Ethics, Pt IV, Prop. 67
SPINOZA
What is Life's epigraph
An introduction to Schrödinger's What is Life
Colleagues of the BGI
(Beijing Genome Institute) in Shenzhen asked me to write
an introduction to the famous work of Schrödinger on what life is.
Here is the English version of the text which is published in Chinese
《什么是生命?》(2023年)中文版序.
The science that studies life, Biology, has long been marked by the implicit idea that a particular principle would animate the objects that compose it. This « vitalism » remains very explicit in Western languages, which systematically tend to represent separately the material body—endowed with mass—of a living being, from an immaterial principle which would give it life, spirit or soul. This is a way of thinking that goes back a long way in time, and in particular to the first stages of what witnessed the creation of the activity we name science, in Greece. There, the first principles, arranged in four categories, fire, air, water and earth, defined in various ways according to the thinkers, were supposed to combine to account for all things in the world. A similar view exists in China, of course, but with a fifth element, wood, somewhat exotic because it introduces de facto life into the original science of nature. But what made Physics original (this name is none other than the one given to the study of nature in Greek), was not in its objects, but in the unique method, invented by the thinkers before Socrates, the Presocratic philosophers, which allowed the scientist (the Philosopher) to account for the world around us in a progressively more adequate way. This method, which should always be at the root of science but is often ignored, understands that facts do not speak, that it is impossible to progress simply by collecting data, and that to understand reality it is therefore absolutely necessary to proceed in a different way than by accumulating facts. It is the event that biology was suddenly entering the real world of science at the beginning of the XXth century that explains why it was theoretical physicists who were at the origin of the most spectacular progress in modern biology.
The underlying Greek idea is that we must be actors in the discovery of the world and not mere spectators. It is neither gods nor priests who make us progress in knowledge, nor, still, any intuition. Science is not a secret that would appear through a revelation, but a human construction, and what is more, a provisional construction. But this provisional has the particularity that it is not contingent by any means, it cannot rest on ideas proposed to be as valid as it is, it progresses unceasingly. It proceeds by accretion of novelties on the basis of what has been previously proposed, and not by rejecting without reason or putting forward any fancy scenario. Xenophanes of Colophon thus noted that science is built from well-formed hypotheses, in a process that is not unrelated to the elaboration of those riddles that the masters of philosophy loved:
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 field of knowledge and not to discover a hidden secret. It is indeed a production of human thought, certainly not a revelation. The method that consists in building a model from temporarily accepted postulates, in order to test its adequacy to reality—in the form of existential predictions, but most often via the refutation of the model's predictions—is well established for physics. It is this way of doing things that explains the remarkable role of Schrödinger's little book What is life? The physical aspect of the living cell published in 1944, while the author was in exile in Dublin to escape the Nazi domination..
What was so new, so revolutionary about this work? Eighty years later, we can understand both how visionary Schrödinger's thinking was, and how well adapted to his subject, but also how much it left aside the central question of biology, that of the physical cause of the apparent « animation » of the chemistry of life. This probably explains why, while physicists were indeed at the origin of modern biology, very early on called « molecular biology », the associated conceptual discoveries dried up after those that made it possible to conceive of DNA replication, the coding table of the genetic code, the regulation of gene expression or allostery. Despite Schrödinger's ambitions, physics has not been able to identify real laws, belonging to physics, whose expression would be specific to life. This is because the apparent « animation » of the chemistry that forms the substrate of living organisms remains, for most people, including physicists, a mystery.
The reading of What is life? allows us to understand this: beyond several concepts of physics that are important for biology, and in particular the irruption of information as a basic currency of reality, we also find in this book, alas, if not the origin, but the first real emphasis of themes that have dominated discussions and surreptitiously reintroduced the archaic magic of the theory of the four elements into biology itself. This magic comes from the hidden assumption of the existence of an enigmatic latent, non-formalized, principle of attraction that would allow collections of objects to organize themselves spontaneously. Indeed, a recurrent idea haunts the contemporary thoughts of those who are passionate about biology without having the real courage or desire to understand. It tries, by means of abusive generalizations, to encompass the world in a single description based on an ideology of a more socio-political than physical nature, invoking what would be an « order » based on the very primitive and very magical idea of « self-organization ». One could have expected much more from physics. Why, then, has modern physics essentially brought to biology only state-of-the-art technologies, albeit in large numbers? Why so few innovative concepts derived from physics? The rule of the genetic code, which maps a polypeptide (a protein) to a nucleic acid, cannot be deduced from Schrödinger's equation, although of course it is perfectly compatible with it. How did it appear in « ordinary » chemistry? Is not that what we should understand? This means understanding its physical foundations, associated with a clear concept, that of discrimination between classes of objects, how does the ribosome accurately recognize the codon-anticodon pairing by choosing the right transfer RNA?
