Have Biologists Really Overcome Gene-Centered Thinking?

Stephen L. Talbott

Contents

Introduction

The Presence of the Past

The dethronement of the gene as the master controller of the cell and organism, may have been widely heralded over the past decade or so, but not many biologists have actually gotten the message.

The persistence of cause-and-effect thinking

The most fundamental problem lies not with the gene as such, but with the cause-and-effect thinking that has fastened itself upon the gene. Until this thinking is overcome and made more appropriate to the plastic organism, efforts to resist the centralized tyranny of the gene will result only in the distributed and confused tyranny of diverse molecules.

The irresistible pull of the gene

Moreover, all these little tyrants will tend to become mere servants of the gene as long as cause-and-effect thinking prevails. This is because genes offer the only (supposedly) stable elements of the sort required to anchor such thinking.

In one of its many forms, a cliché of our day declares that radical new ideas first provoke scorn, then a sense of revolution, and finally a yawn: “What’s the big deal; we already knew that”.

The once-unthinkable idea that “genes are not after all the essential internal determiners and explainers of the organism” has come at least part way along this clichéd trajectory. Certainly chastisement remains for those who too loudly disdain the old conviction. But at the same time an undercurrent of excitement, rising to an occasional rumor of revolution, are unmistakable in the pages of just about any technical journal you choose to look at. And, yes, you can already encounter a dismissive shrug of the shoulders by those advanced few who would like to think they “knew it all along”.

But the actual situation is much more complex than the cliché would have it. It’s not just that the three phases overlap one another, nor that any full acknowledgment of “paradigm change” awaits the passing away of the Old Guard. Crucially: even in their apparent triumph, new ideas may become acceptable only in a distorted or trivialized form — a form concealing old ways of thinking in a new guise — long before they are understood.

The presence of the past. I too, have heard the dismissive remark, “We’ve known this for a long while; what you are saying is old news” — this in response to my various claims that the organism manages its genes more than the other way around. But are genes today really seen in proper perspective by any substantial part of the molecular biological community? And do those who shrug their shoulders actually understand what they are so casually assenting to?

I suppose the first thing to note is the unapologetic and widespread defense of old views. There is, for example, the Nobel laureate geneticist, Sydney Brenner, who recently wrote that because DNA is the bearer of information,

“the whole of biology must be rooted in DNA, and our task is still to discover how these DNA sequences arose in evolution and how they are interpreted to build the diversity of the living world” (2012a*).

Referring to the organism as a kind of computer known as a “Turing machine”, Brenner claims that “at the core of everything are the [DNA] tapes containing the descriptions to build these special Turing machines (2012b*).

Then there is Craig Venter, who rode in with his white hat (or black hat, depending on who’s looking) to “save” the Human Genome Project just in the nick of time. In a New York Magazine profile of Venter, Wil Hylton describes a conversation with the highly accomplished scientist and entrepreneur, who is probably regarded as the leading synthetic biologist of our day:

When I asked Venter about his reception among scientists, he was uncharacteristically nonchalant. “Some senior biologists, who in theory should know better than anybody else, keep talking about the importance of the cell,” he shrugged. “They argue: ‘Well, the cell contributed something. It can’t just be the DNA’.” That’s like saying God contributed something. The trouble for these people, it is just the DNA. You have to have the cell there to read it, but we’re 100 percent DNA software systems”. (2012*)

Usually the assumption about DNA’s primacy is rather less “in your face” than Venter’s brashness might suggest. But it commonly remains no less definite even when the language is toned down. (See Box 1 for some more sober examples drawn from evolutionary theorists.)

Perhaps more surprisingly, a conviction about DNA’s role as the fundamental explainer of the organism finds explicit or implicit expression even in the writing of those researchers engaged in today’s dramatic exploration of all the ways the cell manages its DNA. To give but one example: three researchers prominent in various epigenetic studies refer in one of their papers to the “common ingredients (functional elements) that make up the human genome”. They then proceed to tell us that “When mixed in the right proportions, these ingredients constitute the information needed to build all the types of cells, body organs and, ultimately an entire person from a single genome” (Ecker, Bickmore, Barroso et al. 2012*).

Perhaps I am needlessly straining after the obvious, since even the most desultory browsing of the molecular biological literature will suggest the existence of thousands or hundreds of thousands of references, for example, to the way genes or DNA or the genome encode the information for making organisms and their parts. But I do not enjoy hearing that what I am saying is “old hat”, so I will go a little further in illustrating the facts of the case.

