The Mystery of an Unexpected Coherence
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: May 19, 2019.
Last revision: May 19, 2019.
We heard in
“The Organism’s Story”
that living activity has a certain future-oriented (“purposive” or
“intentional” or end-directed) character that is missed by causal
explanations of the usual physical and chemical sort. This is true
whether the end being sought is the perfection of adult form through
development, or the taking of a prey animal for food.
An animal’s end-directed activity may, of course, be very far from what we
humans know as conscious aiming at a goal. But all such activity
nevertheless displays certain common features distinguishing it from
inanimate proceedings: it tends to be persistent, so that it is
resumed again and again after being blocked; it likewise tends to be
adaptable, changing strategy in the face of altered circumstances;
and the entire activity ceases once the end is achieved.
This flexible directedness — this interwoven play of diverse ends and
means within an overall living unity — is what gives the organism’s life
its peculiar sort of multi-threaded, narrative coherence. Life becomes a
story. Events occur, not merely from physical necessity, but because they
hold significance for an organism whose life is a distinctive
pattern of significances.
The idea of narrative coherence, like the related idea of a governing
is a mystery for all attempts at purely physical explanation. This is why
even the explicit acknowledgment of an organism’s striving for life
— central as it may be for evolutionary theory — is discouraged whenever
biologists are describing organisms themselves. It sounds too much as if
one were invoking inner, or soul, qualities rather than material causes —
acknowledging a being rather than a thing. And it is true that our
physical laws, however combined, nowhere touch the idea of
Biologists much prefer to identify single, definitive causes. The cell
nucleus with its genome has long been viewed as the seat of such
causation. But, as we saw in our
discussion of epigenetics,
the single-minded pursuit of genetic causes has forcibly redirected our
attention to epigenetics, where we have discovered that genes are
circumscribed and given their meaning by the narrative life of the entire
cell and organism.
In what follows below we will consider this narrative coherence in a more
detailed way — first, in relation to one of the many activities of the
cell that can be considered under the heading of “epigenetics”. Then we
will look more briefly at a startling phenomenon that, already on its
face, renders absurd the idea of central genetic control. In both cases
we will be focused on molecular-level activity, which is precisely where
we have been most strictly trained to expect the absence of any coherence
other than that of “blind mechanism”.
The discovery of RNA splicing in the late 1970s was one of the
transforming moments in the history of molecular biology. To put it in
informal terms: the cleanly autocratic mastery of DNA gave way to massive
presumption by various scruffy elements of the cellular “rabble”. The
idea had originally been that a molecule of messenger RNA (mRNA) was
produced as a direct image of the “instructions” in a protein-coding gene
and was then exported from the cell nucleus to the cytoplasm. There it
yielded passively to translation, a process whereby a protein was
supposedly produced according to the exact specifications of the “genetic
code” previously copied from DNA into the mRNA.
Our growing knowledge of RNA splicing has, together with many other
developments in molecular biology, exploded just about every aspect of
this picture. We now know that, via an elaborately orchestrated
improvisational drama, many so-called epigenetic elements in the
come together to help decide what use will be made of any particular gene.
In particular, the cell has innumerable ways to obtain, design, and sculpt
whatever proteins it needs at the moment. RNA splicing is just one of
these — a massive reconfiguration process whereby a cell decides which
portions of an initially produced (precursor) RNA to cast aside for
other uses, and which ones to “splice” together into a mature mRNA. As we
have come to expect by now, these choices are strongly context-dependent,
with different protein variants being produced in different kinds of cell
or tissue, or under different cellular conditions.
This splicing involves much more than a minor stitch or two. The large
human dystrophin gene (whose malfunction is related to some forms of
muscular dystrophy) is said to require 16 hours for its transcription from
DNA into RNA. Of this time, 15 hours and 54 minutes is required for
transcripton of the non-protein-coding RNA sequences that will have to be
spliced out of the RNA in order to obtain a mature messenger RNA. That
may be a somewhat extreme case, but it remains true that the sequences to
be discarded are “commonly orders of magnitude longer” than the remaining
portions fit for the synthesis of protein
(Papasaikas and Valcárcel 2016).
