Max Perutz and the secret of life, by Georgina Ferry

Max Perutz and the secret of life, by Georgina Ferry. Cold Spring Harbor Laboratory Press, Cold Spring Harbor, NY. 352 pp. $39.00 (hardcover) Georgina Ferry has written a superb biography of one of the most influential and likable figures of modern science, Max Perutz of Cambridge University. It may seem strange to some readers to use the term “modern” to describe something that happened half a century ago, but Max was one of a handful of pioneers who began something that nearly all of us benefit from today: Molecular Biology. He first figured out how to solve the crystal structure of a protein and then implemented this with the blood protein hemoglobin. All of us in the field since that time have essentially been developing better and more high-powered ways of doing what Max accomplished in the 1950s with primitive computational facilities that would be scorned today by people with a laptop computer. The bare bones of Perutz's scientific story can be told briefly: In 1936 he came from Vienna to Cambridge to work on his doctorate and became involved in crystalline proteins under J.D. Bernal. After some fantastic wartime adventures (of which more later), he joined a research group in the Cavendish Physics Laboratory headed by William L. Bragg (known later as Sir Lawrence Bragg), the man who essentially “invented” crystal structure analysis and shared a Nobel Prize with his father W.H. Bragg in 1915 for this achievement. Bragg fils had achieved great things in the structures of minerals and inorganic compounds and considered that the next great challenge would be to apply his methods to the structures of proteins and other biological materials. Bragg persuaded the Medical Research Council in 1948 to support Perutz in founding a new laboratory at Cambridge for this work, and Perutz and his graduate student (and later colleague) John Kendrew embarked on their mission. Max continued to work on the four-chain molecule, hemoglobin, while John ultimately chose its one-chain cousin, myoglobin. Progress naturally was easier with the smaller molecule. Kendrew produced a low-resolution 6 Å structure of myoglobin in 1957 and the high-resolution 2 Å structure in 1959. Perutz completed a low-resolution 5.5 Å map of hemoglobin that same year and a high-resolution 2.8 Å map in 1968. In recognition of what they had accomplished, Perutz and Kendrew shared the Nobel Prize in Chemistry in 1962. That same year the Nobel Prize in Biology and Medicine was awarded to Francis Crick and Jim Watson, who in 1953 had solved the structure of DNA in Max's MRC Laboratory. The year 1962 was indeed an annus mirabilis for the Medical Research Council and for Cambridge! This is the bare skeleton of the story. Georgina Ferry's great achievement is to have fleshed out this plot outline into a real drama about real people. In places the book reads like a novel, but its facts are always correct. Max Perutz was not “just” a scientist; he was a fine human being with strong family ties and with interests that ranged far beyond protein structures. In fact, an earlier interest was in the structure and mechanical properties of ice. He was an enthusiastic mountaineer and skier, at home with both granite and glaciers. While I was a postdoctoral with Kendrew in the late 1950s I once asked Max, “Since you like mountains and snow so much, why did you leave Austria to come to Cambridge?” (Topographically, Cambridge has all the character of a pool table.) Max gave a practical answer, “With my working in Cambridge, Gisela (his wife) and I can go back to Switzerland every winter to visit her family and ski to our hearts' content. If I had remained in Vienna, I couldn't have afforded the train fare to Innsbruck!” Max also was a skilled essayist. Two collections, Is Science Necessary? Essays on Science and Scientists (Dutton, 1989) and I Wish I'd Made You Angry Earlier: Essays on Science, Scientists and Humanity (Cold Spring Harbor Laboratory Press, 2003) still make absorbing reading. The title of the latter collection arises from a story that Max tells about his running into the office of Sir Lawrence Bragg and informing him excitedly that he had just obtained experimental proof of the correctness of Linus Pauling's new α-helix model for protein chains. When asked what had impelled him to do the experiments, Max replied “The idea was sparked off by my fury over having missed that beautiful structure myself.” To this, Bragg replied, “I wish I had made you angry earlier!” Ferry presents this