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Evolution As It Was Meant To Be
A work in progress by
Stephen L. Talbott

Chapter 11

A Mess of Causes

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This is a preliminary draft of one chapter of a book-in-progress tentatively entitled, “Evolution As It Was Meant To Be — And the Living Narratives That Tell Its Story”. You will find here a fairly lengthy article serving as a kind of extended abstract of major parts of the book. This material is part of the Biology Worthy of Life Project. Copyright 2017-2019 The Nature Institute. All rights reserved. Original publication: November 14, 2019. Last revision: November 14, 2019.

Tags: explanation/and causation; holism/contextual

The difficulties in talking about causes in biology have been recognized for at least two centuries.1 It’s just that the issues were largely set aside in the era of molecular biology due to the expectation that our rapidly growing powers of minute analysis would bring full causal understanding. Biology would soon be rid of its troublesome language of life in favor of well-behaved molecular mechanisms. And yet today, after several decades of stunning progress in molecular research, the struggle to fit our understanding of living activity into the comfortable garb of familiar causal explanation looks more hopeless than ever.

On one hand, most biologists seem unaware that there is a problem here — or, at least, they are unwilling to betray their awareness in professional circles. On the other hand (as we will see in this chapter), their scientific descriptions could hardly signal more dramatically the failure of the usual causal explanations. We seem to be looking here at another illustration of blindsight (Chapter 2).

In a previous chapter we considered epigenetics, which is commonly taken to be about the way epigenetic “marks” on chromosomes alter gene expression. But no sooner did epigenetics gain biologists’ attention than researchers began puzzling over the question, “Do epigenetic marks alter gene expression, or do changes in gene expression alter the marks?” And the question is still with us. According to Luca Magnani, a cancer researcher at Imperial College London,

It’s an absolutely legitimate question and we need to address it. The answer is either going to kill the field [of epigenetics], or make it very important. (quoted in Ledford 2015)

“Either kill the field or make it very important”. The comment expresses absolute confidence that we can discover unambiguous causation, which will in turn settle the matter: either epigenetic changes cause gene activity (in which case they are very important), or they are mere effects of that activity, with little significance. It must be one way or the other. The general idea is that, if something is to contribute to scientific understanding, it must be the indisputable cause of an indisputable effect. And yet, as we will now see, this stubborn insistence on causal clarity continually prods biologists to offer embarrassingly incoherent explanations.

The seductive appeal
of master controllers

Consider the following remarks about a protein known rather blandly as “p53”. The remarks issue from a perfectly reputable source who is clearly aware of the subtleties and interwoven intricacies of coordinated, molecular-level activity in the cell. And yet this expert is lured by the mirage of unambiguous causation into offering a wondrously self-annihilating description:

The tumor suppressor p53 is a master sensor of stress that controls many biological functions, including [embryo] implantation, cell-fate decisions, metabolism, and aging … Like a complex barcode, the ability of p53 to function as a central hub that integrates defined stress signals into decisive cellular responses, in a time- and cell-type dependent manner, is facilitated by the extraordinary complexity of its regulation. Key components of this barcode are the autoregulation loops, which positively or negatively regulate p53’s activities.

To start with, then, we have a master sensor (p53) that controls various fundamental cellular processes, and yet is itself wholly dependent on the signals it receives and is subject to “extraordinarily complex” regulation by certain autoregulation loops. While all these loops regulate p53 (some positively and some negatively), one of them, designated “p53/mdm2,”

is the master autoregulation loop, and it dictates the fate of an organism by controlling the expression level and activity of p53. It is therefore not surprising that this autoregulation loop is itself subject to different types of regulation, which can be divided into two subgroups … (Lu 2010).

So the master controlling sensor is itself subject to a master controlling process (one of several regulatory loops) that dictates the fate of the organism. But this master loop, it happens, is in turn regulated in various manners (as the author goes on to say in the rest of the article) by a whole series of “multi-layered” processes, including some that are themselves “subject to direct regulation by mdm2” — that is, they are regulated by an element of the regulatory loop they are supposed to be regulating.

