Max Perutz was a central figure in the development of molecular biology. He was a British scientist of the highest international distinction, and pioneered the study of proteins by X-ray crystallography. As director of the Medical Research Council Unit for the Study of Molecular Structure of Biological Systems from 1947 (later chairman of the MRC Laboratory of Molecular Biology until 1979), his magical personal qualities led to an astonishing series of discoveries in the mechanistic understanding of biological molecules. He thus established in Cambridge the most successful institute of its kind in the world. Perutz was a tireless communicator to scientific and lay audiences alike, but was never afraid to express strongly-held views about research freedom to those in control of funds for education and science. Beyond his many achievements, Max Perutz, an emigré to Britain from Austria, remained a disarmingly humble man who used his formidable intellect and quiet charm unstintingly in the cause of freedom and peace.
Max Perutz was born in Vienna, where his father was a textile merchant; after school at the Theresianum, he read chemistry at Vienna University. In 1936, with the rise of Nazism and the incipient anschluss, he moved to Cambridge to carry out research with J D Bernal who, with Dorothy Hodgkin [Munk’s Roll, Vol.X, p.217], was undertaking early X-ray diffraction studies of pepsin. Perutz chose to investigate the structure of haemoglobin and, having obtained diffraction patterns of horse haemoglobin, gained further support from the head of the Cavendish Laboratory, Sir Lawrence Bragg (the founder of X-ray crystallography), who secured for him a stipend.
Perutz’s project was formidable: at that time the structure of only very small molecules or crystallised salts had been determined and the task of solving the structure of a complex protein composed of four sub-units of two types, each of a mass of about 16,500 Daltons, was daunting. However, the unique properties of mammalian haemoglobin and, as was later to be shown, its remarkable allosteric regulation and cooperativity on binding oxygen, captivated Perutz’s imagination from the outset. In the event, it took him more than 20 years to obtain a full structure.
After an intermission during the Second World War, when he was seconded to carry out research into the reinforcement of ice fields for potential military purposes, Max Perutz returned to the Cavendish Laboratory to be joined by his first research student, John Kendrew - with whom he was to share the Nobel prize for chemistry in 1962 (Kendrew had chosen myoglobin, a monomeric oxygen-carrying pigment, as his research project). Perutz’s dogged assault on the structure of haemoglobin was fraught with innumerable methodological difficulties. He was the first to use the method of isomorphous replacement by heavy metal atoms to determine the phase of X-rays diffracted in the crystalline protein. John Kendrew and Max Perutz also exploited developments in Cambridge computer science to solve the complex equations and Fourier transforms relating to their massive data sets, and thus greatly accelerated construction of detailed electron density maps. Studies of myoglobin revealed the first structure of a protein molecule; but years of refinement to atomic resolution at 2Å were needed to examine the molecular physiology of the haemoglobin molecule.
Perutz was not content until he had solved the physico-chemical basis of what he termed this “molecular lung”, and in particular the mechanism by which co-operative binding of oxygen molecules occurs. He showed that the reversible binding of oxygen is an energy-dependent process that destabilises de-oxygenated haemoglobin by initially inducing structural changes in the haem molecules. This required an understanding of electronic field theory in which alterations in the atomic radius of iron within the haem are induced: the binding of oxygen changes the high-spin state of the atom to low-spin, thereby reducing the radius of the iron and allowing the metal atom to move closer to the plane of the haem molecule. Perutz showed this simple movement was in fact the initiating event for a sequence of larger movements transmitted throughout the whole of the haemoglobin tetramer which led to molecular rearrangements associated with the relaxed state. Studies of numerous mutant human haemoglobins, including those with altered affinity for oxygen or effector molecules – as well as sickle haemoglobin - led Perutz to an elegant series of papers on the evolution of haemoglobin function. Ultimately he was able to provide a description of the molecular pathology of the associated diseases in exquisite detail.
Max Perutz carried out his research in Cambridge for 60 years. Throughout he remained faithful to the study of protein structure, and particularly haemoglobin, although in the last eight years he conducted studies on the pathogenesis of Huntington’s disease. These were based on his identification of the unique conformation that repeated glutamine residues adopt within the mutant huntingtin protein. He examined the relationship of the length of glutamine repeats in huntingtin to early appearance of disease, based on the energy requirements for formation of protein aggregates and polyglutamine fibres. It was typical of Perutz, as the dedicated researcher, that his last paper was completed the day before he went into hospital for treatment of his last illness.
