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<\/div>\n<\/div>Physicist Erwin Schr\u00f6dinger also probed questions of molecular biology.<\/span>Credit: Bettmann\/Getty<\/p>\n<\/figcaption><\/figure>\n <\/p>\n <\/p>\n What Is Life? The Physical Aspect of the Living Cell<\/b>\u00a0Erwin Schr\u00f6dinger\u00a0<\/i>Cambridge University Press (1944)<\/p>\n <\/p>\n In\u00a0What Is Life?<\/i>\u00a0(1944), Austrian physicist and Nobel laureate Erwin Schr\u00f6dinger 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 \u201ccode-script\u201d that directs cellular organization and heredity, while apparently enabling organisms to suspend the second law of thermodynamics.<\/p>\n 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\u2019s discovery in 1953 of how DNA\u2019s double helix encodes genes. As Crick wrote to Schr\u00f6dinger that year, he and Watson had \u201cboth been influenced by your little book\u201d.<\/p>\n Elegant and accessible,\u00a0What Is Life?<\/i>\u00a0grew from a series of enormously popular public lectures that Schr\u00f6dinger gave at Trinity College Dublin in 1943, in the depths of the Second World War. Exiled from Austria when it was annexed by Nazi Germany, Schr\u00f6dinger had been invited to Ireland\u00a0to help establish the Dublin Institute for Advanced Studies<\/a>. (This September, Trinity will mark the lectures\u2019 anniversary with a conference called Schr\u00f6dinger at 75 \u2014 The Future of Biology.)<\/p>\n Since the 1930s, biology had been turning from a largely descriptive science into one concerned with mechanism. Thanks to studies such as those by geneticist Thomas Hunt Morgan on fruit flies, researchers were starting to understand heredity in terms of the transmission of genes, envisaged as large molecules arranged on chromosomes. Many expected genes to be proteins. However, even as Schr\u00f6dinger was preparing his lectures, the microbiologist Oswald Avery was finding evidence that they were nucleic acids. Thus,\u00a0What Is Life?<\/i>\u00a0dropped into a tumultuous time for science as well as for sociopolitics.<\/p>\n Schr\u00f6dinger steps into these cross-disciplinary waters cautiously. He declares himself a \u201cnaive physicist\u201d, pondering how life sustains itself and transmits genetic mutations stably across generations. His work on quantum mechanics had earned him a Nobel prize in 1933, but that was hardly qualification for commenting on biology, in which Schr\u00f6dinger had previously shown little interest beyond forays into the physiology of vision. Arguably, that naivety is the source of the book\u2019s strengths as well as its weaknesses.<\/p>\n The puzzle in the title stemmed from how physicists and chemists then thought of the molecular world, as wholly governed by statistical behaviour. In the classical molecular physics of James Clerk Maxwell and Ludwig Boltzmann, atomic motions are random (see\u00a0E. Schr\u00f6dinger\u00a0Nature<\/i>\u00a0153<\/b>, 704\u2013705; 1944<\/a>). Precise, robust physical laws, such as those linking the temperature, pressure and volume of a gas, emerge from the average behaviour of countless atoms.<\/p>\n How, in that case, can a specific macroscopic outcome \u2014 a phenotype, an organism\u2019s observable inherited traits \u2014 arise from an individual genetic mutation at the molecular level? Here, perhaps, is a ghost of Schr\u00f6dinger\u2019s cat, formulated in 1935, whose macroscopic life or death hinges on a single quantum event. (Mathematician Roger Penrose has said of the thought experiment that \u201cit would not surprise me if Schr\u00f6dinger had something of this issue partly in mind\u201d when he wrote\u00a0What Is Life?<\/i>.) Looking at an inherited characteristic (such as the protruding lower jaw common among members of Europe\u2019s Habsburg dynasty), Schr\u00f6dinger asks how the allele responsible remained \u201cunperturbed by the disordering tendency of the heat motion for centuries?\u201d.