It is hard to believe that the confusion here is unavoidable. By now every biologist knows how regulatory processes extend outward without limit, connecting in one way or another with virtually every aspect of the cell. But this only underscores the undisciplined terminological confusion continuing to corrupt molecular biological description today. When key regulators are in turn regulated, and controllers have their fates underwritten or redirected by other players, where within the web of mutual interaction can we single out a master controller capable of dictating cellular fates? And if we can’t, what are reputable scientists doing when they claim to have identified such a controller, or, rather, various such controllers?

More than an innocent abuse of language

Here is a comment from another paper on p53:

Following DNA damage, the transcription factor p53 determines whether cells undergo apoptosis [self-induced cell death] or cell cycle arrest and DNA repair. To enable different cellular outcomes, p53 is regulated through its temporal expression dynamics and post-translational modification, and by interactions with chromatin, chromatin regulators and transcription factors.2

Here again we have the same terminological confusion, with p53 determining cellular outcomes, while it is itself regulated by many pervasive cellular processes. But the authors conclude their paper with these remarkably sensible statements:

The large number of p53 regulatory mechanisms and their cooperation in triggering specific expression programmes remain open areas for investigation. Systematic measurements in multiple conditions together with models integrating the multiple layers of regulation on p53 activity will be required to decipher the complexity of p53 function.

Why not leave the matter there, with this admirable spirit of openness to the phenomena as given, together with an acknowledgment of almost unsurveyable complexity? What is the compulsion to paste on top of this picture a contradictory assertion of open-and-shut causal determination?

And I do mean compulsion. How else to explain a comment that could serve as a fitting postscript to our discussion of RNA splicing in Chapter 9. Brenton Graveley, a geneticist at the University of Connecticut Stem Cell Institute, reported in 2011 on the discovery of a splice variant of the protein known as FOX-P1 — a variant that has a role in the generation of stem cells. After usefully elucidating some of what goes on, he offers this as his conclusion:

What controls the [FOX] 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 in the very act of acknowledging the fundamental “chicken-or-egg” paradox of all biological causation, he reflexively reverts to a kind of creedal affirmation of a still-hidden, but eventually-to-be-found Master Regulator.

If all those who use the language of biologically omnipotent control are really trying to describe something like “important influencers,” then that’s perfectly fine. But influence is not about mechanism and control; the things at issue just don’t have controlling powers. Nor, despite Graveley’s suggestion, is it about a simple flipping of yes-or-no switches. What we see, rather, is a continual mutual adaptation, interaction, and coordination explicable only in terms of the functional ideas through which we grasp the overarching meaning of what is going on (Chapter 7 “Context: Dare We Call It Holism?”).

What we see, that is, once we start following out all the interactions at a molecular level, is not some mechanism dictating the fate or controlling an activity of the organism. Rather (as I have been emphasizing throughout the preceding chapters), we simply observe an organism-wide, narrative coherence — a functional, end-directed, story-like coherence impossible to elucidate from a purely physical point of view. Only so far as they are caught up in this functional story do the individual molecular players find their proper roles.

The misrepresentation of this organic and rational coherence in favor of supposed controlling mechanisms is not an innocent inattention to language; it is a fundamental misrepresentation of reality at the central point where we are challenged to understand the character of living things.

Biological clocks: who
is keeping time?

Pick any topic in biology and you will encounter an egregious failure to “tie down” biological causes. Clockwork mechanisms are nowhere to be found — a fact that becomes particularly poignant in the investigation of “biological clocks” such as the circadian (daily) rhythms that figure so prominently in human and other forms of life. Biologists, of course, set out to identify the “master clock mechanism” that was presumed to “control” these rhythms, and, yes, they found a rhythmic feedback loop involving genes and transcription factors in a certain area of the brain that seemed the perfect candidate. It quickly came to be viewed as the decisive governor of circadian rhythms in the body:

In mammals, the anatomical structure in the brain that governs circadian rhythms is a small area consisting of approximately 15,000 neurons localized in the anterior hypothalamus, called the suprachiasmatic nucleus (SCN). This “central pacemaker” in the SCN receives signals from the environment and, in turn, coordinates the oscillating activity of peripheral clocks, which are located in almost all tissues. (Berger and Sassone-Corsi 2016)

And yet (as this statement already indicates), ongoing research has revealed distinct “clocks” in different mammalian organs and tissues, and indeed in every cell. These “clocks”, it turns out, are not merely on the receiving end of a central, governing coordination, but rather are themselves factors in that coordination, and also, it now seems, are interwoven with just about all aspects of the organism’s physiology — metabolism, reproduction, cell growth and differentiation, immune responses, central nervous system functions …

In each of these areas the quest for causes and master controllers leads to the usual perplexity about who’s doing what to whom. For example: “Although metabolism is thought to be primarily downstream of the cellular clock, numerous studies provide evidence that metabolic cycles can operate independently from or even influence circadian rhythms” (Kumar and Takahashi 2010). At the molecular level, one research team remarks that the enzymatic function of a certain clock protein “may be controlled by changing cell energy levels, or conversely, could regulate them” (Doi et al. 2006). In general: “It seems that connections between the circadian clock and most (if not all) physiological processes are bidirectional” (Yang 2010).

What we’re gaining from all this research is a wonderful portrait of the organism as a rhythmic being. Investigators have not found controlling mechanisms that single-handedly establish or govern the circadian rhythms of the organism, but rather are discovering how those rhythms come to expression at every level and in every precinct of the organism — perhaps more centrally here and more peripherally there, but altogether in a single, organism-wide harmony that is also linked to environmental rhythms. There is no sensible way, as a scientist, to speak of particular mechanisms that explain this harmony. Instead, every isolated “mechanism” is found to be a reflection of the harmony, and we thereby gain further, detailed understanding of how the whole organism functions as a being in time.

Is any of this a surprise? Should we expect, say, that a “master regulator” of digestion exists? Would it be the stomach? The small intestine? The large intestine? The pancreas? The liver and gall bladder? The metabolism taking place in every cell? The brain that sends various coordinating nervous signals to different organs? We would certainly look more to the stomach than, say, to the heart, but the fact remains that the organism as a whole is the closest thing we have to a “master regulator”. What we see in all the functions of the so called “clocks” and “regulators” of circadian rhythms is simply the functioning of those rhythms in the most recognizable or most focal places. But they merely put on more obvious display the rhythmic functioning of the entire body.

A well-studied worm

Or, we can choose a different example. If there was any place where biologists expected a causal explanation of the organism to emerge clearly, it was in the study of Caenorhabditis elegans, a one-millimeter-long, transparent roundworm whose private molecular and cellular affairs may have been more exhaustively exposed than those of any other organism. The adult hermaphrodite has exactly 959 cells, each precisely identified as to origin and type: for example, 302 cells belong to the nervous system. The developmental fate of every somatic cell, from egg to adult, had already been mapped out by 1980. But this mapping and the associated molecular studies did not produce the expected explanations.

Sydney Brenner — who received a 2002 Nobel prize for his work on C. elegans — acknowledged that development “is not a neat, sequential process … It’s everything going on at the same time”. Even regarding the carefully mapped cell lineages of this “simple” roundworm, “there is hardly a shorter way of giving a rule for what goes on than just describing what there is”. In other words, the only “rule” for the development of this worm is the entire developmental description of it. When critics suggested he had not really come to an understanding of the worm, but had “only” described it, Brenner responded, “I’m not sure that there necessarily is anything more to understand than what it is” (Lewin 1984).

The difficulties of linear, causal explanation encountered by the C. elegans researchers were not accidental. You can’t explain an organism of meaning, and you don’t need to. You need only allow it, like any meaningful text, to speak ever more vividly and clearly, in ever greater detail, so as to tell its unique and unrepeatable story.