But the most dramatic transformation involves the sequences remaining
after removal of the non-protein-related (“noncoding”) content. The
splicing activity can often select from among these sequences in differing
ways, thereby determining which functional portions of the precursor
molecule will be included in the mature mRNA. The protein eventually
resulting will vary depending on these alternative splicing
decisions. (The protein variations are referred to as isoforms.)
Over 90 percent of mammalian genes are thought to be alternatively
spliced, contributing greatly to physiological complexity. According to
one paper, “As cells differentiate and respond to stimuli in the human
body, over one million different proteins are likely to be produced from
less than 25,000 genes”
(de Almeida and Carmo-Fonseca 2012).
Further, “even relatively modest changes in alternative splicing can have
dramatic consequences, including altered cellular responses, cell death,
and uncontrolled proliferation that can lead to disease”
(Luco and Misteli 2011).
The title of one technical paper makes the point vividly: “Cell Death or
Survival Promoted by Alternative Isoforms of [the protein] ErbB4”.
You have doubtless heard many times how a mutation or engineered
alteration of such-and-such a gene “causes” this or that result. How
often, by contrast, do you hear that a slight change in the way your cells
orchestrate the sculpting of this or that protein can make the difference
between life and death?
The central player in the splicing drama is known as the
spliceosome, which is not so much a rigidly fixed thing or
structure as it is a complex performance. The performers include a few
critically important small RNAs and over 150
Together — although in several, separate, coordinated groups that must
continually reconfigure themselves during the process — they excise the
protein-unrelated pieces of the RNA and then stitch together a selection
of the ones remaining. Misjudging any of the potentially many places to
cut the mRNA — shifting the point of severance by a single “letter”, or
nucleotide base, out of (in many cases) thousands — could well render the
resulting mRNA useless for producing protein, if not downright harmful.
We heard a little bit in Chapter 3,
“What Brings Our Genome Alive?”,
about the puzzle of topoisomerases. In a way that is difficult to fathom,
these molecules make cuts in the DNA double helix in order to release
knots and “untangle” the seemingly indecipherable spatial complexity of
chromosomes (46 in the human case) that are tightly packed into the cell
nucleus. But the challenge for the spliceosome as it does its work seems
no less daunting. And the fact that there is indeed coherently
describable work to do already takes us beyond normal physical
explanation to the idea of an unfolding story.
The key, chemically active part of the spliceosome complex “is short lived
and reconstructed from individual pieces for each splicing event”.
(Papasaikas and Valcárcel 2016).
This is the part that actually cuts and stitches together the RNA once the
end-points for the next excision are chosen. Moreover, few of the scores
of proteins required for the activity stay together throughout the
intricate work on a single RNA. “At all transitions in the splicing
process, the spliceosome’s underlying RNA-protein interaction network is
compositionally and conformationally remodeled and at each step there is a
massive exchange of proteins”
(Wahl and Lührmann 2015).
But it gets worse. In multicellular organisms the mRNA being remodeled
possesses particular sequences that are supposed to act as signposts for
“attracting” the elements of the spliceosome to the correct sites for
cutting and stitching. But these signposts are often ambiguous or
contradictory, and provide only more or less vague hints. This is despite
the extraordinary complexity of the task facing the spliceosome, and the
large number of segments that commonly require removal.
“It has been proposed” [write two researchers] “that thousands of
different sequences” can function as directives for the spliceosome, with
only a few of the key “letters” in those sequences even being reliably
present. Further, many sequences that look rather like splice sites are
ignored by the spliceosome, while other sequences, despite lying at a
distance from the splice sites, nevertheless contextually influence site
recognition. So it appears that “hundreds of regulatory motifs may need
to be integrated” (and understood) in order for the spliceosome to
accomplish its surgery in harmony with current cellular needs
(Papasaikas and Valcárcel 2016).
