LIE TSE 列 子
Where does the 'animation' of biological chemistry come from? Where a little-known role for physics is revealed
Antoine Danchin © 2022
This text has been published in French in the magazine of the association a-Ulm in the 32th issue of the Archicube.
n a theater play that has remained unpublished, The Well of Syene, Jacques Monod stages the struggle of Science against all obscurantism (including the quest for power or glory), at the time of Hellenistic Egypt. Epistemos, the hero with whom he clearly identifies, sums up what science is for him: "To enslave nature? A strange expression. To achieve this, Philokratos, you must first respect her, listen to her, obey her. That's what I'm trying to do, clumsily. Look at this top. I can throw it, not enslave it; it does not obey me, but a law [...], a law I do not yet know". Through this vision, we understand that the purpose of Science is to discover, to reveal the secrets of nature through the uncovering of original laws. This somewhat naïve vision—and one that ignores the process of constructing scientific thought—is still very prevalent. This is where the 'authority' of scientists comes from, as they are imagined to be the priests of a universal religion that would teach us the revealed Truth. This is not only anecdotal: we often notice today in the mass media this attitude expressed by the pretentious words of conceited scientists.
cience is Greek, of course, but it has taken many paths where secrecy played a very different role from one school of thought to another. We remember, for example, that nothing taught by Pythagoras was to be disclosed to the general public. The initiates themselves were distinguished into two classes, the students privileged in the knowledge of the Master's thoughts (μαθηματικοί), and the listeners capable of knowing something of that teaching (᾽ακουσματικοί) but unworthy to be called Pythagoreans. Something of this hierarchy remains today in the use of the secret of equations which are often found to arouse intimidated admiration when they appear in a text. The influence of this science went beyond those who knew it and, in order to avoid the common illusion that some people believe they are the authors of a discovery (when they are only fortuitously the concrete support of the revelation of this discovery), any thought and any novelty resulting from the reflection of the Pythagorean circles were attributed to the Master, even long after his death. It is thus probable that the famous theorem that bears his name was created much later than his time. Moreover, there is a certain tyranny of secrecy: it had to be well guarded, and relatively few of the Pythagoreans left any written records. It is even said that some were punished with death (by fate, or with the help of zealous colleagues, as was Hippasos) for divulging the esoteric knowledge they had acquired.
Y et, as another Greek tradition shows, the true relationship of Science to secrecy does not appear through revelation, but rather through the opposite. Xenophanes of Colophon noted that science is built from well-formed hypotheses, but by a process not unlike the elaboration of those riddles that the masters of philosophy loved: "And for a certain truth, no man knows it, just as no man can ever know anything about the gods and about anything else I am talking about. For even if he were to succeed entirely in telling the truth to the best of his ability, even then he does not know, for it is opinion that is built up about all things." It follows that the object of the work of scholars is to construct a set of coherent propositions assembled in the form of laws that govern this or that area of knowledge, not to discover a hidden secret. This time it is a production of human thought, not a revelation. The method of constructing a model from temporarily accepted postulates and testing its adequacy to reality—in the form of existential predictions, but more often through the refutation of the model's predictions—is well established in physics. On the contrary, the idea that one could with this approach identify specific laws of life is still in its infancy. This is because the apparent 'animation' of the chemistry that forms the substrate of living organisms remains, for most people, a mystery.
