has been accepted for inclusion in the book, pending approval by the eventual publisher.
— One consequence of my sending that paper to a few qualified people for criticism is that I received a request to contribute a separate paper for the journal, Studies in History and Philosophy of Science (Part C, Biological and Biomedical Sciences). This paper, more than anything else I have written, focuses on what you might call the inwardness of all organisms — the directed, meaningful, expressive, and non-mechanistic character of their lives, as borne out by work in molecular biology.
— The New Atlantis, an influential journal dealing with science, technology, and public policy, is committed to publishing a series of my articles dealing with the revolution in molecular biology and its broader implications for science and our understanding of the living organism. The editors, having become convinced of the importance of this project, and wanting their publication to take a leading role in public education, plan to promote the articles as widely as possible. The New Atlantis goes to all congressional offices as well as to numerous government officials, policy makers, think tank scholars, and many others, in addition to its regular subscriber list. It also maintains a stimulating website where its contents are available to the public (thenewatlantis.com). The first article in the series will likely have appeared by the time you read this.
— Finally: just as this article was being readied for press, I received an invitation to contribute a chapter to a book dealing with the ethics of synthetic biology. The book is being prepared by the Hastings Center (see first bullet item above) as a follow-up to its conference and in recognition of the fact that today there is “considerable interest nationally in the ethics of synthetic biology.”
To have such opportunities fall in one’s lap is a little unnerving for someone with no extensive background in biology! But, on the other hand, the biological sciences seem to be moving, however clumsily and however unconsciously, in a direction fully vindicating the contextualizing stance Craig took up in his 1996 book, which is very much the stance I, too, have assumed. It’s comforting — if also more than a little dangerous — to feel that you have history on your side!
What follows is a brief look at one of the latest pages in this history.
Assessing the Human Genome Project
Back in July 2009 (in NetFuture #177), I ventured the prediction that, “within a year or two some highly placed researcher, secure enough in his or her position of authority to take the risk,” would publish a dramatic statement to the following effect:
What are we doing? Every month we gather more data on the genome and epigenome in an ever-rising flood. We learn more and more details about more and more minute processes, and the dizzying pace of discovery provokes use of the word “exciting” in one technical paper after another. But has no one noticed that we seem to be getting farther and farther away from an understanding of cell and organism?
We used to have a clear framework for saying what made what happen. DNA gave us a blueprint or instruction book or program as a First Cause to which everything else could be traced. At the head of the chain of causes was a single set of crystal-precise molecules, and further on down the line was everything else we see in the living organism.
That instruction book, however, has disappeared. What is there to take its place? The satisfyingly clear lines of cause and effect are, with every exciting new discovery, dissolving further into a chaos of causal arrows pointing in all possible directions. Where are the higher-level ordering principles? Yes, we clearly are gaining countless useful facts, but is there anything causal, anything explanatory, holding these facts together in the way that the organism itself so obviously holds together?
It was, of course, rash to predict a single, dramatic outburst of this sort. While I still think such an event entirely possible, I would have done better to focus on a near-certainty: the radical implications of recent molecular researches, corrosive of so much prevailing thought, will progressively dawn upon the more open and flexible biologists and will even begin to be voiced in mainstream technical journals. In this connection I was struck by a recent collection of articles in Nature celebrating the tenth anniversary of the completion of the Human Genome Project.
If a single theme runs through all these articles, it is the contrast between the almost unbelievable technical sophistication of our data-collecting tools, on the one hand, and our incomprehension of the data, on the other. “Never before has the gap between the quantity of information and our ability to interpret it been so great,” writes one group of authors (Khoury, Evans and Burke 2010).
In their introduction to “The Human Genome at Ten” the editors of Nature refer to the “mismatch” between the “rapidly increasing ease of gathering genomic data versus the continuing difficulty of establishing what the genetic elements actually do”— a sentiment put in stronger terms by James Collins, a bioengineer at Boston University: “We’ve made the mistake of equating the gathering of information with a corresponding increase in insight and understanding.” (quoted in Hayden 2010).
Likewise Nature columnist Philip Ball, citing newer data-gathering projects such as an expensive initiative to solve protein structures, counsels restraint:
Before animal spirits transform this into the next ‘revolution in medicine’, it might be wise to ask whether the Human Genome Project has something to tell us about the wisdom of collecting huge quantities of stamps before we know anything about them (Ball 2010).
And finally, mathematical biologist Joshua Plotkin, referring to the discovery of vast regulative processes bearing on DNA, concludes:
Just the sheer existence of these exotic regulators suggests that our understanding about the most basic things — such as how a cell turns on and off — is incredibly naïve (quoted in Hayden 2010).
The Frustrating Search for Cures
The strongest selling point for the Human Genome Project was that it would lead to numerous cures for diseases. And one of the most striking realizations to emerge from work of the past decade is that the link between any particular genetic feature and any particular complex trait — including most traits of interest — is extremely tenuous. This is true even of highly heritable traits. For example, although human height has about an 80 percent heritability, the top 20 gene features influencing height explain only about 3 percent of the variation from one person to the next. The same is true of most diseases. In all the relevant studies, as Emmanouil Dermitzakis and Andrew Clark observe in Science,
. . . the magnitude of genetic effects is uniformly small . . . . The lesson is that we do not yet fully grasp the genetic architecture of complex disorders in humans, and we will not be able to make accurate individual predictions of risk until we do. Predicting individual risk of complex traits is a tall challenge, in part because of the context-dependent way that the genotype manifests its effects on disease risk.
