Notes from the book,

Georgina Ferry, “Max Perutz and The Secret of Life”, Chatto & Windus, London, 2007. ISBN 9780701176952

by the reader, Don Vanselow, 2019

Material directly from the book is shown in this regular font. Comments by Don Vanselow are in italics.

The story of Max Perutz as told by Georgina Ferry, and as told in earlier biographical works, is full of enigma and contradiction. It is part tribute and part disclosure. Some of it derives from Perutz's autobiographical works, not always reliable as to facts and motivations. Note that these notes do not attempt to be a fair reflection of all that was written by Ferry nor said in tribute by his colleagues. I have noted only those parts that are consistent with Perutz's scientific work and give insight into how it all went wrong. Max Perutz was born 19 May 1914 and died 6 Feb 2002.

Preface (ix)

Hb....makes blood red. “Posterity mattered to Max”. Ferry writes of Perutz's efforts to bring a new branch of science into the mainstream. This reader comments that in 1946, Perutz and his mentors inserted a fault into the science, probably for personal convenience. The personal reasons are outlined by Ferry in the rest of her book. The fault prevents this branch of science from being reconciled with the mainstream. Perutz's struggle early on was to fend off criticism from mainstream science. Eventually his success in winning funding and awards strengthened his position and largely silenced the critics.

(x)

“He had kept hardly anything” (of personal letters and unpublished papers). Wife Gisela had kept every letter secreted. This suggests Perutz was gathering, and maybe destroying, all he could. Later in the book we read that he suspected old paper of harbouring spores that harmed his health. But would he destroy them or have then archived? Was he collecting them because of health fears or because he knew his reputation exceeded the actuality? And if posterity mattered to him, would he not have preferred archiving by someone who could be trusted to keep them secret until no harm could result?Does his institute still hold secret archives?

p1

Perutz claimed to have learnt scientific rigour.

p12

“Not everything I was taught was necessarily true.” Written tests.....induced diarrhea.”

p14

(top) Chemistry impressed Perutz.

(bottom) Perutz's new passion was photography. From p13 we know he was 16 years old.

p15

Spring 1932 (Perutz having been born in 1914). Perutz was a keen photographer and maker of prints and enlargements in the darkroom.

p17

“What the course did not provide was any explanation of why matter had the properties that it did.” This is presumably quoted from Perutz.

p19

Later in life, Perutz painted a picture of having no interest in politics when he was young in Austria, but his letters of the time show otherwise. Presumably he later found it advantageous to deny he was in any way a refugee.

p21

Later in life Perutz insisted he left Vienna for the sake of a scientific career, not out of fear, but his letters show otherwise. He expressed his anxiety with.....arrogance...and self-deprecating humour.

p22

Perutz never doubted he would be one of the best scientists. In 1935 Perutz set his heart on working with the biochemist Hopkins in Cambridge.

pp22, 23, 24 and 25

This account of how Perutz secured an introduction to Cambridge seems to be largely from Perutz's own recollections. Hermann Mark, Head of Inorganic and Physical Chemistry at the University of Vienna, was the key figure. Perutz's later career showed a reluctance to practise chemistry, no particular aptitude for scientific originality and weakness in physics and maths. It is tempting to speculate that Mark helped Perutz to leave Vienna not so much because of Perutz's scientific promise but for humanitarian reasons in the face of rising hostility to people of Jewish background in Vienna. See the contents of p19. See Wikipedia entry for Hermann Mark. He himself had earlier left Germany for Austria in fear of Nazism, and eventually fled Austria for the USA in 1938. It is noteworthy that Perutz left for Britain when Jewish refugees were already streaming out of Germany into any country that would allow them entry. British immigration was restricted to those with money, a sponsor or a job offer in Britain. Mark's letter of introduction would have been very helpful in allowing Perutz to enter Britain and probably saved Perutz's life. Note that Mark again became important to this story in the 1940s.

p23

Perutz was impressed by Physical Chemistry.

Perutz was accepted into Cambridge because he could pay for himself.

p24

Perutz was determined to go to Cambridge.

p26

“The Secret of Life” Perutz later recalled this as his vision. In this quote Perutz seemed to attribute the vision to Bernal.

Perutz always insisted it was science alone that propelled him to Cambridge.

p27

Bernal “very rarely completed....(work)....himself but provided an endless supply of ideas”. The Rockefeller Foundation regularly supported former students or colleagues of Bernal.

p30

Bernal had been Bragg Senior's student. Bernal agreed with Astbury that their respective interests in x-ray crystallography would be divided, with Astbury studying hair and wool and Bernal studying biomolecules.

p31

Bernal solved sterol structures. In 1934 Bernal took the first x-ray image of a protein crystal, pepsin.

p32

Bernal and Crowfoot (Hodgkin) 1934 pepsin x-ray. 1935 Crowfoot published x-rays of insulin.

