Gregorio Weber in Cambridge (1952-1956)

Brian S. Hartley

Immediately after I joined the Enzyme Unit in the Cambridge University Department of Biochemistry in 1952, Gregorio came to be one of my heroes, as I have explained in the attached article. It may be useful for the modern generation to amplify these reminiscences by explaining how ignorant we biochemists were in those days.

At that time, great breakthroughs were then being made in energy and intermediary metabolism. Enzyme catalysis, specificity and regulation were the obvious key to understanding metabolism, but we didn’t actually know what enzymes were. The active sites of metabolic enzymes all contained coenzymes, prosthetic groups and/or metal ions that could plausibly explain their catalytic activity, but proteins were considered to be simply scaffolds that bound these catalysts. Few believed that a catalytic site could be constructed from amino acids alone.

I had already had a tussle with scientific establishment on this issue when my first scientific paper on the mechanism of action of chymotrypsin was rejected by the Biochemical Society on the grounds that “…it appears to suggest that the substrate reacts with a serine side chain in the enzyme. Could you please correct this misimpression?” In response, shortly after I arrived in Cambridge, I was emboldened to give an address to the British Association for the Advancement of Science entitled ‘Enzymes are Proteins’ Even 20 years later, many chemists found this concept uncomfortable. Sir Geoffrey Wilkinson, Nobel Prize winner in Chemistry, who was my next door neighbour at Imperial College, complained to me that “the trouble with enzymes is that they don’t obey the Laws of Chemistry”!

GW in Cambridge

But when I arrived in Cambridge in 1952, I found kindred spirits. I particular, Gregorio was entirely happy with the concept. He was sure that protein conformation was the secret of enzyme activity, and had made great strides in inventing novel ways to study this. At that time, the ultracentrifuge was the only available instrument to determine protein conformation, but it was an expensive and blunt instrument. Although X-ray crystallographers had solved the structure of a few fibrous proteins few believed that they would ever solve the structures of large globular proteins, and they needed even more money and facilities. Gregorio had realised that fluorescence might be a subtle, delicate and simple tool to study protein conformation. Working entirely on his own in a tiny little darkroom next to my own laboratory, he had constructed novel instruments and techniques that had already revealed conformational changes in serum albumin after ligand binding, so it is no surprise that Vince Massey and I became his acolytes. He taught us his techniques and always allowed us to use his equipment. Consequently we and an American visitor, Bill Harrington published a Faraday Society paper in 1995 entitled “Certain physical properties of chymotrypsin and chymptrypsinogen using the depolarisation of fluorescence techniques” Typically, Gregorio refused to put his name on the paper.

However our ways parted shortly thereafter, because Frank Young refused to appoint Gregorio to a Lectureship and Quentin Gibson snapped him up for his new team in Sheffield, where Vince Massey soon followed him. I found a new hero in Fred Sanger down the corridor, and dedicated myself becoming a Protein Chemist and eventually a Molecular Biologist. However I shall never forget my debt to Gregorio Weber, who remained my friend, he was a king and brilliant man, whose scientific influence on others far exceeds his own considerable achievements.

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