‘Many call me a famous scientist but few know what I am supposed to be famous for’ is the quotation that aptly prefaces Georgina Ferry's account of Max Perutz's life. And it is true, too. Most scientists know Perutz as a founding figure in molecular biology and as the driving force in the establishment of the Laboratory of Molecular Biology in Cambridge—but what exactly did he do? As Ferry records, Linus Pauling scooped him in defining the ordered structure of polypeptides. Then the way in which these ordered polypeptides were in turn enfolded in a globular protein became evident from the crystallographic structure of myoglobin solved by Perutz's independent colleague John Kendrew. Even when Perutz obtained resolvable X-ray diffraction data, it was his postdoctoral fellow Michael Rossman who, to Perutz's chagrin, produced the first map of the structure of the haemoglobin molecule and recognized that it was made up of four myoglobin-like subunits. Both Kendrew and Perutz received Nobel prizes, yet all of those who knew their work would agree that whereas John Kendrew was an outstanding scientist, Max Perutz was a great scientist. The difference was in clarity of purpose and vision. Max Perutz initiated the task of determining the X-ray crystallographic structure of a protein in 1937 and Kendrew joined him in 1945, at a stage when it still seemed an almost impossible aim. The impasse was broken when Perutz solved the critical ‘phase problem’ in 1953, but it was Kendrew who obtained the first structure, in 1957. Having solved the structure of myoglobin, however, Kendrew then promptly moved on to other work. For Perutz the subsequent structure of haemoglobin was just a beginning. What was its biology? How did it change its shape? Literally, how did it breathe? This was the beginning of an approach that now underpins medical and biological research. In this new discipline of structural biology, X-ray crystallography is just a starting point in understanding the way in which molecules adapt their structures to allow the modulated interactions that constitute life.
Georgina Ferry narrates, in an absorbing way, how two of the central motivations in Max Perutz's life developed—his love of science and his love of Cambridge. Underpinning these were his devotion to his family, both in his formative years in Austria and subsequently with his wife, Gisela, and children in Cambridge. Max (as he was known to all) was born into a comfortably prosperous family in Vienna and with this came the expectation that he would follow the family tradition of a life in commerce and manufacturing. The impetus to escape from these expectations came with his introduction to chemistry as a schoolboy and grew in strength as he studied it further at university in Vienna. This he decided was what he really wanted to do, and what especially excited him were reports of the biological chemistry then flourishing in Cambridge under Gowland Hopkins. His unsuccessful attempts to get a place with Hopkins fortuitously led to the offer of an unpaid post with J. D. Bernal in a new unit in the Cavendish Laboratory of the Physics Department in Cambridge. And what good luck this was, because the questions Bernal was addressing were the very ones that had motivated Perutz's interest in chemistry and, in a wider sense, his lifelong interest in science. What determines the properties of substances? What makes a diamond hard and wax soft? Why is a leaf green and blood red? Bernal had set out to answer such questions by using the new approach of X-ray crystallography, the foundations of which had been established by Lawrence Bragg, who subsequently succeeded Rutherford as head of the Cavendish. Max Perutz eventually chose the greatest challenge of all among these questions—the quest to solve the structure of a globular protein. His focus, in the simple words he used in lay lectures, was ‘haemoglobin—the red oxygen-carrying pigment of blood’. It was a research project that would take 30 years to reach full completion. This truly was big science, requiring a dedication driven by the strongest of all motives—a deep curiosity and a love of science. His enthusiasm for science and research never flagged. It inspired all who worked with him and was a permeating influence in the development of the Laboratory of Molecular Biology.