Early secrets and the revival of an ancient category of Reality
n this context, many pioneers of biology began by imagining its laws as requiring the revelation of a secret. Thus, in 1936, when Max Perutz left Vienna, Austria, for Cambridge, England, to meet the so-called Wise Man, Desmond Bernal (a famous Irish Catholic convert to communism and a specialist in X-ray crystallography), he asked him: "How can I discover the secret of life?” Bernal replied: "The secret of life lies in the structure of proteins, and there is only one way to find it, and that is to use crystallography”. Later, uncovering the structure of DNA—a nucleic acid this time, not a protein—Watson and Crick kept the same idea of secret. Crick called this discovery, only half-jokingly, 'the secret of life', which Watson found pretentious, especially when presented to an English audience where understatement is commonplace. It is true that the way in which DNA replicates itself, opening and copying each strand of the double helix like a silver photograph and its negative, provides a good example of what could be a biological law, the first secret of life. This is also what Jacques Monod understood when he thought he had discovered the second of these secrets. Agnès Ullmann recounts this in her memoirs: “Late one evening in 1961, Jacques walked into my lab. His tie was loose and he looked tired and worried. He stood silently at my bench and after a few minutes he said, “I think I have discovered the second secret of life.” I looked at him rather alarmed and I suggested that he sit down and have a drink. After downing his second or third glass of scotch, he started to explain his discovery of a phenomenon he had already named “allostery.” He then pointed out that the regulatory role of allosteric proteins was absolutely fundamental, arguing that the ‘‘invention’’ of indirect allosteric interactions in the course of evolution opened the way to an infinite number of possible regulations. This secret, if it is one, exposes a fundamental facet of Monod's thinking, the extension of the role of selection to the molecular level. And certainly, it has long been known that what revolves around the concept of selection is close to what we expect from a law governing the nature and fate of living organisms.
llostery imagines families of entities (proteins in general, most often enzymes) existing as two distinct states in dynamic equilibrium with each other, one functional and one inactive. One of these states can bind an 'effector', while the other cannot. It follows that in the presence of the effector the equilibrium between the two states gradually shifts towards the form that binds it. This will therefore change the functional capacity of the entity in question according to the amount of effector present. As there is no reason why the spatial structure of the binding site of the effector should be directly relevant to the function of the protein, it is normally located in a separate place from the sites that ensure its activity. Understandably, this is the origin of the term allostery.
onceptually, the theory of allosteric control is an archetype of the role of natural selection, but in a quasi-mechanical process that operates not in the course of millions of years of evolution, but immediately, within present-day living organisms. It is indeed a remarkable process, essentially because it brings to light, in a different way from what happens in the course of DNA replication or the coding process at the origin of protein synthesis, the irruption of an authentic currency of Reality, like mass, energy, space and time, that of information. Life depends critically on processes that are not directly dependent on mass, but on processes that specifically require the management of information. It is thus a manifestation of the importance of one of the ten Aristotelian categories, akin to the one that was named πρός τι (ad aliquid in the Middle Ages), and which requires the explicit consideration of the relations between material objects. This is the category of things that is so well illustrated in the story of the Ship of Theseus that Plutarch relates. This vessel wears out in the course of time, and there comes a time when all the planks that form it have been changed. Something remains, however, which is not the materials of which it is made, and that something is information.
n biology, this new category manifests itself first of all through a concept whose definition has evolved over time and which would deserve a separate discussion that I cannot develop here, that of complementarity. One strand of DNA is complementary to the opposite strand, and the binding site of the allosteric effector in the ad hoc state is complementary to the shape of this effector. This is the first process in which information management appears, that of the recognition of one entity by another. But is this a biological law? I doubt it: indeed, a process such as crystallisation in a saturated salt solution is based on a property of this type. However, if there are laws specific to biology to be sought, it is around the category known as information that they should be identified. But rather than measuring its presence in the phenomenon of recognition, which is in some ways trivial, life uses it well beyond the classic model of the lock recognised by its key, by managing the future not of individual objects, but of classes of objects. How is the discrimination between classes made? This is a question that goes far beyond the usual physics questions and to which life provides a little-known but essential answer.
Life manages information in an original way
t is not easy to relate information to what makes up life, biological chemistry in particular. However, it is by resorting to it that a singular biological law appears, derived from physics, but rarely appreciated at its true value, and which I will try to illustrate. Although it is widely accepted by a whole section of physics, the real implication of information as an authentic category of Reality is not seriously taken into account by most biologists. The word is in common use but without those who use it understanding what it implies. It is true that it is only very recently that the importance of the physical reality of information has begun to be understood. This is due especially to the work of Rolf Landauer from 1961 onwards, linking information and energy in an unexpected way, and to that of Charles Bennett which followed. In short, contrary to a still prevalent but false idea, producing information does not dissipate energy. It is in fact the erasure of the memory that had to be used to enable this creation that is energy consuming.