Perutz arrived in Cambridge in Oct 1936.

p35

Perutz said that he wanted to work like Bernal – very slapdash and never checked anything.

p38

In 1937 Perutz wrote a “confused account” of some radioactivity work. Perutz rewrote it but in 1938 it was still “distinctly careless in detail” Lawrence Bragg said it was too discursive and superficial.

p39

...which must (if such a thing were possible) have increased his ambition to succeed.

p40

August 1937, Perutz was interested in finding two isomorphous crystallised porphyrins for x-ray study. There are remarks on this page about the cultural significance of blood.

p41

Haurowitz persuaded Perutz that haemin (porphyrin) structure was already well known and that Hb was more interesting. Perutz had youthful optimism and inexperience.

p43

Bernal backed Perutz's haemoglobin idea as a subject for a PhD thesis. Adair gave Perutz his first crystals of methaemoglobin. They were brownish-red.

p44

Perutz ultimately became more like Keilin (tidy and methodical) than Bernal (slapdash). Perutz was weak in maths and physics.

p46

Late 1937, Rutherford died and Heads of Physics start moving between institutions. Bernal moved to London taking Fankuchen but Perutz stayed in Cambridge. Perutz's £500 fund from his father was running out.

p47

Perutz was happiest with hands-on bench work.

p48

“Trial and error” used in x-ray crystallography. Perutz and Fankuchen worked on chymotrypsin crystals.

p50

March 1938, Germany annexed Austria. Perutz's parents fled. Perutz's funds would have been exhausted in a few months. There is some indication that Bragg was not interested in Max Perutz. See also p51.

p52

Bragg becomes Head of Physics at Cambridge in 1938. Perutz visited Bragg and enthused him.

pp53 and 54

Bragg approached Rockefeller Foundation and got £275 per year which he used to pay Perutz from the start of 1939.

p55

A summary of Perutz's position at the start of 1939.

p57

“There are some inconsistencies in this (Perutz's) story” regarding how Perutz financed his parent's move to Britain in March 1939.

p58

May 1939, Perutz was collaborating with Dorothy Hodgkin on Hb.

p59

Perutz offered to help the war effort as a chemist in late 1939 but was told to carry on with his research.

p59

Perutz was inspired by Pauling's book.

pp60 and 61

March 1940, Perutz's thesis submitted. (see p297 for actual title). A copy sent to Fankuchen in the US. 12 May 1940, Perutz arrested along with many others from Cambridge University.

p63

Perutz applied for release in late May 1940 and asked his parents to use any means to get him released.

p64

Bragg reluctant to help Perutz get out of detention in May and June 1940.

pp 65 and 66

In July 1940 Perutz was shipped to Canada for internment and got his mother to lobby the Cambridge professors to help get him released. Bragg began to support Peutz's cause by asking the Rockefeller Foundation to find Perutz a job in America. At the same time Bernal wrote to Pauling at Caltech suggesting Perutz could work there. In the letter Bernal listed Perutz's skills as “preparing, mounting and photographing protein crystals”. Bernal told Pauling it was a way of getting protein crystallography to “take root” in the US.

p69

Perutz was (self-) reported to have learnt mathematics and physics from Hermann Bondi and Klaus Fuchs while interned in Canada. Perutz regarded himself as never much of a mathematician.

p71

It seems that the release of Perutz became a cause that led to exaggerated praise from Perutz's contacts as well as some who had not met him. This led the Rockefeller Foundation official to state that Perutz was “quite first class” and not “just a pair of hands for Bragg”.

pp73 and 74

In November 1940 the British Home Office ordered Perutz's release. Along with 280 other prisoners he arrived in Britain (Liverpool) in January 1941. He was given a train ticket and released while many of the other prisoners were further interned on the Isle of Man. This reader notes that there is no public record of which high-up government official(s) were told what by Perutz's supporters to secure this favourable treatment. It is notable that the mathematicians/physicists Hermann Bondi and Thomas Gold spent a further 9 months in internment. The physicist Klaus Fuchs, a refugee from Nazism, was released at the same time as Perutz following representations from Professor Max Born of Edinburgh University, also a refugee from Nazism. We don't know whether the same high-up government official(s) ordered the release of Max Perutz and Klaus Fuchs, nor whether Prof Born worked with Bernal to lobby the government. Certainly Bernal and Born were both physicists at Cambridge in 1934 and 1935 and could have been friends. The release and employment of Fuchs was to prove a disaster and embarrassment for the British Government. It is therefore possible that the records of these releases from internment have been destroyed. See pp101 and 102 for further speculation about the identity of the responsible official.

p75

Perutz noticed that he was held in higher regard by his colleagues at Cambridge after his return from Canada.

p76

In early 1941 Perutz felt that Bragg treated him well out of guilt. Perutz's proposed grant from the Rockefeller for work at Caltech was transferred to Cambridge. Bernal and Perutz 1938 paper suggested crystal shrinkage might enable solution of the phase problem.

p77 Perutz commenced growing his own crystals and drying them. He found shrinkage almost only in one dimension.

p78

Perutz's crystal shrinkage work published in Nature 1942.

p80

Late in 1941, Perutz was engaged to Gisela.

p82

Christmas 1941, Perutz got his first gastric trouble.

p83

Married 28 March 1942

p85

Summer 1942, Perutz and his wife entertained Dorothy Hodgkin to dinner. (Dorothy was the expert on x-ray structure of smaller biological molecules.)

p86

During summer and autumn 1942, Perutz and assistants did more work on Hb crystals, supported by Rockefeller Foundation. In December 1942 Perutz was recruited into war research.

p87

Perutz spent Jan to Aug 1943 working on project Habbakuk in London and then Sep to Nov 1943 in Canada and the US. In order to visit the US, Perutz needed to be made a British citizen and Lord Louis Mountbatten asked the Home Office to do it. Perutz was told that it was the quickest naturalization the Home Office had ever done. Perutz was very happy with this reward which he said was “quite out of proportion with the importance of my achievements.”

p89

Presumably Perutz's war research had ended in early 1944. It looks like he was in Cambridge until the war's end. Doing what?

p90

In late 1945 Perutz had secured a research fellowship.

p91

It seems the fellowship was from ICI for 3 years. Perutz asked for 2 months leave for summer 1946.

p94 and preceding.

