What Is Life? The Physical Aspect of the Living Cell. Based on Lectures Delivered Under the Auspices of the Institute at Trinity College, Dublin, in February 1943

Cambridge: at the University Press, 1944. First edition. INTRODUCED THE CONCEPT OF A GENETIC CODE.

First edition, first impression, of Schrödinger's famous and influential series of lectures on the physical basis of life. Even Schrödinger himself did not suspect that "the book would introduce a new concept to biology, that of a genetic code, and also be considered the most significant cause of an intellectual migration, from physics to biology, that would fully establish the emerging discipline of molecular biology" (Sarkar, p. 631)." "Even during wartime in England Schrödinger's lectures gained enough publicity to be reported on in the April 5, 1943, issue of Time magazine. The lectures were published as a small book in 1944 by Cambridge University Press. In this form they profoundly influenced James D. Watson and others, such as Francis Crick, whose background was in physics. Watson wrote: "From the moment I read Schrödinger's What is Life I became polarized toward finding out the secret of the gene" (Watson in Cairns, Phage and the Origins of Molecular Biology, 239)" (). "In the book, Schrödinger introduced the idea of an "aperiodic crystal" that contained genetic information in its configuration of covalent chemical bonds. In the 1950s, this idea stimulated enthusiasm for discovering the chemical basis of genetic inheritance. Although the existence of some form of hereditary information had been hypothesized since 1869, its role in reproduction and its helical shape were still unknown at the time of Schrödinger's lecture. In retrospect, Schrödinger's aperiodic crystal can be viewed as a well-reasoned theoretical prediction of what biologists should have been looking for during their search for genetic material" (Wikipedia). "In What Is Life? (1944), Austrian physicist and Nobel laureate Erwin Schrödinger used that (still-unresolved) question to frame a more specific but equally provocative one. What is it about living systems, he asked, that seems to put them at odds with the known laws of physics? The answer he offered looks prescient now: life is distinguished by a 'code-script' that directs cellular organization and heredity, while apparently enabling organisms to suspend the second law of thermodynamics. These ideas inspired the public and a number of scientific luminaries, but exasperated others. Although their elements were not original, the formulation brilliantly anticipated Francis Crick and James Watson's discovery in 1953 of how DNA's double helix encodes genes. As Crick wrote to Schrödinger that year, he and Watson had 'both been influenced by your little book'" (Ball, p. 548).

Provenance: Signature of former owner dated February 1945 on front free endpaper.

In March 1943, "at the height of World War II, the quantum physicist Erwin Schrödinger delivered a series of lectures at Trinity College Dublin with the ambitious title 'What is Life?'. While most prominent theoretical physicists outside the Nazi ambit were working feverishly on the atom bomb, Schrödinger was speculating instead on the physical basis for life. He had just been 'honoured,' in his own words, by the Nazi government with pensionless dismissal, without notice, from his academic chair in Austria. He had then settled in Dublin as a professor at the Institute for Advanced Studies, newly founded by Éamon de Valera, the Irish premier, who had a lifelong fascination with mathematics.

"The lectures were in a statutory responsibility. The intended audience was not limited to scientists. It was expected that most of Dublin's intellectual elite would attend. Perhaps because of this, Schrödinger turned to a favourite hobby - biology - rather than his professional work in physics. It appears that he intended the lectures to be published as a book, even as he completed them" (Sarkar, p. 631).

"Mostly through research with maize and with the fruit fly Drosophila, the foundations of genetics were firmly established by 1940. It was known that heredity was determined by genes located on chromosomes, and that each of the cells comprising any organism contains a chromosome set. When cells divide, genes are duplicated in mitosis. The only exception is during sexual processes, which are accompanied by meoisis. Occasionally a new variant of an organism, a mutant, arises spontaneously, and this variation is associated with a change in a specific gene. A particularly exciting result dating from 1927 was that mutations could be induced by irradiating organisms, in this case Drosophila, with X-rays. The genetic determinants derived from the two parents in a mating were known to be mixed in the offspring by a process of recombination, and this knowledge had been already utilized to map the determinants for various characters at specific locations on a chromosome.

"It had been known for a long time that the important molecules associated with living organisms contain carbon -thus the term 'organic' chemistry. Much was known about small organic molecules such as alcohols and esters; the atoms forming these molecules were held together by covalent bonds, the nature of which had been first explained in terms of quantum theory by London and Heitler in 1926. Much larger 'macromolecules' with molecular weights of between 104 and 105 were also known to exist in cells, including enzymes that accelerate reactions. There was some early knowledge about the composition of other proteins, and an awareness that nucleic acids were also present in cells. But techniques were not available to investigate these macromolecules in detail. There was no X-ray crystallography, chromatography or electron microscopy. The only meager evidence of the size and shape of these macromolecules came from studies using centrifugation.