Using the thing-oriented (rather than process-oriented) language available
to us, it is difficult not to speak of the spliceosome as a fixed
structure, and equally difficult to avoid suggesting that it has a
specific and well-defined task. What we see, however, is a remarkable
plasticity. This is illustrated, for example, by the fact that “nearly
all ‘activators’ of splicing can, in some cases, function as repressors,
and nearly all ‘repressors’ have been shown to function as activators
… it is clear that context affects function”
(Nilsen and Graveley 2010).
But this context-sensitivity extends also to the very definition of the
entire task, which looks utterly different, and requires wholly different
approaches and capabilities on the part of the spliceosome, depending on
the situation. Is the task to skip the next protein-coding segment of the
RNA? Is it to make sure that a choice is made between two such segments —
to retain only one and remove only one? Is it to choose an alternative
location for the beginning or end of a particular segment? Is it, in at
least some cases, to make the radical choice of preserving a
non-protein-coding segment in the final mRNA?
Each of these operations demands a different sort of coordination among
the many molecules involved, and the ways of approaching the work can
vary, one might almost say, “wildly”. “Mechanisms of alternative splicing
are highly variable, and new examples are constantly being
So there is not just one “spliceosome machine” (as some would like to call
it), and not just one task. The cloud of molecules participating (or
capable of participating, but “electing” not to) in the various splicing
operations face the challenge of working together in an unimaginably
sophisticated manner that somehow reflects the wider context and the needs
of the cell.
Who will disagree with the researchers who write, in what might even be an
understatement: “Working in a highly orchestrated manner, [the many parts
of the spliceosome] perform incredible feats of molecular gymnastics with
each round of splicing”
(Chen and Moore).
We have a problem
The problem of what it actually means to say that “molecules do the
work of splicing” is one of those vast blanks in scientific understanding
that are easily papered over today in favor of informational generalities
and convenient pictures of tiny machines busily, and in a
“mechanistically” respectable fashion, carrying on the work of a cellular
We already heard about the essential problem from cell biologist Paul
who spoke about the many degrees of freedom possessed by the cell’s
constituents in their watery medium, and about how these degrees of
freedom are so remarkably constrained and disciplined toward intricate
biological order at higher levels of observation. But it would be well to
consider the issues in a specific and more detailed context, such as that
of RNA splicing — and also to notice the general avoidance of these same
issues within the biological community.
“Avoidance” seems the right term, for the problem is, in a way,
widely recognized, although not meaningfully engaged. Referring to the
“huge number of potentially regulatory elements in a very crowded
nucleus”, University of Massachusetts geneticist Job Dekker wonders, “How
do cells ensure that genes only respond to the right regulatory elements
while ignoring the hundreds of thousands of others?”
It’s a good and obvious question. An editor of Science amplifies
it in a slightly different context this way: “If you think air traffic
controllers have a tough job guiding planes into major airports or across
a crowded continental airspace, consider the challenge facing a human cell
trying to position its proteins”. A given cell, he notes, may make more
than 10,000 different proteins under any particular set of conditions, and
it typically contains more than a billion individual protein molecules at
any one time. “Somehow, a cell must get all its proteins to their correct
destinations — and equally important, keep these molecules out of the
And once more: after a study showed that 70 percent of mRNAs in a cell are
specifically localized, Robert Singer of Albert Einstein College of
Medicine in New York City called it a “staggeringly large number”. He
went on: “It’s almost as if every mRNA coming out of the nucleus knows
The entire problem is perhaps most vividly framed when we consider one
further fact about RNA splicing. Not only is the spliceosome “a
remarkably dynamic and flexible molecular machine; its transitions are so
malleable that the whole reaction can eventually be reversed to generate
precursor mRNA from spliced products”
Rather than being the one-way pathway typically drawn in textbooks, almost
every step in the spliceosome cycle is readily reversible … [For
example, regarding the first and second chemical steps in splicing,] not
only can the spliceosome catalyze both chemical steps in forward and
reverse, it can even convert spliced products … back into unspliced
(Chen and Moore)
That is, the splicing choreography can take an already spliced RNA along
with a section previously removed from it, and reinsert that
section into the RNA.