Dermitzakis and Clark go on to remark on the deceptive quality lent to genetic studies by reliance on “model organisms” in laboratory settings. Several gene variants in fruit flies have been precisely mapped to specific effects on the number of bristles on the fly, yet “those same variants within a natural population have little bearing on bristle counts.”
Difficulties persist even when one starts with natural populations. While genome-wide association studies (GWAS) have turned up hundreds of mutations that can be statistically correlated with various diseases and traits, their biological relevance remains to be demonstrated, and they typically lead to no diagnostic or therapeutic benefit. For example, “a recently published 12 year follow-up study of cardiovascular disease in more than 19,000 women found that the 101 [genetic features] identified by GWAS as risk variants for cardiovascular disease did not predict cardiovascular outcomes” (McClellan and King 2010).
The difficulty of finding genes to “account” for traits is especially difficult in the study of cancer. Compare a tumor tissue with a normal tissue in the same individual, and you will find a remarkable number of genetic differences. For example, one study of an African woman with metastasized breast cancer revealed a total of 27,173 point mutations in the primary tumor and 51,710 in a metastatic tumor. “The difficulty,” according to Bert Vogelstein, a cancer researcher at the Ludwig Center for Cancer Genetics and Therapeutics at Johns Hopkins, “is going to be figuring out how to use the information to help people rather than to just catalogue lots and lots of mutations” (Ledford 2010; Ding et al. 2010).
All of which has led many researchers to search for key mutations that are primary “drivers” as distinct from “by-products” of cancerous conditions. And one way to do this is to look for clusters of mutations that affect the same key biological processes — say, a particular signaling pathway — which in turn might be functionally related to the cancer of interest. Such mutation clusters, it is thought, should contain the truly causal genes.
The problem is not only that many “drivers” seem to occur at an extremely low frequency — say, in less than 1 percent of cancers — making risk prediction or causal explanations in individual cases extremely difficult. It’s also that the processes affected by particular genes tend not to be well-defined and restricted, but rather merge seamlessly with the wider life of the cell and organism. A gene might play into any given process via innumerable direct and indirect routes. “We tend to talk about pathways and processes as if they are discrete compartments of biology,” write Dermitzakis and Clark. “But genes and their products contribute to a network of interactions”— and these interactive networks “differ radically among tissues.”
It is certainly reasonable to look for key points of influence where therapeutic intervention might prove most profitable. But the message of current work in molecular biology seems to be that, if we want to get our bearings amidst all the interacting variables, we should de-emphasize the search for neat and precise causes. We need to take in a larger picture, alert to coherent patterns and qualities that play throughout an organism. And whether we have any chance of succeeding in that task solely by burying our heads in molecular-level processes is a live question. Further, even when we do come face to face with a larger picture, we’ll never see it except by looking at least partly with a qualitative and aesthetic eye. You will never “get” Da Vinci’s The Last Supper if you are content with a mathematical analysis of pixels. Nor will you see the Taj Mahal if your engineer’s eye notices only joints, beams, and fasteners.
If a playwright, having decided that the first draft of a play was too “bright” or “optimistic,” should undertake to give it a rather darker or more tragic feel, we would expect the final drama to be changed throughout — perhaps more obviously in some places, but also very subtly in many others. One could not effect the transformation merely by inserting a “causal” sentence here or a revised stage gesture there. That’s how it is with organic structures, whether works of art or organisms. So it is perfectly reasonable to assume that when a disease such as cancer overtakes a person, the difference will have to be recognized in qualitative changes potentially coloring everything in body and psyche.
It may be hard to imagine contemporary molecular biologists being reconciled to such a view. But acknowledgments of ignorance such as we heard above are a healthy start. One hopes that, coming as they do after a half-century of extraordinary — sometimes almost arrogant — confidence that molecular biology was laying bare the “mechanistic” secrets of life, the professions of ignorance will prove cathartic and signal an openness to new beginnings. The implosion of the gene-centered model of the organism should, after all, raise questions at the most fundamental level. What is the nature of the organism, and what distinguishes biological explanation from explanation in the physical sciences?
The articles in that special Nature collection did not lack for expressions of optimism. The sense of being at an impasse or an important turning point is certainly not universal among molecular biologists today, and perhaps not yet even widespread among those bench scientists busily gathering data and testing extremely narrow hypotheses. But, nevertheless, an awareness of an uncommon need for change and for receptivity toward new insights is, I think, the current “cutting edge” of biology. And the amazingly powerful research tools now in the hands of researchers will guarantee a stream of surprises that can only continue disturbing old dogmas.
References
Ball, Philip (2010). “Bursting the Genomics Bubble,” Nature online column (March 31). doi:10.1038/news.2010.145
Dermitzakis, Emmanouil T. and Andrew G. Clark (2009). “Life after GWA Studies,” Science vol. 326 (Oct. 9), pp. 239-40. doi:10.1126/science.1182009
Ding, Li, Matthew J. Ellis, Shunqiang Li et al. (2010). “Genome Remodelling in a Basal-like Breast Cancer Metastasis and Xenograft,” Nature vol. 464 (April 15), pp. 999-1005.
Hayden, Erika Check (2010). “Life is Complicated,” Nature vol. 464 (April 1), pp. 664-7.
Khoury, Muin J., James Evans and Wylie Burke (2010). “A Reality Check for Personalized Medicine,” Nature vol. 464 (April 1), p. 680.
Ledford, Heidi (2010). “The Cancer Genome Challenge,” Nature vol. 464 (April 15), pp. 972-4.
McClellan, Jon and Mary-Claire King (2010). “Genetic Heterogeneity in Human Disease,” Cell vol. 141 (April 16), pp. 210-7. doi:10.1016/j.cell.2010.03.03