Max Perutz was also a great scientific leader. In the early years of the establishment of the MRC Laboratory a constellation of as yet unknown scientists joined the group. These included men of exceptional brilliance such as Sydney Brenner, Francis Crick, Hugh Huxley, Aaron Klug, Cesar Milstein, Frederick Sanger, Jim Watson and, much later, John Walker – many of whom, like Perutz, were to be awarded the Nobel prize (in Sanger’s case, the almost unparalleled achievement of a second Nobel prize). These scientists had disparate talents, and not all had the chemical outlook of “Max”, their revered leader – like him, however, all sought to understand the function and structure of biological molecules in physico-chemical terms and with a level of precision that would reveal the very essence of their living action. To support this work Max Perutz persuaded the Medical Research Council, then headed by Sir Harold Himsworth [Munk’s Roll, Vol.IX, p.238], to invest in a new, large laboratory at a site separate from the old and overcrowded Cavendish. The new laboratory, opened in 1962, has since been the jewel in the crown of British biological science. From it have emerged studies on the organisation and structure of viruses, on the means to determine primary sequence of proteins and of the bases in nucleic acids, the creation of monoclonal antibodies, and the mode of action of muscle contraction - to name but a few achievements of direct application to medicine. Structural biology continues to have a powerful influence on the laboratory where the foundations of modern protein crystallography were established directly by Perutz. Perutz’s success as a leader stemmed from his view that his only duty was to provide light guidance to talented people, allowing them freedom to pursue what we now know as “blue skies” research in the interests of knowledge and to encourage them to attack fundamental problems. He fostered seminar programmes but also the more rapid, informal exchange of ideas in the tea-room of the laboratory that was supervised by his loving wife Gisela, while he himself remained dedicated to work at the bench. By these means, the laboratory in Cambridge somehow achieved international status and continues to attract great numbers of talented scientists from all over the world.
Of Max Perutz it can be said that he was one of the first great figures of the school of molecular biology remaining active in the 21st century. He was an indefatigable writer and had a broad range of intellectual interests in science and the arts; through his writings he also carried the torch for political independence of scientific research and for the sustained support of talented people. Perhaps with Francis Crick, more than anyone Max Perutz created the lexicon of structural biology and was a major influence on the direction of biological research for the last 40 years. Having heard his brilliant expositions, one had the feeling that ordinary people appreciated him for his powers of communication and the universality of his mind. We are bound to ask what other qualities Max Perutz brought to his life’s work and how was he able to achieve what he did. In part his achievements related to his generosity of spirit and his unquenchable curiosity; these qualities certainly exceeded in his mind any capacity for vanity or the desire to use power for personal gain. Max Perutz as a Jew never failed in his admiration of Sir Lawrence Bragg who provided him not only with a lifeline in the form of a research stipend but also an environment of peace and freedom in which he could quietly develop his genius. He was aware that the new environment was not always going to be easy and, indeed, it proved to be somewhat humbling for his parents, who escaped Austria for a reduced employment in England.
Never a truly political person nor an active committee man, Max Perutz occupied the larger stage of science by his prolific reviews and articles as well as popular and accessible books - as well as by his brilliant lectures. In the background, however, his gratitude to Bragg, and to Britain and Cambridge as his home institutions, was undimmed: he campaigned on issues of asylum and on human rights, especially for disadvantaged scientists working under conditions of political repression. He maintained his contact with public figures and published adroitly in broadsheet newspapers, thereby campaigning for freedom in dark corners of the world including Bosnia, Kosovo, and latterly, Afghanistan. Examining all of this we have in Max Perutz a man of gratitude, of humility, of immense talent and stamina - and above all absolute integrity. Throughout his life his goal was truth.
T M Cox
[The Daily Telegraph 7 Feb 2002; The Guardian 7 Feb 2002; The Independent 7 Feb 2002; Nature 2002,415,851-852; The Times 7 Feb 2002]