- Thinking about science: Max Delbrück and the Origins of Molecular Biology by Ernst Peter Fischer and Carol Lipson
Norton, 334 pp, £13.95, January 1989, ISBN 0 393 02508 X
- Is science necessary?: Essays on Science and Scientists by Max Perutz
Barrie and Jenkins, 285 pp, £14.95, July 1989, ISBN 0 7126 2123 7
In 1944, the physicist Erwin Schrödinger, who had earned a Nobel Prize for his contributions to the invention of quantum mechanics, published What is life?, a remarkable book in which he argued that vital processes must obey the laws of physics but could probably not be reduced to them. In micro-physics, order tended to give way to disorder; the behaviour of single atoms could be predicted only in statistical terms. In living organisms, the genes governing heredity and development seemed to consist of a particular arrangement of atoms. Yet, in essential respects, offspring resembled parents; order produced order. The apparent disparity between atomic and life-cycle events led Schrödinger to contend that a ‘new type of physical law’ – not a ‘super-physical’ but a ‘genuinely physical’ type, consistent with known physical laws – must prevail in living matter.
Schrödinger’s book, a tour de force in its demonstration of how physical reasoning might be applied to biological problems, stimulated a number of young physicists to enter the rapidly-burgeoning field of molecular biology. The French geneticist and Nobel laureate François Jacob recalled:
After the war, many young physicists were disgusted by the military use that had been made of atomic energy ... Some looked to biology with a mixture of diffidence and hope ... To hear one of the fathers of quantum mechanics ask himself, ‘What is life?’ and to describe heredity in terms of molecular structure, of inter-atomic bonds, of thermodynamic stability, sufficed to draw towards biology the enthusiasm of young physicists and to confer on them a certain legitimacy. Their ambitions and their interests were confined to a single problem: the physical nature of the genetic information.
It is likely, however, that Schrödinger’s book led more people to attack problems in biology than to search for new laws of physics. Schrödinger’s was the speculation of a theorist, and a philosophically-inclined one at that. Pure theory – the pursuit of first principles to logical consequences – has rarely figured in modern biological inquiry, at least not in its Anglo-American mode. To be sure, Charles Darwin – despite his protestations to the contrary – had strong theoretical inclinations, but he constantly tested and modified his ideas against an enormous array of observational data. Max Perutz, who was for many years the director of the Medical Research Council Unit for Molecular Biology at the Cavendish Laboratory in Cambridge, had a front-row seat during many innings of molecular genetics. He reports in Is science necessary? – a collection of engaging essays and reviews, including one occasioned by the 1987 reissue of What is life? – that few molecular biologists, including the recruits from physics, appear to have been much, if at all, concerned with the seemingly deep issue Schrödinger discussed. The pioneers of molecular biology may have imported analytical attitudes and techniques from the physical sciences, but they were problem-solvers, working at the laboratory bench to tease out the mechanism of heredity.
Perutz, who shared the 1962 Nobel Prize in Chemistry for his work on the structure and function of haemoglobin, more than once makes the point that the stuff of biology does not lie primarily in isolated thought but in the connection of thought with the details of observation and experiment. Like Schrödinger, Perutz is a native of Vienna, but he left in 1936 for postgraduate work at Cambridge, where he became imbued with the scientific values characterised, he says, by ‘extreme devotion to hard experimental work, and strong aversion to speculation beyond what is justified by the experimental results’. Peter Medawar once extolled imaginative guesswork as part of the scientific process. Perutz comments: ‘During the first 33 years of my own research imaginative guesswork proved useless: only after my colleagues and I had solved the structure of haemoglobin by X-ray analysis could I begin to guess how the molecule works.’