Perutz's love of mountains surpassed his love of science.

p96

Perutz “was able to bag some more peaks for his diary”

p97

Perutz claimed to have learnt to be humble in his approach to nature. This is at odds with his subsequent career where arrogance seems to be dominant.

p98 Perutz returned from Canada Jan 1941 (note that this section of the book is not in chronological order with the rest of the book) and worked on Hb swelling and shrinkage until about March 1942. Then he was contacted by Pyke, an adviser to Mountbatten, about tunnelling in ice (p99).

p99 Bernal appointed Scientific Advisor to Combined Operations (Mountbatten) in early 1942. This is at the same time that Pyke was appointed. Sept 1942, Pyke proposed an ice ship. See p86 for what Perutz was doing for most of 1942.

p100 Mountbatten lacked scientific background. Bernal's nature was always to encourage rather than discourage. Perutz said Bernal “lacked critical judgement”.

p101 On 23 Dec 1942 Bernal asked Bragg to allow Perutz to work for Pyke in Cambridge, at the request of the Chiefs of Staff Committee. Perutz subjected ice to stresses and strains during January. He found it very brittle. Then Pyke gave Perutz a file of results from Prof Mark in Brooklyn USA who had been working on fibre-reinforced ice since July 1942. Thereafter all Perutz's work was on this reinforced ice. This was the same Prof Mark who had helped Perutz escape from Austria before he, himself, fled. It was Mark's work that formed the basis of Pyke's proposal for an ice ship. This is not a coincidence. Mark and Bernal had been friends for years. Mark used the connection to help Perutz flee Austria. Bernal used the connection to get Mark to collaborate with Pyke on the ice ship.

pp101 and 102. Lieutenant Douglas Grant, secretary to the ice ship committees, referred to Perutz as “our brightest pupil” in early Feb 1943. This was soon after Perutz started work in London. It suggests Perutz had acquired a reputation for brilliance even before he started. We may guess that Bernal had started this idea in order to get Perutz released in late 1940 and that it was a view subsequently held by people very high up in Combined Operations. Was it Lord Mountbatten himself, the Head of Combined Operations, who had been given this impression by Bernal? Mountbatten's ship, HMS Kelly was undergoing repairs throughout the second half of 1940, so we may assume Mountbatten was located in London during that time. Mountbatten's politics were socialist. He had his daughters evacuated to the U.S. in 1940 as a precaution against a Nazi takeover. Arguably the daughters were already refugees. Was Mountbatten the obvious person for Bernal to approach to get Max Perutz released? The same memoir from Grant indicated that Perutz seemed to be having difficulty cooperating, as if handicapped by not knowing the purpose of his proposed experiments, that Perutz was then given limited information about the purpose of the work and that the new information energised Perutz. This reader surmises that the difficulty was that Perutz was not competent in physics or engineering, whereas the officers with whom he worked had been led to believe that Perutz was very competent.

pp102 and 103. In late Feb/early March 1943 Perutz started work on reinforced ice in a new, larger lab in London. Perutz was assisted by a physics student and others. By 8 March they had made their first block of reinforced ice and a week later Perutz put on a demonstration for Mountbatten, the Canadian High Commissioner and others. Pyke and Bernal had left for Canada at the end of February, so the demonstration was mainly conducted by Max Perutz.

p104. Perutz described this demonstration as”carefully designed stunts” in a letter to Bernal. Later in March, Perutz, who returned to Cambridge each weekend, set up a smaller research effort in Cambridge on creep in reinforced ice. For this he was assisted by his newly recruited Hb research assistant, Edna Davidson. Notably, on the train trip to Cambridge, Perutz recounted that he carried some reinforced ice specimens in a thermos, together with some dry ice (solid carbon dioxide) and was surprised when the inner container exploded as carbon dioxide gas was produced. This indicates that he had mistakenly sealed the container. The story carries many implications. Firstly, the lab work and lab research team in London must have ended soon after the demonstration to officials. Secondly, the work in Cambridge was probably Perutz's own idea. It is hard to imagine the London officials approving this work, given their obsession with secrecy.

