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My Life

Arnold Burgen

I was born 20 March 1922 at 101 Cricketfield Road, Clapton, London. I had a sister Marguerite (Peggy) who was four years older than me. My father Peter Burgen and his family were Jewish refugees from a pogrom in Poland and arrived in London in 1895 when my father was a year and a half old with his older sister. He went to school in London eventually to City of London College and became a Chemical technician at a firm of Chemical analysts headed by A Chaston Chapman FRS. My mother Bessie nee Wolfson was a Londoner, her grandparent on her fathers side came from Amsterdam but her mothers family were an old established Sephardi family called Simmons.

I had a happy and uneventful childhood. I remember enjoyable summer holidays in the usual coastal resorts from Clacton to Sandown. When I was about twelve I once went walking in the Forest of Dean with my father. I married Winifred Ellen Judith Browne in 1946; we met when she was a nurse at the Central Middlesex Hospital and I was a medical student there. She was brought up by her grandmother in the Lake District at Watendlath. She later became interested in nineteenth century Russian Literature and assembled a small book collection. She died in 1993.

I married for the second time Olga Kennard FRS (qv) in 1993 who I met as a result of a collaboration on vancomycin:, she had two daughters, Susan and Julia from her previous marriage.

There were three children of my first marriage. Andrew, born 1947, studied sociology and psychology at Exeter and Lancaster Universities. He has been involved in social services in Wales later in Thailand and Vietnam and lives in Anglesey and is married to Joan. Jennifer (Jennie) born 1949, studied Art and Nursing. She was for a considerable time in nursing but more recently teaching Art and Hygiene at a Further Education College in London. She lives in Wimbledon, her hobby is making stained glass windows. She has two sons, Jack and Simon. Stephen born in 1951, has never been to university but is self-educated. He was on the Editorial staff of the Times for many years, but has moved to Barcelona in Spain. He is a freelance journalist as well being the Editor of the English language daily, Catalonia Today, at present (2008) he is finishing his second novel. He is married to Sara, a New Zealander and they have two sons, Louis and Ruben.

I was born and grew up in London, mostly in Finchley. I went to local schools, Squires Lane Elementary and then to Christ’s College, Finchley. After School Certificate, I moved to the Woodhouse School, because Christ’s College did not offer biology, which I needed for Higher Certificate since I had decided on a career in medicine. I obtained an Entrance Scholarship to the Middlesex Hospital Medical School in London in 1939.

I enjoyed school, especially the last two years in which I was given facilities for carrying out advanced practical work in chemistry and physics, which gave me a taste for research.

I entered the Middlesex just about the time of the Declaration of War. The war caused great disruption in studies in London so that my medical course was a peregrination, first to Bristol in September 1939, back to London in January 1940, then to Leeds in 1941 and then back to London again. Subsequently my clinical studies were carried out at the Middlesex, Aylesbury, Mount Vernon, Northwood and the Central Middlesex. I should say that in London it was a rich fare of clinical exposure since through private initiatives we also attended a number of other hospitals. I especially valued the attendances at the Hospital for Nervous Diseases, Queen Square. My clinical studies were interrupted in 1943 by period of hospitalisation for pulmonary tuberculosis, undoubtedly acquired from a patient, I spent part of the time learning Russian, which I have subsequently completely forgotten. I graduated MB.BS London in January 1945 with distinctions in five of the six subjects (I missed only Forensic Medicine, I found it difficult to read about murders, etc and thought the subject repellent! Interesting that I now enjoy thriller fiction.) with the University Gold Medal.

In my pre-clinical studies I was greatly influenced by my Professor of Physiology, Samson Wright who was an exceptionally fine teacher, using the Socratic approach, he was also the author of the best textbook of physiology of the time. I had also very fine teaching in Anatomy and related disciplines by John Kirk. Unfortunately the teaching of Biochemistry was abysmal, the Professor, E.C. Dodds was away on war work and his assistant was hopeless. I encountered a number of excellent clinical teachers, but no one stands out in my memory.