The situation is perhaps most extreme in the field of study considered foundational to all of biology: evolution. As I point out at some length in “Genes and the Central Fallacy of Evolutionary Theory” (Talbott 2012*), the core logical structure of evolutionary theory is rooted in a conception of organisms that have been reduced to little more than their genes. As the standard story, reiterated in countless textbooks, now has it, evolution depends on variation, inheritance, and differential fitness:

• The variation required for evolutionary change via natural selection consists solely or almost solely of mutations in the DNA sequence.
• The word “heritable” in the evolutionist’s vocabulary is a virtual synonym for “genetic”, so that the transmission of the genome becomes the whole content of inheritance so far as it matters for subsequent organisms and the evolutionary future.
• Differences in the fitness of organisms, determining their evolutionary success, are explained primarily by the way genes supposedly determine the form and features — the phenotype — of the organism.

Or, you can look at the thriving field of synthetic biology, where the overwhelmingly dominant assumption is that “engineering” a new kind of organism is more or less synonymous with stitching together novel DNA sequences. And, again, there’s the recent fervor over the idea of recovering extinct species by extracting DNA or an intact nucleus from fossil remains (for example, a mammoth) and inserting this into the egg of a related species (an elephant).

The assumption, of course, is that the “hybrid” egg and its contribution as a functioning whole can be ignored, because the DNA alone will be sufficient to define and resurrect the lost species. As an article in National Geographic puts it without so much as a second thought: “If the DNA inside the nucleus is well preserved enough to take control of the egg, it just might start dividing into a mammoth embryo” (Zimmer 2013*). No mention here of the reams of contemporary literature documenting how determinedly the cell gives direction to its nucleus and DNA.

Finally, we can hardly ignore British evolutionary biologist, Richard Dawkins. Controversial though he may be in some regards, his influence as both an effective popularizer of evolutionary theory and a contributor to it may be unequalled today. His notion of the “selfish gene” has become part of the common thought-world of the biologist. Dawkins captured the genocentric nature of that thought-world very well when he wrote: "It is easy to think of DNA as the information by which a body makes another body like itself. It would be more correct to see a body as the vehicle used by DNA to make more DNA like itself” (1996*). And again: “living organisms exist for the benefit of DNA rather than the other way around” (2006*). The pervasiveness of this kind of thought shows no signs of diminishing.

The persistence of cause-and-effect thinking. The strange thing is that, despite the stubborn persistence of gene-centered thinking, rapidly increasing numbers of biologists today want to disparage it. At times they seem indeed to be seeking something like a whole-organism point of view, and their growing sense of excitement is often expressed as a realization that “genes are not everything”; that there are many layers of gene regulation extending throughout the cell; that the three-dimensional organization of the nucleus is crucial to gene expression; that RNA splicing and editing, translational regulation, and post-translational protein modification are central determinants of all sorts of processes; that activities ranging from cellular signaling to membrane modification to molecular localization are subject to infinite variation, with those variations all potential bearers of meaning for the cell; and finally that, as we read in one paper after another, “context matters”. Many imagine biology to be moving toward new, unexplored territory¹.

So here we come to the crux of the matter. How do we reconcile the enduring influence of gene-centered thinking with the rising anticipation of a biology that will in one sense or another carry us “beyond the gene”?

We need to begin by recognizing why genes took central place as explainers of the organism in the first place. The answer, I suggest, is that they offered a kind of platform within the organism for launching physical, cause-and-effect thinking. The difficulty for such thinking, when it operates one-sidedly as our only respectable form of thinking, is that it has no firm anchor. It needs always to be pushed further and further back; the explanation of one cause can only reside in a preceding cause, which in turn demands another behind it, and so on without end. The process lying immediately before us never comes to expression as meaningful and understandable in its own right. We point to its antecedents, but the language of antecedents is not a language for describing phenomena in their own characteristic terms. By itself, this language cannot capture the insistent and very present character of a rose or hawk or wolf.

The mere pursuit of causal antecedents never fully satisfies. We can hardly refrain from seeking a reliable stopping place for the sake of our own mental orientation². That is, we seek a First Cause or Unmoved Mover, to which all the diverse phenomena of our investigations can be related, even if that stopping place offers little to our understanding. For the physicist, the First Cause became that preternatural act of creation ex nihilo known as the Big Bang, conjoined secondarily with belief in the absolute primacy of fundamental particles as the oddly insubstantial and conceptually remote “building blocks” of the familiar universe we find ourselves living in. The ultimate end of all explanation amounts to this: “The Big Bang did it”. Or it would amount to this if scientists actually stuck to cause-and-effect explanation, which turns out to be impossible despite their belief in its absolute primacy (Talbott 2004*).