The reversibility and flexibility underlying the finely gauged,
activity of RNA splicing are hard to overestimate. It’s not just that
“every major subcomplex addition step along the yeast spliceosome assembly
pathway” has been shown to be
Beyond this, many of the individual proteins coming together in the
spliceosome (or remaining apart) are themselves subject to modifications
that are often decisive for how the proteins will function within their
And these modifications, too, are dynamic and reversible. They are also
mutually entangled, with one kind of modification in one protein likely
affecting, or being affected by, diverse modifications in other proteins.
The untraceable lines of cause and effect blur into — and become
subordinate to — the overall
Everything I have said about RNA splicing testifies to a balance of
conformations and movements that have the potential to tell any number of
greatly or slightly differing stories, depending on the cellular context.
But this is not a truth that many are eager to acknowledge. Instead, the
topic gets changed. Job Dekker, who asked above how genes recognize and
respond only to a minuscule proportion of the available regulatory
stimuli, immediately went on to offer what he thought was one part of the
Recent work has revealed a surprisingly simple strategy for matching genes
to only some regulatory elements, which involves the spatial organization
and folding of chromosomes inside the nucleus.
Certainly this folding, which we encountered in
is an important part of the answer — the answer, that is, to a different
question: “What are the physical and chemical processes at work
underneath the storyline?” But the question about the narrative
thread itself is only broadened by this answer. Now we need to know: How
does the extraordinarily intricate spatial coordination of events in the
nucleus, including chromosome folding and the taming of “tangles”, occur
in just the right way? What guides all the molecules involved in
chromosome dynamics to manage the complex folding and spatial distribution
of chromosomes so as to connect all the “right” loci to each other
according to needs that may continually change during development and
under varying conditions?
Dekker concludes his statement with this: “Future studies will no doubt
unveil how [certain chromosome domains] are established and how they
insulate genes from the wrong crowd.” Yes, and those studies will
continue to reveal the explosively expanding universe of interweaving
regulatory factors that only make even more remarkable the integral and
unified, narrative performance of a single cell.
Despite Dekker’s choice of language, we can be sure that individual
molecules do not “know” right from wrong — and he is surely not saying as
much. But the language he so naturally feels pressured into using does
serve to keep the real problem in view: cells and organisms do
somehow work to avoid or correct errors and to achieve the right outcomes.
But this is also to say: the explanatory task that researchers are
supposedly addressing — How does the cell manage to accomplish what it
does? — is not yet being touched by the enumeration of physical
interactions that know nothing of right and wrong.
The central question of today’s biology is being ducked.
Shattering the Genome
Our second case is a long way from RNA splicing — and also, it might seem
at first, from the human being.
A dose of ionizing radiation equal to 10 grays (a measure of absorbed
radiation) is lethal to the human body. Most bacteria cannot survive 200
grays. But then there is the bacterium known as Deinococcus
radiodurans: it can endure over 17,000 grays and do quite well, thank
you. Never mind that its genome is thoroughly shattered by the assault.
Here’s what happens. Ionizing radiation can damage DNA in various ways,
perhaps worst of all by causing double-strand breaks. These are breaks
across both strands of the double helix. The familiar bacterium, E.
coli, not at all untypically, dies when it suffers about four
double-strand breaks per each of its four-to-eight circular DNA molecules.
Deinococcus radiodurans, by contrast, can survive over a thousand
double-strand breaks. This means that it continues life after its genome
is broken into many hundreds of small fragments. It does so by proceeding
to put its genome back together again when living conditions improve — a
daunting task, to say the least.
Deinococcus radiodurans is one of a small class of single-celled
organisms with extreme radiation tolerance. Actually, it tolerates
various other extreme conditions as well — some of which, such as
dessication, likewise reduce its DNA to genomic shards. It can, for
example, survive in a waterless desert for years until moistened again —
which could happen, for example, when winds lift it in a cloud of dust
from the Sahara, high into the atmosphere (where it is exposed to damaging
ultraviolet radiation 100 to 1000 times that on earth’s surface), and
across the Atlantic ocean to the South American jungles. D.
radiodurans can be found on Antarctic ice, on dry frozen marble, and
in the farthest depths of the sea.
