Professor Vernon Ingram

Molecular biologist who uncovered the secrets of sickle cell disease
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The Independent Online

Werner Adolf Martin Immerwahr (Vernon Martin Ingram), molecular biologist: born Breslau, Germany 19 May 1924; Lecture Demonstrator in Chemistry, Birkbeck College 1945-47, Assistant Lecturer in Chemistry 1947-50; Rockefeller Foundation Fellow, Rockefeller Institute 1950-51; Coxe Fellow, Yale University 1951-52; scientific staff, MRC Unit for Molecular Biology, Cavendish Laboratory, Cambridge 1952-58; Associate Professor, Massachusetts Institute of Technology 1958-61, Professor of Biochemistry 1961-2006, John and Dorothy Wilson Professor of Biology, 1988-2006; Lecturer in Medicine, Columbia University 1961-73; Guggenheim Fellow, University College London 1967-68; FRS 1970; married 1950 Margaret Young (one son, one daughter; marriage dissolved), 1984 Elizabeth Hendee; died Boston, Massachusetts 17 August 2006.

Vernon Ingram discovered the chemistry of the gene for sickle cell disease. It was the first disease gene to be analysed, and Ingram is therefore known as the father of molecular medicine. It was a brilliant, ingenious and sublime discovery, and it was the first abnormal gene to be analysed. It enabled the prenatal diagnosis of sickle cell disease.

In 1957, at the Cavendish Laboratory in Cambridge, working under the future Nobel laureate Max Perutz, he discovered one tiny but hugely meaningful difference between sickle-cell and normal haemoglobin: of about 300 amino acids one, glutamine in the normal version, was replaced by valine. He also discovered that thalassaemia has two variants, alpha and beta, which is diagnostically and theoretically important.

Ingram was 33 years old and had gone to Cambridge three years earlier because Perutz, who was an X-ray crystallographer, wanted a protein chemist who could develop a way of placing a "heavy atom" in a specific location in the haemoglobin crystals he had isolated. Shortly after this project was completed, Tony Allison, a cell biologist, visited the lab, bringing some sickle-cell haemoglobin with him. Allison had discovered that carriers of a single copy of the gene were malaria-resistant, which explained why the gene was so common in Africans.

Perutz, who had the best X-ray equipment in the field, had already shown that sickle-cell haemoglobin formed "one-dimensional crystals" that deformed the red blood cells, which are normally disc-shaped. At this time, Linus Pauling had shown that sickle-cell haemoglobin had a different electrical charge from normal haemoglobin, but it was anyone's guess whether it was caused by one, or several, or a whole chain of wrong amino acids. A few years earlier, Fred Sanger, another Cavendish future Nobel laureate, had deciphered the amino-acid sequence of insulin, but the haemoglobin molecule was 30 times larger and a much tougher nut to crack.

Allison had moved on, but had left some sickle-cell haemoglobin. Ingram was developing methods for characterising large fragments of proteins, particularly haemoglobin. In 1956, adapting Sanger's methods, Ingram used a digestive enzyme to break the molecule into 26 fragments. He then, as an initial strategy, checked each fragment to see if it differed in the two forms of haemoglobin. He invented a technique he called fingerprinting, by separating the peptides by a combination of paper chromatography, which separated them vertically, and electrophoresis, which separated them sideways, giving a two-dimensional "fingerprint". The resulting "negative" was developed by spraying with a reagents that turned the peptides (and their fingers) purple. This clearly showed that only one of the 26 fragments was different in the two forms of haemoglobin.

The finding led to an explosion in molecular medicine using his technique, and a great increase in awareness of the importance of sickle cell disease.

Working in a well-equipped but draughty former bicycle shed in the courtyard of the main laboratory, he repeated the experiment using haemoglobin from other sickle-cell patients, which confirmed his findings. Other workers later confirmed that he was correct. Less than year later he analysed the sequence of amino acids in the fragments and conclusively showed that the two haemoglobins differed by only one amino acid: normal haemoglobin has glutamate in position four, whereas sickle haemoglobin has valine in the same location.

Ingram's discovery has a practical application: people who inherit the gene from both parents are severely and chronically ill and die young. As adult haemoglobin, whether normal or sickle-cell, is not made until about two years of age, prenatal diagnosis became possible, with patients having the option of abortion. The discovery's conceptual importance was that molecular biologists could reformat the hypothesis "one gene, one enzyme activity" to "one gene, one peptide chain". It strengthened the concept of a direct relationship between the linear DNA chain, whose structure had recently been elucidated by James Watson and Francis Crick, with the linear peptide chain, newly established by Sanger for insulin.

Vernon Ingram had been born Werner Immerwahr in Breslau, Germany (now Wroclaw, Poland). His father imported and exported timber. They were a Christian Jewish family who escaped to England in 1938. After matriculation he worked from 1942 as an analytical and research chemist for Thomas Morson & Son in Middlesex, taking a part-time degree in chemistry at Birkbeck College, London, and graduating in 1945. He then did a PhD in organic chemistry at Birkbeck, graduating four years later, and working at the college as demonstrator and then lecturer - changing his name during this time.

He followed this by a one-year fellowship at the Rockefeller Foundation in New York, learning how to purify a yeast enzyme, and two years in Joseph Fruton's laboratory at Yale working on peptide chemistry. When this was coming to an end he wrote 32 letters to England, searching for a job in academic research, when by chance a new postdoc came to the Yale lab from Cambridge (England) - who knew that Max Perutz was looking for a protein biochemist.

In 1958, when Ingram was in his mid-thirties, he left Cambridge, England, for Cambridge, Massachusetts, and MIT, the Massachusetts Institute of Technology. He was assistant professor, and intended staying a year. He liked it so much he remained there for the rest of his life. For 12 years he also lectured part-time at Columbia University in New York, and he took a year out to return to Britain as a research fellow at University College London.

In later years his research was on thalassaemia and on the molecular biology of ageing and of Alzheimer's disease. He never retired and worked at full speed till the end. Birkbeck College awarded him a doctorate in science in 1961 and in 1970 he was elected a Fellow of the Royal Society.

From 1985 until 2001, Ingram and his second wife, Beth, were housemasters at a student "dormitory" at MIT. They were greatly loved for this. In 2002, a former resident petitioned to have an astral body named after them. The asteroid, discovered in 1981 drifting between Mars and Jupiter, is now officially (6285) Ingram.

Vernon Ingram was interested in art, photography, and most especially music (an accomplished pianist, he was very involved in the Rockport chamber music festival). He was a modest man, who attributed his discoveries to serendipity and who gave full acknowledgment to the contributions of others, particularly Linus Pauling, who had shown that sickle-cell was an inherited "molecular disease".

Caroline Richmond

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