As early as 1935, the German physicist Max Delbrück, as a naïve physicist (according to Schrödinger's expression), had wondered about the physico-chemical basis of life. The problem was to try to link the formal and very abstract laws of genetics, which indicated in a predictive way how certain hereditary characters are transmitted, and the physical nature of the components of the cell, the nucleus and the chromosomes in particular, which were known to have some connection with heredity. The starting point of this reflection was the study of mutations, understood as abrupt, discontinuous and stable variations in the progeny of an individual. The action of ionizing radiation, such as X-rays, on cells allowed Delbrück and his colleagues to concretely link the hereditary units, the genes, with the main target of ionizing radiation in the cell. The calculation showed that this target was so small that it had the dimensions of molecules, made up of a few thousand atoms at most. This is the starting point of Schrödinger's reflection, associated with an epistemological presupposition that can be summarized by the following questions and statements:
And Schrödinger showed that isolated atoms or small molecules would be unable to conserve the memory necessary for the correct transmission of hereditary characters. This was an opportunity for him to link the physics he knew to that of the atom, and to impose that of statistical mechanics on biological reality. In particular, he devoted a long moment of his reflection to an essential property of life, often neglected today despite its major importance, that of the ability of all life to behave in a global, macroscopic way. How to link the swarming of atoms to the movement of a cell, to the organization of the human brain? The whole question is to give a form, a structure, to this swarming: only assemblies of atoms will be able to do this, provided that the assembly is sufficiently stable, has a sufficient life span at the temperature where life develops. The dialogue between the microscopic and the macroscopic can take place when a large number of basic elements are brought together: from simple examples such as paramagnetism, Brownian motion or diffusion, our author demonstrates that there can exist a spatial and temporal macroscopic order and that an appropriate back and forth between local and global dynamics can create a stable macroscopic form. One finds there, for example, all the reflections of certain thinkers who are very critical of molecular biology, such as the famous mathematician René Thom. It would certainly be useful today not to lose sight of this important dimension of life, the coupling between the macroscopic and the microscopic. But, as we shall see, there are other properties, not associated with the physics of large numbers, which account for the global character of cellular behavior
Schrödinger's great merit (contrary to what some critics say, obsessed by the theoretical defect they see in the reflections of biologists, forgetting the relevance of the choice of a minimal scale in the objects to be considered) was to show that the molecular level, however small, can be considered as a relevant level of analysis, even for the organization of heredity. This is what fascinated physicists now known to be among the creators of molecular biology, such as Wilkins or Crick, when they read Schrödinger's text. The image we usually have of physics or chemistry is that of regular arrangements of atoms (this is the basis of crystallography) when considering an organized structure. The crystal is the model or the symbol of the inorganic world but also of the world of the physical laws of matter..
The living world is characterized by movement, irregularity, change. Its matter is often fluid, sticky, viscous. And, in fact, chemists at the time called colloids the products extracted from living systems. By postulating an absolute identity of the laws presiding over the shaping of matter, whether inert or living, Schrödinger had to reconcile these two extreme characters, the crystal of the inorganic and the amorphous glass of the organic. He needs another detour to get to the heart of his idea of a material center of life, which is the support of heredity: inorganic collections of atoms would be too sensitive to thermal fluctuations, so they must be organized into molecules to play this role. And if he does not use the term macromolecule, corresponding to a relatively new concept at his time, and mostly used by chemists, Schrödinger supposes that the atoms of heredity are organized according to the imposed order of a crystalline structure, but that this order is not the simple regular repetition which would lead to the poverty of inert structures, but that it contains variable motives, carried by the regular matrix of the crystal. This aperiodic solid is the support of the hereditary memory. It is easy to understand this metaphor, and it is not surprising that curious minds have been fascinated by its power, and especially by the fact that it points the way to discover the real organization of the matter of genes:
with, as a note, a sentence that concretely indicates what to look at:
The road is paved: purify the chromosome material, and you will discover a very thin filament (the dimensions are known from Delbrück's work on X-ray mutations) which will have the structure of an aperiodic crystal!