The separate processes do not make tidy explanations because they are not really separate and are not doing just one thing. They are harmonizing with everything else that is going on in the organism. We gain understanding when we learn to recognize this harmony in every aspect of the organism. Various analyses can play a crucial role in bringing clarity to our understanding, but (to shift our metaphor slightly) the full picture takes shape only when the analytical threads are woven back into the larger fabric of meaning.

Of crosstalk, horror
graphs and collaboration

One final example. Molecular biologists speak about signals arriving at receptors on the cell surface. The signals are said to bear messages, which are then transferred (as it often happens) from the receptors to a series of further messengers internal to the cell, who may, among other possibilities, finally convey the message to the cell nucleus. There the message may be interpreted to require the increased or decreased expression of a gene coded for a particular protein. The players in the signaling are, of course, molecules, with proteins being the usual focus of research.

The terminology so naturally resorted to here vividly evokes language, meaning, and communication — something we saw exemplified in Chapter 2, “The Organism’s Story”. But, of course, due to habits of blindsight within biology, this usage is typically treated as “mere metaphor”. Signaling pathways have long been regarded as neat, linear sequences of molecular interactions by which an initial encounter — say, the binding of a hormone to a cell membrane receptor — leads to a predetermined result. It’s almost as if the language of molecules and cells were merely one of mechanism and logic — not a true language at all.

But the language is in fact much richer than that. Signaling pathways help to maintain a coherence of meaning within and between cells. Take, for example, the work by a team of molecular biologists at the Free University of Brussels. They investigated how signaling pathways interact or “crosstalk” with each other. Tabulating the cross-signalings between just four such pathways yielded what they called a “horror graph”, and quickly it began to look as though “everything does everything to everything” (Dumont et al. 2001), much like the way any given term in a meaningful text can modify the meanings of all the other terms. Other researchers speak of a “collaborative” process that can be “pictured as a table around which decision-makers debate a question and respond collectively to information put to them” (Levy et al. 2010).

Even considering a single membrane receptor bound by a hormonal or other signal, you can find yourself looking, conservatively, at a billion possible states, depending on how that receptor is modified by its interactions with other molecules. Despite previous belief, there is no simple binary rule distinguishing deactivated receptors from those activated by some combination of signals in a particular context. “The activated receptor looks less like a machine and more like a … probability cloud of an almost infinite number of possible states, each of which may differ in its biological activity” (Mayer et al. 2009).

Our problem lies in adequately imagining the reality. When a single protein can combine with several hundred different modifier molecules, leading to practically infinite combinatorial possibilities, and when that protein itself is an infinitesimal point in the vast, turbulent molecular sea of continual exchange that is the cell, and when the cell is one instance of maybe several trillion cells of some 250 different major types in the human body — in muscle and bone, liver and brain, blood and artery — well, it would be understandable if some of those seeking mechanistic or computer-like “controllers” preferred not to stare too long at this picture.

Nevertheless, we should keep in mind that the “collaborative” process mentioned above involves not just one table with “negotiators” gathered around it, but countless tables with countless participants, and with influences radiating in all directions as countless local “decisions” are made in a manner somehow disciplined by the unity and immaterial, multidimensioned interests of the organism as a whole.

In other words, not only are the elements of an individual signaling pathway extremely flexible and adaptive; the individual pathway itself, once thought of as discrete and well-defined, doesn’t really exist — certainly not as a separate “mechanism”.

In sum: messages are not physically discrete, and they do not fly back and forth as elements of a predefined cellular logic. They move as dynamically sculptured, interwoven patterns of force and energy. Their meanings are mimed or gestured — neither translated into, nor reduced to, a kind of expressionless Morse code, nor impelled along precisely incised channels like computer instructions. And what holds them together amid the ceaseless flow and crosstalk and molecular transformation of the cellular plasm is the unity of meaning that is the whole cell and whole organism. This unity is there for us to observe directly, and we all recognize it, whether with blindsight or otherwise.