For biologists, who face a discouraging instability and continual transformation of causal factors (Talbott 2010*; 2011*), the starting place for cause-and-effect reasoning became the gene. It was the single, more or less inert and fixed entity (at least so far as its bare sequence is concerned) that could be counted on (or so they thought) to remain faithfully itself. Therefore it seemed the only thing available to ground all their diverse analyses of biochemical and physiological processes. As we heard from Stephen Jay Gould (see Box 1 above), the gene is supposed to “lie at the base of a causal cascade in the development of organisms”. Never mind that, for the organism, this “base” has no basis apart from everything it is supposed to explain. Like the drowning man grasping at a hollow straw, the biologist hopes against hope for a solid, stable foundation in order not to feel adrift within a sea of criss-crossing and chaotically shifting causal arrows.

But, unfortunately, the organism itself as a dynamic, living presence is the only true foundation the biologist has. The central pathology of gene-centered thinking lay not so much in the fact that the gene was chosen as the First Cause, as in the fact that a molecular and local First Cause was appealed to at all. It was a thinking that sought to explain the organism by appealing to a chain of causes rooted in a single, inertly conceived part of the organism rather than by getting to know the organism as a whole. It failed to reckon with a truth that, at some level, we are all capable of recognizing: to understand an organism is more like entering deeply into a biography or life story than like watching a series of causes and effects. This remains true even when we see that story only as it is reflected back to us from the molecular level. (This theme is touched on in many of the papers in this “Biology Worthy of Life” collection.)

Yes, we do need to penetrate every part-aspect of the organism we possibly can, and there is a great and respected place in biology for analytical methods. But the results of our analyses gain meaning only so far as they find their proper place within a revealing portrayal. A single brush stroke by a great portrait artist tells us little when isolated from the profound intentions and aesthetic unity of the whole canvas.

And so the fixation upon genes themselves was never by itself the cardinal sin of the biologist. After all, in an organic unity, every part has unbounded potential to reveal the whole, and that potential certainly resides in our DNA as well as in membranes, signaling pathways, metabolic transformations, and all the rest. No, the essence of the trouble has remained largely unnoticed in the way twentieth century biologists seized upon a part of the cell or organism as a “controlling” element holding the decisive explanation for all the rest.

Admittedly, the problem became much worse when the chosen part turned out to be a bare and inert sequence — a sequence scarcely seen as a material reality at all, but rather as an abstract string of informational bits, as if the embodied chromosome and all the rest of the cell, just because they were so alive and dynamic and spoke so fluently, could thereby be dismissed as bearers of eloquent meaning. But the central problem for biologists today goes far beyond the now-apparent impotence of the gene as an isolated entity. It lies in the fact that, for the most part, even those scientists who, with heroic effort, pry themselves loose from the imperialistic gene, remain bound by the causal reasoning that tries to explain organic processes from the bottom up, as if those processes were constructed from building blocks.

The symptoms of failure on this latter count are everywhere. Nearly every attempt at understanding the functioning cell today produces a burgeoning number of “little first causes” (mechanisms) — causes that quickly multiply out of control like the brooms of the sorcerer’s apprentice. The imagined causal explanations become chaotic and mutually contradictory. There are “governing” factors, “controlling” elements, and “master regulators”, that do not in fact govern, control, or regulate with anything like the implied sort of law-like consistency. (See Box 2 for an example.)

It is hard to find a paper in molecular biology today that does not reflect, whether implicitly or explicitly, the mess biological explanation has gotten into. The language hovers between the biologist’s yearning for the straightforward causal mechanisms of the engineer and, on the other hand, a desire to do justice to the reality of organisms whose lawfulness is manifested in complex relations continually adapted to the organism’s own purposes, or life story.

The only way out of the dilemma is to realize that, in the organism, there are no linear chains of cause and effect insulated from contextual “interference” — a point I make in “From Physical Causes to Organisms of Meaning”. The one consistency in the plastic tangle of causes is the fact that they are, through the organism’s remarkable power of coordination, drafted into harmonious service of an ever-adapting whole. Or, better, the artifically isolated causes are in reality well-integrated expressions of that whole. Rather than explaining the whole, they embody and illustrate it, they participate in and have their share in its guiding intentions. The hope for biologists is that when they look in the right way, all the causally respectful details will enable them to see the governing unity for what it is.

As for the kind of situation molecular biologists find themselves in when they try to develop a strictly causal understanding of nuclear organization in general and gene expression in particular, please see Box 3.