At the same time, Avery and his colleagues detected the transforming power of DNA: the chemical nature of genes was discovered. And it was not more than ten years after What is life? that the secret of the nature of the aperiodic crystal was discovered, by researchers who had been marked by reading Schrödinger's little book.
The text of our author also contained many other seeds of discovery. Stemming from his reflection, and from simple images, as it is often the case in physics, where « thought experiments » have a leading role, Schrödinger tries to highlight what it is necessary to look at in the living matter. The relevance of the question is paramount: it decides the importance of the answer. And Schrödinger understands that it is not enough to know the medium of heredity, but that it is also necessary to understand how the organization of this medium is transformed into actions related to life: after all, a living being must be able to exchange matter with its environment, perhaps move, and certainly reproduce. At a time when computer science did not yet exist and when the word « program » existed mainly with a connotation associated with theater, Schrödinger used a metaphor: to describe this transformation and the role of the gene matrix, he used, as many computer scientists do today when they speak in jargon, the word « code » (but in the form of « code-script », we would use the word program today). It is a kind of program that decides, in a strictly deterministic way, the future development of an organism:
Here is a use, not very widespread at the time, except in the context of the exchange of secret messages, of the concept of coding. Schrödinger develops the analogy with the Morse code to show that with very few basic elements it is possible to create an infinite number of meaningful combinations. This is the fundamental biological law, which is still often misunderstood nowadays, especially by the general public. And what is central to Schrödinger's argument, and what only some of his readers will understand, is that the model on which the organism will be built, Buffon's « inner mold », is a physical object, itself manipulated by the rules it specifies. But then Schrödinger takes an erroneous shortcut by thinking that the aperiodic solid is itself an actor in the construction of the cell:
Or,
However, this sentence introduces a misunderstanding because it makes as if the aperiodic solid had a builder's craft. As we know today, the builder's craft corresponds to the expression of genes, not to the genes themselves. And Schrödinger was unable to make this observation explicit. It was necessary to conceive that the program implements a machinery, which had to be identified. Moreover, the confusion between code-script and builder's craft / program undoubtedly created an obstacle to the discovery and especially to the understanding by the public of the rule of the genetic code. This rule allows an amino acid of a protein to correspond to a sequence of nucleotides present in the gene, through an RNA, as understood by Crick with his concept of adaptor, all rewriting rules well ignored by Schrödinger.
How to understand the permanence of the program, and its stability from generation to generation? Schrödinger, the theorist of quantified matter, did not evade the question, even if it seemed formidable. Understanding that a gene is a polyatomic structure, he believes that he must apply to it the usual rules that govern the destiny of atoms at the temperature where life takes place. He therefore tries to represent the « aperiodic » character of the gene in terms of energy levels, and "quantum jumps » between these levels. In parenthesis, we should note here how lucid Schrödinger is, as we would like many « quantum » physicists of today to be: he still knows that the « quantum jump » is a paradoxical mystery of the discontinuous nature of the quantum model. The whole problem lies in the stability of the molecule supporting heredity, and in the precision of its reproduction, since it must be reproduced from generation to generation. Schrödinger shows that the very idea of a molecule, a multi-atomic edifice, can involve a sufficient stability constraint on the time scale of organisms. The real problem is that it is also necessary to be able to take into account mutations, a very large number of possible different structures, from the same model. Schrödinger then imagines isomers of a typical large molecule. But of course his description stops there. He misses the central idea of the linguistic metaphor: the material support of the gene consists of a linear sequence of four basic motifs whose order determines the nature of the gene product. A thousand of these motifs allow such a large number of combinations that any spatial structure could, in principle, find a representation there. But how to get from the gene to what it specifies? And how to make sure that its product does not vary as time passes?
In spite of its necessary imperfection —it must be admitted that Schrödinger could only make more or less gratuitous hypotheses at that time by taking up Delbrück's experiments and models— his text contains the germ of a fundamental reflection which, curiously enough, was only evoked thirty years later by a physicist, John Hopfield, in the United States, and much more recently by our own studies of the dissipation of energy associated with the precision of gene expression and discrimination of classes of biological entities. He shows indeed that the problem of the stability of the support of heredity is crucial, and that the effect of thermal agitation is to introduce, with a finite probability, « spontaneous » changes in the nature of the gene. These changes take place after a finite time which depends on the nature of the molecule supporting the « aperiodic solid » and they necessarily have the discontinuous nature expected of mutations.
