Professor Alan Lehmann
The team in 1976 outside the original Cell Mutation Unit
Sir Paul Nurse opens the Genome Damage and Stability Centre in 2003
As the Genome Damage and Stability Centre celebrates its 21st anniversary, Professor Alan Lehmann CBE explains why the centre's research is internationally renowned.
“I don’t think anybody foresaw the revolution that happened in DNA sequencing. If you had said to me in 1980 that we would be able to do the things we can do now, I would have said you were living in cloud cuckoo land.”
For more than 50 years Alan Lehmann has been working at the University of Sussex in an area of research that has seen such dramatic advances in our understanding of genetics that he can hardly believe it.
But as Professor of Molecular Genetics in the Genome Damage and Stability Centre (GDSC), his work has played no small part in furthering our understanding of how faulty genes can lead to disease.
Alan was elected a Fellow of the Royal Society in 2010, and in 2020 he was made CBE in recognition of his work and support for patients and their families affected by rare genetic diseases, including Xeroderma Pigmentosum (XP), a disorder with a 1000-fold increased susceptibility to skin cancer, and Cockayne syndrome (CS), a fatal degenerative disorder.
“When I first started working on repair of DNA damage, it was seen as rather abstruse and only of interest to academics,” he says. “Now it’s known to play a central role in protecting us, not only from cancer, but also from neurodegeneration and immune deficiencies.”
As the GDSC celebrates the 21st anniversary of its official launch this year, Alan is also reflecting on the contribution the world-renowned centre – and its many researchers and alumni – has made towards global knowledge in genetics and clinical treatment.
“We are unique because we have worked on the interface between fundamental research and clinical research – both for diagnostics and for therapy.”
strength and rapid progress
Alan was the Centre’s first chairman (until 2011) and recalls that bringing together researchers working in related fields was key to their strength and their rapid progress.
“Evidence of our success was our winning large research grants and getting our work published in high-profile science journals. If you don’t publish in such journals, you don’t get the funding to continue.”
The construction of the centre’s dedicated science building, which involved Alan and his colleagues giving guidance on lab design, was initially funded through a £5m government grant and a £750,000 gift from the Wolfson Foundation.
In 2002 the researchers moved in. In 2003 it was formally opened by Nobel Prize winner Sir Paul Nurse, who set up his first research group in biological sciences at Sussex during the 1980s.
At the opening ceremony, Sir Paul remembered his “exciting” early days at Sussex and predicted that the centre, which already housed 10 research groups, would have “a remarkable and productive future”.
While Sir Paul’s words have proved true, Alan’s journey to Sussex began much earlier.
The son of refugees from Nazi Germany, Alan attended Manchester Grammar School before taking a place at Cambridge University to study natural sciences, specialising in biochemistry. He followed this with a PhD on DNA damage at the Institute for Cancer Research.
"mind-blowing"
“I had originally planned to do chemistry, but in my second year at Cambridge (1965) I enrolled on a biochemistry module and that was a revelation to me,” he says. “Up until then, I hadn’t realised that living things were carrying out chemical reactions. That was quite mind-blowing.”
After university, Alan continued research at Oak Ridge National Laboratory in the United States on translesion synthesis (the ability of a cell to make a copy of its DNA even when it’s damaged), before arriving at Sussex in 1971 to be a research fellow in the lab of Sydney Shall.
At the time, Sussex also had a research centre called the Cell Mutation Unit (CMU), which was funded by the Medical Research Council. When a research position became vacant in 1973, Alan was invited to join the Unit.
The building – a PortaCabin made from wooden panels – was rather basic for a lab, Alan remembers. “Every time we had a large new piece of machinery delivered, we had to remove a wooden panel to get it in.”
By 1980, CMU had moved to a brick building on campus (now occupied by Brighton and Sussex Medical School’s clinical imaging team).
extremely rare diseases
Meanwhile, Alan was working on understanding the rare skin cancer disease XP, which was first identified as a DNA repair disorder in 1968. People with XP cannot repair DNA in skin that has been damaged by ultraviolet radiation (sunlight) and may also have other health problems. Without full UV protection and treatment, life expectancy for patients is about 33.
Alan’s research involved studying a group of “XP variants” whose cells seemed able to repair the damage quite normally. Alan explains: “Before a cell divides, it needs to make a copy of its DNA. Normal cells are able to do this, even if their DNA has been damaged. I was able to show that XP variants had a problem in copying DNA that had been damaged by UV light.”
His discovery helped lead to greater understanding and better diagnosis of the disease – and, since 2010, Alan has been consultant scientist for a multidisciplinary specialist clinic for XP at Guy’s and St Thomas’s Hospital in London, where almost all the affected XP patients in the UK attend for treatment, advice, management and support.
For Alan, meeting people who suffer from the extremely rare condition (120 in the UK), and those with other related rare conditions who are also treated in the clinic, is a highly rewarding aspect of his work.
“The specialist clinics make a huge difference to the patients. They now see a multidisciplinary family of doctors and specialist nurses who are experts on the condition: dermatologists, ophthalmologists, psychologists, neurologists. XP cannot yet be cured but the life-saving treatments can give many of them a normal life expectancy.”
Studying rare diseases has a significant role in advancing knowledge, he says. “One of my colleagues used to say that we study the abnormal to understand the normal.”
Frustratingly, despite the successful sequencing of the human genome - completed in 2003 after 15 years of research at a cost of $3bn - we are still a long way from being able to cure most genetic disorders.
Alan says: “It was thought that gene therapy would happen very quickly after the human genome was sequenced, but we are 20 years on and the number of disorders for which gene therapy can be used is still pretty small.”
One method called CRISPR has successfully shown how to modify the DNA of living cells in a lab setting. The next – and far more complicated stage – will be how to transfer modified genes into the appropriate organs in people without the risk of causing harm somewhere else in the body.
But with teams such as those at GDSC continuing to attract the world’s top researchers for the excellence of their work, the next major development in gene therapy or cancer therapy could also be just around the corner.
Alan says: “As scientists, what drives us is the hope that we may discover something that is important and might ultimately help the human race.”