"This, very briefly, was the state of knowledge when Schrödinger's book appeared. The foundations of formal genetics were well laid, but there were no real ideas about biochemical genetics (that is, about the chemical composition of genes or how they act), although there was a suspicion that genes were proteins and that they controlled the synthesis of other proteins.

"At the very start of his book Schrödinger sets its main question in these words:

'How can the events in space and time which take place within the spatial boundary of a living organism be accounted for by physics and chemistry?'

And the answer to this question he also gives at the beginning of the book, in these terms:

'The obvious inability of present-day physics and chemistry to account for such events is no reason at all for doubting that they can be accounted for by these sciences.'

"The book itself consists of seven chapters. The first three are by way of introduction to the main argument. Early on in the first chapter he makes the point that organisms exhibit extremely orderly behavior, and that this in turn must reflect the operation of precise physical laws. He goes on to say that, in classical physics, physical laws rest on atomic statistics, that they are only approximate, and that their precision is based on the intervention of large numbers of particles. He gives a number of examples, including paramagnetism, Brownian movement, and diffusion. Finally, he discusses the degree of accuracy that can be expected from such a physical law in terms of the square-root of the number of particles taking part in a reaction, and shows that this argument leads directly to the conclusion that for orderly behavior the number of particles contained in the key parts of an organism must be extremely large.

"The next two chapters give a clear resume of what was known about formal genetics in the 1940s. They start by emphasizing that heredity is determined by a code-script enshrined in the chromosomes. There is then a summary of the properties of genes and of the processes of mitosis, meoisis, and crossing-over. This is followed by a section that considers the genetic and cytological evidence bearing on the size of genes, which put an upper limit on them of about 106 atoms. Finally comes a discussion of the nature of mutations, with particular attention being given to the experiments on the induction of mutants with X-rays.

"The real argument of the book begins in Chapter 4, and starts by posing an apparent paradox. The mere fact that we speak of hereditary properties indicates that we recognize they have an almost absolute permanence. This permanence must be determined by the structure of the genetic material. Also determined by the structure of the genetic material must be the ability of a gene to mutate into another stable state. And all this has to be accomplished by a gene containing less than 106 atoms. This requirement is inexplicable in terms of classical physics. The answer to the paradox must be therefore that genes are stabilized by some non-classical force. The obvious candidate is the covalent bond, that peculiarly quantum phenomenon which gives stability to molecules. In other words, a gene must be a macromolecule. Schrodinger acknowledges that in one sense to say that a gene is a macromolecule is a trivial statement, in that even if it had not been stated precisely before, the idea was clearly implicit in a number of genetic discussions. His whole point was to emphasize, however, that in order to understand life - the stability and permanence of the genetic material - classical physics was inadequate, and one had to go to the very basis of quantum theory.

"In the next chapter he develops the thesis that a gene is a macromolecule held together by quantum forces. He takes up an idea that was proposed around 1935 by Max Delbrück, himself a quantum physicist, that a gene can be likened to a stable state of a quantum mechanical system. A mutation can then be considered as a discontinuous shift of this stable state to another, the change occurring spontaneously or being induced by X-rays or some other disturbance. He discusses this scheme of Delbrück in some detail, and concludes that it can explain in a natural way all the facts that were known at the time about the stability of genes and about the frequencies of spontaneous and induced mutations.

"Among these considerations, almost as an aside, he introduces two small sections that encapsulate ideas that are probably the most original in the whole book, and have become absorbed into the fabric of modern biology. The first of these makes an analogy between a gene and an aperiodic crystal and is best explained in Schrödinger's own words:

'A small molecule might be called 'the germ of a solid.' Starting from such a small solid germ, there seem to be two different ways of building up larger and larger associations. One is the comparatively dull way of repeating the same structure in three directions again and again. That is the way followed in a growing crystal. Once the periodicity is established, there is no definite limit to the size of the aggregate. The other way is that of building up a more and more extended aggregate without the dull device of repetition. That is the case of the more and more complicated organic molecule in which every atom, and every group of atoms, plays an individual role, not entirely equivalent to that of many others (as is the case in a periodic structure). We might quite properly call that an aperiodic crystal or solid and express our hypothesis by saying: We believe a gene - or perhaps the whole chromosome fibre - to be an aperiodic solid' (p. 60).

"The second of the ideas, which had not been expressed explicity before, was a clear statement indicating the necessity for a genetic code:

'It has often been asked how this tiny speck of material, the nucleus of the fertilized egg, could contain an elaborate code-script involving all the future development of the organism? A well-ordered association of atoms, endowed with sufficient resistivity to keep its order permanently, appears to be the only conceivable material structure, that offers a variety of possible ('isomeric') arrangements, sufficiently large to embody a complicated system of 'determinations' within a small spatial boundary. Indeed, the number of atoms in such a structure need not be very large to produce an almost unlimited number of possible arrangements' (p. 61).

