In this materialist era, we like our reality hard and our truths weighty and rock solid. We may accept that there are states of matter less substantial than rocks, but in our imaginations we turn even fluids and gases into collections of tiny particles more or less closely bound together. Similarly, in our reconstructions of physiological processes, material structures come first, and only then can movement, flow, and meaningful activity somehow occur.
How, after all, can there be movement without things to do the moving? (It’s easy to forget that energy, fields, and forces are not things!) Ask someone to describe the circulatory system, and you will very likely hear a great deal about the heart, arteries, veins, capillaries, red blood cells, and all the rest, but little or nothing about the endless subtleties of circulatory movement through which, for example, the structured heart first comes into being (see Chapter 6, “The Unmechanical Heart”).
Yet there is no escaping the fact that we begin our lives in a thoroughly fluid and plastic condition. Only with time do relatively solid and enduring structures precipitate out as tentatively formed “islands” within the streaming rivers of cells that shape the life of the early embryo. As adults, we are still about seventy percent water.
One might think quite differently based on the scientific rhetoric to which we are daily exposed. This could easily lead us to believe that the real essence and solid foundation of our lives was from the beginning rigidly established inside those very first cells. There we find DNA macromolecules that, in a ceaseless flood of images, are presented to us as crystalline forms in the shape of a spiraling ladder — a ladder whose countless rungs constitute the fateful stairway of our lives. So, too, with the proteins and protein complexes of our bodies: we have been told for decades that they fold precisely into wondrously efficient molecular machines whose all-important functions are predestined by the DNA sequence.
The trouble is, biological researches of the last few decades have not merely hinted at an altogether different story; they have (albeit sometimes to deaf ears) been trumpeting it aloud as a theme with a thousand variations. Even the supposedly “solid” structures and molecular complexes in our cells — including the ones we have imagined as strict determinants of our lives — are caught up in functionally significant movement that the structures themselves can hardly have originated. (See Chapter 3, “What Brings Our Genome Alive?”, and Chapter 4, “The Sensitive, Muscular Cell”.)
Nowhere are we looking either at a static sculpture or at controlling molecules responsible for the sculpting. In an article in Nature following the completion of the Human Genome Project, Helen Pearson (2003) interviewed many geneticists in order to assemble the emerging picture of DNA. One research group, she reported, has shown that the molecule is made “to gyrate like a demonic dancer”. Others point out how chromosomes “form fleeting liaisons with proteins, jiggle around impatiently and shoot out exploratory arms”. Phrases such as “endless acrobatics”, “subcellular waltz”, and DNA that “twirls in time and space” are strewn through the article. “The word ‘static’ is disappearing from our vocabulary”, remarks cell biologist and geneticist Tom Misteli, a Distinguished Investigator at the National Cancer Institute in Bethesda, Maryland.
Everywhere we look, shifting form and movement show themselves to be the “substance” of biological activity. The physiological narratives of our lives play out in gestural dramas that explain the origin and significance of structures rather than being explained by those structures.
Hannah Landecker, a professor of both genetics and sociology at UCLA, having looked at the impact of recent, highly sophisticated cellular imaging techniques on our understanding, has written: “The depicted cell seems a kind of endlessly dynamic molecular sea, where even those ‘structures’ elaborated by a century of biochemical analysis are constantly being broken down and resynthesized.” And she adds: “It is not so much that the structures begin to move, but movements — for example in the assembly and self-organization of the cytoskeleton — begin to constitute structure” (Landecker 2012). See Figure 5.1.
And in a paper that appeared as I was writing this chapter, a team of biochemists from Duke and Stanford Universities point out how inadequate is our knowledge of the action of biomolecules when all we have is a frozen structure of the sort commonly reported in the literature. “In reality”, they say, “all macromolecules dynamically alternate between conformational states [that is, between three-dimensional folded shapes] to carry out their biological functions”:
Decades ago, it was realized that the structures of biomolecules are better described as “screaming and kicking”, constantly undergoing motions on timescales spanning twelve orders of magnitude, from picoseconds [trillionths of a second] to seconds. (Ganser et al. 2019)
Why, after all, should we ever have expected our physiology to be less a matter of gesturings than is our life as a whole?