Who’s on first — genes or proteins (or neither)?
Biologists have been intrigued by this peculiar survivor (along with some
of its kin) for several decades, and of late they have clarified its story
considerably. A central feature of that story is striking, because it
points toward a truth about organisms in general, not merely those with
extreme survival capabilities. The key finding is this: damage to DNA is
not, in the most direct sense, what proves lethal about radiation. The
primary issue, instead, is damage to proteins. As long as its proteins
remain functional, a cell can reassemble even a badly fractured genome;
but with damaged proteins, a cell is done for, with or without an intact
D. radiodurans employs a number of strategies for preserving its
rather commonplace “proteome”, or total inventory of proteins. These
strategies include (1) preventing the oxidative damage that results from
radiation, a goal it achieves in good part by means of an especially rich
supply of antioxidants; (2) eliminating, before they can cause mischief,
any proteins that do get damaged, while recycling their constituents; (3)
scavenging amino acids and peptides (protein constituents) from the local
environment, a capability that, together with the recycling, supports (4)
newly synthesizing any proteins that need replenishing.
The proteome thus preserved is then able to go about the task of
reconstructing a shattered genome — a task whose complexity at the
molecular level is stunning. (Many a bright but befuddled graduate
student has twisted his imagination into knots while trying to picture the
actual textbook sequence of DNA damage repair in human cells.)
Nevertheless, the task is accomplished in the cells of all organisms.
What distinguishes D. radiodurans is its ability to carry out this
task to an exceptional degree by maintaining its store of proteins intact
under extreme duress.
In sum, according to Anita Krisko and Miroslav Radman, researchers at the
Mediterranean Institute for Life Sciences who have been studying D.
radiodurans, “biological responses to genomic insults depend primarily
on the integrity of the proteome … This conclusion is the
consequence of the fact that dedicated proteins repair DNA, and not vice
versa”. Moreover, “this paradigm is fundamental in its obviousness (no
living cell can function correctly with an oxidized proteome) and, if it
is true, must be universal, that is, hold also for human cells”.
All this says something powerful about the longstanding genocentric
(gene-centered) bias of biologists. Krisko and Radman delicately hint at
the issue when they write in their paper:
The science of molecular biology was dominated by the notion of
information, its storage, transmission, and evolution as encrypted in the
nucleotide sequence of nucleic acids. But the biological information is
relevant to life only to the extent of its translation into useful
biological functions performed, directly or indirectly, by proteins.
(Krisko and Radman 2013)
This truth, as they also point out, applies to our understanding of cancer
and its treatment, which have long been focused on DNA abnormalities. But
instead, “an effective cancer therapy by tumor cell killing should target
the proteome, or both the proteome and genome, rather than the genome
alone”. Which is almost to say: it should reckon with the coherent life
narrative of the organism as a whole.
A sense of the whole
It was always a strange thing when biologists, attempting to penetrate the
thickly matted tapestry of cellular activity at one or another point and
disentangle the threads for analysis, decided that one type of element —
the gene or DNA sequence — was the place where all the activity logically
begins and from where it is controlled. There is in fact no starting
place and no part acting as controller. Any attempt to think in such
terms immediately crashes against the facts of cellular behavior.
no more shows proteins to be the
“controlling” elements than it does DNA.
The work on D. radiodurans can remind us that the activity of an
organism always reflects something like what we can only refer to
metaphorically as a “sense of the whole”. Repeating what was said above:
surely the protein molecules in this bacterium do not “know” what their
“goal” should be in dealing with all those disordered snippets of DNA.
But if the overall living context
remains sufficiently intact, then the mysterious power of self-realization
that we have been gently stalking in these several chapters — the coherent
storyline of a life — continues to assert itself. The narrative, whatever
its unexpected twists and turns, remains unbroken. If parts can be more
fully constituted from their shattered fragments, it is because a
functioning whole, with its intelligence, was already there.