After graduation, I had the misfortune to fall ill again and spent some time as a patient. During this time Samson Wright came to see me and on one occasion said that when I was better it would be impractical for me to immediately continue in clinical medicine, how about coming to work in physiology? I replied that I would do so for one year but then return to my chosen path of paediatrics. Little did I foresee the influence that physiology would have in my life! I actually found myself working in the new Pharmacology department directed by Cyril Keele with David Slome as a close colleague, and teaching a full course on Clinical Pharmacology. I had little idea of what research to do, but I started working on cholinesterase and the new irreversible inhibitors, DFP and TEPP, analysing their kinetics and mechanism of action, I was already showing some promise as an experimentalist. I registered for a PhD at the University of London; they told me this would take a minimum of four years because of my teaching commitment. After one year I had finished the research program, so I gave up on the PhD. An important influence on my development was once more Wright, we had lunch together daily when he would question me intensively on my work and made me examine carefully the logic of both my experiments and their interpretation. The most interesting work done in this period while I was an Assistant Lecturer was on the mechanism of the neuro-muscular block produced by botulinum toxin. It came about because one of the Professors of Biochemistry, Frank Dickens, had intended to follow up a report that the toxin inhibited oxidative metabolism in the brain. He had acquired a grant and a postdoc but his initial experiments failed to reproduce it; the reported effect was probably due to an impurity, whereas he had highly purified toxin from the Research Defence Centre at Porton. He asked if I could help and with his postdoc Leonard Zatman, we found an admirable test object in the isolated nerve-diaphragm of the rat on with which we could demonstrate that the toxin had no postsynaptic action, but that it prevented the release of the neurotransmitter, acetylcholine. This was completely blocked by anti-serum and fully established then the mode of action.

An important influence on my development was attendance at the monthly meetings of the Physiological Society through which I became acquainted with a wide range of contemporary research. A prominent member of the Society was Sir Henry Dale, PRS; of course at that time he had long ceased to do research, but he was very active in questioning presenters, and I remember my anxiety when I read my first paper there, but to my relief was able to answer his questions without difficulty. It was also through these meetings that I became friends with many of the members notably William Paton FRS (who was going to be my opposite number at Oxford when I was at Cambridge), Lindor Brown FRS, Bernard Katz FRS and Wilhelm Feldberg FRS among others.

My daughter Jennie was borne in January 1949 and when going home after visiting my wife, I met a friend, F.C. (Hank) MacIntosh FRS who was working at the National Institute for Medical Research (NIMR). He enquired what I was doing and when he heard about the happy event, he suggested I came home with him to “wet the Baby’s Head”. In the course of conversation he mentioned that he was returning to Canada, after having been in England for ten years, as Professor of Physiology at McGill University. To my surprise he suddenly said “would you like to come too”. I had told my wife that I had had an offer from Edinburgh, so the following day I said “what about Montreal?”; it must have been very confusing for her, but the outcome was that in September 1949, I found myself at McGill as a second Professor of Physiology!

I found Montreal a stimulating place, whose only disadvantage was the weather, the cold and snow in winter, the hot humid summer and the virtual absence of spring. One could ski in winter on Mount Royal or in the Laurentians and there were delightful lake areas not far away, I especially loved St. Helen’s Island in the middle of the St. Laurence River, which at that time was completely unspoiled. However, McGill was a very friendly milieu with many outstanding scientists, I would especially mention Donald Hebb in Psychology and Wilder Penfield at the Montreal Neurological Institute, and altogether an excellent place to work. The department was rather quiet and lacking in equipment but within a few months it was buzzing with a strong teaching program; the following year it was reinforced by the arrival of B Delisle Burns FRS.

At first I continued work on cholinesterases in the central nervous system, but one piece of equipment we did have was an electrocardiograph which I used to record the action potential of the frog auricle, I found that the duration of electrical activity was greatly reduced by acetylcholine with concurrent reduction of contractile force. With the arrival of an oscilloscope and camera I was able to start microelectrode recording from the rat auricle with Kay Terroux. The equipment now seems very crude; the amplifier I built and the arrangement for making the microelectrodes was primitive, nevertheless, this was a first report of intracellular recording from the heart. The results were similar to the those on the frog, but we were now able to show that the resting potential was increased by acetylcholine and titration of the resting potential against potassium concentration pointed to an increase in permeability to potassium which could also account for the accelerated repolarisation; we had no idea at that time how the reduced contraction was produced.

Alas in the winter of early 1952 I became seriously ill with a recurrence of the tuberculosis and retired to hospital. Fortunately at this time streptomycin became available and I recovered without the need of the threatened thoracoplasty; however, it meant nearly a year away from the lab and in that time others were making progress with intracellular recording on the heart and I felt dismayed by the thought of trying to catch up. For this reason I started a new line of research on mechanisms of secretion, using the mammalian salivary glands as the objects, probably as a result of talking to Boris Babkin, a Russian who had been a previous Professor of Physiology at McGill. This became the main core of my research for the remaining period in Montreal. This revealed a complex process in which a primary secretion by the acini was extensively modified in the ductal system; in some respects it was similar to the organisation of the kidney.

One outcome of my hospitalisation was the hint from my physician that there was virtually nothing known of the dynamics of pleural effusion; this led to a thorough study of pleural dynamics in the dog with Brian Stewart using double labelling techniques.