According to the old story of the machine-organism, a protein-coding DNA sequence, or gene, is not only mirrored in an exact messenger RNA (mRNA) sequence, but the mRNA in turn is translated into an exact amino acid sequence in the resulting protein, which finally folds into a fixed shape predestined by that sequence. It was a picture of perfect, lawful, lockstep necessity, leading from DNA through mRNA to a final, functional protein.
“There is a sense,” wrote Richard Dawkins, “in which the three-dimensional coiled shape of a protein is determined by the one-dimensional sequence of code symbols in the DNA”. Further, “the whole translation, from strictly sequential DNA read-only memory to precisely invariant three-dimensional protein shape, is a remarkable feat of digital information technology” (Dawkins 2006, p. 171).
And these proteins in turn were thought to carry out their functions by neatly engaging with each other in a machine-like manner, snapping into place like perfectly matched puzzle pieces or inserting into each other like keys in locks.
We now know, and already knew when Dawkins published those words, that everything about this narrative was wrong — and not only the parts about DNA and RNA. Among proteins (those “workhorses of the cell”) every individual molecule lives in transformational movement — as a dynamic ensemble of rapidly “morphing”, or interconverting, conformations — and therefore does not have a “precisely invariant three-dimensional shape”.
But there is much more that wholly escaped Dawkins’ computerized imagination.2 Quite apart from the fact that each protein molecule rapidly shifts between distinctly different, folded structures, we now know that intrinsically disordered proteins — proteins that, in whole or in part, have no particular, inherent structure at all — are crucial for much of a cell’s functioning. Researchers refer to “fluid-like” and “surface-molten” proteins (Grant et al. 2010; Zhou et al. 1999). This is why biophysicist Konstantin Turoverov and his Russian and American colleagues tell us that “the model of the organization of living matter is changing to one described by highly dynamic biological soft matter”. For decades, they note, protein interactions were “considered to be rigid, where, for a given protein, a unique 3D structure defined a unique biological activity.” However,
it is now realized that many protein functions rely on the lack of specific structure. This recognition has changed the classical consideration of a functioning protein from a quasi-rigid entity with a unique 3D structure resembling an aperiodic crystal into a softened conformational ensemble representation, with intrinsic disorder affecting different parts of a protein to different degrees.3 (Turoverov et al. 2019, emphasis added)
Clearly, the finally achieved protein need not be anything like the predetermined, inflexible mechanism with a single, well-defined structure imagined by Dawkins. Proteins can be true shape-shifters, responding and adapting to an ever-varying context — so much so that (as the noted experimental biologist, Stephen Rothman has written) the “same” proteins with the same amino acid sequences can, in different environments, “be viewed as totally different molecules” with distinct physical and chemical properties (2002, p. 265).
Many intrinsically unstructured proteins are involved in regulatory processes, and often serve as Proteus-like hub elements at the center of large protein interaction networks (Gsponer and Babu 2009). They also play a decisive role in molecular-level communication within and between cells, where their flexibility allows them to modulate or even reverse the typical significance of a signal,4 in effect transforming do this into do that (Hilser 2013).
But the troubling question arises: if unstructured proteins, or unstructured regions in proteins, are not “pre-fitted” for particular interactions — if, in their “molten” state, they have boundless possibilities for interacting with other molecules and even for reversing their effects — how do these proteins “know” what to do at any one place and time? Or, as one pair of researchers put it, “How is the logic of molecular specificity encoded in the promiscuous interactions of intrinsically disordered proteins?” (Zhu and Brangwynne 2015). In the next section we will look at one of the most recent and dramatic developments in cellular physiology, which has seemed to many biologists to offer an approach to this problem.