The demonstration of this surprising property of Reality brought to light a genuine "secret", hidden for years within physics, and for this reason little known. This secret is illustrated by an imaginary agent proposed by James Clerk Maxwell in his Theory of Heat in 1871 and which is almost never invoked by biology. And this goes beyond biology: I was surprised recently to find that young physicists, at the highest level of university training in this field, were unaware of what it was all about! It is therefore clear that there is still a long way to go before the concepts associated with this reasoning reach biology. And this, despite its involvement since the end of the 19th century, when Maxwell proposed a very 'animated', alive, image, challenging the second law of thermodynamics and which deserves to be quoted in extenso: “if we conceive a being whose faculties are so sharpened that he can follow every molecule in its course, such a being, whose attributes are still as essentially finite as our own, would be able to do what is at present impossible to us. For we have seen that the molecules in a vessel full of air at uniform temperature are moving with velocities by no means uniform, though the mean velocity of any great number of them, arbitrarily selected, is almost exactly uniform. Now let us suppose that such a vessel is divided into two portions, A and B, by a division in which there is a small hole, and that a being, who can see the individual molecules, opens and closes this hole, so as to allow only the swifter molecules to pass from A to B, and only the slower ones to pass from B to A. He will thus, without expenditure of work, raise the temperature of B and lower that of A, in contradiction to the second law of thermodynamics.
This very special agent has been named Maxwell's demon, after its author. This represents an unexpected irruption of biology (this demon has all the attributes of an animal) into physics. And yet it is precisely agents of this type that we observe, if we look closely, present everywhere in living organisms. Here is a remarkable experimental illustration with brewer's yeast: when the cell buds to produce a new cell, its proteins, some of which have aged, are not distributed uniformly. We observe that the aged proteins are only found in the mother cell, and not in the bud, which contains only young proteins! How is this sorting possible? Special proteins, the septins, carry out this function. To do this they have to dissipate energy in a process that is incredibly similar to what Maxwell's demon does, i.e. distinguish what is old in a mixture, and only allow what is young to pass from one compartment to the other.
This is not an anecdotal example, but one of the very many processes associated with life where a crucial, rarely emphasised function is at play, the discrimination between classes of objects (or more abstractly, processes) distributed in an homogeneous mixture. We have here, in fact, a real law of physics, which has curiously gone unnoticed, but which is massively used by the living world and remains inseparable from life. If there is a secret of life, it is there. This function is omnipresent, characteristic of life and essential to its development. To manage the information of this critical process, we expect cells to encode proteins that function as Maxwell's demons capable of sorting similar entities and mixed together into relevant classes, made of similar but different objects, or different positions of these objects in the cell, for example. The materialisation of these fictitious agents takes place in the form of proteins that manage a large number of families of highly specific or spatially localised targets at specific sites in the cell or organism.
In concrete terms, the smallest genome encoding the functions of a self-sustaining organism, Mycoplasma mycoides Syn 3.0, contains the genes encoding only 500 functions, which are sufficient for the organism to live and reproduce. Of these, about 50 clearly act as Maxwell demons. This is a huge proportion. And you can't do without them: inactivating just one of these genes means that the mutilated organism can no longer live. These proteins are used to discriminate between classes of objects such as young or old entities and to lead them to a specific position in the cell or to aggregate or to be destroyed, for example. They are also used to discriminate between what is well or poorly folded (cellular functions are carried out by nucleic acids or proteins that are in fact very long strings folded in space into a functional structure, and misfolding is the norm).
It is remarkable that this view, now blinded by obtuse but diabolically dominant thinking, was envisaged early on by Charles Sherrington, even before the discovery of the DNA double helix: "We seem to watch battalions of specific catalysts, like Maxwell’s “demons” lined up, each waiting, stop-watch in hand, for its moment to play the part assigned to it, a step in one or other great thousand-linked chain process. Yet each and every step is understandable chemistry [...] In the sponge-work of the cell foci coexist for different operations, so that a hundred, or a thousand different processes go forward at the same time within its confines. The foci wax and wane as they are wanted. That the cell’s field is a colloidal field makes explicable much which would otherwise not be so. But the cell is much more than merely a drop of colloidal jelly. The processes going forward in it are co-operatively harmonized. The total system is organised. The various catalysts work as co-ordinately as though each had its own compartment in the honeycomb and its own turn and time. In this great company, along with the stop-watches run dials telling how confrères and their substrates are getting on, so that at zero time each takes its turn “. Another example of such discrimination is offered by membrane transport proteins known to play a role in drug resistance and which export foreign compounds while keeping the authentic metabolites in the cell. These transporters, of course, use energy not only for the transport itself (when necessary), but more importantly to distinguish and select the class of objects to be exported out of the cell from those to be retained within it. To understand what life is, it is now necessary to take stock of these agents and the functions they perform. This is a crucial research programme from a conceptual point of view, of course, but also for the development of synthetic biology, which has completely ignored their existence until now.
