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Research chemist who outlined the path of cholesterol synthesis

Konrad Bloch, who died on 15 October 2000, was one of the small group of biochemists who first used stable isotopes to study the biological synthesis of complex molecules. His brilliant dissection of how cholesterol is made in living tissues was a remarkable achievement, especially given the state of knowledge in the 1940s and 1950s of how living organisms synthesize molecules.

Bloch was born in 1912 in Neisse, eastern Germany (now Nysa in Poland). When the Nazis came to power in 1933, he was a chemistry student in Hans Fischer's laboratory at the Technische Hochschule in Munich. Bloch, who was Jewish, was told that he was ineligible to continue at the institute because Fischer had declined to accept him as a graduate student. But this was a lie. It was the new racial laws that blocked further study and, having gained his degree in chemical engineering, Bloch left Germany in 1934.

After a brief stay in Switzerland, and with the help of R. J. Anderson at Yale, Bloch moved to Columbia University, New York, where he received his PhD in biochemistry. He joined the laboratory of Rudolph Schoenheimer, another refugee, who had started to use stable isotopes to trace biochemical pathways. After Schoenheimer's untimely death in 1941, his students divided the work among themselves and, by chance, Bloch inherited lipids as his research area.

Bloch made rapid progress in his studies on the biogenesis of cholesterol. With David Rittenberg at Columbia, then in his own laboratory at Chicago, and from 1954 at Harvard, Bloch explored the synthetic pathway that leads from acetic acid to cholesterol and involves more than 30 reactions. A major breakthrough was the prediction that a symmetrical C₃₀ hydrocarbon, squalene, was an intermediate in the pathway. Bloch's group subsequently showed that squalene could be cyclized to form the sterol called lanosterol. In 1953, Bloch and the organic chemist R. B. Woodward proposed a mechanism for this cyclization reaction that turned out to be largely correct.

But squalene formation needs an isoprenoid precursor, and the identity of this elusive molecule was unexpectedly revealed at the Merck Sharp & Dohme laboratories during studies on bacteria that do not synthesize sterols. The six-carbon mevalonic acid was quickly recognized as the possible missing link in sterol biosynthesis, because eliminating a carboxyl group and water from the molecule generated the necessary isoprenoid precursor for squalene.

Bloch's laboratory made some of the key findings, with important contributions also coming from the joint efforts of John Cornforth and George Popják in Britain, and from Feodor Lynen's group in Germany. Eventually, two phosphorylated compounds arising from mevalonic acid were identified as the biological isoprene units. Six of these five-carbon isoprenes are joined together to form squalene, which is then converted to the 27-carbon cholesterol. Bloch's work in this area was recognized by the award of the Nobel prize in Physiology or Medicine, which he shared with Lynen in 1964. Cornforth received a Nobel prize in Chemistry in 1975.

Information about the pathway from acetic acid to cholesterol greatly aided the later discovery of statins, drugs that interfere with cholesterol synthesis. These drugs are now widely used to treat high levels of cholesterol in the blood.

Bloch was a scholar who was driven by curiosity. He maintained his interest in cholesterol throughout his life, and in the 1970s and 1980s provided an explanation for why cholesterol, rather than other sterols, had evolved as a functional component of cellular membranes.

But as a young scientist Bloch also made substantial contributions to the area of peptide synthesis. He showed that in yeast, turning a saturated fatty acid (one which contains no carbon–carbon double bonds) into an unsaturated fatty acid requires molecular oxygen. This led him to wonder how bacteria that grow only in the absence of oxygen are able to make unsaturated fatty acids. His studies led him to propose an anaerobic pathway for the formation of the carbon–carbon double bond. Extension of this work led to the discovery of an acetylenic 'suicide substrate', one of the first of this class of enzyme inhibitors. Bloch once stated that his only regret in science was that he and many co-workers had wasted so much time in the intractable process of trying to purify from membranes the enzymes involved in fatty acid and cholesterol biosynthesis.

Bloch was a dedicated teacher. For decades he taught the basic biochemistry course at Harvard. Thousands of students, many of whom are now scientists, physicians and scholars themselves, first learned their biochemistry from him. Bloch trained over 125 graduate and postdoctoral students, virtually all of whom remember the time in his laboratory warmly and as being formative in their careers. His gentle, subtle humour, usually accompanied by a distinct twinkle in his eyes, was keen but rarely destructive. His habit was to make the rounds of his co-workers at least once a day, asking what their latest findings were. Any promising result was discussed immediately and the implications for further experiments were explored. But he was not a hard taskmaster — the spirit in his laboratory was one of cooperation rather than competition.

As a result of a cultured middle-class upbringing in Germany between the two world wars, Konrad Bloch had a lifelong interest in music and the visual arts. His fascination in chemistry blossomed in Fischer's laboratory after finding the study of metallurgy uninspiring. He was then led to biochemistry through his early contacts with lipid research in Switzerland, but most importantly through his association with Schoenheimer. He is survived by Lore to whom he was married for 59 years, a son Peter, a daughter Susan, and two grandchildren.

http://www.nobel.se/medicine/laureates/1964