The problem of causation
is fundamental to biology

The powerful compulsion to identify decisive causes, even at the expense of painfully self-contradictory language, strongly suggests that a one-sided and unrealizable ideal of biological explanation is at work. Under its influence we aim to discover a physical lawfulness reflecting, above all, our experience with machines — a lawfulness of precise, unambiguous control, where one thing can be said, without unwelcome qualification, to make another thing happen.

Think of a machine. Having conceived what we want it to do, we design it to be a closed system whose intended functioning is more or less immune to contextual interference. And we try to do much the same in many scientific demonstrations. For example, we can create a vacuum in a chamber, and then release a leaf from the top of the chamber. It falls like a stone.

Of course, leaves in nature often travel upward. But the experiment in the chamber enables us to observe the singular and lawful play of gravity, without any disturbing “interference” from the resistance or movement of air. We can then — and only then — say that gravity appears to make the leaf fall, just as the simple laws governing the gears and springs of a mechanical watch make the watch perform as a reliable keeper of time.

But when the biologist tries to see an animal in the same mechanistic light, as a closed system without interfering factors, the attempt fails miserably. This is because, for the organism, contextual interference is the whole point. As the meaning of its activity shifts from moment to moment, so, too, does the contextual significance of all the details of its life.

For example, when a deer is grazing in a meadow, its glimpse of a vaguely canine form in the distance changes the meaning of everything from the flowers and grass the deer was eating, to its own internal digestive processes, to the expression of its genes. This happens, not because the distant form is exerting some strange physical force upon the deer, but because that form becomes part of a now suddenly shifted pattern of meaning.3

Or (to focus on the cellular level): when a cell enters into mitosis, just about every detail of its physiology and chemistry takes on an altered meaning in light of the changing narrative context. Everything is now heading toward a new outcome. Molecules that had been participating in one set of interactions (and could easily still do so in purely physical terms) now enter into very different intermolecular relations. Similarly with a cell experiencing heat shock, oxygen deprivation or other stress, a cell coming into contact with new neighbors, or a cell proceeding along a path of embryonic differentiation.

Certainly we can still identify unambiguous causes in the organism. It is always possible to narrow the conditions of our experiments so severely that a consistent “causal arrow” for a particular interaction emerges under those conditions. But the whole point of life’s adaptability is to seek altered conditions according to present needs and interests. This is why there can be no fixed syntax, no mechanical constancy of relations among the parts. Rather than being a closed system relative to this or that cause, the organism is forever abandoning the coordinating principles of its old context in favor of a new and ever-changing meaning. Its story is always evolving.

More to come

I have argued here that biologists are facing a “causal mess” in their own backyard, and that the refusal to acknowledge it leads to painfully self-contradictory thinking. At the same time, I have hinted here and there that we have a better way to frame the entire issue of causation and explanation. We can, in particular, recognize the role of meaning, idea, and agency as organizing principles of biological phenomena — which, as I have pointed out in various chapters, biologists already do, even if in a blindsighted manner.

Unfortunately, however, my suggestion that we take our true understanding seriously is, in its present, rather undeveloped form, likely to strike contemporary biologists as itself confusing, as well as wholly unexpected. Many will ask in disbelief, “Can proper biological explanation really be bound up with meaning, idea, and agency?”

So it is time to confront this question more expansively. I will do my best in the following chapters.

Meanwhile, for the sake of any who may not yet be convinced about just how thoroughly the problem of cause and effect has bedeviled molecular biologists, I present Box 11.1 as a kind of appendix to this chapter. To keep the survey brief, I focus narrowly on certain issues of gene regulation, especially in relation to epigenetics and the organization of the cell nucleus. (You needn’t worry about the technical details; the general sense of the remarks is all that matters here.)

Box 11.1

Cause — Or Effect?

“Technological advances are … revealing an unexpectedly extensive network of communication within and between chromosomes. A crucial unresolved issue is the extent to which this organization affects gene function, rather than just reflecting it” (Fraser and Bickmore 2007).

“Together, these results further emphasize the role for RNA polymerase in shaping the chromatin landscape of the genome and point toward the difficulty in disentangling cause and effect in the relationship between chromatin and transcription” (Weiner et al. 2010, p. 98).