Thirdly, Perutz was a 28 year old scientist without wide general knowledge in science and therefore prone to make silly mistakes.

p104. While Perutz was working in London, Bernal did not bother to communicate with the London team about his research progress in Canada, although Lieutenant Grant in London was writing regularly to Bernal. We do not know what Grant was writing about. Pyke and Bernal returned to London mid May 1943. The implication is that Bernal did not regard the London team as relevant. They had been useful in producing samples according to the method of Prof Mark and conducting a demonstration for officials, but were not expected to make further technical contributions.

p106 Aug 1943. Bernal and Mountbatten travelled by ship to Quebec, Canada for a demonstration of the properties of reinforced ice. Bernal demonstrated its resistance to melting to Churchill and Roosevelt. An Anglo-American Committee was set up to further the project. Perutz was directed to go to the U.S. It seems likely that Mountbatten still had the impression that Perutz was the star of the team and therefore ordered him to join the Anglo-American effort.

p107 Mid Sept 1943, Perutz flew to the U.S. Germany was beginning to lose the war. Mountbatten was appointed Supreme Allied Commander in South East Asia. This took Mountbatten out of his role in Combined Operations. As Mountbatten had been the chief advocate for the ice-ship, the project was in trouble.

p108 Sep/Oct 1943, Perutz in New York. He visited the Rockefeller Center to discuss his grant. He met Hermann Mark at the Brooklyn Polytechnic. He also met up with Fankuchen, also at Brooklyn Polytechnic, and Bernal. Bernal was returning to London. There was a growing sense that the ice-ship side of the trip had been in vain. Perutz then went to Washington to wait for the Anglo-American Committee to convene. This meeting between Perutz, Bernal and Fankuchen was pivotal for the future of protein crystallography. We have to read Bernal's biography to learn that the problem of forces in crystals was discussed.

p109 Early Oct, Perutz's British colleagues on the Committee sent him back to New York to talk to Prof Mark. In his absence the Committee met and concluded the project had serious problems. Perutz took the opportunity to spend time with Fankuchen, who introduced him to the Biochemist, John Edsall. Perutz then left for Canada for a few days. This reader thinks it likely that the U.S. Navy members of the committee did not trust the former enemy alien and delayed meeting until Perutz was given a reason to go back to New York.

p110 The ice-ship project was dead by the end of 1943. After his few days in Canada in October, Perutz returned to the U.S. to give a talk on his work at Harvard, organised by John Edsall, and also to visit Prof Buerger at MIT, another crystallographer. Perutz left for Britain in mid November.

p111 Christmas 1943 (the book says 1944) Perutz's gastric health was bad. It had started while he was in the U.S. Perutz was “always a believer in going to the top”. For the remainder of the war, Perutz did Hb research. Perutz faced no certainty of support after his ICI fellowship ran out, so he kept his hand in with glaciology. He wanted some chance of results in the short term.

p112 November 1946 Perutz presented a report on mechanical properties of ice and pykrete (reinforced ice) to the British Glaciological Society.

p114 Perutz went to Switzerland for a glaciological expedition. It can be worked out that the expedition started on 22 June 1948 and Perutz began collecting readings in mid August. This is not in chronological order.

p117 Aug 1958, the Perutzes and Dorothy Hodgkin and family jointly holidayed in Austria. This is not in chronological order.

p120 Perutz reappeared in the Cavendish at the start of 1944 after almost a full year on the ice-ship project. The Rockefeller Foundation was still paying his salary plus 2 female assistants (Boyes-Watson and Davidson). They had kept working through 1943 on 135 pictures of horse MetHb crystals.

p121 Fourier Synthesis. It would take the invention of electronic computers to make the calculations a realistic possibility. Perutz had 7000 reflections recorded. Dorothy Hodgkin used Patterson maps.

p122 Having spent so much time on it, Peruz had to see it through (Patterson maps). By April 1946 Perutz had lost both his first two assistants.

p123 However, he had secured the services of Olga Weisz (now Kennard) from late 1944 or early 1945. They eventually grew oxygen-free Hb crystals. Olga found that Perutz discouraged innovation and favoured practical experience over theory. Boyes-Watson had also felt that the work she did for Perutz would never amount to a PhD thesis for her, so she left. On the other hand, Perutz expressed frustration with his (female) assistants in a report to the Rockefeller Foundation, citing lack of initiative and originality. One may conclude that the project suffered from lack of initiative and originality and the Leader and Assistants differed as to who was to blame.

p124 Perutz thought that Dorothy Hodgkin's crystallographic insight was greater than his own. Another new assistant, Herbert Gutfreund, had an unusual experience, being mainly used as a babysitter for the Perutzes. Gutfreund had done his PhD work before joining Perutz. He used some of his time to write up his thesis and, once it had passed, he moved to the Colloid Science Department. He continued to participate in lively discussions in the protein crystallography group.

p125 John Kendrew arrived to work as Perutz's PhD student in Jan 1946. He had gone to Ceylon in 1944 as scientific adviser to the Commander of the Air Force. There he met Louis Mountbatten in his new role in charge of South East Asia operations. There Kendrew met Bernal who was still Mountbatten's adviser. Kendrew had started a PhD in physical chemistry and Bernal encouraged him to work on x-ray crystallography of proteins when the war ended. Kendrew visited Pauling in California and was further enthused and so eventually returned to Cambridge to switch his PhD topic to protein structure. Formally his supervisor was a Cambridge academic. Perutz did not have an academic position but was de facto supervisor.

p127 In Aug 1944 Perutz had written to the Rockefeller Foundation that “I am still very anxious (to work on) proteins smaller and ….simpler than Hb, notably myoglobin. So far it has not been possible...... because it would take a trained biochemist several months to isolate and purify them.”

Kendrew produced suitable crystals in a few months in early 1946. Perutz began to feel anxious about his own position in 1946.

p128 Perutz was haunted by insecurity in late 1946, early 1947, but had been worried since July 1944.

p129 Bragg and Keilin recommend funding of Perutz to the Medical Research Council in May 1947.

p130 Late in 1947 Bragg wrote to the MRC thanking them for their support and, inter alia, compared Perutz and Kendrew, appearing to favour the future prospects of Kendrew. In January 1948 Perutz became Head of the MRC Unit.