Information depends on its context
The role of information in biology has been discussed for a long time, but without much progress. Strangely enough, the discussion revolves around the only existing theory, that of the communication of messages through a noisy channel, even though this has only a very remote connection with what happens within the cell. The theory in vogue, proposed by Claude Shannon in 1949 and very useful for managing telecommunications, for example, calculates a certain quantity linked to a type of message, and this, it must be emphasised, without any concern for its meaning. Obviously, what is important in biology is precisely this qualitative, and not quantitative, aspect associated with the meaning of things. The central biological idea of function only makes sense in context, which amounts to giving biological elements a meaning insofar as they are placed in relation to each other in space and time. It is known, for example, that transplanting a chromosome from a blue-green alga into a bacterium such as Bacillus subtilis simply leads to its replication when the host cells multiply, and this without any other effect, as if it were merely the burden of having to pass on an incomprehensible archive from generation to generation. On the contrary, the transplantation of a mycoplasma genome into a different but evolutionarily close species will lead to its progeny being altered to the point of being progressively replaced by that of the transplanted genome.
Another peculiarity of life adds an additional element to the relevant information. What is living is limited in space and cannot increase in volume indefinitely, except by division and creation of a new living being when the organism grows. The 'atom' of life is the cell, and the size of its envelope and compartments has a key role in the genesis and management of the corresponding information. This is easy to understand if we return to the idea of information as a relationship between objects: moving objects closer together or further apart considerably changes their interactions and therefore their mutual information. This property is undoubtedly a key to understanding why it is so difficult, and for the moment actually impossible, to reproduce life in a test tube. Opening a cell, or even just piercing its envelope, causes it to die. The components must be kept together, and in a certain order, for life to continue, and that is what makes it so fragile. The geometric arrangement of objects in relation to each other is crucial, and so is minimising the number of irrelevant objects that occupy the available space. This involves at least two families of discrimination processes, spatial discrimination—the same object does not have the same meaning in one place as in another, and discrimination between classes of objects that tend to mix together. It should be noted that this last point is related to an aspect often invoked when we talk about life, the distinction between self and non-self, which is found at the origin of the immune response for example.
The management of relevant (meaningful) information in the cell will therefore depend on the management of its volume (here we can guess the role of osmosis, long associated with the perception of what life is). This relevant information tends to disappear when the volume of the cell increases, and also in the presence of irrelevant objects, for example when proteins age and therefore occupy part of the cell volume in an altered, often—but not always—non-functional form. It is therefore necessary, in order to maintain this information, for there to be a set of agents capable of selecting objects and their position to maintain them at a rate equal to or greater than the rate of degradation of the corresponding information. In other words, the organisation of the cell, or of a living organism in general, must be kept at a distance from two extreme types of organisation, the homogeneous state, and the random state. This is what is achieved by those agents whose Maxwell demon function we have shown. The spontaneous drift in the quality of the physico-chemical processes associated with the dynamics of life, which is imposed in the course of time, must be combated by selective processes that tend to recreate the specific organisation that is recognised in the active cell or organism. This implies that a continuous production of 'useful' information is generated within the cell by a kind of selection process, and this at a rate equal to or greater than the rate of degradation of specific structural information.
Resetting memory to produce relevant information dissipates energy
The cell must therefore constantly renew its relevant information by replacing its components in the right place, retaining only those that have the right shape, eliminating those that have aged or been damaged, and controlling its growth. All this dissipates energy, but not only in the process of renewing the cell's components, but especially in the management of the relevant information. In order to function, each Maxwell demon must compare the features that are specific to the function whose informational quality it manages, which means measuring, and memorising this measurement. This can be done in a reversible way, as Landauer has shown. But in this case, it is a one-shot function: if the demon has to renew its action, it must then erase the memory of its previous action. It is this resetting of the memory that costs energy. So far, this is a simple conceptual view, a hypothesis of the type that founds Science according to Xenophanes. But this view has a remarkable implication in terms of experiments, and this is what makes it interesting. Indeed, since it is a question of consuming energy for a process that does not directly involve mass and the associated chemical bonds, then we can consider that this function must show, when the processes involved develop, an excess of energy dissipation compared to what we would expect if mass only were involved. In short, this gives us the means to identify the concrete agents that play the role of these demons.