But first we should note the continuing mechanistic bias in the negative descriptors, “disordered” and “unstructured”, which I have grudgingly adopted from the conventional literature. Contrary to this usage, the loose, shifting structure of a protein need be no more disordered than the graceful, swirling currents of a river or the movements of a ballet dancer. Given the many living processes these proteins harmoniously support and participate in (including the movements of the ballet dancer), it would be strange to assume that their performance is anything less than graceful, artistic, purposive, and meaningful.
It has become increasingly clear in recent years, that, quite apart from its cytoskeleton and membrane-bound organelles (Chapter 4), the fluid cytoplasm in each cell is elaborately and “invisibly” organized. Various macromolecular complexes and other molecules, in more or less defined mixes, congregate in specific locations and sustain a collective identity, despite being unbounded by any sort of membrane. Here we’re looking at significant structure, or organization, without even a pretense of mechanically rigid form. How do cells manage that?
The problem was framed this way by Anthony Hyman from the Max Planck Institute of Molecular Cell Biology and Genetics in Dresden, and Clifford Brangwynne from the Department of Chemical and Biological Engineering at Princeton University:
Non-membrane-bound macromolecular assemblies found throughout the cytoplasm and nucleoplasm … consist of large numbers of interacting macromolecular complexes and act as reaction centers or storage compartments … We have little idea how these compartments are organized. What are the rules that ensure that defined sets of proteins cluster in the same place in the cytoplasm?
Even more puzzling, a “compartment” can maintain its functional (purposive) identity despite the rapid exchange of its contents with the surrounding cytoplasm. “Fast turnover rates of complexes in compartments can be found throughout the cell. How do these remain as coherent structures when their components completely turn over so quickly?” (Hyman and Brangwynne 2011).
Part of the picture that has recently come into focus has to do with the phases of matter and the transitions between these phases. (Think, for example, of the solid, liquid, and gaseous phases of water, or of solutions and gels — matter in different states.) For example, it’s possible for well-defined droplets of one kind of liquid to occur within a different liquid, like oil droplets in water.
We now know that molecular complexes containing both RNA and protein often gather together to form distinctive RNA-protein liquids that separate out as droplets within the larger cytoplasmic medium. Like liquids in general, these droplets tend toward a round shape, can coalesce or divide, can wet surfaces such as membranes, and can flow. The concentration of particular molecules may be much greater in the droplets than in the surrounding fluid, conferring specific and efficient functions upon the assemblies.
Enzymes and reactants can rapidly diffuse within the liquid droplet, while also moving with relative ease across the boundary between droplet and surrounding medium. Yet this boundary can remain distinct until phase-changing environmental conditions occur — conditions that might involve slight changes in temperature, pH, salt concentration, electrical charge, molecular densities, the addition of small chemical groups to proteins, degradation of proteins, the activity of gene transcription, or still other factors.
In this way, a very subtle change — originating, say, from an extracellular influence — can yield a dramatic transformation of cytoplasmic organization, just as a slight change in the temperature or salinity of water can shift an ice-forming condition to an ice-melting one, or vice versa.
Moreover, these phase-separated droplets can be highly organized internally: “multiple distinct liquid phases can coexist and give rise to richly structured droplet architectures determined by the relative liquid surface tensions” (Shin and Brangwynne 2017). Also, some parts may become gel-like,5 and others may form more or less solid granules. Many such droplets may pass through stages, from more liquid to more solid, before dispersing. They form in response to particular needs, perform their work, and then pass away. Others are more or less permanent. Phase separation has been called “a fundamental mechanism for organizing intracellular space” (Shin and Brangwynne 2017) — one where “function derives not from the structures of individual proteins, but instead, from dynamic material properties of entire [protein aggregates] acting in unison through phase changes” (Halfmann 2016).