Had Schrödinger paid more attention to chemistry, Perutz notes, he might not, even in 1945, have been so quick to think that explaining how the gene works might require new physical laws. It was known that, under the right conditions, an enzymatic catalyst would direct the formation at a high rate of a structurally-specific biological compound, thus producing order from disorder; and that the stability of the polymers composing living matter could be accounted for by the theory of the chemical bond. Schrödinger did speculate that genetic information might involve some type of linear code, analogous to the Morse Code, embedded in an aperiodic molecular structure, but he did not take up the central problem of how that structure might be faithfully transmitted from one generation to the next. This was the problem which utterly absorbed James Watson and Francis Crick as they struggled at the beginning of the Fifties, in Perutz’s group at the Cavendish, to unravel the structure of DNA. They spent a lot of time lounging around and arguing – indulging in imaginative guesswork, one might say, instead of doing experiments. Perutz, who thought that they were wasting their time, concedes in the face of their triumphant success that ‘there is more than one way of doing good science.’ Yet, however imaginative, their guesswork was not pure: it was tied to real data – notably those of X-ray crystallography, arrangements of chemical bonds and structural angles, proportions of molecular constituents. The dénouement – the famed double helix – revealed that the key to the transmission and expression of genetic information inhered not in some new physical laws but in a particular molecule – a supple, compact and beautiful molecule, to be sure, but one whose functions were explicable in terms of conventional chemistry.
The nature of the dénouement disappointed Max Delbrück, who in 1969 would share the Nobel Prize for Physiology or Medicine for his pioneering work in viral and bacterial genetics. He was one of the founders of molecular biology and, more important, a guiding and exacting spirit in its early development. When Delbrück died in 1981, he was working on an autobiography with the assistance of Ernst Peter Fischer, who was one of his latest graduate students. Fischer, now an accomplished science writer in Germany, went on to write Delbrück’s life story in collaboration with Carol Lipson, a member of the English faculty at Cornell University. The result is an informative and sympathetic portrait.
Delbrück was a product of Germany’s academic and intellectual aristocracy – a maternal forebear was the great German chemist Justus Liebig. His father was Hans Delbrück, who had served briefly in the Prussian Parliament and the Reichstag and was a professor of history at the University of Berlin. Young Max knew broods of Bonhoeffers and Harnacks, who were close family friends and met with each other every Sunday evening. His biographers suggest that, growing up in this bustling, engaged milieu, he withdrew into science as a way of establishing his own identity. He trained as a theoretical physicist at Göttingen University, where he arrived for postgraduate work in 1926, as quantum mechanics, which had just been invented (partly at Göttingen), was bursting upon the world of atomic physics. He was caught up in the quantum mechanics enthusiasm of several of the brilliant young scientists – they included Robert Oppenheimer, Pascual Jordan and Victor Weisskopf – who had come to the university to pursue the new theory. ‘I learned at an early age that science is a haven for the timid, the freaks, the misfits,’ Delbrück later mused: ‘If you were a student in Göttingen in the Twenties and went to the seminar “Structure of Matter”, ... you could well believe you were in a madhouse ... Every one of the persons there was obviously some kind of severe case. The least you could do was put on some kind of stutter.’ Much of theoretical physics involved calculations. Delbrück found calculating tedious and judged himself less good at it than others, such as Weisskopf. He wished to explore new ideas.
Gradually, Delbrück identified biology as a suitable field and fastened upon it as a potential source of new ideas on hearing Niels Bohr, with whom he had studied after his doctorate, deliver a lecture in Copenhagen, in 1932, entitled ‘Light and Life’. Here Bohr proposed that some type of complementarity might prevail between vital processes and atomic physics analogous to the complementarity which he discerned in the duality of waves and particles. Although Bohr’s reasoning differed from Schrödinger’s later logic – Bohr’s pivoted on experimental rather than theoretical considerations – he roughly adumbrated Schrödinger’s contention that the development of biology would require concepts that could not be reduced to those of atomic physics. What fascinated Delbrück about biology was precisely that it might ultimately yield such concepts, some new principle inherent in the human observer’s attempt to comprehend vital new nature. He would tell Bohr, in 1962, that the question of complementarity in biology had ‘through the years provided the sole motivation for my work’.
