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Sir John Cornforth obituary Sir John Cornforth obituary
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The distinguished organic chemist and Nobel laureate Sir John Cornforth, who has died aged 96, is renowned for solving the details of the chemistry of the complex biosynthetic pathway in which acetic acid, containing two carbon atoms, is converted in nature into the steroid cholesterol, which contains 27 carbon atoms and has a structure containing four rings, via the non-cyclic triterpene squalene. There are many enzyme-catalysed steps in a biosynthetic pathway, along which simple compounds are modified, converted or joined together into other products, known as intermediates, to eventually yield the end-product of the pathway. The enzymes of the cholesterol pathway have become potential targets for the design of drugs in its clinical control, one such enzyme being HMG-CoA reductase, which is now targeted by statin drugs. The distinguished organic chemist and Nobel laureate Sir John Cornforth, who has died aged 96, is renowned for solving the details of the chemistry of the complex biosynthetic pathway in which acetic acid, containing two carbon atoms, is converted in nature into the steroid cholesterol, which contains 27 carbon atoms and has a structure containing four rings. There are many enzyme-catalysed steps in a biosynthetic pathway, along which simple compounds are modified, converted or joined together into other products, known as intermediates, to eventually yield the end-product of the pathway.
Cornforth's initial work was on the late stages of the pathway. By "feeding" samples of acetate labelled with the isotope carbon-14 to rat liver slices, and chemically degrading the samples of cholesterol and squalene produced, he defined the origin of all of the carbon atoms in each of these compounds. These results provided experimental proof of how squalene is cyclised to form cholesterol in nature. The contributions Cornforth made have stimulated studies on the mechanism of a very large variety of enzyme-catalysed reactions, many of which are important targets in drug discovery. The enzymes of the cholesterol pathway, for instance, include HMG-CoA reductase, now targeted by statin drugs.
In further experiments, which are now regarded as classics of the use of isotopes in biology, Cornforth was able to explain how methyl groups are rearranged during the conversion of squalene to cholesterol via the 30-carbon atom triterpene lanosterol. It was for his work on the three-dimensional structural aspects (ie stereochemistry) of enzyme-catalysed reactions that Cornforth was awarded the Nobel Prize in Chemistry in 1975. The press release issued by the Nobel foundation stated frankly, "This subject is difficult to explain to the layman"; and much to Cornforth's amusement, in the citation presented with his Nobel medal, the artist had mistakenly drawn two identical structures for samples of acetic acid labelled with the isotopes deuterium and tritium, rather than drawing them as mirror images of each other.
Following the discovery that mevalonate is a key intermediate in cholesterol biosynthesis, Cornforth and his wife Rita synthesised a range of samples of mevalonate in which specific carbon and/or hydrogen atoms were replaced by their isotopes. This allowed the enzyme-catalysed steps between mevalonate and squalene to be studied and fully understood.
Study of the three-dimensional structural aspects (ie stereochemistry) of the various enzyme-catalysed reactions was begun at this time and led, after many years, to the discovery of the precise stereochemical origin of all 50 hydrogen atoms in squalene biosynthesised from mevalonate.
This work included synthesis of intermediates in which one of the hydrogen atoms of a CH2 group was stereospecifically replaced by the isotope deuterium or tritium, and, in a final, groundbreaking series of experiments, two samples of acetic acid specifically labelled in the methyl group with both deuterium and tritium were synthesised in such a way that they were mirror image isomers of each other and used to investigate enzyme stereochemistry.
The contributions Cornforth made in this work have stimulated studies on the stereochemistry and mechanism of a very large variety of enzyme-catalysed reactions, many of which are important targets in drug discovery. It was for this work that Cornforth was awarded the Nobel Prize in Chemistry in 1975. The press release issued by the Nobel foundation stated frankly, "This subject is difficult to explain to the layman"; and much to Cornforth's amusement, in the citation presented with his Nobel medal, the artist had drawn two identical structures for the isotopically labelled samples of acetic acid, rather than drawing them as mirror images of each other.