Mid 1948, Hugh Huxley joined as Kendrew's PhD student.

p131 Huxley repeated and improved the 1942 swelling and shrinkage work on Hb crystals, and then moved on to muscle structure. Perutz took photos of the 10 stages of shrinkage. The earlier shrinkage work had been published in 1947 in the Proceedings of the Royal Society. In it Perutz had suggested the “hat-box” model for the structure. Note that protein helices were unknown at that time. Perutz claimed evidence that the shape of the Hb molecules did not change on swelling and shrinkage. This reassured him that maybe/probably protein molecule shape is not affected by crystallization. At the time the objection of biochemists was that protein shape could be affected by crystallization and therefore x-ray crystallography results were in question.

p132 Perutz began using an electronic computer in early 1947, but for Patterson maps, not solving the phase problem. Perutz was curt with Bernal when he asked him to present his results in July 1947.

p133 Perutz was simultaneously working on glaciology in late 1947.

p134 Perutz recalled he had “great and childish faith in regularity in protein structure.” The author, Ferry, concluded that none of his mentors knew enough to put him right. But Haurowitz in early 1948 raised the idea that forces in solution (thermic oscillations) would break down the discs proposed by Perutz. There is no evidence that Perutz ever replied to this point. Haurowitz kept such complete records that it is very likely Perutz never replied.

pp134, 135 and 136 The newly arrived Francis Crick pointed out a flaw in Perutz's calculations. Crick had a degree in physics. He had been bored by an incomplete PhD on viscosity of water and later research on the physical properties of cytoplasm. The MRC suggested he join Perutz.

p136 Crick joined Perutz in late 1949.

p137 Crick learnt practicalities from Perutz and theory from textbooks and re-thinking. He was 33 years old. Crick's new PhD was completed in 1953 under the title “X-ray diffraction: polypeptides and proteins.”

p138 In early 1950, Perutz's papers had raised his international profile. Pauling's group had looked at his 2 most recent Hb papers and considered them sound, but Perutz was not convinced.

p139 Perutz lacked mathematical insight.

p141 Perutz and Bragg regarded computers with suspicion in the early 1950s, but once it was clear that computers and crystallography would be forever linked, Perutz was happy for them to be used by others in his group – not by him.

p143 In 1950 Bragg got Perutz and Kendrew to start work on modelling the alpha-helix in protein.

p146 June 1951. Perutz missed discovery of a correct alpha-helix structure because of failure of imagination, corralled by received wisdom instead of opening his mind to all possibilities. Perutz took the initiative of looking for an x-ray reflection that would support Pauling's proposed alpha-helix. This is one of few examples of Perutz taking scientific initiative. He was clearly excited that it paid off.

p147 Bragg was not overtly disappointed or angry with Perutz over the alpha-helix failure although Perutz and John Kendrew both had qualifications in chemistry. Instead it appears that Bragg blamed himself. He revealed to the Chemistry Department Head (Todd) that they had consulted a chemist at Oxford and he also directed that Todd should be consulted in future. It seems that Bragg had no great expectations of Perutz to have high level competence.

p148 Perutz and Bragg had published 2 Royal Society papers by early 1951. In July 1951 Crick criticised those models in a paper he delivered entitled “What Mad Pursuit”. This was at a seminar of British protein crystallographers, including Bernal and Dorothy Hodgkin. Kendrew had been consulted beforehand but it seems Perutz and Bragg had not. Bragg accused Crick of “rocking the boat” and asked him to leave Cambridge. Again Bragg seems to be committed to defending Perutz.

p149 Crick had made it clear that the problem was too complex to be solved by more and better photographs. Obviously Crick was a polymath in science. At this stage he was still a PhD student. Perutz later reflected that he, Perutz, had wasted the best years of his life using the Patterson Maps.

p153 In early 1953, Watson and Crick published the structure of DNA. These events are controversial. The author (Ferry) notes “highly uncharacteristic departure from strict truthfulness” by Perutz in his letter to the Medical Research Council (MRC).

p154 Watson and Crick had discovered the secret of life. MRC funding of 5 years ran out in Oct 1952 but was extended for 1 year. The double helix ensured continued funding. Bragg nearing retirement.

p155 Bragg largely wrote the 1952 papers on which Perutz appears as a co-author. Bragg was 62 years old. Bragg calculated that Hb in a crystal was an ellipsoid 55x55x65 Angstrom.

p156 Isomorphous replacement was not a new idea. It had been mentioned by Bernal in 1939 but Bragg, Perutz and Kendrew dismissed it until Crick suggested it again in 1951 in his “What Mad Pursuit” seminar.

p159 Early in 1953 Perutz received a letter about a mercury derivative of Hb that retained some of its oxygen binding character. Perutz got a new member of his group to make the derivative and crystallize it. Perutz found that its x-ray pattern was mostly the same as pure Hb (actually at this time all reference to Hb was really the ferric form, methemoglobin) except that the intensities differed because of the phase interactions with the diffraction pattern of mercury. This provided a path towards solving the structure (isomorphous replacement). Perutz later wrote “Bragg went around generously telling everybody that I had discovered a goldmine.”

