Gathering no moss.

* Abstract I never imagined that I would be asked to write an autobiography in a microbiology tome. For that matter, little did I think that I would consider microbiology the most intriguing subject in the life sciences and the only field I wanted to study. My formal scientific training was in chemistry. This is a recounting of my conversion and the opportunities I have had to work in the microbial sciences with some of the major figures (and characters) during a period of marvelous intensity and productivity. I want to recognize and thank my many distinguished colleagues for the ways in which they have helped me to experience a fruitful and stimulating life as a microbiologist.

Key Words Aminoglycosides, antibiotic resistance, ribosomes, peripatetics, streptomycetes

 
CONTENTS 
 
GROWING UP 
UNIVERSITY DAYS 
AN INNOCENT ABROAD 
BACK TO BRITAIN 
SCIENCE IN BEANTOWN 
  Misreading at Harvard Medical School 
  Translation at UW 
THE PASTEUR INSTITUTE 
  Learning About lac 
  A Summer at MRC 
MIDDLE YEARS IN THE MIDWEST 
  Resistance in Madison 
  Transposition in Geneva 
AN UPSTART AT A START-UP 
PARIS ENCORE 
MOVING ON 

GROWING UP

I am proud of having been born in Wales, but I am not nationalistic; the only manifestation of my origins is my support of the Welsh rugby team (especially when they are playing the historic invader, England) and a life-long ambition to play for Wales. My mother and father had a tobacconist/barber shop near Swansea; I remember little of this, as we left when I was five years old for a suburb of London to be near my mother's family. My life as a rolling stone had begun.

In 1939 we moved to Kent, where my father had obtained a job in the Chatham Naval Dockyard. He was a shipwright and carpenter by training, with a deep love of the sea. Then the Second World War began, and I was "evacuated" with my sister and all the other children to a supposedly safe area elsewhere in the county. With the typical wisdom and forethought of the authorities, we were billeted with families near a major Royal Air Force base that soon came under serious air attacks, so we were taken back to Chatham, where school seemed to be a perpetual test of our ability to troop to the air-raid shelter in an orderly manner and wear gas masks for extended periods in class. Sporadic bombing of the dock area had started and we were under constant blackout. In 1940 when the Battle of Britain began and Chatham was again deemed hazardous, we were shipped by train to Wales and billeted with families in small mining towns in the valleys. I quickly learned about the rigors of life in a mining community; the father of the family with whom I stayed had been killed in a mine accident just before I arrived in Llanharan and the oldest son perished in a rockfall shortly thereafter. Education seemed to play little role in my life there. I spent a lot of time larking about with the lads and learned how to whistle piercingly through my lingers, but the only science I practiced in this period was building dams in streams in the woods so that we could make muddy pools for swimming. My sister was billeted in a village about eight miles away. I saw her occasionally, but our parents managed only a few visits.

By 1942 the air raids had calmed down and we returned home to get on with schooling, which was now focused on passing the "11-plus," an examination required for entry into the grammar school system. It was about this time that I manifested an interest in science--specifically chemistry--for no particular reason that I am aware of. Gradually, I built up a decent home chemistry set with glassware and chemicals that I bought with my pocket money from a local chemist's shop (pharmacy) or by mail; it seemed that one could buy almost anything one wanted--there were no restrictions on poisons, for example. I had no idea what I was doing, but I enjoyed creating dramatic color changes and mixing potassium nitrate and sulfur to make fireworks, the louder the better. So far as the war was concerned, rather than worrying about bombs, my mates and I concentrated on spotting planes, collecting choice bits of shrapnel, and asking the Yanks massing in Kent before D-Day, "Got any gum, chum?"

I passed my 11-plus and started at the grammar school, which was recognized in the county for its high educational standards. The Headmaster was a fearsome man and (I realize in hindsight) a masochist. Punishment, usually a caning or "500-lines" (some inane sentence written legibly 500 times in after-school detention), was normally administered by teachers. Major crimes (like going in the air-raid shelters when there was no raid on) were the Headmaster's purview. He had a collection of canes in a cupboard in his office and would take his time choosing the one with the correct whippiness before administering "six-of-the-best." The words "Bend over, boy" were the fateful prelude. The marks of the cane lasted several days and were inevitably exposed at home on bath night--my parents usually commented that I must have deserved it.