I was invited to spend the summer of 1957 at the Marine Biological laboratory in Woods Hole, Massachusetts with Stephen Kuffler. We worked on inhibitory fibres to lobster muscle. I greatly admired Kuffler’s technical skill in fine dissection, which was far beyond my modest abilities; as a side line I was looking for neurotransmitters in the lobster and noted the potency of a number of amino acids, including glutamate, aspartate and gamma-aminobutyrate. We generated a lot of lobster parts which became an item of diet, with the protest from the children- not lobster again!

I had become secretary of the Montreal Physiological Society, which met regularly in the evenings in term time; at one of these I was chatting to Douglas Cameron who was newly arrived from Oxford as Professor of Medicine at the Montreal General Hospital, one of the two teaching hospitals of McGill. The MGH had a fine clinical tradition but was not very active in research. Cameron invited me to come and set up a research section in the Department of Medicine, which was known as the University Clinic. I was able to do this whilst retaining my activities in the Department of Physiology. Cameron’s speciality was haematology so it was natural to start with a study in that area with some studies of folic acid metabolism including in patients with idiopathic steatorrhea and the effect of gluten free diet on its absorption. Cameron and I taught medical students together, with him dealing with the clinical problems and I with the pathophysiology; it was a very stimulating way of teaching, especially since neither of us new beforehand anything about the patients that were presented. I was able to put together a strong research group that continued to be very active long after I had departed and which provided a number of Professors of Medicine across Canada.

With these flourishing activities in progress, I had no intention of moving and was surprised by an approach to move to Pharmacology in Cambridge, but it seemed a challenge that I could not resist, so in 1962 I went to Cambridge as Professor of Pharmacology and found a nice old house to live in the village of Great Shelford. I also became a Fellow of Downing College.

A Department of Pharmacology hardly existed, it was effectively a section of Physiology with a small staff doing research in physiology and the teaching was restricted to a short course of lectures in the Long Vacation. It was a struggle to get a proper department organised and to have pharmacology admitted as a full subject in the Tripos, but it was achieved over the next few years. My initial research was a continuation of work on the salivary glands, while I was developing a new program. This was essentially outlined later in a short review paper entitled “The drug-receptor complex” in which the major current problem of pharmacology was identified as the understanding of the complexes formed between drugs and specific receptors, which could be summarised as “molecular pharmacology”. The program which I developed, investigated considered intermolecular forces, the kinetics of complexes, conformation change, models of receptors using antibodies and so on. It entered another new field as a result of a chance encounter with Oleg Jardetzky (who was at that a visiting worker in the Department of Biochemistry in Cambridge). Oleg introduced me to Nuclear Magnetic Resonance (NMR) and its possibility as a tool in molecular pharmacology. As a result I spent the summer of 1967 at Harvard (together with a postdoc Jim Metcalfe) working with Oleg, learning the elements of NMR and applying it to a drug-antibody complex. It was an entirely new field for me and I had to master the basic mathematics of the subject. We were working with an unlocked NMR machine which took a lot of trouble to set up; before starting an experiment, we had to enquire whether there was a baseball game on in Boston, in which case the mains voltage was too unstable for us to work!

I should interpose here that a crisis situation had developed in Cambridge in relations with with the Physiological Laboratory, in addition I had been approached by Harvard to become their Chairman of Pharmacology. The Cambridge Vice Chancellor advised me not to make a decision about Harvard until my return to Cambridge. In fact, the VC was able to offer new space to Pharmacology which removed us from the Physiology Building and hence resolved the problem and so I elected to stay in Cambridge. I also went to see the Secretary of the Medical Research Council, Sir Harold Himsworth FRS and told him what I wanted to do, including developing NMR methods He said, go next door and tell John Gray FRS (The Deputy Secretary) what you want! The result was that the MRC set up a Molecular Pharmacology Research Unit in Cambridge in which NMR was an important component. The University found space for us in the Old Press Building and we able to assemble a very active group working on various aspects of the drug-receptor complex. Colleagues of the present day would be very happy if things happened as simply now!

I was very lucky to persuade Jim Feeney, a real professional NMR man to join us from industry (Varian), which I am sure prevented some bad mistakes. Other major colleagues were Jim Metcalfe, Rodney King, Palmer Taylor, Gordon Roberts and Nigel Birdsall. There were two main themes in the Unit. One was on Muscarinic receptors, in which we investigated extensively, drug-receptor profiles and the kinetics of binding. One interesting study was with Laurence Spero in which we looked at the ability of acetylcholine to contract smooth muscle and simultaneously increase the flux of radioactive potassium; there was marked difference in the activity of acetylcholine in producing these actions, while the sensitivity to antagonists was the same for both activities, further the activity profile producing the contractile response was sensitive to electrolytes and temperature, whereas the ionic flux was not . This pointed to different mechanisms for the two activities. It was also through development of precision in ligand binding to the receptor that we discovered with R Hammer that a new antagonist, Pirenzipine had different binding constants to muscarinic receptors from different parts of the brain; this was the real beginning of the recognition of subtypes of the receptor. There were many other interesting studies on the receptor which I will not go into further here.