p160 Perutz later described this event as “ the most exciting moment in all my research career.” In 1970 Perutz claimed that isomorphous replacement in proteins was “my idea and my discovery. If you like, it is what I am famous for.” We know from preceding pages that it certainly wasn't his idea. The method had been suggested to Perutz for years. Perutz's contribution was to read a letter from another scientist and recognise that the derivatised Hb he described might allow an isomorphous replacement experiment.

p161 In 1953 Kendrew settled on sperm whale myoglobin as the subject of his PhD thesis. It being smaller than Hb, the solution of its x-ray structure was expected to be simpler.

p164 September 1953, Bragg at a conference described Bragg and Perutz like two mountain climbers roped together.

p166 May 1953, Bragg accepted the post of Director of the Royal Institution (RI) to start in Jan 1954. This was going to leave Perutz to run his own project.

p167 Perutz had been very dependent on Bragg. At the MRC, Hinsworth was not as supportive as Mellanby had been. Oct 1953, Bragg lobbied Cambridge Uni to get a Lectureship for Perutz. Perutz accepted but took a pay cut.

p168 Feb 1954, the new Head of the Cavendish wrote to Perutz suggesting that the protein crystallography unit should go elsewhere. Ever since accepting the post of Director of the RI, Bragg had been trying to establish protein crystallography there but Perutz didn't want to leave Cambridge. Bragg wanted to move the MRC unit to the RI under his direction and suggested to the MRC that Perutz be left in Cambridge but still in contact. He argued to the MRC throughout 1953 that he, Bragg, was the main leader of protein crystallography.

p169 Weaver of the Rockefeller Foundation believed Bragg was the most important figure in the protein crystallography group. Starting in 1952, Bernal had been trying to get Perutz elected a Fellow of the Royal Society (FRS). Bragg would not support the election until Perutz achieved something. The progress in protein crystallography was attributed to Perutz and he was elected FRS in Mar 54. This increased Perutz's drive to stay independent of Bragg so Bragg tried really hard to recruit Kendrew to the RI in Apr 54.

p170 Kendrew liked living and working in Cambridge and Peterhouse but was tempted to escape from Perutz. We don't know a specific reason. Perutz, on the other hand, thought Kendrew was jealous of his success and was “a thorn in my side” Ingram compared Kendrew and Perutz, saying Kendrew was very intelligent, very bright and very well organised, while Perutz was driven by the scientific content and how it affected other areas of science. Both Bragg and Kendrew may have wanted to distance themselves from Perutz in 1953. Possibly they knew about the dubious behaviour of Perutz that brought about the DNA structure coup of early 1953 and feared it might come out and implicate themselves by association.

p171 By mid 1954, Perutz's research had stalled again. Late in 54 Perutz began to experience his gastric problems again. Dorothy Hodgkin had pointed Perutz towards a paper by Bijvoet suggesting a way to produce a 3D electron density map, but Perutz couldn't see how to put it into practice.

p172 Jim Watson wrote that Perutz's illness was psychosomatic.

p173 Perutz lost a year of work at least, but the lab continued to work. His absence had little effect. There were many talented visitors who were highly productive. In 1956 Crick began moves to bring Sidney Brenner to Cambridge.

p174 Crick suggested Brenner be given a visiting fellowship but Perutz went to the MRC for the funds and came back with authority to make Brenner a full member of MRC staff. 1957 was the ten year anniversary of the Unit. It adopted the new name “Molecular Biology”. John Kendrew was appointed the first editor of the Journal of Molecular Biology. An MRC official wrote that he thought Perutz exercised quiet personal control of the Unit.

p175 Perutz felt underpaid in relation to his staff. 1953-1958 there was little progress in Perutz's protein crystallography. Perutz was just a hands-on participant. It was not obvious that Perutz stood out from his colleagues. There were no new ideas. Kendrew's group, however, was close to solving the structure of Mb.

pp176 and 177 Perutz's role was in providing for the logistical needs of the researchers. Through the Rockefeller Foundation he provided the latest equipment. He also dealt with his researchers with tact. He did not lead intellectually or socially – in fact he was left out.

pp178 and 179 Early 1950s, Sanger in the Biochemistry Department of Cambridge sequenced a protein. In early 1957 Sanger asked the MRC to fund a free-standing Laboratory incorporating Sanger's work and Perutz's Unit's work. The MRC assured Perutz that his Unit held the key position and therefore it was Perutz and Crick who set out the case. April 1958 Perutz presented the case in person to the MRC.

p180 It is clear that the MRC and the Ministry of Health were very comfortable dealing with Perutz.

p182 Kendrew remarked on the complexity of Mb structure and its lack of symmetry.

p183 From Oct 58 to Aug 59 Perutz was too cautious to run a 3D Fourier of Hb. He wanted more data first.

p184 It is clear that Perutz had very little scientific input to the solution of the Hb structure. Perutz refused to start the the computer program – afraid of things going wrong.

pp184 and 185 When the figures came out of the computer, Perutz found the electron density maps uninterpretable. His staff member, Rossmann waited a week for Perutz to work on it and then did it himself. Perutz was angry with him. Most likely Perutz was unable to work on the maps because he could see straight away that they did not support his preconception of great regularity of structure.