Delbrück’s strategy in pursuit of biological complementarity was to investigate a simple biological system – something akin to the hydrogen atom in physics – pressing its analysis until paradoxes appeared, just as they had done in the exploration of atomic physics. The system he was lured to was the gene. At the Kaiser Wilhelm Institute for Chemistry in Berlin, Delbrück collaborated with the Russian geneticist Nicolai Timofeeff-Ressovsky and the physicist K.G. Zimmer to study the effect of ionising radiation on genetic mutations. In 1935, the three men published a paper. Although ultimately proved wrong in important respects, the paper was a landmark because its findings conjoined to indicate that genes were not abstract entities but relatively stable macromolecules susceptible to analysis by physical and chemical methods. Perutz sings its praises, noting that Delbrück’s part showed ‘the maturity, judgment, and breadth of knowledge of someone who had been in the field for years’. Schrödinger’s reading of the paper stimulated him to write What is life?.
The merits of his research did not earn Delbrück a regular academic post in Nazi Berlin. Unlike his family, he was doggedly apolitical, alienated from state and society by the First World War – in which he had lost his oldest brother – and by the ugly passions that had bubbled, not always below the surface, in Weimar Germany. Even so, in the Thirties he made no secret of the fact that he found the Nazis contemptible, as did other members of his family, some of whom actively opposed them. Despite his impeccable German (and nominally Christian) credentials, he was considered politically unreliable and was unable to obtain a university post. Coveting one greatly, he went to some lengths to prove that he was not Jewish, and he submitted to courses at Nazi indoctrination camps – all to no avail. However, the paper on genetic mutations led to a Rockefeller Foundation Fellowship and the opportunity to spend the 1937-38 academic year in the United States, mainly at the California Institute of Technology.
In Pasadena, Delbrück was exhilarated by the work being done by biochemist Emery Ellis with bacteriophage – a virus that multiplies itself in bacteria. In 1935, another biochemist, Wendell Stanley, had succeeded in crystallising a tobacco virus, which indicated, as Delbrück put it, that a virus is a ‘living molecule’. Bacteriophage presented a simple system – a hydrogen atom for biology – and Ellis’s methods revealed that they could be scrutinised with astonishingly simple experimental techniques to find out how they managed to reproduce themselves in the bacterial cell. Delbrück promptly entered upon a programme of phage research, remaining in the United States, initially for a further year, and then, when war broke out in Europe, indefinitely, thanks to an appointment, in January 1940, to the faculty of Vanderbilt University.
In the summer of 1941, Delbrück went to the Cold Spring Harbor on Long Island to work on bacteriophage with the Italian refugee scientist, Salvador Luria. This led to the publication in 1943 of a paper in bacterial genetics that was of fundamental importance – both because it demonstrated that mutation occurred spontaneously (not, as Lamarckians had it, in response to environmental change) and because it laid out powerful methods and modes of analysis by which heredity in bacteria could be studied efficiently. In 1943, too, Delbrück and Luria took Alfred Hershey, a chemist on the faculty of the Washington University Medical School, in St Louis, Missouri, into their partnership, thus initiating what came to be known as the Phage Group, a small, informal network of viral and bacterial geneticists. (Luria and Hershey would be Delbrück’s co-recipients of the Nobel Prize.) Dissemination of the group’s approach acquired some institutional leverage in 1945, when Delbrück established an annual summer phage course at Cold Spring Harbor – the course, increasingly well attended, would continue for 25 years – and still more in 1947, when Delbrück himself returned to Caltech as professor of biology.