The irresistible pull of the gene. Here is what we have seen so far. The gene continues to dominate biological explanation. At the same time, there is a growing awareness that the explanatory “imperialism” of the gene doesn’t square with the facts; it needs to be overcome. But because the more fundamental (and largely unrecognized) issue lies not so much with the gene itself as with the associated cause-and-effect thinking, attempts to move beyond the gene have resulted in the rather chaotic distribution of causes and effects among other elements of the cell, as if those elements were “little first causes”.

Such a situation is hardly sustainable. Biologists who occupy themselves in tracing out endlessly regressing, linear chains of causes will never grasp what presents itself here and now as the integral unity of the whole organism, whole cell, or even whole chromosome. Hints about this problem are voiced with increasing frequency today, often in the form of laments:

“We have learnt, for example, which molecules control cell division, cell polarity and cell fate, how transcription is regulated in both normal and stem cells, and how mechanical forces regulate gene expression. However, nowadays, despite the knowledge accumulated, we still do not know how all these molecules and cellular events work together in an integrated manner” (Castanon and González-Gaitán 2011*).

Note the cause-and-effect language of “control” and “regulation”, juxtaposed with the desire for an “integrated” vision. The real problem is evident right there on the face of the text. Integration cannot be characterized with the language of control. It becomes visible only through our ability to portray the whole organism as a unique, species-specific power of mutual coordination among parts, a dynamic, fluid, living process. Through such a portrayal we recognize how the organism, far from being a product of master causes, is itself the master weaver, continuously knitting kaleidoscopically shifting causal relations into coherent, adaptive patterns serving current need. Getting the clearest possible picture of this organically centered and highly directed activity in all its details and contextuality is what constitutes biological understanding.

Look again at a symptomatic text. (Don’t bother with the technical details. The problem I’m pointing to emerges clearly enough on the surface of the passage. I’ve added italics to highlight relevant terms.)

Despite changing our understanding of the regulatory network controlling pluripotency and reprogramming, this work also raises many questions to be addressed in future studies. For instance, what controls the FOXP1-FOXP1-ES splicing switch? What splicing factors are responsible for flipping this switch, and how are their expression and activities regulated? Answering these questions is like hunting down the ‘chicken-or-the egg’ paradox, but they will ultimately uncover the master regulator of stem cell pluripotency. (Graveley 2011*)

So we have a regulatory network controlling pluripotency. RNA splicing plays a part this network, and it in turn is controlled by certain “switching” factors. The interactive play of cellular constituents even brings the author face to face with the causally ambiguous chicken-and-egg problem. And still, despite this invitation to transcend the ceaseless quest for more fundamental causes — a quest that, as experience shows, will widen out into ever more tortuously distributed patterns of mutual interaction — this biologist clings to the bizarre conviction that, in the end, a single master regulator (whatever that could conceivably mean) will cut through the Gordian tangle, showing itself to be the one effective power explaining all the other aspects of pluripotency.

The immediate topic of the quoted passage has to do with pluripotency. But — and this is my central contention here — the kind of thinking it reveals inevitably drives one back toward the gene. Amid all the mutually intertwined, unstable, and ambiguous causes, the more or less constant double helix looms for machine-like thinking as a kind of pole star for navigation. It remains the one apparently reliable foundation for chains of cause and effect. Never mind the contradictions this entails.

And few do seem to mind the contradictions. Swiss-born genome and cell biologist, Tom Misteli, has been one of the more articulate spokesmen depicting various aspects of cellular dynamism, especially in the nucleus. Now a senior investigator at the National Cancer Institute, he assures us that “a true understanding of genome function requires integration of what we have learned about genome sequence with what we are still discovering about how genomes are modified and how they are organized in vivo in the cell nucleus”. His use of the passive verb (“are modified” and “are organized”) implies the guiding authority and coordinating activity of the larger cellular environment. But in the very next sentence Misteli returns to what apparently presents itself to his mind as an inescapable truism: “The genome is what defines an organism and an individual cell” (2013*).

We saw in the previous section that, for those engaged in the quest for causal explanations of the organism, the stable hitching post of the DNA sequence exerts an irresistible force of attraction. The nearly crystalline fixity of the double helix, when imagined in isolation from its cellular entanglements, provides a foundation for initiating in one’s mind countless “causal cascades”.