p187 Perutz used the phrase “Secret of Life” in 1962 in a letter to his children.

p188 Perutz had a child-like desire for recognition. He showed vanity and liked to be in the public eye. In 1960 Perutz did well on BBC TV. Bragg started to campaign for Perutz, Kendrew and Hodgkin to get the 1960 Nobel Prize. His campaign was not successful until 1962 when Watson and Crick and Perutz and Kendrew won Nobel Prizes.

p190 Bernal and Haurowitz both wrote congratulations to Perutz on his Nobel.

p192 Perutz was modest at the Nobel dinner.

p193 Perutz found new confidence. In 1969 he turned down a knighthood because he didn't want to be known as “Sir”. But he accepted plenty of British honours.

p195 Himsworth of the MRC devised a structure for management of the mooted Laboratory for Molecular Biology (LMB) after learning of Kendrew's reservations about personalities. The structure comprised autonomous Divisions under the Chairmanship of Perutz. Perutz not the Director. Kendrew had his own Division. The LMB opened in March 1962.

p196 MRC units usually wound-up on the retirement of their Director.

p197 The Board rarely held meetings. There are no Minutes. Michael Fuller became a fairly autonomous storeman.

p200 In the 1960s Perutz adopted a style of asking naive or stupid questions at internal seminars. Crick would tease Perutz “Explain it so even Max can understand it.” Perutz vigorously edited the papers of his juniors.

p201 Majority of the workers were young visitors with their own funds.

p204 In 1965 Aaron Klug began using Fourier methods on electron micrographs of viruses to give 3D images.

p205 An account of Perutz dismissing Rossmann and keeping Blow in 1963. Could this have anything to do with Perutz's anger with Rossmann in 1959?

Perutz did not direct research but created suitable conditions. He easily got funds for extensions to the building.

p206 Kendrew ceased practising science after his Nobel and went into scientific civil service while still the Division Head of Crystallography at the LMB.

p207 Kendrew and Watson started a European initiative in Molecular Biology in 1962. Perutz involved later. Perutz had more modest aims for the initiative, but got elected Chair. Perutz's favoured option (cheaper?) was implemented first but Kendrew's proposed lab was built in 1978 (15 years later! See p208. Was this a case of Kendrew and Watson wanting to leave Perutz behind but Perutz using influence to delay them?

p208 Kendrew stayed Head of Structural Studies at LMB until 1975 but rarely visited. He and Perutz were not friends. Crick left LMB in 1976. He had been the towering intellect of the LMB. “Max wasn't a particularly quick thinker. He was a plodder.”

p209 Discussion of the review of the early 70s. It seems it was 1971 after the election of the Heath Government. Perutz should have retired in May 1974. David Phillips was asked by the MRC to review all of Molecular Biology. He had previously been the Head of Crystallography at the Royal Institute, set up by Bragg. Some hint that Perutz wielded more influence than people realised.

p210 The review led to an immediate 25% cut in LMB budget. (see p209. The MRC was to lose 25% of its whole budget). Brenner took over the finances from 1977 to 1979 at which time he succeeded Perutz as Director.

p211 Brenner left the Directorship in 1986.

p213 In 1965 there was an expectation that structure would explain function but for Hb it was not clear. In the following chapter I think we see Perutz succumb to scientific arrogance. He had always been capable of outbursts of arrogance. He had received too much encouragement by Bragg but was held in check by various encounters with brighter scientists. Perutz became not just adversarial but combative and bullying, armed with his new fame.

p214 Haurowitz wrote to Perutz in 1938 about dark red deoxy Hb crystals turning into scarlet needles of oxy Hb as he watched.

p215 In 1959 Hilary Muirhead started PhD on deoxy Hb structure. She finished in 1962.

p216 Perutz tentatively concluded that the difference between horse oxy Hb and human deoxy Hb indicated a shape change caused by oxygen. Some were skeptical. Monod in 1959 had suggested allostery of enzymes.

p217 Monod was ecstatic about Perutz's conclusions about Hb. Perutz decided to look for the cause of it.

p218 Bragg was about to retire in 1963. “Max never really responded to the intellectual challenges and opportunities computing offered ….... growing, mounting and collecting data from crystals remained his forte.”

p219 In 1970 Perutz had a structure for horse deoxy Hb. He already had horse metHb.

p220 Perutz created the term “salt bridges” to describe electrostatic interactions between charged amino acids. See p226. Perutz used the term in a paper in 1969. The idea that different spin states of iron led to Hb cooperativity was from Bob Williams in 1961. Then in late 60s, J. Lynn Hoard did x-ray crystallography of haem-like compounds and deduced that deoxy (high spin) irons are forced out of the porphyrin plane. Hoard suggested a “trigger” effect. Perutz took up the word “trigger”. Williams suggested that the bond to histidine would be stretched by 0.1 to 0.2 Angstrom in deoxy Hb. Perutz published his mechanism in 1970. See p222 where it says Bragg died a year later.

p222 Bragg died in 1971.

p223 Perutz recalled that “(the model) failed to convince even my closest colleagues”. Perutz said that Crick, the dying Bragg, and Monod supported him. Perutz then began the haemoglobin battles to chase down every objection. Determination to come out on top and unshakeable belief in his own correctness were characteristic.

p224 Perutz had moved into territory occupied by biochemists (i.e. outside his silo). Perutz suspected they objected out of bitterness.

