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By Roger Highfield on

Total immersion, creativity and the world’s best selling drug

In the run up to the opening of our Medicine Galleries later this year, Roger Highfield reports on an unlikely story of how a road rage attack provided the secret of scientific success, leading to a Nobel Prize.

The unlikely story of how a road rage attack provided the secret of scientific success was recounted earlier this month by Sir Greg Winter, who shared a Nobel Prize last year for research that paved the way for the world’s best-selling drug.

Sir Greg, a pioneer in engineering proteins, told an audience in Oxford how six of the top ten best-selling drugs in the world today are based on antibodies, which are exquisitely-shaped proteins produced by the immune system that are able to bind to targets in the body for a vast range of uses, from diagnostics to drugs.

Sir Greg Winter. Image: Trinity College Cambridge

After giving the Norman Heatley Lecture at the Oxford University Museum of Natural History, Sir Greg was asked how he had been so creative, not least in finding three ways to create antibody drugs: humanising mouse antibodies, creating a way to shuffle a library of genes by harnessing the power of evolution, and creating a variety called bicyclic peptides, or Bicycles.

Aside from hard work, the protein chemist said the secret of success came after being ‘attacked on the way to work,’ after which he was unable to use his right arm and was in constant pain. In the attack his right arm was dislocated badly causing severe nerve damaged paralysis.

With his right arm in a sling, Sir Greg trained himself to use the latest computer graphics with his good arm so he could study the details of the molecular shape of antibodies. ’When I was looking at antibodies, the pain stopped,’ he said. ‘It was a distraction therapy.’

The ‘total immersion’ in antibody structures for 12-hour days helped to distract him from the ‘terrible pain’ and gave him the insights to develop humanised antibodies. His biggest ideas have come from working day and night. ‘It loosens up my brain a bit and ideas come floating through your head.’

Previously, it had proved impossible to make human antibodies to fight diseases such as cancer or rheumatoid arthritis – we are self-tolerant, that is, we can’t readily make antibodies against our own tissues. Meanwhile, the corresponding rodent antibodies, had provoked an immune response when given to patients.

The 27th Norman Heatley Lecture taking place at the Oxford University Museum of Natural History

Sir Greg is credited with inventing techniques to humanise rodent monoclonal antibodies in 1986, where monoclonal means of one type that binds to one target substance, and to create fully human monoclonal antibodies in 1991. This remarkable ability to bind to one target can be used in many ways, from spotting a disease agent to highlighting a target in the body and delivering a toxin to a cancer cell.

For his work on ‘harnessing the power of evolution’, Sir Greg was awarded the 2018 Nobel Prize in Chemistry, along with George Smith and Frances Arnold.

Sir Greg was cited specifically by the Nobel academy ‘for the phage display of peptides and antibodies’, the technology that led to the fully human antibody ‘Humira’, which is now the world’s top-selling pharmaceutical drug and used to treat rheumatoid arthritis, among other conditions.

However, Sir Greg added that it is important not to be too focused: he and a colleague came close to devising a way to amplify genes a few years before the development of another Nobel Prize winning innovation to do just this, called PCR, or polymerase chain reaction.

‘The reason we missed it was that we were too focused on what our goal was,’ he said, though he added that, though a ‘terrible mistake’, it might have diverted him from his antibody work if he had succeeded.

Sir Greg founded three Cambridge-based start-up companies to help develop therapeutic drugs based on his inventions, and his research career has been based almost entirely at the Medical Research Council’s Laboratory of Molecular Biology and the MRC Centre for Protein Engineering, in Cambridge.

Over a 25-year period Sir Greg has generated something like £900 million for the Medical Research Council and his secret of scientific creativity was ‘total immersion’ and to forget work-life balance, he told the packed audience.

His lecture was introduced by Prof Matthew Freeman, head of the university’s Dunn School, one of the UK’s top biomedical research departments, which organised the event: ‘Sir Greg has probably done more than anyone in the world to apply the tools of fundamental molecular biology to transform human health. A third of new drugs are based on his technologies. Given the impact he has had on human health, he may be a rare case where the Nobel Prize itself is not his proudest achievement.’