A celebrated career in DNA repair: Tomas Lindahl

In 2015 we were proud to receive news of the seventh Nobel Prize awarded to a CRUK-funded scientist. Tomas Lindahl, Emeritus Professor at the Francis Crick Institute in London, together with Aziz Sancar and Paul Modrich, won the Nobel Prize for Chemistry for their work identifying key DNA damage and repair processes.

Here we look at how Professor Lindahl’s discoveries have profoundly changed our understanding of cell response to cytotoxic therapies, and the substantial implications this has for cancer prevention and treatment today.

Discovering a problem

Tomas Lindahl, recognised as one of the founders of the DNA repair field, began his career in genetics at a time when the field of nucleic acid biochemistry was just opening up. Undertaking post-doctoral research on transfer RNA in the 1960s, and encountering the usual difficulties of working with RNA, he was the first to show that the molecule’s instability in the laboratory could not be blamed exclusively on contamination with ribonucleases. Having established that RNA is naturally unstable, this raised a question for Professor Lindahl: Is this true of DNA?

This simple question challenged long-established scientific dogma: that genes, as a conduit of inherited characteristics, are very stable over time and across generations, so the molecules carrying them must themselves be tough and well protected. Indeed, before the discovery of the structure of DNA and the first mechanistic insights into molecular biology, there was little reason to believe that DNA is as unstable and prone to mutation as we now know it is.

Tomas was amongst the first to recognise the existence of DNA repair mechanisms early in his career at the Karolinska Institute in the 1970s. He realised that, in addition to presenting interesting scientific challenges, studying these mechanisms might provide great insight into disease, propelling him into a career devoted to chronicling them. He is particularly celebrated for his work on one particular pathway – the workhorse repair mechanism which corrects the most common forms of damage, DNA single strand breaks.

It’s nice at the end of your career to have recognition that what you have done is actually important.

In 1981, drawn by its unique environment for conducting discovery research, Tomas moved from his native Sweden to the Imperial Cancer Research Fund (ICRF) laboratories – our London Research Institute. In 1986 he was appointed Director of a new outpost of the institute, at Clare Hall on the edge of London. These small laboratories could only house 10 research groups, but Professor Lindahl assembled a formidable team of the brightest minds and rising star researchers, focussing their efforts on mechanistic studies of the various aspects of DNA and chromosome damage and repair, alongside replication, transcription and cell cycle control.

The future of DNA repair research and the hunt for new treatments

Today, inspired by Tomas’ pioneering work, the field is still making exciting progress, says Laurence Pearl, Professor of Structural Biology at the University of Sussex. “We think there are at least 450 proteins involved in the DNA damage response, and there’s also a huge amount of chatter between the different processes, so it’s a complicated system. Understanding the many ways this affects the cell is a huge undertaking, and there’s still so much more to learn,” says Laurence.

Understanding DNA repair has already made a huge impact. And it is clear this is just the beginning, with several new treatments now in clinical trials. “The cell’s response to DNA damage is absolutely fundamental to the origins of cancer, and understanding how it works is bringing us to new medicines that attack the common features of the disease,“ says Laurence.

The discovery that inherited mutations in DNA repair genes, notably the BRCA genes, are behind many familial cancers opened up new opportunities, such as ‘synthetic lethality’ strategies, to treat these cancers. And understanding that tumour cells can use DNA repair mechanisms as a defence against chemotherapy and radiotherapy has led to the pursuit of co-targeting strategies that are helping to challenge therapeutic resistance.

Looking to the future…

Following the discovery and approval of olaparib, the first PARP inhibitor to be licensed for clinical use, other PARP inhibitors are now being tested in clinical trials. The majority of these are monotherapy trials in BRCA-mutated tumours, but they are also being tested in non-BRCA-mutated tumours with mutations in other DNA damage response-related genes. And beyond PARP, new treatments targeting other DNA damage response processes could be on the horizon. At 2016’s American Association for Cancer Research (AACR) Annual Meeting, there was much cause for optimism with promising results from several new experimental drugs targeting DNA damage response proteins.

Tomas served as Director at Clare Hall for 20 years, before handing over to another of the institute’s team of international DNA-damage experts, John Diffley. In 2015, teams at the laboratory officially became a part of the Francis Crick Institute, and this year move into the new state of the art building in central London. It is the end of an era for this compact laboratory with its concentration of high impact science, and the beginning of an exciting new one in the diverse, multidisciplinary environment of the Crick.

We are delighted that Tomas Lindahl’s research has been recognised with this well-deserved Nobel Prize, and proud that CRUK has played an important part in the development of a field with so much potential for people with cancer in the years to come.