p225 Shulman measured that Fe-N distances in haem were changed very little by the T to R transition. This dispute lasted 11 years. Note on geometry: (out of plane)^2 + r^2 = (Fe-N)^2 where r is a constant dimension of the porphyrin ring. Therefore (out of plane) = SQRT[(Fe-N)+r][(Fe-N)-r] where [(Fe-N)+r] is almost constant for many values of (out of plane).

pp226 and 227 In 1980 Chien Ho held a meeting to honour Perutz's retirement and told him the NMR did not support Perutz's Bohr effect mechanism. How did this fit in with Perutz's paper claiming NMR evidence for his structure? And then Ho's later retraction of his part of Perutz's paper? In 1984 Perutz wrote to his sister convinced that he was right.

p228 In 1997 Perutz published a chapter on “the Haemoglobin battles”.He referred to scientific enemies and showed paranoia about their influencing juniors not to publish, committing fraud and being incompetent. (This could be a case of projection onto others of matters he himself had thought about, if not committed).

Ho said “It was difficult to work in his field if your results did not agree with his thinking.”

facing p229 “In Science truth always wins.” was one of Perutz's favourite sayings.

p229 The cartoon of a see-saw analogy for haem-haem interaction has the benefit of at least being reversible. A trigger mechanism is not. In 1997 there was still a list of niggling observations that could not be explained by Perutz's model.

p232 A dispute with Pauling over sickle cell haemoglobin in 1949 or 1950. Perutz wrote to Pauling “I have spent much effort trying to convert unbelievers to your scheme.”

p232 We read of an interned German doctor who missed out on deportation to Canada and was released in October 1940 after representations by friends. Many years later Perutz worked with him on abnormal haemoglobins

p236 President Richard Nixon of the USA began funding sickle-cell disease in 1971. In 1980 Perutz met Donald Abraham who wanted to design drugs based on structure of targets.

p239 There is an implication by the author that discovery of drugs based on structural knowledge is lagging behind the accumulation of structural knowledge, especially with regard to haemoglobin. Schechter thought the Hb disorders study was evidence of x-ray structures being useful.

Perutz attributed his early support to the foresight and courage of Himsworth.

p241 In 1983 Perutz set out to show which mutant differences between species produce selective advantage. He recruited Nagai.

p242 Nagai's student, Komiyama started work on a crocodile/human haemoglobin chimera.

p243 Nagai briefly worked on a Hb substitute but stopped Hb work by 1990. Nagai became joint head of Structural Studies unit when Sydney Brenner resigned as Director. Was this 2002?

p244 In 1986 Perutz argued with Popper about scientific method. Perutz said that crystallography could not be tested as to whether it was false – it was unambiguous.

p248 Alan Fersht helped Perutz with his last papers.

p250 There is a suggestion that a hip pain was partly psychosomatic.

p251 Perutz lost his voice with no medical explanation in 1977. Also in that year he had other health preoccupations.

p253 In the late 1970s Perutz started throwing out his old papers and books for fear of mould spores.

p254 More detail of Perutz's health concerns and eccentricity (rudeness and self-absorption.) Klug said "We used to wonder how real all these things were".

p255 The author says " health and happiness were perhaps even more inextricably entangled in Max than is usual."

p259 Perutz was a good writer from student days.

p260 In 1943 Perutz wrote "Proteins: the machines of life." The author, Georgina Ferry, is clearly impressed by his writing skill at that time.

pp267 and 268 Perutz slowly realised that Watson's "Double Helix" book meant trouble for Perutz. All the protagonists ended up looking not very good.

p269 Perutz wanted his early mis-steps cut out of Judson's book. Judson decribed Perutz's intelligence as being like an elephant (meaning not quick but weighty) mirroring Perutz's own opinion.

p273 Perutz wrote "far from preventing people from stealing (my idea), I have always had to ram any new idea of mine down their throats."

p274 Some of Perutz's colleagues grumbled about his writing outside his field, but he usually consulted experts.

p275 Perutz complained about criticism of the long-dead Pasteur. He admitted Pasteur was "domineering, intolerant, pugnacious and a hypochondriac." In many ways like Perutz.

p277 In the 1980s Perutz made little effort to conserve his papers. In 1999 Perutz sold his remaining papers to Al Seckel on behalf of Jeremy Norman. Norman sold them to Craig Venter in 2005.

p280 In 2002 Perutz planned to deliver a talk entitled "In Science, Truth Always Wins" but was shortly diagnosed with terminal cancer.

p285 Perutz hated to see his heroes shown to have personal failings. He walked out of the play "Amadeus" which showed Mozart in a poor light.

p286 Perutz

had been virulently anti-German in the years after he fled his home.

p287 At 86, in a radio interview he revealed his early despair that he would ever solve the problem of protein structure that so many others regarded as impossible. He also confessed to a sense of inferiority in the Cavendish days that lasted until he won the Nobel prize. "somehow the Nobel prize told me I was probably quite good at research and that really boosted my determination to carry on."

p297 Title of Perutz's PhD Thesis to Cambridge University was "The Crystal Structure of Horse Methaemoglobin"

p298 Perutz wrote to his parents on 17 June 1940 "For Heaven's sake shake my professors" indicating a wish to be released from detention. Other documents relating to his release are detailed on this page.