A Mess of Causes
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
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 2017-2021
The Nature Institute.
All rights reserved. Original publication: November 14, 2019.
Last revision: November 14, 2019.
The difficulties in talking about causes in biology have been recognized
for at least two
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
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
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
(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
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
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
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
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
— 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
What controls the
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
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
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
“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
coherence — a functional, end-directed,
coherence impossible to elucidate from a purely physical point of view.
Only so far as they are caught up in this functional
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
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”
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
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
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”
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
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
“The Organism’s Story”. But, of course, due to habits of
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
(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
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
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
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
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
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
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
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 10.1 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.)
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”
“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”
“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
(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
“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”
“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
(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.
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
(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.
The quotation is from a Table of Contents description in Nature Reviews
Molecular Cell Biology for
Hafner, et al. 2019.
I make this same point with the wildebeest and lion in the chapter on
“The Organism’s Story”.
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