We also know now that weak, transient interactions among intrinsically unstructured proteins and RNAs can result in crucial, flexible “scaffolds” that help to assemble these phase-separated aggregates, drawing in a set of functionally related molecules. “Weak”, “transient”, and “flexible” in my description here might be taken as indicators of the living, responsive, and non-machine-like character of the activity.
When things happen in the cell, phase transitions often play decisive roles, as a University of Colorado group discovered when looking at phase transitions in a small roundworm. According to the researchers, these transitions “are controlled with surprising precision in early development, leading to starkly different supramolecular states” with altered organization and dynamics. “Reversible interactions among thousands of [these phase-separated] complexes”, the authors found, account for “large-scale organization of gene expression pathways in the cytoplasm” (Hubstenberger et al. 2013).
All this is, if you think about it, an amazing departure from the kind of picture once burned into the minds of biologists such as Richard Dawkins, from whom we heard some errant words above. Once there were dreams of compelling digital instructions in DNA; of machine-like interactions between molecules; of deterministic formation and functioning of proteins; of the cell as a collection of cleanly separate, well-defined structures; and of cellular processes with fully predictable outcomes. But this dream has faded in the clear light of an entirely different reality where, among many other things, we watch a subtle and almost incomprehensible play of material changes of state.
These state changes can be affected by infinitely varying factors, such as the momentary interaction between a few molecules of a particular sort, the “minor” modification of a molecule, the increasing concentration of molecules in a particular location, or the slight temperature change of a degree or two — the kind of change that, in the larger world of nature, can freeze the surface of a lake where, a few days previously, fish routinely breached the surface to feed on insects.
Ice cools a drink, water carves a canyon, steam powers a locomotive … But ice brings down power lines, water floods towns, steam scalds skin. The context for these states matters, and there can be consequences if the appropriate state is perturbed or dysregulated. Now more than ever, we understand that physical states dictate biological function, and … recent papers have highlighted, at the subcellular and tissue levels, the importance of understanding those states and the conditions in which they occur. (Szewczak 2019)
We heard it asked earlier how intrinsically unstructured proteins “know” what to do at any one place and time. The old model assumed, rather puzzlingly, that random encounters between freely diffusing molecules accounted for many of the biological interactions we observe. But numerous researchers are now embracing the emerging picture of biological phase transitions as offering a very different understanding. Peter Tompa, a structural biologist from Vrije Universiteit Brussel in Belgium, sees certain phase transitions as directing “the movement of regulatory proteins in and out of organized subcellular domains” — part of the systematic maintenance of order in the cell7 (Tompa 2013).
This is all well and good, but does it tell us (as is often implied) what “controls” and “directs” molecular engagements in relation to the distinct needs of the cell at different locations and times? If the organization of phase-separated aggregates is what coordinates the activity of proteins, then we shouldn’t have to ask, as researchers are now asking, “Why do some proteins localize to only the nucleolus, while others can be found in both the nucleolus and Cajal bodies?” (Zhu and Brangwynne 2015). (Cajal bodies, like the nucleolus, are non-membrane-bound organelles found in the cell nucleus.) And, even if that question had a ready answer, the more fundamental issue would remain: if we assume that phase-separated droplets lead to properly coordinated protein interactions, then what explains the well-timed and intricately organized formation, structuring, and dissolution of the condensates?
This illustrates how (to get ahead of ourselves just a little bit) all attempts to answer questions of regulation in strictly physical terms never do really answer them. Rather, they lead only to an elucidation of previous physical states that again raise the same broad questions. There is no way to step outside the endlessly regressing physical explanations except by truly stepping outside them — except, that is, by turning to the play of intentions and end-directed activities that are implicit in the stories we find ourselves looking at.
After all, questions about biological regulation are questions about the significant patterning of living events, and these just are questions about a story — about the relation of continually adjusted means to the needs, strivings, and qualities of a particular life. It is no surprise, then, that our answers must be gained in the way we come to understand a story — not in the way we grasp the play of physical laws in, say, the movements of walking or speaking. (See Chapter 13, “Form and Cause in Biology”, and Chapter 14, “Biological Explanations — Or Biological Portraits?”)