Cornforth was born in Sydney, Australia, the second of four children of John William Cornforth, a British-born teacher of English and classics, and his wife Hilda (nee Eipper), an Australian-born nurse. When he was 10 years old, he noticed the first signs of deafness. Total loss of hearing from the condition otosclerosis occurred over a decade, allowing Cornforth to consider professions in which deafness would not be an insuperable handicap.Cornforth was born in Sydney, Australia, the second of four children of John William Cornforth, a British-born teacher of English and classics, and his wife Hilda (nee Eipper), an Australian-born nurse. When he was 10 years old, he noticed the first signs of deafness. Total loss of hearing from the condition otosclerosis occurred over a decade, allowing Cornforth to consider professions in which deafness would not be an insuperable handicap.
He studied chemistry at the University of Sydney and, unable fully to hear lectures, learned through reading textbooks and the original literature, teaching himself German in the process. He graduated in 1937 with first class honours and the University Medal. In his Sydney years he acquired the nickname "Kappa", after the Greek letter he used to identify his personal laboratory glassware.He studied chemistry at the University of Sydney and, unable fully to hear lectures, learned through reading textbooks and the original literature, teaching himself German in the process. He graduated in 1937 with first class honours and the University Medal. In his Sydney years he acquired the nickname "Kappa", after the Greek letter he used to identify his personal laboratory glassware.
In 1939 he and Rita Harradence, a fellow Sydney organic chemist, were awarded the two 1851 exhibition scholarships given in Australia each year. This allowed them to complete their doctorates at Oxford University with Robert Robinson on the synthesis of steroids. Kappa then worked on the wartime research programme on penicillin, making major intellectual and practical contributions to it. Kappa and Rita married in 1941 and over the years collaborated on more than 41 scientific papers.In 1939 he and Rita Harradence, a fellow Sydney organic chemist, were awarded the two 1851 exhibition scholarships given in Australia each year. This allowed them to complete their doctorates at Oxford University with Robert Robinson on the synthesis of steroids. Kappa then worked on the wartime research programme on penicillin, making major intellectual and practical contributions to it. Kappa and Rita married in 1941 and over the years collaborated on more than 41 scientific papers.
In 1946, the Cornforths joined the National Institute for Medical Research, first at Hampstead and then at Mill Hill, north London, and Kappa continued his collaboration with Robinson there, completing the first total synthesis of a non-aromatic steroid simultaneously with a synthesis by RB Woodward at Harvard. Cornforth began collaborating with the medical biochemist George Popják on cholesterol biosynthesis at the institute and this continued when Popják moved to Hammersmith hospital.In 1946, the Cornforths joined the National Institute for Medical Research, first at Hampstead and then at Mill Hill, north London, and Kappa continued his collaboration with Robinson there, completing the first total synthesis of a non-aromatic steroid simultaneously with a synthesis by RB Woodward at Harvard. Cornforth began collaborating with the medical biochemist George Popják on cholesterol biosynthesis at the institute and this continued when Popják moved to Hammersmith hospital.
In 1962 Lord (Victor) Rothschild recruited Cornforth and Popják as co-directors of Shell Research's Milstead laboratory, near Sittingbourne, Kent, (which became informally known as "the Popcorn laboratory") by promising them that they could spend 50% of their time on their own research interests and have a laboratory built to their own specifications. Because Cornforth's deafness made using the telephone impossible, Rothschild had one of the earliest types of fax machine installed so that he could communicate quickly and accurately with him. Popják left Milstead for UCLA (the University of California, Los Angeles) in 1968.In 1962 Lord (Victor) Rothschild recruited Cornforth and Popják as co-directors of Shell Research's Milstead laboratory, near Sittingbourne, Kent, (which became informally known as "the Popcorn laboratory") by promising them that they could spend 50% of their time on their own research interests and have a laboratory built to their own specifications. Because Cornforth's deafness made using the telephone impossible, Rothschild had one of the earliest types of fax machine installed so that he could communicate quickly and accurately with him. Popják left Milstead for UCLA (the University of California, Los Angeles) in 1968.