In telling the story of the years of effort that went into the solving of the structure of haemoglobin and subsequently in the revealing of its mechanism of action, Georgina Ferry also details the frustrations, false leads, and side paths that this involved. The problem is that some reviewers of her book have focused on these difficulties and, taking a comment by Crick somewhat out of context, have labelled Perutz as a ‘plodder’. This is not so. There was a mutual respect and liking between Francis Crick and Max Perutz but also a polar difference in that one was a theoretician and the other an experimentalist. In the Cavendish the experimentalists were supreme: Bragg had little time for Crick, and Rutherford even less for Bernal ‘spraying out ideas’ and leaving others to pick them up and work them out. Max Perutz was an experimentalist who persistently pursued a goal that defeated others but that he knew was achievable. His success came from insights as well as from dogged determination. Two such insights were the realization that the oxygen release mechanism of haemoglobin was promulgated by a small displacement of the iron from the haem group, and, later in his career, the recognition of the general mechanism of the protein inter-linkage that underlies Huntington's and related degenerative diseases. But it is the dogged determination that brings success in long-term research. Years later, a graduate student, Penelope Stein, asked Max's advice after her repeated efforts to crystallize a new protein had been fruitless. He repeated then the counsel given to him by Lawrence Bragg—in Max's own words, ‘Just keep hitting it on the head till it lies down’ (figure 1). She did, and it did! Not profound advice, you may say, but the result was the first new protein structure for five years in the Laboratory of Molecular Biology and the opening of a new field of studies in structural biology.
Perutz's special place in science was not just that he solved the structure of a protein but that he then went on to show how it works. I was to see this at first hand after my arrival in Cambridge in 1965, as a graduate student with Hermann Lehmann, in the Medical Research Council (MRC) Abnormal Haemoglobin Unit based in the Department of Biochemistry. Lehmann's interest was in the genetic variants of human haemoglobin, almost all of which had been detected because of a change in their overall electrical charge. At that time, and indeed for years afterwards, there was a general belief that the key interactions determining the structure and function of proteins were electrostatic, a belief strengthened by the finding that sickle-cell anaemia resulted from the replacement in haemoglobin of a glutamate residue, with a negatively charged side chain, by valine, with an uncharged side chain. My interest, however, was aroused by a group of suspected haemoglobin abnormalities that, perplexingly, were not associated with any detectable change in electrical charge. The suspicion of the presence of these silent variant haemoglobins came from the observation that several congenital anaemias seemed to result from the intracellular precipitation of one of the globin subunits of haemoglobin. One by one, abnormalities were identified in each of the affected subunits, but the results seemed so different from those found in other studies that there was understandable scepticism as to their veracity. The changes consistently involved the replacement of one uncharged amino acid by another. How could such small changes, in one case the loss of just a single methyl group in only one of the four subunits of haemoglobin, result in a life-threatening anaemia? The answer became apparent to us on consulting the recently completed atomic model of myoglobin. The myoglobin crystallographers were helpful and interested, but the crucial evidence and support that convinced others came from Max Perutz. He had gone on to show how the three-dimensional structure of myoglobin provided a template onto which each of the globins could be projected to allow, for example, the accurate deduction of the structures of each of the subunits of haemoglobin. Moreover, comparative alignments from these projections identified the relatively few amino acids that were critical in defining the shape and stability of all the globins. These alignments immediately confirmed the validity of the mutations identified in the congenital anaemias, because each of the changes were seen to affect conserved amino acids whose side chains pinion the haem group within the globin molecule. Perutz subsequently showed how similar alignments of haemoglobins from different species identified the amino acids involved in the subunit interactions and overall conformational changes accompanying the binding and release of oxygen. His predictions of the role of each of these amino acids in haemoglobin were confirmed by the subsequent finding that their mutation in disease resulted in either a decreased oxygen affinity, to give a familial cyanosis, or in an increased oxygen affinity, to give a familial increase in red cell production (polycythaemia). This correlation of the three-dimensional anatomy of proteins with their individual molecular physiology and pathology was the defining study in what has now become the science of structural biology.