And he goes on to illustrate the last point with the example of the Morse code.

"In the last two chapters Schrodinger takes up another line of argument. No specific information about how genes work can be expected to come from the very general proposal of Delbrück concerning genes and quantum states; that is a subsequent problem for biochemistry and genetics. But, he goes on:

'. . . there is just one general conclusion to be obtained from it, and that, I confess, was my only motive for writing this book. From Delbrück's general picture of the

hereditary substance it emerges that living matter, while not eluding the 'laws of physics' as established up to date, is likely to involve 'other laws of physics' hitherto unknown, which, however, once they have been revealed, will form just as integral a part of this science as the former' (p. 68).

"The argument that leads to this conclusion runs thus. Consider how a single cell, the germ cell, turns into an organism. It does this via a series of reactions, each one of which has to be exquisitely tuned in order that the complex organism should have the characteristics determined by the code-script contained in the genes. It seems that orderliness is increased in the system. How can one explain this? There are in fact two problems. One concerns entropy, because superficially the entropy of the system seems to decrease, which is contrary to the second law of thermodynamics. This problem of entropy in living organisms is not too difficult to dispose of, as one can enlarge the system to include the environment, and then consider how the developing organism can feed on energy, or 'negative entropy,' as Schrödinger calls it. This is a classical argument and does not introduce any new ideas.

"The more subtle problem is that living organisms seem to be examples where order of one kind, that which originally is in the code-script of the genes, breeds order of a different kind, that of the concerted reactions that occur during the development of an organism. This situation, where a small number of molecules determine a whole series of ordered reactions with fantastic accuracy, is unknown in ordinary physical and chemical systems, and suggests that underlying it there may be new laws of an 'order breeding order' kind" (Symonds, pp. 221-224)..

"The concept missing from his analysis is information. The information theory of Claude Shannon and the cybernetics of Norbert Wiener in the 1940s and 1950s began to fill that lacuna, although only more recently have researchers begun to under- stand how information truly features in biology. As Schrödinger's talk of negative entropy hinted, life is a pocket of out-of- equilibrium order in an open system, and the DNA code is just part of what sustains it. It's a shame that Schrödinger didn't touch on fellow physicist Leo Szilard's work on Maxwell's demon, a thought experiment that revealed how entropic disorder could be undone by making use of molecular- level information that looks like mere statistical noise at the macroscopic level.

"What's more, Schrödinger gave his code-script too much agency by imagining that its readout was mapped directly onto the phenotype. This isn't how it works: you can't read the arrangement of the body's organs in the genome. The information functions as a resource, not a step-by-step guide. To acquire meaning, it must have context: a cell's history and environment. Tracing how the phenotype emerges from interactions of genes with each other and with their environment is the key puzzle of modern genomics.

"What is Life? helped to make influential biologists out of several physicists: Crick, Seymour Benzer and Maurice Wilkins, among others. But there's no indication from contemporary reviews that many biologists grasped the real significance of Schrödinger's code-script as a kind of active program for the organism. Some in the emerging science of molecular biology were critical. Linus Pauling and Max Perutz were both damning about the book in 1987, on the centenary of Schrödinger's birth. Pauling considered negative entropy a 'negative contribution' to biology, and castigated Schrödinger for a 'vague and superficial' treatment of life's thermodynamics. Perutz grumbled that 'what was true in his book was not original, and most of what was original was known not to be true even when the book was written'.

"Although these judgements are uncharitable, they are not without substance. Why, then, was the book so influential? Rhetorical theorist Leah Ceccarelli argues that it was down to Schrödinger's writing style: he managed to bridge physics and biology without privileging either. But today, we can find more than that. Schrödinger's thoughts on the entropic balance of life can be regarded as precursors to studies of how biological prerogatives such as replication, memory, ageing, epigenetic modification and self-regulation must be understood as processes of non-equilibrium complexity that cannot ignore the environment. It is intriguing that similar considerations of environment and contingency are now seen to be central in quantum mechanics, with its ideas of entanglement, decoherence and contextuality. Whether this is more than coincidence, we can't yet say" (Ball, pp. 549-550).

Ball, 'What is Life?' Nature 560 (2018), pp. 548-550. Sarkar, 'What is Life? Revisited,' BioScience 41 (1991), pp. 631-634. Symonds, 'What is Life? Schrödinger's influence on biology,' The Quarterly Review of Biology 61 (1986), pp. 221-226.

8vo (193 x 121 mm), pp. viii, 91, with 4 plates on 2 leaves, numerous diagrams in text. Original green cloth, spine lettered in gilt. With dust jacket.