Delbrück modelled the Phage Group on the group that had gathered around Niels Bohr and had created quantum physics: ‘it was open and co-operative in strict imitation of the Copenhagen spirit in physics,’ he was later to remark. It must be said that he sometimes co-operated more in the irascible manner of Wolfgang Pauli, with whom he had studied briefly and who was quantum physics’ uncompromising intellectual conscience, than in that of the tactful Bohr. Delbrück’s criticism could be devastating. He might comment on a seminar by stalking out after five minutes or, worse, by telling the speaker afterwards that it was ‘the worse seminar I ever heard’. (He kept a bottle of brandy in his desk for the restoration of the distressed.) Still, he was an unusually engaging, humorous and generous colleague, devoting ‘great effort and intelligence’, Hershey once noted, ‘to encouraging, appreciating and steering the work of others, probably often at the expense of his own’. Fischer and Lipson observe: ‘Max was the intellectual of molecular biology. There are others whose original contributions had greater impact on the development of science, but it was Max whose nagging questions guided researchers toward the right experiments. He was the Socrates of biology; Cold Spring Harbor and Caltech were his marketplaces.’
Delbrück continued all the while to hope that the study of the genetics of micro-organisms would expose some deep paradox, compel the forging of a new principle. However, the evidence – manifest, as he had recognised, in Stanley’s crystallisation of the tobacco virus – had kept accumulating that genetics was chemistry, particularly that it was DNA. What disappointed Delbrück about the double helix was that the biology of heredity did not reveal any profound new principle. He thought the structure of DNA was marvellous, to be sure. But, as he wrote in 1981, ‘with one blow the mystery of gene replication was revealed as a ludicrously simple trick, making those who had expected a deep solution feel as silly as one might feel when shown the embarrassingly simple solution to a chess problem one may have struggled with in vain for a long time.’
Delbrück maintained the search for a paradox that might yield a new principle, hoping to find it in an explanation of why phycomyces, a single-celled organism, grew in the direction of light, the subject that came to dominate his later research. He became somewhat less disengaged from the world of affairs, partly thanks to the involvement in the world of liberal politics of his wife, the former Manny Bruce, whom he had met in 1940, partly because he felt the terrible losses suffered by friends and relatives who had stayed in Germany. He considered those who had remained and resisted the regime – like his brother-in-law Karl Bonhoeffer and Karl’s brother Dietrich, both of whom were murdered by the Nazis – prisoners of conscience, and he donated his Nobel Prize money to Amnesty International. He continued nonetheless to lead a largely apolitical life – the house kept clear of radio, TV and magazines – holding to the belief that ‘the pursuit of scientific truth, of poetic truth or of mystic truth, is ultimately far more important and influential in shaping man’s fate than the power game of those with political aspirations who try to change the world directly.’
A highly debatable point of view, of course, and one with which Perutz, to judge by Is science necessary?, wouldn’t agree. While Delbrück’s non-technical writings mainly concern philosophy and art, Perutz’s include knowledgeable, instructive and often wise reflections not only on science and its practice but on science in relation to such matters as food supply, energy, health and politics. Perutz was bruised by his rejection as a Jew by his native Austria, which he loved, and his internment as an Austrian by the English early in the war. His alienation did not diminish – perhaps it enhanced – his propensity to find social meaning in rice yields, demographic trends or the incidence of children’s diseases and mortality. Delbrück may have felt private pain as a result of public events, but he responded by insulating himself from the world of affairs.
The insulation was made that much easier by the conditions that prevailed in the United States. He was favoured by the increasingly abundant resources of American science, and also by his marriage. His biographers report that his wife ‘sheltered him, allowing him to concentrate on science’. ‘Manny,’ they write, ‘ran the house, looked after the car, did the income tax, and later on guided the children.’ Yet if politics and public affairs meant little or nothing to Delbrück, neither did material goods or fame. He lived modestly. When he won the Nobel Prize, he acknowledged the congratulations that poured in from friends by sending them a handwritten extract from a Japanese poem that he had read out at the end of the press conference occasioned by the award:
The temple bell echoes the impermanence of all things ...
Before long the mighty are cast down
And are as dust before the wind.
He was to the end clear-eyed and courageous. When he learned that he had multiple myeloma – the disease that eventually killed him – he gathered his students together for a seminar on the subject and, as the disease progressed, told his son Jonathan that he was embarked on his ‘last great adventure’.