Sir Christopher Dobson
Chemist whose work on proteins advanced research into diseases such as Parkinson’s and Alzheimer’s
PROFESSOR SIR CHRISTOPHER DOBSON, who has died of cancer aged 69, was Master of St John’s College, Cambridge, and one of the world’s leading experts on protein “folding” and “aggregation”, phenomena which underlie a whole range of human disorders, from Alzheimer’s and Parkinson’s diseases to type II diabetes.
In 1906 Alois Alzheimer, a German neurologist, first found the clumps of fibrous proteins that are characteristic of the disease that now bears his name. These “amyloid plaques” have become synonymous not just with Alzheimer’s disease, but with several other illnesses that wreak havoc in the brain. But some nine decades after Alzheimer first discovered the plaques, nobody had a clear idea of how they damage the brain.
The body manufactures proteins by chaining together smaller molecules called amino acids. Once chained together they fold to form complex three-dimensional shapes, the shapes determining how the proteins work together to enable living cells to carry out their functions.
Until the 1990s it was believed that only a few proteins out of the 100,000 or so found in the human body were susceptible to malfunction by forming amyloids – and that this was largely because those proteins themselves were somehow defective.
It was partly by accident that Dobson ended up in the field of protein aggregation. His research had begun in the field of nuclear magnetic resonance (NMR) spectroscopy when the technique was beginning to be applied to the study of protein molecules.
In the 1990s Dobson was studying a protein called lysozyme when he was contacted by a medical colleague who had found that some of his patients were suffering from a condition that appeared to be caused by huge quantities – kilogrammes – of defective lysozyme being deposited in vital organs such as kidneys and livers in clumps startlingly similar to those found in the brains of Alzheimer’s victims.
The encounter changed the direction of Dobson’s work. Using chemical agents and heat, Dobson and his colleagues stressed a number of common and usually harmless proteins, including lysozyme, and found that it was in fact relatively easy to unfold and misfold the molecules and that, once unfolded, the proteins were remarkably vulnerable to aggregating into amyloid forms which proved toxic to healthy cells in laboratory cultures.
Dobson’s “generic hypothesis”, according to which most proteins have the intrinsic ability to convert into these alternative pathological structures, led to the realisation that our bodies must have evolved means of keeping proteins in their functional states. He thus suggested that rapid changes in our lifespan and lifestyles had led to a proliferation of situations in which these protective mechanisms are overwhelmed, causing proteinmisfolding diseases to occur.
“A typical protein is about 300 amino acids long,” Dobson explained in 2005. “Twenty different amino acids can be assembled in 10 to the power of 60 different combinations, so the proteins we see are an infinitesimally small fraction of the potential repertoire, and they are very atypical in their behaviour. With their core structures and side chains, natural selection has exquisitely designed them to pack together in cells.
“As long as the conditions inside our cells remain within the normal range, stabilising mechanisms carefully maintain their shape and function, so they can persist for long periods of time before being turned over, minimising the aggregation of damaged proteins. But as we get older, these stabilising mechanisms begin to fail, there is increasing reversion to unstable, toxic forms, and we develop amyloid diseases.”
Dobson’s main discovery was that the amyloid conformation is a fundamental new state that protein can populate. This paradigm shift has offered a clear route towards finding treatments for some 50 diseases associated with protein misfolding. Progress in this field, much of it carried out at Cambridge, where Dobson was the John Humphrey Plummer Professor of Chemical and Structural Biology, led him to suggest that, given time, disorders such as Alzheimer’s and Parkinson’s had the potential to be avoidable and treatable.
“These are unwanted processes that our bodies can manage completely up to our normal evolutionary lifespan,” he told an interviewer in 2014. “The disease-causing aggregates do not fight back and evolve like bacteria and viruses but are due to a lack of control in our normal housekeeping methods. They could, in principle, be easier to treat than many typical viral diseases, heart disease or cancer.”
Christopher Martin Dobson was born on October 8 1949, the son of Arthur Dobson and Mabel, née Pollard, and educated at Abingdon School and Keble College, Oxford, where he took a First in Chemistry before going on to take a Dphil at Merton College.
He held research fellowships at Merton College then at Linacre College before spending three years, from 1977 to 1980, as an assistant professor of Chemistry at Harvard and visiting scientist at MIT. Back in Oxford with a fellowship at Lady Margaret Hall, he became a University Lecturer, and later Reader, then Professor, of Chemistry.
In 2001 Dobson moved to Cambridge as John Humphrey Plummer Professor of Chemical and Structural Biology with a fellowship at St John’s College, of which he was Master from 2007 until his death, and where he introduced a scheme, the St John’s Studentships, offering additional grants to undergraduates from lower-income families.
In 2012 Dobson, together with two Cambridge colleagues, founded the Cambridge Centre for Misfolding Diseases to bring together researchers from a wide variety of scientific backgrounds to investigate the molecular processes underlying neurodegenerative diseases. In 2016 he co-founded Wren Therapeutics, a Cambridge-based biotech start-up which focuses on the discovery and development of new drugs to treat protein misfolding diseases.
The author of more than 800 papers and review articles, Dobson remained involved in collaborative research until shortly before his death. He was an inspiring mentor for a students and young researchers, and had a profound impact on the lives and careers of the people who had the opportunity to work with him.
Dobson was elected a Fellow of the Royal Society in 1996 and was awarded its Royal Medal in 2009. In 2014 he was awarded both the Heineken Prize for Biochemistry and Biophysics and the Feltrinelli International Prize for Medicine. He was knighted in 2018 for his contributions to science and higher education.
In 1977 he married Dr Mary Schove, a historian of medicine, who survives him with their two sons, Richard and William.