I have long thought that some day water will be seen as the single most fundamental, “information-rich” physical constituent of life, and that revelations in this regard will outweigh in significance even those concerning the structure of the double helix. Not many biologists today would countenance such a suggestion, and I am not going to mount a serious defense of it here, if only for lack of ability. Time will decide the matter soon enough. But I was particularly pleased to find that the widely read and respected Nature columnist, Philip Ball, once entitled a piece, “Water as a Biomolecule”. In it he wrote:
Water is not simply ‘life’s solvent’, but rather an active matrix that engages and interacts with biomolecules in complex, subtle and essential ways … Water needs to be regarded as a protean, fuzzily delineated biomolecule in its own right. (Ball 2008a; see also Ball 2008b)
In another paper, Ball (2011) summarized some work bearing on the role of water in biological contexts. The main topic had to do with the relation between water, the binding cavity of an enzyme, and the substrate molecule to which the enzyme binds. It turns out, according to the authors of a study Ball cites, that “the shape of the water in the binding cavity may be as important as the shape of the cavity”. Ball goes on to remark:
Although all this makes for a far more complicated picture of biomolecular binding than the classic geometrical “lock and key” model, it is still predicated on a static or quasi-equilibrium picture. That, too, is incomplete.
Then he cites another paper on enzyme-substrate binding. There it is revealed that, before the binding is complete, water movement near the enzyme is retarded. “Crudely put, it is as if the water ‘thickens’ towards a more glassy form, which in turn calms the fluctuations of the substrate so that it can become locked securely in place. It is not yet clear what causes this solvent slowdown as a precursor to binding; indeed, the whole question of cause and effect is complicated by the close coupling of protein and water motion and will be tricky to disentangle. In any event, molecular recognition here is much more than a case of complementarity between receptor and substrate — it also crucially involves the solvent”.
All this suggests to Ball that “changes in protein and solvent dynamics are not mere epiphenomena, but have a vital role in substrate binding and recognition”.
Structural biologists Mark Gerstein and Michael Levitt (the latter a 2013 Nobel laureate in chemistry) wrote a 1998 article in Scientific American entitled “Simulating Water and the Molecules of Life”. In it they mentioned how early efforts to develop a computer simulation of a DNA molecule failed; the molecule (in the simulation) almost immediately broke up. But when they included water molecules in the simulation, it proved successful. “Subsequent simulations of DNA in water have revealed that water molecules are able to interact with nearly every part of DNA’s double helix, including the base pairs that constitute the genetic code” (Gerstein and Levitt 1998).
Early attempts to simulate protein molecules rather than DNA produced an analogous difficulty, with the same, water-dependent resolution. Gerstein and Levitt concluded their article with this remark:
When scientists publish models of biological molecules in journals, they usually draw their models in bright colors and place them against a plain, black background. We now know that the background in which these molecules exist — water — is just as important as they are.
That was in 1998. More than twenty years later the background remains to be filled in, even if we are now seeing signs of change. Philip Ball (who likes to cite that Gerstein/Levitt remark, and who reproduces two images like those to the right), has recently noted “an interesting sociological question”, namely, “why certain communities in science decide that particular aspects of a problem are worth devoting a great deal of attention to while others become minority concerns, if not in fact regarded as somewhat suspect and disreputable”. He adds:
Why should we place so much emphasis, for example, on determining crystal structures of proteins and relatively little on a deep understanding of the [water-related] forces … that hold that structure together and that enable it to change and flex so that the molecule can do its job? (Ball 2013)
Certain peculiar historical episodes have contributed to the disreputability of water as a “molecule of life”. (Too many researchers have thought they glimpsed something about water that went beyond current principles of understanding, so that work of this sort came to be seen as mystically tainted or “on the fringe”.) But surely part of the answer to Ball’s question has to do with the longstanding distortion of biology due to the emphasis upon code and mechanism. It is much easier to imagine the step-by-step execution of a computer-like code or the clean insertion of a key into a lock than it is to come to terms with fluid transformations — that is, with what is actually life-like.