The difficulties that Max Perutz experienced in his first years in England left their mark, as seen in the deep resentment he harboured against those who had, in his mind, undermined his work. There was an early need to succeed demonstrably in science to reassure his parents after what they saw as his desertion from the family business. Even years later, his father's response to Max's election as a Fellow of the Royal Society was, ‘They don't pay a thing for that.’ Added to this, Max's decision soon after his arrival, that Cambridge was where he wanted to spend the rest of his life, brought with it several years of insecurity. The dictum of Ernest Rutherford, that ‘Cambridge is a place to be young in or to be old in’, is true even now. Mid-career university fellowships carry heavy teaching and tutorial commitments that can be crippling for the experimental scientist. Ernest Rutherford's reason for leaving Cambridge at the age of 27 years was not, as suggested by Georgina Ferry, just due to the unlikelihood of a Fellowship at Trinity but because McGill University in Canada offered him ‘possibly the best research facilities in the world’ with most importantly ‘no very great emphasis on teaching duties’. The belief, implied in Ferry's biography, that Max, too, was in some way unfairly treated by the university, is readily answered. Arriving in Cambridge without a college place, he was soon admitted as a graduate student in Peterhouse and by the time he had completed his PhD he had also gained an influential university mentor in Lawrence Bragg. Bragg must have sensed that a teaching fellowship would have drained Max's time and instead he concentrated all his efforts and reputation into gaining funding for him from the MRC. So, by the age of 33 years, in 1947, Max gained assured tenure as head of what was to become the MRC Laboratory of Molecular Biology, and then at the age of 48 years he was deservedly awarded a non-teaching honorary Fellowship at Peterhouse. It is a record of support that would be hard to beat today.
Great scientists attract and nurture great talent. Fourteen of Rutherford's associates became Nobel laureates, as also did Crick, Watson, Kendrew, Sanger, Milstein and Klug, among others from Perutz's stewardship of the MRC Laboratory of Molecular Biology. What seems especially remarkable is the insight shown by Bragg in promoting that initial appointment. What made Max Perutz such an outstanding research leader? As Ferry points out, it was not so much a matter of leadership as of creating an environment, free of impediments and bureaucracy, in which individual talent could flourish. His measure in making appointments or renewals was not written applications or plans, but ‘Is there a record of productivity? If so, then you will continue to get productivity.’ For younger colleagues it was always a joy to show Max a new finding. His eyes would light up; he would share their interest and excitement and spread the word to others in a way that encouraged further work. Equally, if he read of a breakthrough in molecular biology elsewhere he would bound down the corridor, photocopy in hand, to tell the news to all he met. He regularly attended seminars, not out of duty but out of interest. He would give the same attention, the same deference and ask the same probing questions independently of whether the presenter was a Nobel laureate or a first-year graduate student.
Georgina Ferry's biography places Max Perutz's science within the context of an active life, lived in interesting times. It is a fascinating read. The activity includes a period in glaciology both soon after his arrival in Cambridge and then again in the extraordinary project that freed him from internment during the war. We should not laugh at the misfortunes of others, but any scientist needing cheering up after a day of experimental mishaps should take her book from the shelf and read on pages 113–115 of the Pickwickian cascade of calamities that befell Max's expedition to Jungfraujoch. Feel free to laugh, for it has a happy conclusion. But there were sombre times too. The book tells of the travails of a Jewish family in central Europe in the 1930s and 1940s. These experiences were reflected in the humanity and concern that Max Perutz later showed for others, as recorded in the tribute by John Meurig Thomas.1 A notable addition to his list is Max's wholehearted and energetic support for Jean Pierre Allain, the Professor of Transfusion Medicine in Cambridge, during the persecutions in the 1990s that followed the HIV-haemophilia tragedies in France. Max was in all ways a true liberal, but independently and individually so. Reminiscing in his final illness, he spoke of the dinners of the Order of Merit and its German equivalent, and of the distinguished people he had met there in science and the arts. When asked who was the most memorable, he thought for a while and then answered with a smile, ‘This will surprise you … Margaret Thatcher—she was always interesting.’ For those who did not know him, the best evidence of his liberality and lucidity of thought is the collected essays that he wrote later in his life. His wisdom is encapsulated in his response, in the Independent, to Richard Dawkins on science and theology: ‘Scientists may not believe in God, but they should be taught to behave as if they did.’
- Received June 13, 2008.
- Accepted July 1, 2008.
- © 2008 The Royal Society