The conformity of heredity in the course of time thus raises questions. Schrödinger proposes an ad hoc reasoning based on quantum physics, in terms of possible thresholds due to quantum transitions allowing to avoid the unifying consequences of thermal fluctuations, but he does not push his reasoning further: if mutations are inevitable, is there a way to correct them or, at least, to control them at the time of reproduction of the hereditary heritage? The question of precision is a pressing one: today's linguistic metaphor, which sees the expression of genes as the rewriting of their text into RNA and then into proteins, lends itself well to this, but it did not exist in 1944. How do you ensure that the final printing of a book is free of typographical errors, how do you properly proofread the text to allow for effective correction? This subject is central to the stability of species. And Schrödinger's model of reasoning should have been, and still is, useful in allowing us to highlight the important points of the physical constraints on the precision and fidelity of the reproduction of the living. The mechanisms to be discovered presuppose that the cell can distinguish between classes of objects, those that are identical and those that have varied, and can find ways to eliminate as much as possible the variants. This concept is completely foreign to the reflection of our author.
How did this remarkable view become distorted, leading the vast majority of physicists irreparably down the wrong road? The starting point was unequivocal, and without error:
but it was quickly altered in a questionable form, not in its detail but in its abusive generalization:
This is correct, of course, but only if one avoids the reflection that immediately follows and which removes physics from the idea of a program and its expression:
which is illustrated as a first example the forms produced during paramagnetism, with no doubt an implicit allusion to the models proposed by Ising in 1925 and very fashionable in 1944. The question is not indeed that of the precision acquired thanks to the large number —in fact, many objects of the cell are in very small numbers— but rather to a reflection on the nature of information as an authentic currency of reality, and the concrete ways to preserve the quality of what is produced by the cell. This is where a new physical approach becomes necessary, based on the discrimination between classes of more or less similar objects (for example young and old), a concept that was absent at the time and that remains almost entirely ignored in contemporary physics.
Moreover, Schrödinger deviates from his first reflection, where he had correctly identified the molecular level, to analyze heredity not only from the simple cell, but, by an unfortunately widespread anthropocentrism, to be particularly interested in multicellular organisms, animals in particular. And finally he comes back to the « marvelous » world from which science is absent, writing even that the link between heredity, the genotype, and its manifestation, the phenotype, may be impossible to understand:
Understanding mutations, on the other hand, becomes accessible with the metaphor of the aperiodic solid:
So far, Schrödinger's contribution to the impact of physics on the development of biology has been remarkably positive. Unfortunately, and it is the time in which he lived that is undoubtedly responsible for the warping of his thought, an ideology of the inevitable degradation of the world requiring the struggle against disorder was then dominant. Schrödinger, influenced by the statistical idea of the physics of large numbers and forgetting that the cell is far from always being composed of a large number of meaningful objects, associates it with the idea of inevitable disorder. He links this idea to a usual —but erroneous— conception of what entropy is. He identifies entropy and disorder and invokes the second principle of thermodynamics as the driving force against which life must constantly struggle by feeding on « negative entropy ». Schrödinger is careful to point out, however, in a long note, that his physicist colleagues do not agree with him:
Entropy necessarily increases, indeed, but this does not automatically imply an increase in the disorder of the objects involved. The idea of disorder is already present in part in Boltzmann's texts on statistical mechanics. But the associated « demonstration » is not an authentic demonstration, it is only a certain look at the world. Why would we need two words, disorder and entropy, to say the same thing? Can we not, on the contrary, see in the spontaneous behavior of matter an aptitude for exploration, for invention? The fact of occupying all the available space allows things to go in front of unforeseen interactions in their initial space: by mixing the yellow and the blue create the green, is there disorder there? Exploration tends to disorder, or to order, depending on the context. And, in fact, we know today that it is thanks to the second principle of thermodynamics, which imposes a spontaneous increase in the entropy of any material system, that many major forms of macromolecules that define life are created. A DNA molecule dissolved in dimethylformamide constitutes a set of randomly folded strands without any particular shape, but as soon as we dilute the whole in water, a double helix is formed. There is indeed a creation of order, in parallel with an increase of entropy, and this order is driven by the rearrangements of the water molecules: the increase of entropy of the mixture tends to give as much space as possible to the water molecules by imposing a particular conformation to the foreign molecules. But Schrödinger's remark about his colleague Simon also opens up a question that has been understood only very recently. There is indeed something to understand in the dissipation of energy associated with life, as we will see in the conclusion.