In 1975 Cornforth left Shell to become Royal Society research professor at the University of Sussex, Brighton, where he embarked on an ambitious project to develop purely synthetic compounds which would mimic some of the catalytic reactions performed by enzymes. Cornforth's initial work on the cholesterol pathway was on its late stages. By "feeding" samples of acetate labelled with the isotope carbon-14 to rat liver slices, and chemically degrading the samples of cholesterol and its non-cyclic intermediate squalene produced, he defined the origin of all of the carbon atoms in each of these compounds. These results provided experimental proof of how squalene is cyclised to form cholesterol in nature.
In further experiments, which are now regarded as classics of the use of isotopes in biology, Cornforth was able to explain how methyl groups are rearranged during the conversion of squalene to cholesterol via the 30-carbon atom triterpene lanosterol.
Following the discovery that mevalonate is a key intermediate in cholesterol biosynthesis, Cornforth and his wife Rita synthesised a range of samples of mevalonate in which specific carbon and/or hydrogen atoms were replaced by their isotopes. This allowed the enzyme-catalysed steps between mevalonate and squalene to be studied and fully understood.
Study of the stereochemistry of the various enzyme-catalysed reactions was begun at this time and led, after many years, to the discovery of the precise stereochemical origin of all 50 hydrogen atoms in squalene biosynthesised from mevalonate.
This work included synthesis of intermediates in which one of the hydrogen atoms of a CH2 group was stereospecifically replaced by the isotope deuterium or tritium, and, in a final, groundbreaking series of experiments, two samples of acetic acid specifically labelled in the methyl group with both deuterium and tritium were synthesised in such a way that they were mirror image isomers of each other and used to investigate the stereochemistry of an enzyme-catalysed reaction.
In 1975, the year his Nobel prize was awarded, Cornforth left Shell to become Royal Society research professor at the University of Sussex, Brighton, where he embarked on an ambitious project to develop purely synthetic compounds which would mimic some of the catalytic reactions performed by enzymes.
After retirement when he was 65, he continued to work at Sussex until he was nearly 90. During this period, in a paper subtitled A Comedy of Errors, he solved a longstanding structural problem for which several erroneous "solutions" had been published. He also provided a synthesis of the plant hormone abscisic acid and continued work on heterocyclic chemistry. Cornforth was a formidable chess player and enjoyed gardening, poetry and playing tennis.After retirement when he was 65, he continued to work at Sussex until he was nearly 90. During this period, in a paper subtitled A Comedy of Errors, he solved a longstanding structural problem for which several erroneous "solutions" had been published. He also provided a synthesis of the plant hormone abscisic acid and continued work on heterocyclic chemistry. Cornforth was a formidable chess player and enjoyed gardening, poetry and playing tennis.
He received many scientific awards, including the Chemical Society's Corday-Morgan (1953), Flintoff (1965) and Pedlar (1968) awards, and the Royal medal (1976) and Copley medal (1982) of the Royal Society. He was elected to the Royal Society in 1953 and was a member of many foreign scientific societies. He was appointed CBE in 1972 and knighted in 1975 and, having joint British-Australian nationality, was appointed Companion of the Order of Australia (1991), named Australian of the Year (1975) and awarded the Centenary medal (2001). He received many scientific awards, including the Chemical Society's Corday-Morgan (1953), Flintoff (1965) and Pedlar (1968) awards, and the Davy (1968), Royal (1976) and Copley (1982) medals of the Royal Society. He was elected to the Royal Society in 1953 and was a member of many foreign scientific societies. He was appointed CBE in 1972 and knighted in 1975 and, having joint British-Australian nationality, was appointed Companion of the Order of Australia (1991), named Australian of the Year (1975) and awarded the Centenary medal (2001).
Rita died in 2012. He is survived by his children, Brenda, John and Philippa, two grandchildren and four great-grandchildren.Rita died in 2012. He is survived by his children, Brenda, John and Philippa, two grandchildren and four great-grandchildren.
• John Warcup Cornforth, organic chemist, born 7 September 1917; died 8 December 2013 • John Warcup Cornforth, organic chemist, born 7 September 1917; died 8 December 2013
Videos of interviews with Sir John Cornforth may be found at vega.org.uk/video/series/1 and vega.org.uk/video/series/8Videos of interviews with Sir John Cornforth may be found at vega.org.uk/video/series/1 and vega.org.uk/video/series/8
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