incident well, and also tells you why Bragg was so sensitive about not having been the first to arrive at the helical structure of a protein chain. The issue of whether the folded “sausages” of the low-resolution myoglobin map would turn out to be Pauling's α-helices remained. At 2 Å resolution, would they be hollow (the “garden hose” model), and would they show a helical backbone? In 1959, when we completed the high-resolution map of sperm whale myoglobin, John Kendrew celebrated with a garden party at dusk on the lawn of Peterhouse. The electron density sections through the protein were drawn on Plexiglas and stacked atop a light box. I watched Bragg excitedly drag one attendee after another over to the map, point at one particular helix that moved diagonally down the Plexiglas stack, and exclaim excitedly, “Look! Look! It's hollow!” Max's contributions during World War II are curious, and again Ferry tells them well. When Germany annexed Austria in 1938, Austrian citizens in England such as Max Perutz suddenly became “enemy aliens.” Max was questioned and deemed not to be a threat. But 2 years later when Germany invaded Norway and the Netherlands, Britain reacted by rounding up nearly 7000 Austrian and German men over the age of 16, Max among them, and shipped them off to internment camps in Canada! When they heard of this, both Linus Pauling at Caltech and Martin Buerger at MIT quickly offered Max a visiting fellowship, and the Rockefeller Foundation agreed to fund it. But his colleagues in Britain had been raising a storm of protest, and by the middle of January 1941 Max was safely back in Cambridge. Max later wrote up the entire episode entitled “Enemy Alien” in the August 12, 1985, issue of the New Yorker and included a revised and expanded version in both Is Science Necessary? and I Wish I'd Made You Angry Earlier. By an odd twist of fate, Max found himself back in Canada again (and the United States as well), as an expert on the structures and properties of ice, part of a fantastic program to build floating iceberg airfields in the North Atlantic. The organizer of this plan was Geoffrey Pyke, and the iron-hard frozen mixture of sawdust and water was known as “pykrete.” Max was recruited because of his knowledge of ice and glaciers. The project, not surprisingly, came to nothing. One such airfield of reinforced ice would have been 26 times as heavy as the Queen Elizabeth. Again, Ferry tells the story well and illustrates it with contemporary drawings of the proposed frozen aircraft carrier. Max himself wrote everything up after the fact in a 1947 scientific paper for the Journal of Glaciology entitled “A Description of the Iceberg Aircraft Carrier and the Bearing of the Mechanical Properties of Frozen Wood Pulp upon Some Problems of Glacier Flow.” This surely must be Max's least-cited paper, but he includes it in a collection of his scientific papers entitled Science Is Not a Quiet Life: Unraveling the Atomic Mechanism of Haemoglobin (Imperial College Press, 1997). Ferry does a magnificent job of expressing the doubts, difficulties, and uncertainty of Max Perutz's life. Too often “official” biographies have an unrealistically orderly tone: I got up one morning. I had an inspiration. I ran some experiments. I discovered something new and exciting. I published my findings. I received a Nobel Prize. This is far from describing Perutz's life. He began as an upper middle-class child in Vienna, Jewish by ancestry but Catholic by upbringing. He entered the University of Vienna in 1932 at the age of 18, to commence a 7-year program in chemistry that ultimately would conclude with a doctorate. After 3 years he became disillusioned with the intellectual and political atmosphere in Vienna and longed to move to Cambridge to work with the chemist Frederick Hopkins, who had earned a Nobel Prize in physiology in 1929 for his work on vitamins. His mentor in Vienna, Hermann Mark, inexplicably forgot to contact Hopkins to tell him that Max was coming to visit. But while in Cambridge he did meet the physicist and crystallographer J.D. Bernal and was so captivated by the research that he applied and was accepted into Bernal's group in 1936. When Hitler annexed Austria 2 years later, Max's parents and siblings had to flee the country quickly. His brother was a businessman in Prague and happened to have a car with Czech license plates, so parents, brother, and sister grabbed what they could carry and drove north. His brother and sister later elected to flee from Prague to the United States, but his