The Golden Age of Physical Biochemistry in a Gray Industrial City: Gregorio Weber and colleagues at Sheffield 1952-1963

by David Lloyd

In November 1957, aged 16 11/12, I went with my sixth-form classmate for an interview for admission to the Biochemistry Department of Sheffield University. Raymond Adams told me that if they asked “Why Biochemistry?”, he would quote Pope “To study nature is to study man”. I had not prepared myself so well.

The journey from Penygraig via Dinas railway station, in that coal-mining area of south Wales known as the Rhondda valley, by steam train via Cardiff, Gloucester, Birmingham, Burton-on-Trent and Derby took about 7 hours. My father got up especially early to accompany me to the station. The ticket cost £1.13s.6d. At that time of day the valley was already a hive of industrial activity, and apart from the grinding noise of the winding gear of the coal mines working around the clock, the sight of the coal-tip-scarred hills and the rows of miners’ cottages following the contours of the narrow valley landscape, the most prominent sensation, during the 18 mile journey to Cardiff, was the squealing line-upon-line of coal trucks emerging from the colliery sidings. So even at 5.30am, after the colliery hooter (siren) had sounded, the valley was wide awake; noisy and busy with the double-decker red buses bringing the miners to work for the day shift.

Arrival at Sheffield Midland station was entry to an even more industrially-ravaged landscape. Dominated by the newly-built Park Hill flats and with a sulphurous smog catching the back of the throat, the red brickwork and sandstone buildings had been blackened with layers of grime. Graham Palmer was a research student working with Dr Vincent Massey. Graham, who was originally from the same street in Penygraig, where I lived, had the job of taking us around the University and the Department (Figure1).

The afternoon interview (by Professor Q.H.Gibson and Dr S. R. Elsden, departmental heads of Biochemistry and Microbiology respectively; these Departments shared the teaching of the Hons Biochemistry course) was held in a room in the house, now long demolished, on the corner of Winter Street and Western Bank; it was short and informal. The question, “why Sheffield?” was answered: “Because, Sir, with the possible exception of Oxford or Cambridge, this is the best place to study Biochemistry” was met with evident approval, and a nod and a wink from Gibson to Elsden. The latter asked me about my hobbies, and again I made a suitable reply: “microscopy, Sir”. Have you ever found an amoeba?”, “Yes, Sir, just once”. “Well, if you include a little potassium dihydrogen phosphate in your hay-infusion growth medium you will be more likely to be successful”. And if you get A’s in your Advanced Level you can come here next October! Raymond too was successful, and I never did ask whether Pope had helped him. At tea in the Scala foyer, (Figure 2) there was the biggest tea-pot I had ever seen, (of perhaps 2 gallons capacity).

Figure 1 Sheffield University and the Department of Biochemistry

Figure 2 Scala Cinema

Graham introduced us to Dr Vincent Massey and several others including Dr Gregorio Weber, whom I sensed clearly was already a highly-revered father-figure. In the evening, Ray and I went to a concert of the Hallé Orchestra conducted by Sir Adrian Boult (Walton’s First Symphony) in the City Hall, before taking the 11.30pm overnight service (change at Gloucester) back to Cardiff and then to the Rhondda.

Figure 3 University of Sheffield Biochemistry Department and MRC Unit for the Study of Cell Metabolism, January 1955

Gregorio Weber had arrived in Sheffield in 1953 after working with Malcolm Dixon for a Ph.D., and continuing to spend his postdoctoral years in the Cambridge Biochemistry Department. We were a class of 9, and I was fortunate indeed to have “Dr Weber” for first year tutorials. So Chris Ball (later to become President of Panlabs Ltd., Seattle and Taipei, a small pharmaceutical company wherein was based the “Penicillin Club”, a world-wide problem-solving group), and myself would attend weekly one-hour sessions.

On arrival at Dr Weber’s room we would sometimes have to wait for a calculation to be completed (a slide-rule held perhaps two inches from his eyes, already his sight was becoming a major problem), or a protein filtration to be performed, talking to us as he worked. Dr Weber was clearly an extremely active practising scientist. Other times, Lorna Young, his technician, would have to go into his dark room to tell him we had arrived. On one occasion he told us that he couldn’t see us, as he had only just realised it was Wednesday (I think Lorna had actually put him right), but he had organized his day as if it were a Tuesday! As we had not yet started to study Biochemistry (that came in the last two of the three years), the main topic for conversation was the physical chemistry that we were learning in the Chemistry Department, where Professor George Porter was Head.