<\/p>\n Here, he cites experiments by another former quantum physicist, Max Delbr\u00fcck, whose use of high-energy radiation to induce genetic mutations allowed him to estimate a gene\u2019s size at around 1,000 atoms. Schr\u00f6dinger claims that this seems too small for \u201clawful activity\u201d \u2014 durable inheritance \u2014 to persist in the face of statistical fluctuations. But he asserts that quantum mechanics can explain the matter. Atoms in molecules can typically be arranged in many stable ways, and each configuration has an associated energy; this is how Schr\u00f6dinger envisages different gene alleles. But \u201cquantum jumps\u201d between them are generally inhibited by high energy barriers.<\/p>\n He goes on to propose that such gene-encoding molecules (he was among those who suspected that they were large proteins) have enough potential variety in their configurations to encode huge amounts of information, and that this variety can furnish a cell\u2019s \u201ccode-script\u201d. The position of each atom matters, but the pattern does not repeat \u2014 hence his description of the molecules as being like an aperiodic (irregular) solid. It wasn\u2019t an entirely new idea; Delbr\u00fcck had suggested something of the kind in 1935. And biologists Hermann Muller and J. B. S. Haldane had independently proposed that chromosomes might act as templates for their own replication, in the same way that new crystal layers build up on pre-existing ones.<\/p>\n None of this, Schr\u00f6dinger admits, answers the deeper question of \u201chow the hereditary substance works\u201d \u2014 that is, how it is used in development and metabolism, enabling an organism to build and sustain itself from moment to moment in what Schr\u00f6dinger calls its \u201cfour-dimensional pattern\u201d in space and time. But he makes a start on that issue by posing the question in thermodynamic terms.<\/p>\n This isn\u2019t a matter of energy (organisms\u2019 energy intake and output must be balanced, or they\u2019d burn up), but of entropy, the measure of atomic disorder. The second law of thermodynamics states that entropy must increase in all processes of change. But organisms somehow stave off entropic dissolution. As Schr\u00f6dinger put it, they feed on \u201cnegative entropy\u201d, using it to sustain the organization apparent in the structures and functions of cells, while paying their thermodynamic dues by heating the environment.<\/p>\n How they mine negative entropy, he could not say. He was forced to suggest that, in living systems, \u201cwe must be prepared to find a new type of physical law\u201d. Today, no such drastic solution seems to be needed.<\/p>\n 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 understand how information truly features in biology. As Schr\u00f6dinger\u2019s 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\u2019s a shame that Schr\u00f6dinger didn\u2019t touch on fellow physicist Leo Szilard\u2019s work on Maxwell\u2019s 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.<\/p>\n What\u2019s more, Schr\u00f6dinger gave his code-script too much agency by imagining that its readout was mapped directly onto the phenotype. This isn\u2019t how it works: you can\u2019t read the arrangement of the body\u2019s 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\u2019s 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.<\/p>\n What is Life?<\/i>\u00a0helped to make influential biologists out of several physicists: Crick, Seymour Benzer and Maurice Wilkins, among others. But there\u2019s no indication from contemporary reviews that many biologists grasped the real significance of Schr\u00f6dinger\u2019s 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,\u00a0on the centenary of Schr\u00f6dinger\u2019s birth<\/a>. Pauling considered negative entropy a \u201cnegative contribution\u201d to biology, and castigated Schr\u00f6dinger for a \u201cvague and superficial\u201d treatment of life\u2019s thermodynamics.\u00a0Perutz grumbled<\/a>\u00a0that \u201cwhat 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\u201d.<\/p>\n 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 Schr\u00f6dinger\u2019s writing style: he managed to bridge physics and biology without privileging either. But today, we can find more than that. Schr\u00f6dinger\u2019s 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\u2019t yet say.<\/p>\n <\/p>\n<\/div>\n Nature<\/span>\u00a0560<\/strong>, 548-550 (2018)<\/p>\n <\/p>\n