All we have to do is to look for processes in cellular biochemistry that require more energy than we would expect. This is the case for a large number of selective processes. For example, the decoding of the message specifying the sequence of amino acids forming a protein uses a protein complex whose only role is to ensure that the process is accurate. This involves distinguishing each time an element is added to the protein chain under construction, the one specified by the genetic message, from the set of those waiting to be used in turn. And it has been well established that this complex does indeed consume energy. Similarly, within the cell, there are enzymes that break down proteins. But of course, these enzymes must avoid destroying functional proteins, and only do so for those that are not functional. Here again energy is dissipated, and this is apparently all the more surprising as the very fact of reducing a protein to its basic elements should normally produce energy-this is what happens during digestion, for example, and certainly not consume it! To go further, we need to follow the intracellular management of chemical energy. There is a family of compounds in cells, the nucleotides, which serve as a reservoir and exchange value for energy. Their stores and dynamics can be easily assessed. This should lead us to imagine a straightforward research programme. It would involve an in-depth exploration of the nature and function of all genes encoding proteins whose binding to nucleotides would predict that they dissipate energy in an unaccounted for way. This cataloguing should systematically reveal the presence of an information management process.
The physical secret of what life is
Having reached this point in our reflection, we must be surprised that these observations have not led us to understand earlier that the real secret of life lies in the very existence of Maxwell demons-like agents and in the management of the processes of discrimination between classes of objects. This is not the place to give a history of the obstacles that have led and continue to lead to this unfortunate situation. But, in fact, the great discoveries of science remain very rare, and only very slowly penetrate thought. The enormous increase in the number of people involved in scientific research certainly does not help the spread of innovative ideas. On the contrary, mass creates fashion and there is no wisdom in the crowd, which imposes its attributes and tends to push aside anything that does not follow it. As early as 1963 Horton Johnson noticed an inexplicable anomaly in mammalian physiology: the kidney consumes much more energy than the heart, whereas its function of maintaining the osmotic pressure of the blood should only lead to a marginal consumption. But the kidney has another, particularly important function: it maintains a very fine balance between structurally very similar elements, the sodium and potassium ions for example, mixed up in the blood. But discriminating between these ions requires the management of an activity of the exact type we discussed in relation to Maxwell's demon, and this is very energy consuming. Johnson was not aware of Landauer's work, although it was contemporary and perhaps the reason for it. It is only today that this irruption of physics into biology is taking on its full meaning, in particular from the work of Chérif Matta on the enzyme that produces the nucleotide that is the central store of cellular energy, and who has observed a significant excess of energy dissipation during the process. Let us hope that the lesson will, once and for all, be well understood. Physics has much more to contribute to biology than an infinite number of advanced techniques. But this implies freeing ourselves from the thinking that retains only the anecdote, however fascinating, from biology, and this is no easy task!
Bennett, C.H. (1988) Notes on the history of reversible computation.
IBM Journal of research and development 44: 270–277.
Boel, G., Danot, O., de Lorenzo, V., and Danchin, A. (2019) Omnipresent Maxwell’s demons orchestrate information management in living cells. Microb Biotechnol 12: 210–242.
Danchin, A. (2021) Three overlooked key functional classes for building up minimal synthetic cells. Synthetic Biology 6: ysab010.
Johnson, H.A. (1970) Information theory in biology after 18 years. Science 168: 1545–1550.
Landauer, R. (1961) Irreversibility and heat generation in the computing process. IBM Journal of research and development 3: 184–191
Vigneau, J.-N., Fahimi, P., Ebert, M., Cheng, Y., Tannahill, C., Muir, P., et al. (2022) ATP synthase: a moonlighting enzyme with unprecedented functions. Chem Commun (Camb) 58: 2650–2653.