“Epigenetic modifications in Alzheimer’s disease: cause or effect?” — title of a paper. The conclusion: “Further studies are necessary” (Piaceri 2014).

“A long-standing question is whether [cell] replication timing dictates the structure of chromatin or vice versa. Mounting evidence supports a model in which replication timing is both cause and consequence of chromatin structure by providing a means to inherit chromatin states that, in turn, regulate replication timing in the subsequent cell cycle” (Gilbert 2002).

“While several studies using next-generation sequencing have revealed genome-wide associations between epigenetic modifications and transcriptional states, a direct causal relationship at specific genomic loci has not been fully demonstrated …” (Fukushima et al. 2019).

“Despite the difficulties in proving cause and effect, these examples convincingly illustrate how chromatin crosstalk can functionally increase the adaptive plasticity of the cell exposed to the changing microenvironment” (Göndör and Ohlsson 2009).

“A related unresolved question is whether chromatin loops are the cause or the effect of transcriptional regulation” (Deng and Blobel 2010).

“The enthusiasm for establishing whether epigenetic mechanisms link the environment with disease development must be tempered by the knowledge that the epigenome is dynamic and has as much potential to respond to disease as respond to the environment. Therefore it is very difficult to disentangle cause from consequence when studying epigenetic variation and disease” (Relton 2012).

“Despite abundant evidence that most kinds of tumor cells carry so-called epigenetic changes, scientists haven’t yet worked out exactly whether such glitches are a cause or a consequence of disease” (Kaiser 2010).

“The clarification of the cause-and-effect relationship of nuclear organization and the function of the genome represents one of the most important future challenges. Further experiments are needed to determine whether the spatial organization of the nucleus is a consequence of genome organization, chromatin modifications, and DNA-based processes, or whether nuclear architecture is an important determinant of the function of the genome” (Schneider and Grosschedl 2007).

“Although there is widespread agreement that genome form [such as folding and topological domains] and function [gene expression] are intimately connected, their causal relationship remains controversial” (Stadhouders et al. 2019)

“The spatial organization of the genome into compartments and topologically associated domains can have an important role in the regulation of gene expression. But could gene expression conversely regulate genome organization? … Recent evidence suggests a dynamic, reciprocal interplay between fine-scale genome organization and transcription, in which each is able to modulate or reinforce the activity of the other” (Steensel and Furlong 2019)

So we have, on one hand, an ongoing preoccupation with what is thought to be a “fundamental issue”:

Despite intensive studies of genome organization in the past decade, a fundamental issue remains regarding genomic interactions and genome organization as a cause or a consequence of gene expression. This problem is also pertinent to RNAs, which may have regulatory functions in transcription rather than being simply products of transcription. (Li and Fu 2019)

On the other hand, there is little if any effort to elucidate just what hangs upon this “fundamental issue” — or what might be the implications of the fact that the issue appears irresolvable so long as we insist upon unambiguous physical causation as the basis for biological understanding.

Notes

1. In his influential 1790 work, Kritik der Urteilskraft (subsequently published in English as Critique of Judgment), the philosopher Immanuel Kant wrote of the organism that “every part not only exists by means of the other parts, but is thought as existing for the sake of the others and the whole … also [the] parts are all organs reciprocally producing each other” (Kant 1790, Div. 1, para 65.)

In speaking of purely physical causation, we certainly would not say that parts exist for the sake of each other. But Kant’s treatment of these issues was central to a great deal of biological discussion during the following decades — and still surfaces frequently today, at least among philosophers of biology. But the technically oriented training of biologists themselves no longer encourages a familiarity with decisive issues at the foundation of their own discipline.

2. The quotation is from a Table of Contents description in Nature Reviews Molecular Cell Biology for Hafner, et al. 2019.

3. I make this same point with the wildebeest and lion in the chapter on “The Organism’s Story”.

Tags: explanation/and causation; holism/contextual

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Steve Talbott :: A Mess of Causes