Like almost all authors who want to generalize their knowledge, Schrödinger found himself carried away by his impulse. He wanted to give, with the obvious risks that this entails, a universal dimension to his reflection. Could not the quantum model, so powerful when it demonstrated that the support of heredity necessarily had a molecular polyatomic nature, also be used, through statistical mechanics, to take into account the role of form in life? Here the question of organization, order and disorder in the living phenomenon is obviously raised. But was the ideology of 1944 conducive to this reflection? Nazism had tried to dominate the world, and, at the time of writing Schrödinger's book, its domination was still on the agenda. It is therefore not surprising, in a reflection where genetics holds a central place, to find very debatable elements, and which Schrödinger realizes are so. A first witness of this state of affairs is the curious introduction of the word and concept of « elbow room » (recalling the « Lebensraum », the living space claimed for Germans by Hitler) in connection with the diffusion of molecules: when molecules diffuse, is it really to have more living space? But it is of course about mutations that the context of the time is most evident:
or with an obvious humanitarian stance:
This is another manifestation of Schrödinger's role as a precursor: is not this sociobiology before its time? And yet our author had remarkably understood the contingent character of mutations. His analysis of Delbrück's work leaves no ambiguity in this respect:
Schrödinger thus reinterpreted Darwin, as did geneticists such as Dobzhansky at the same time, taking into account Mendel's laws and the work of De Vries on mutations. In this sense, he is one of the creators of the neo-Darwinian current that will preside over the birth of molecular biology. And he made the same mistake as many thinkers of the time (and still common today) by not clearly distinguishing between what belongs to the phenotype and what belongs to the genotype, and by not understanding the two fundamental aspects of heredity, its genetic character (the exact replication of DNA) and its epigenetic character (the accurate production of a state of expression of DNA). But he understood very well, which is rare even today, that selection is based on a prior choice of mutations, without any instructive effect of the environment. He was undoubtedly aware of the beautiful experiments of Luria and Delbrück carried out in 1943, which demonstrate the purely contingent character of mutations, prior to any selection. But, as the author himself admits, his sole purpose in writing this book was to show that, in addition to the laws of physics, there are other laws which, without violating the former, are specifically revealed by the life sciences. And the idea that he retained, well in line with the ideology of the time, is that the world spontaneously moves towards disorder, and that the role of the laws specific to living beings is to constantly oppose this natural tendency. And since the consequences of Schrödinger's argumentation, which are highly debatable, are still present today in many of the comments made in the trite discussions in a certain intellectual world, it is appropriate to come back to them in some detail.
This is the fundamental question: how is the ordered organisation of living beings maintained? We have seen above how the question of predicting the reproduction of macromolecular structures was at the center of the perpetuation of life. But for a cell to last, without even asking the question of its reproduction, it is also necessary, as time goes by, that its elements remain as close as possible to the norm and that its spatial organization is preserved, for example. In the face of the apparent complexity of living structures, this has seemed and still often seems magical. And one understands why many appeal to ideas where hints of vitalism appear. At the beginning of thermodynamics, in the XIXth century, some people invoked energy, a vague concept where a « vital energy » could slip in, which we find today in the advertising aimed at the less educated people. But a similar misguidance was introduced in the more educated circles thanks to the mysterious and certainly more difficult to define concept of entropy. Vitalism is far from being dead today, even if it is masked under the name of « self-organization », a pseudo-concept based on the erroneous vision of the idea of « complementarity » between entities of the same type proposed by Pascual Jordan in the 1930s and refuted in 1940 by Delbrück and Pauling.
As we have seen above, physics and its laws have indeed a crucial role. It was the work of a physicist, Rolf Landauer, in 1961 (which Schrödinger could not have known) that gave a serious lead to understanding the animation of biological chemistry. This involves two key steps:
1 / A « constrained (tense) » step loaded with information, associated with the capture of an energy source, not yet dissipating energy, and retaining a quantum of information (typically via the selection of a specific molecule, in an environment containing molecules of a neighboring type, for example an aged molecule, with respect to its young counterpart).
2 / A reset (or « relaxed ») step, during which energy is dissipated, in order to restore the system to its fundamental state, allowing the process to restart.
The functions of this type now identified in the minimal synthetic genome play a role similar to that of an agent proposed by Maxwell in his Theory of Heat in 1872, and known today as « Maxwell's demon ». These agents can discriminate a substrate among other similar substrates, identify a specific position in a spatial structure, or a particular instant in a set of successive events. This provides us with a hopeful message. Better late than never: less than a century after What is life? Schrödinger's dream of identifying the physical laws behind the unique properties of living organisms is about to become reality.
唐善 安东(Danchin
Antoine)