parents went to Zurich, from where they depended on Max to get them into Britain somehow. He succeeded, but the unemployed business executive and the upper-class society wife found little in England to their pleasure. Georgina Ferry relates one aspect of this anti-Nazi exodus that I cannot avoid passing on. It concerns Hermann Mark, Max's mentor. “Mark and his wife also arrived in London via a ‘skiing holiday’ in Switzerland, having converted his wealth into platinum wire which he disguised as coat hangers.” Max's parents, unfortunately, brought no coat hangers with them, and life was difficult at first. Skipping over the Canadian internment and the pykrete mess that have already been described, Max found himself after the war's end still in a junior position at Cambridge with no permanent university appointment and no job security. When John Kendrew came to work with him in 1946, he had to be enrolled officially under W.H. Taylor, the head of the Crystallography Division, because Max had no university status. It was not until the Medical Research Council funded the MRC Laboratory of Molecular Biology in 1948 that Max acquired a permanent Cambridge University appointment. There were no guiding spirits to whisper to the Cambridge administration, “Hire this man. In another 14 years he will win the Nobel Prize!” Max's research also did not go smoothly. His first “pillbox” model for hemoglobin was dead wrong. Bragg, Kendrew, and Perutz failed to beat Pauling to the α-helix, although if they had given their published fourfold helix a little less twist to 3.6 residues per turn, they would have had it. By the mid-1950s they were at an impasse. The best of conventional techniques, Patterson analysis, failed with such a complex molecule. And then Max had a flash of inspiration that led him and John straight to Stockholm. In 1936, the year Max first came to Cambridge, a Glasgow crystallographer named J.M. Robertson had solved the structure of phthalocyanine, using a new method to surmount what was called the “phase problem.” (If you really want a nonmathematical explanation of what this entailed, see my book, Present at the Flood: How Structural Molecular Biology Came About, Sinauer Associates, 2005.) Robertson bound a heavy metal atom to the phthalocyanine molecule, measured the changes in intensities of reflections in the X-ray pattern, and used this information to break the phase paradox. But phthalocyanine has only 40 atoms (not counting hydrogens); hemoglobin has roughly 4800, or 120 times as many. No one believed that binding even the heaviest metal atom to hemoglobin could produce visible changes in X-ray intensities. No one, that is, except Max. With Vernon Ingram's help, he prepared derivatives of hemoglobin in which each molecule had added to it two atoms of either silver or mercury. The consequence was large and measurable changes in X-ray intensities, and this isomorphous replacement process led to a solution of the phase problem and calculation of an electron density map of the protein. Green, Ingram, and Perutz published their paper in 1954: “The Structure of Haemoglobin IV. Sign Determination by the Isomorphous Replacement Method” (Proc. Roy. Soc A 225: 287) and the battle essentially was over. We knew how to solve protein structures. (A footnote to the title page of that paper observes that Perutz was elected a Fellow of the Royal Society in March 1954. Wise move.) Ferry's book is especially valuable in telling us about Max's early years, before he and his laboratory became famous, and in conveying the personal drama behind the bare outline that I have sketched above. Later matters are also covered in Horace Judson's The Eighth Day of Creation (Simon and Schuster, 1979), Soraya de Chadarevian's Designs for Life (Cambridge University Press, 2002), and my own Present at the Flood. Judson covers the entire field of molecular biology, not just structure. Chadarevian focuses primarily on achievements in protein and DNA structure at Cambridge University (admittedly, the most formidable player). Flood is a collection of reprints of key papers, and explanations of them, covering a period roughly from 1933 to 1963. In all of these sources Max Perutz plays a major role. But only in Ferry's book is he placed at the center of attention, and only her book conveys so much of what Max was really like. Unreservedly recommended! RICHARD E. DICKERSON Molecular Biology Institute University of California, Los Angeles Los Angeles, CA 90095-1570, USA

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