The high era of molecular biology that followed upon discovery of “the” structure of the double helix, was indeed the Age of Simplicity. We can be thankful that the feverish enchantment of code and crystal is now giving way to an increasing recognition of movement, flow, dynamically flexible interaction, and the continual transfiguration of form — prime narrative elements in the organism’s story.
1. Figure 5.1 credit: Copyright Margot Quinlan. Reproduced with permission.
2. In “The Mystery of an Unexpected Coherence” we will look at alternative splicing of RNAs, one of many ways the DNA sequence is radically overridden by the larger purposes of the cell.
3. A terminological issue: Turoverov and colleagues speak more specifically of “highly dynamic biological soft matter positioned at the edge of chaos”. The abstract and perhaps rather tiresome notion of “the edge of chaos” is better captured in this context by a picture of lifelike processes — powerfully organized, but in a dynamic manner that continually adapts to circumstances from a purposive, and therefore not physically predictable, center of agency. The predictability, such as it is, lies in the reasonable expectation of coherence in the interweaving meanings we observe. (See Chapter 2, “The Organism’s Story”, Chapter 9, “The Mystery of an Unexpected Coherence”, and Chapter 10, “Biology’s Missing Ideas”.)
4. Biologists often speak of communication in terms of signals and signaling, where signal can hardly be distinguished in any absolute way from cause. However, “signals” tend to be spoken of where there are repeated, more or less stereotypical sequences (“pathways”) of molecular interaction between different cells, leading to more or less consistent consequences. This happens, for example, when a gland secretes a hormone (“signal”) that subsequently has effects in other parts of the body.
Wikipedia offered this definition of “cell signaling” in August, 2019: “Cell signaling is part of any communication process that governs basic activities of cells and coordinates multiple-cell actions. The ability of cells to perceive and correctly respond to their microenvironment is the basis of development, tissue repair, and immunity, as well as normal tissue homeostasis.” This easy acknowledgment of “communication”, “coordination”, “governance”, “perception”, and “correct response” — all within a science that, on the surface, refuses the normal and unavoidably immaterial meaning of these terms — illustrates the Biologist’s Blindsight described in Chapter 2, “The Organism’s Story”.
5. A sol-gel transition occurs when a solution (in which one substance is dissolved in another) passes into a gel state. The latter consists of a solid molecular lattice that is expanded throughout its volume by a fluid — water, in the case of a hydrogel. The fluid may constitute over 99% of the volume of the gel, yet the solid lattice prevents the gel from flowing like a liquid.
6. Figure 5.2 credit: Gerum, R. C., B. Fabry, C. Metzner et al. (2013). “The Origin of Traveling Waves in an Emperor Penguin Huddle”, New Journal of Physics vol. 15 (Dec.). Available at https://iopscience.iop.org/article/10.1088/1367-2630/15/12/125022 under the Creative Commons Attribution 3.0 license.
7. Here is one of innumerable examples of the role of phase separation in physiological processes: “Cells under stress must adjust their physiology, metabolism, and architecture to adapt to the new conditions. Most importantly, they must down-regulate general gene expression, but at the same time induce synthesis of stress-protective factors, such as molecular chaperones … [We] propose that the solubility of important translation factors is specifically affected by changes in physical–chemical parameters such [as] temperature or pH and modulated by intrinsically disordered prion-like domains. These stress-triggered changes in protein solubility induce phase separation into aggregates that regulate the activity of the translation factors and promote cellular fitness” (Franzmann and Alberti 2019).
8. Figure 5.3 credit: © Richard Wheeler (GNU FDL).
9. Figure 5.4 credit: From H. Frauenfelder et al. (2009). PNAS vol. 106, p. 5129.
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Steve Talbott :: Our Bodies Are Formed Streams