The thermodynamics (provided by H.J.V.Tyrrell, and we thought excellently taught) was basic closed-system theory; Gregorio was keen to point out that of course far-from-equilibrium living organisms dance to a different and more complex tune. How complex, we were soon, in the second year chemistry, to discover with Dr. P.A.H.Wyatt.

To another tutorial I remember bringing Albert Szent-Györgyi’s “Bioenergetics” (1957). Gregorio was not impressed with the mystical properties ascribed therein to the fluorescence of biologically-occurring molecules. He was keen to point out that the frequency of occurrence of these is no more than for synthetic organic compounds. He suggested that I read instead a book by Ludwig van Bertalanffy called “Problems of Life”. This book would provide an excellent introduction to a Systems Biology approach to the organism, metabolic fluxes and the turnover of cellular components. This was in 1958, and I still make extensive use of these ideas forty-seven years on!

Figure 4 The paper by Gregorio Weber in Nature 1957

It was a fast-track education to be with Gregorio Weber in those tutorials. He told us of his heroes: James Clark Maxwell, whose unification of the magnetic and electrical forces was perhaps the greatest leap forward in the physics of the 19th century, and the major achievements of the Americans, Willard Gibbs and G.N.Lewis in thermodynamics and solution chemistry. He set us interesting essay topics: “The dynamics of life”, “The government and administration of cellular metabolism”, and one which still puzzles me “Does nature favour the survival of the fittest (Darwin) or conservation of the mean (Lotka-Volterra)?”.

The energy transfer in the photosynthetic light reaction was the topic of a recently published Weber article (work with John Teale and George Porter), Weber had made an original theoretical reappraisal; I still have the reprint that he gave. At one session, Chris asked him about the German exam. It was a Chemistry Department requirement that all students should be able to read the extensive German chemical literature, and for the biochemists, Gregorio was in charge. “Did I pass my German exam?”. “Yes”. “But how can that be! I didn’t write more than a page”. “You passed”. This was, I felt, typical of Gregorio’s disdain for any bureaucratic red tape!

In the second year, Weber’s lectures were on spectrophotometry, protein chemistry, redox reactions and photosynthesis. His notes were bound in a thick loose-leaf book bound with heavy green covers and his blackboard writing neat and orderly with very simple diagrams. That year we set up a student-run Biochemical Society (Figure 5) financed by the Student’s Union.

Figure 5 The Sheffield University Biochemical Society, November 1960

In retrospect, the rosters for this or the following year could hardly have been more distinguished (Figure 6).

Figure 6 The Biochemistry Society, University of Sheffield, membership cards 1959-60, 1960-61

Weber’s comment on first seeing the society neck-tie, a very sober dark blue with numerous small white porphyrin rings was, “it’s quite good and especially appropriate to the interests of the Department; you can actually wear it!”, and what’s more, I saw him wear it frequently thereafter.

Third year lectures were on fluorescence and phosphorescence and were a tour de force: Maxwell and Debye, Wavilov and Gaviola, and Perrin. More than forty years on I still refer to them and use them as the basis for my own teaching. The practicals that accompanied them were also really excellent, and always illustrated some fundamental principles. For example, the pH dependence of fluorescence of FMN and FAD were nothing short of revelatory. We were not told what to expect and couldn’t possibly explain the result. This student didn’t get it quite right (Figure 7 ).

Figure 7 My lab book, October 1960; the pH dependence of the fluorescence of flavin coenzymes

At the end of the afternoon, Gregorio returned to see how we were getting on and to finally give a blackboard session on the intra-molecular energy transfer between the adenine and the isoalloxazine rings in the folded FAD. We used red “chinagraph” pencil to number test tubes (these were pre-ink marker pen times). With a cavalier abandon my neatly-plotted points were chinagraph smoothed. Then he said “but your solutions were not equimolar!” Another stroke of the wax pencil provided that correction, and with a kind smile off he went.

Left in charge of the Department during the Head’s 6-month sabbatical (Quentin Gibson worked extensively with Antonini and Brunori in Rome) Gregorio had the task of interviewing us on our intended career plans. I explained to him that I was obliged for personal reasons to return to Wales, as my father had become ill. When the DSIR (Department of Scientific and Industrial Research) form came for the Cardiff department studentship, I took it to him for a reference. His response was immediate: between two steps of his protein purification and as we spoke, he wrote “We would have been very pleased to have Lloyd work for a Ph.D. here in Sheffield”.