The information we conceive as statically encoded in DNA is a kind of
bland reduction of the living intelligence at work in cellular
processes. When we occupy ourselves one-sidedly with genocentric
information, it is (to employ a rough analogy) as if we elevated a
notebook containing selected words, phrases, definitions, and grammatical
guidelines to a pinnacle high above Moby Dick or Faust or
War and Peace, worshipping the former as “information” while
ignoring the informed and meaningful activity through which inert
words and phrases are woven into soul-stirring tales.
A phrase-book or dictionary can be an essential resource, but it is the
organism (Deinococcus radiodurans in the case we have been
considering) that uses the dictionary to weave its own story — and even
reconstructs the dictionary when the pages fall into a disorganized heap
on the floor.
Estimates of the number of proteins participating in the spliceosome vary
widely. Some have said there are more than 300, and others “only” 80 — a
good indication of a fluidity of structure that is hard to nail down.
Wikipedia article, “Alternative Splicing”, accessed May 11, 2019.
Obviously, I am not referring to our own conscious perceptive capacities.
But neither am I referring to something less effective than our power of
perception. Whatever brings the biologically coherent and needful results
out of the currently inconceivable, creative “chaos” of the cellular plasm
is far beyond our efforts to follow, let alone to reproduce. We have to
think of a capacity higher than anything we consciously possess,
even if — as the psychosomatic unity of the organism suggests — our
consciousness is somehow contiguous with this higher capacity.
Chen and Moore 2014.
Chemical reactions are in general reversible. But the authors here are
noting that these particular reactions of the spliceosome occur under
conditions where they are “readily” reversible.
There are many other aspects of RNA splicing
not considered here — for example, the role played by certain metal ions
in the shift between different protein conformations (and therefore
between different protein functioning). Such ions are a long way from the
macromolecules in which biologists normally invest their sense of cellular
information, and yet their well-informed role is crucial to
Chen, Weijun and Melissa J. Moore (2014). “The Spliceosome: Disorder and
Dynamics Defined”, Current Opinion in Structural Biology vol. 24,
de Almeida, Sérgio F. and Maria Carmo-Fonseca (2012). “Design Principles
of Interconnections between Chromatin and pre-mRNA Splicing”, Trends in
Biochemical Sciences vol. 37, no 6 (June), pp. 248–53.
Dekker, Job, Joanna Wysocka, Iain Mattaj et al. (2013a). “Nuclear
Biology: What’s Been Most Surprising?”, Cell vol. 152 (March 14),
Graveley, Brenton R. (2011a). “Splicing Up Pluripotency”, Cell
vol. 147 (Sep. 30), pp. 22-4.
Krisko, Anita and Miroslav Radman (2013a). “Biology of Extreme Radiation
Resistance: The Way of Deinococcus radiodurans”, Cold Spring
Harbor Perspectives in Biology 2013;5:a012765.
Luco, Reini F. and Tom Misteli (2011). “More Than a Splicing Code:
Integrating the Role of RNA, Chromatin and Non-coding RNA in Alternative
Splicing Regulation”, Current Opinion in Genetics and Development
vol. 21, pp. 366-72.
Nilsen, Timothy W. and Brenton R. Graveley (2010). “Expansion of the
Eukaryotic Proteome by Alternative Splicing”, Nature vol. 463 (Jan.
28), pp. 457-63.
Papasaikas, Panagiotis and Juan Valcárcel (2016). “The Spliceosome: The
Ultimate RNA Chaperone and Sculptor”, Trends in Biochemical
Sciences vol. 41, no. 1 (Jan.), pp. 33-45.
Travis, John (2011). “How Does the Cell Position Its proteins?”
Science vol. 334 (Nov. 25), pp. 1048-9.
Wahl, Markus C and Reinhard Lührmann (2015). “SnapShot: Spliceosome
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Steve Talbott :: The Mystery of an Unexpected Coherence