Our second theme was investigation of binding of ligands to proteins using mainly UV fluorescence, fast kinetics and NMR. The first study was of carbonic anhydrase. We started with the hypothesis was that for simple ligands like enzyme or receptor antagonists, the association rate would be near diffusion limited and very similar for different ligands, whereas the dissociation rate should be the determinant of affinity. However, for carbonic anhydrase the association rates were much smaller that expected for diffusion limitation and were the main determinants of the binding strength. The explanation seemed to be that the details of the coordination to the zinc in the active centre was the kinetic determinant. We soon turned to dihydrofolate reductase, an enzyme of considerable pharmacological importance.

Thus began a long series of interesting studies in which the conformational changes in the enzyme due to substrate, inhibitor and coenzyme binding were examined in detail both by fast kinetics and by NMR. The complexity of binding in this enzyme illustrated vividly how limited were the usual considerations of structure/activity relationships.

Our interest in stereo chemistry of ligand binding was also developed in studies on the antibiotic vancomycin. This agent had been shown to exert its action by binding to the terminal peptide of a precursor mucopeptide used in forming the bacterial wall. A peculiarity of the peptide was its unique termination in two “unnatural” D-alanines. It had been shown that the short peptide Acetyl-D-ala-D-ala bound to vancomycin. We were able to use this system to investigate the stereochemistry and structure-activity of binding.

In 1971 I was approached to become the Director of the National Institute for Medical Research at Mill Hill, an organisation I had long admired. I was told that there was no intention that the Institute should follow the same path as the Laboratory of Molecular Biology (LMB) in Cambridge. Although I did not see how it could match that unique organisation, I thought this instruction misguided, if that meant that the Institute should not attempt to be in the forefront of medical research. I took it as a limitation on any revolutionary change in the Institute’s remit; I believe in retrospect that I respected this instruction too much and should have been more radical in my direction of the Institute.

Anyway the outcome was that I accepted the directorship and so for a year I divided my time between Cambridge and Mill Hill until I could move the Unit, which became the Division of Molecular Pharmacology at the Institute. I carried on with my research program noted above as well as my other duties in directing the Institute and other activities particularly for the MRC. The period at Mill Hill was fascinating, the problems of guiding a multifaceted research organisation were new to me. I believe that I was successful in keeping a balance in the Institute activities, but was a failure in redirecting it and introducing new activities. My predecessor, Peter Medawar, had concentrated attention on Immunology, but much of that had dispersed when he retired. Although I did not realise that at the time, I think that was a lost opportunity.

With the retirement of John Gray as Secretary of the Medical Research Council looming, in 1976 there was intense pressure on me to succeed him. This would have meant giving up research, which I was not willing to do, so I did not succumb. In fact, I did act as the Secretary for a short time in 1977 until James Gowans was able to take up the post.

One of the posts that I held was as Chairman of the Tropical Medicine Board of the MRC from 1977. This I found of great interest and gave me an interest in far places and may have been one of the reasons that in 1981 I accepted the invitation to become the Foreign Secretary of the Royal Society in the knowledge that I had arranged to accept retirement from NIMR in 1982 at the age of 60. The MRC had generously agreed to set up a laboratory for me in the Department of Pharmacology in Cambridge which was acceptable to then head of the Department, Professor Alan Cuthbert FRS. I also agreed to become the Master of Darwin College, Cambridge. As it turned out I had taken on more than I had bargained for, the post at the Royal Society was busy and involved not infrequent absences on overseas visits; it was the research that had to go and by 1984 I gave up working in the lab. However, both new activities were exciting and I developed an increased interest in international science. In 1985 the Royal Society was asked to investigate a proposal made by one of the Ministers in the Foreign Office about the desirability of creating a European Academy of Sciences. After consideration within the Society, it was decided to pursue this idea in Europe and it eventually lead to me being instrumental in setting up the Academia Europaea which had its Foundation Meeting in Cambridge in 1988 and its first Annual meeting in London in 1989. I had in the meantime ended my period as Foreign Secretary in 1986 and my Mastership in 1989. I was elected President of the Academia Europaea at the Foundation Meeting in Cambridge in 1988 and continued in that office until 1994. In 1993 I founded the European Review, an interdisciplinary publication of the Academia which I continued to edit until 2007. I have omitted so far my activities in the International Union of Pharmacology of which I became President 1972-5 as a result I was President of the Congress in Helsinki 1975 and was also a member of the International Council of Scientific Unions (ICSU).

Video Interview on www.ae-info.org under Professor Sir Arnold Burgen