And this central force of attraction, it now appears, remains undiminished in the minds of most biologists even when they are tracing the lines of influence radiating from any number of other cellular factors. These factors can still, out of habit, be related to the genome as a kind of implicit administrative center. Each “little first cause” supposedly gains its relevance from the way it acts as a mere modifier of the “controlling behavior” of DNA (DNA that, in reality, has no behavior of its own). Thus, epigenetic marks on chromosomes become a “regulatory layer” immediately superimposed upon the genome, a layer whose whole importance is commonly imagined to reside in its effects upon gene expression. Likewise, signaling pathways and transcription factors become (to employ a rough metaphor) something like ambassadors directed at the genome in order to stimulate particular responses, much as courtiers placate and flatter the king in order to gain their share of royal largesse.

It all comes down in the end to the fact that biologists can abstract from the raw sequence of nucleotide bases in the genome something like a code. Codes are familiar and comforting territory for the contemporary scientific mind. But living processes are quite another matter; certainly they remain mostly alien to the thought-world of the molecular biologist. Nothing else in the molecular realm of the cell can match the convenient fixity of the genetic code — a fact that, as I point out in “Free Life and Confining Form”, makes the genome stand at the opposite pole from anything we might call the “Book of Life”, even if there were such an element in the organism. (Actually, I suspect we will some day understand that water, which qualifies and helps to organize everything that goes on in the cell, comes closest to filling the bill, although “wellspring” and “fountainhead” of life come to mind as far more appropriate phrases than “Book of Life”.)

Having begun this essay with a trite expression about the trajectory of new ideas, I might as well end in the same fashion. There is indeed a minority faction of biologists today who question the all-important role of genes in the evolution and development of organisms. We can only welcome the many signs that a new and fresher understanding is being sought. But at present this hope remains obscured under the long shadow of the genetic First Cause. The most fitting motto of the nascent movement for change might well be “The Gene is dead! Long live the Gene!”

Not yet quite a revolution. But perhaps a moment to be seized.

Notes

1. I do not attempt to document this new movement here, considering the task superfluous. Many relevant quotations are in the main paper (to which this article is a kind of sidebar) and all the other papers in this collection. But, for the sake of any doubtful minds, here are a few additional references:

• In the April 25, 2013 issue of Nature, columnist Philip Ball* wrote that sixty years after the discovery of the double helix, “we do not know what most of our DNA does, nor how, or to what extent it governs traits. In other words, we do not fully understand how evolution works at the molecular level”. He concluded his piece by suggesting that we “do DNA a favour and lift some of the awesome responsibility for life’s complexity from its shoulders”.
• The gene is “an old-fashioned concept” according to one of the most published RNA and epigenetics researchers, the Australian John Mattick (quoted in Finkel 2010*).
• In a press release citing research led by the prominent geneticist, Joseph Ecker, the Salk Institute for Biological Studies in La Jolla, California, noted that “The more biologists map the genomes of various organisms (their entire genetic code), the more they are discovering discrepancies between what the genetic code dictates and how organisms actually look and function”. Ecker himself is quoted as saying that “Our study shows that it’s not all in the genes”, and “Since none of these patterns of variation and inheritance match what the genetic sequence says should happen, there is a clearly a component of the ‘genetic’ heritability that is missing” (Salk Institute 2011*).
• “Yet today, even as we know the genomic parts list of the cell, we realize that there is a huge gap in our mechanistic understanding of the logic of how these systems work. On the one hand, we can observe these beautiful systems that yield complex cellular structures, movements, and regulatory decisions; on the other, we have a list of molecular parts that somehow underlie these behaviors and decisions. But the middle ground linking how these parts fit together and work as a system is often missing. We have a serious gap in the mesoscopic mechanistic understanding of how microscopic molecules work together to yield complex macroscopic behavior” (Lim, Alvania and Marshall 2012*).

  The persistence of old modes of thinking alongside puzzlements begging for a new sort of understanding is particularly obvious in this quotation.

For more on the changing understanding of genes, see the associated article, “Indefinable Genes and the ‘Wild West’ Genomic Landscape”. And, if you’re interested in the defensive reaction often provoked by any “downgrading” of the gene, see some of the responses to Philip Ball’s article given in Salleh 2013*.

2. For true satisfaction, that stopping place would have to be in one way or another understandable in its own terms, even though it were connected to much else. Otherwise, how could it anchor any further understanding along the chain of causes? But the only stopping place scientists in general know to seek is a place where the causal chain arbitrarily, and without providing any illumination, comes to an end. See immediately following text. I am not, by the way, arguing that we should look for any such stopping place; the felt need for it is an artifact of one-sided, cause-and-effect thinking. Rather, we must try to understand everything before us as fully as we can in its own terms — terms that include its participation in the conditions around it.

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Steve Talbott :: Have Biologists Really Overcome Gene-Centered Thinking?