I visited the Department a year later. By then the news that almost all the staff with their research students were to move on had become headlines in national newspapers. At tea in the Scala I overheard a conversation between Vincent Massey and Quentin Gibson, who had been away on the previous day.

"The newspaper people were here again yesterday”.
“What did you tell them?”
“I told them that the whole problem here is with the University administration”
“Oh, no! You didn’t tell them that did you?”

In fact I was later to learn that discontent in the Department arose largely because of repeated refusals to promote Gregorio to the research Chair he so evidently deserved. Links with Urbana-Champaign, Illinois were already strong (Gibson, Massey and Weber had spent sabbaticals there; R.E.Hungate, Ralph Wolfe and Woody Hastings had been on sabbaticals in Sheffield. It was therefore no surprise when Gregorio announced his intended departure for that campus. He took with him Jim Longworth (his first research student) and Lorna Young (his technician).

Then Vince Massey, Graham Palmer and their research students (Ben Swoboda, and Steve Mayhew who had worked with John Peel in Microbiology) left for Ann Arbor, Michigan; and Rod Bennett went to Dartmouth N.H. Theo Hofmann left for Toronto’s Biochemistry Department. Keith Dalziel and Mark Dickinson went to Oxford. Quentin Gibson and Colin Greenwood went to the Johnson Foundation, University of Pennsylvania at Philadelphia.

The Microbiology Department was to undergo a similar dissolution when Elsden became head of the Food Research Institute in Norwich taking John Peel and Martin Knight with him. In that case it was Bernard Fry who was left to maintain the continuity of the teaching, just as Maurice Kaye, Pauline Harrison and John Sykes were left to hold the biochemistry fort. Maurice was used to the problems of a Department in transition, having previously weathered the Krebs exodus.

By 1982 many of the ideas I had received from Gregorio had consolidated and I wrote a book with two of my young collaborators, Robert K. Poole (now Prof. of Microbiology at Sheffield) and Steven W. Edwards, Head of Life Sciences at Liverpool) entitled The Cell Division Cycle: Temporal Organization of Growth and Reproduction (Academic Press, 1982). The Academic Press Editor, Dr Tony Watkinson, a Cambridge – trained theologian suggested that the subtitle was open to an alternative interpretation. He pointed out that the word “temporal” has two meanings: the one that a scientist would not imply infers “earthly as opposed to heavenly”. Had it been a decade later, I could have made a smart response by quoting Gregorio’s dedication for his 1992 book: “To Those Who Put Doubt Above Belief”.

My predecessor as Head of Microbiology in Cardiff, David Hughes, had previously been a member of the Medical Research Council Unit for the Study of Cell Metabolism established for Sir Hans Krebs in Sheffield and later in Oxford. When Gregorio went for interview there in 1953, David Hughes was given the important duty of showing the already distinguished applicant around and reporting back to “Prof” as everyone called Krebs. Hughes told me that he felt quite insignificant by comparison to this young genius, and that there was no one whom could question Gregorio’s suitability. So his response to Krebs was: “Let’s not interview, but just appoint”.

I met Gregorio for the last time at Britton Chance’s 65th Birthday Conference in Philadelphia in 1978 (Frontiers of Biological Energetics: from Electrons to Tissues). There he presented (Fig. 8) his proposal for a radical rehaul of ideas in mechanisms of energy conservation in coupled reactions (his PNAS paper eventually).

Invited to Woody Hastings’ 70th birthday celebration at Wood’s Hole in June 1997, together with about a hundred others, we were told that Gregorio would not be coming as he was too ill to travel. The following month he passed away.

Figure 8 Gregorio presenting his contribution at Britton Chance’s 65th Birthday Congress (1978)

As Krebs said of Warburg, so could we say of Gregorio: his influence has spread far and wide. He was an intellectual genius, a colossus who changed everyone he touched. I am told that he did not believe in an afterlife, but rather that we just stop. But as on a snooker table the cue ball that collides sends the others on into their separate trajectories.

A few years later when Rod Quayle had come to Sheffield to succeed Sidney Elsden in the Chair of Microbiology, he asked me what it was like to be an undergraduate in the Biochemistry Department. I replied “Just wonderful – a terrific experience, it couldn’t have been better”. “Did you realize”, he said “that The Administration were not sorry to see them all go, as they were of the opinion that people like that, who were so obsessive about their research, and such frequent international travellers, couldn’t possibly be doing their teaching here properly”.