In 1944 we moved to southwest Wales for family reasons and there I had the time of my fife. We had never lived in one town for so long! My sister and I attended a first-rate coed school and I had lots of good friends, albeit we existed in a competitive environment; four or five of us always vied for "top of the class." My performance in classical subjects was mediocre, but I competed well in chemistry, physics, and mathematics. In these courses I had excellent teachers who were keen to see their students do well, and my interest in organic chemistry was fanned by the Headmaster of the school, an Oxford chemistry graduate. The structure of penicillin, the first complex organic structure I ever committed to memory, fascinated me and I liked to draw it out on paper. Another monitor and I had the job of preparing and cleaning up after chemistry demonstrations, which gave us free run of the lab on Saturday mornings. In addition to routine preparations, we took the opportunity to try out all sorts of reactions, some of them more violent than expected, but causing no damage more serious than an occasional burn.

Life outside of school was also good; the war had ended and although chocolate was still rationed, there were fewer restrictions. I became active in sports (twice disqualified for running in a walking race!) and performed in a number of the productions of the local playhouse, which may have helped me later in giving lectures and seminars. I am always a little nervous before any presentation in public, but once on my feet, I have no fear.

Entry to university involved two national examinations. At 16 I passed School Certificate (including French, which amazed my teacher and came as a great relief to me!) and moved into the ratified atmosphere of small classes and special assignments in preparation for the Higher School Certificate, which I took in 1950, winning a national scholarship and admission to almost any university in the country. The Headmaster was insistent that I go to Oxford, but I refused, since that would have meant a test in Latin--I could not face another foreign language. A friend recommended Nottingham University, where he had received his B.Sc. in Chemistry. So I visited, was offered a place, and left Milford Haven to embark on my university training. I still had my chemistry set.

UNIVERSITY DAYS

My three years of undergraduate training at Nottingham were typical university years. A lot of time was dissipated on nonessential activities, but I learned that I really did want to do chemistry. The University Chemistry Society organized occasional visits to companies in the area, but as I recall, the main benefit of these trips was the meal in the factory canteen (much better than in digs!) and the raucous bus ride home with several stops at pubs. Academically speaking, I did quite well at Nottingham, in mathematics as well as in chemistry. (I would have fared better in the chemistry final had I been able to remember all the reactions that could take place at a methylene next to a carbonyl!)

Deciding to go on for a Ph.D. and remembering my fascination with penicillin, I asked a professor who worked on microbial products if he would take me on. He was diligent and helpful and gave me free rein in my approach to the project he suggested, which was the total synthesis of a fungal naphthoquinone called flaviolin in order to confirm a proposed structure. (In those days all structures were confirmed by synthesis, since infrared, NMR, and mass spectroscopy were not generally available.) Things went well (apart from a setback when the dessicator holding two-months worth of a precious key intermediate was knocked off the bench by a highly apologetic cleaning lady), and the structural identity of the synthesized and natural product was confirmed. We were excited about this, only to learn that A.J. Birch, a well-known Australian chemist, had completed the synthesis of flaviolin by a "more biological" route! Scooped on my first research! Anyway, the work was published (10) and I looked for another project to finish my thesis. I wanted to work on a natural compound of unknown structure and chose sterigmatocystin, a fungal metabolite that had been isolated some years earlier. It was not known at that time that sterigmatocystin and flaviolin are polyketides; I was working on a large and very important class of secondary metabolites that includes many important antibiotics. Nor did I know that sterigmatocystin is a close relative of the highly mutagenic compound, aflatoxin! Not that this made much difference, since everyone in the lab used most organic reagents with abandon and employed grams of nitrosoguarfidine and dimethyl sulphate on a regular basis! I isolated lots of sterigmatocystin and weighed all these chemicals on an open balance. It was common practice to wear a necktie, which was part formality and part having somewhere to wipe a spatula before weighing something else. As far as I am aware, all students in the lab survived, which suggests that natural product chemists must have excellent DNA repair systems!

Life in the chemistry research lab at Nottingham was hard work but very enjoyable. We put in long hours in the lab but also had our good times together, rugby and cricket matches, pubs and dances. I had several close friends and shared digs with them now and then (I moved five times, but only once was I actually thrown out.) Studies on the chemical degradation of sterigmatocystin went well, and I wrote my thesis in 1956 with a proposed structure based almost entirely on chemical modification and degradation (11). I did have one infrared spectrum (which was not much help, since interpretation of such information was primitive) and it was included in my thesis, a first at Nottingham. At this point Alan Johnson, the Head of Department, suggested postdoctoral study to the United States, and when I expressed an interest in continuing work on natural products, he wrote to Gilbert Stork at Columbia University in New York. Imagine my thrill …