Back to basics

Setting up a new group is exciting and daunting. Two group leaders who joined the Signalling programme in 2019 – Dr Hayley Sharpe and Dr Rahul Samant – talk about their research and the supportive, collaborative and open environment that they say marks out the Institute.

Lots of ingredients go into building a successful new research group. Great ideas, a productive team and the right environment are all part of the mix. A great illustration of the Institute’s ethos was a colleague’s reaction to news that Sharpe had been selected as an EMBO Young Investigator. “I was at my computer, saw the news and leapt up. One of the Principle Investigators happened to be passing and just walked in and gave me a big hug,” Sharpe remembers. “Everyone is so supportive – and everyone’s made a real effort to make us feel very welcome.”

Sharpe’s group works on a family of enzymes that – for the past two decades – has been largely ignored but which Sharpe believes is ripe for a renaissance. These Cinderella enzymes are receptor tyrosine phosphatases, which play a vital role in intercellular communication and in the 1990s were seen as promising therapeutic targets. “There was huge interest in them 20 years ago and lots of work was done,” Sharpe explains. “But they proved very hard to drug, so the pharmaceutical industry fell out of love with these enzymes and abandoned them,” Sharpe explains.

Recent advances, however, have rekindled research interest. Big data, CRISPR and other new tools point to tyrosine phosphatases being important in many diseases – including some cancers and diabetes-related macular degeneration – as well as spinal cord injuries and skin ageing. “When you’re setting up a lab you want to go into an area where you can work for the next 30 years, hence the appeal of these enzymes,” she says. In a neglected field, developing new therapies means going back to basics, which is part of Sharpe’s approach. She is working at a molecular level to discover how these enzymes help build up the layers of our skin and other tissues. She’s also using mouse models to understand their role in disease, aiming to translate new knowledge into future new therapies.

Basic biology is also what drives Dr Rahul Samant. Reflecting on his impressions as a new appointment at the Institute Samant says that what struck him most about the Institute was its openness. “The environment here opens up broader scientific thinking; conversations are like relaxed brainstorming, and having people to bounce ideas off is important for me,” he says. “I do science because I want to know how things work. I want to be able to follow where the science leads me. And the Institute is one of the few research centres that has such a strong focus on fundamental, mechanistic biology.”

As a cell biologist, Samant is fascinated by misfolded proteins and the way our cells prevent them from building up. Our cells are complex machines with many moving parts; to work smoothly, proteins must be the right size, shape, and in the right place. It only takes one misfolded protein to trigger a chain reaction that can lead to disease, so our cells invest heavily in sophisticated quality control systems to deal with misfolded proteins before they cause damage.

This quality control machinery declines as we age. As a result, most age-related diseases, including Alzheimer’s disease, Parkinson’s and cancer, are related to misfolded proteins. “There is good evidence that these quality control machines get deregulated during many ageing-related diseases,” he says. “So I’m trying to study these machines in great detail: how they work normally and how they get deregulated during these diseases.”

Despite being crucial for healthy ageing, this cellular clear-up process is shrouded in mystery. Text books tell us the major misfolded protein clearance route involves attachment of a ubiquitin tag, which serves as a fast-track protein disposal signal. But, says Samant, we have known for the past 15 years that this is too simple to be true. “It’s very context dependent, and only now are we developing the tools to look at all the different type of ubiquitin tags in sufficient detail,” he explains. “I’m interested in using this increased resolution to go back to these basic questions that we’ve assumed to be true, but which the data now shows to be vague and hand-wavy.”

To study the process, Samant combines tools he honed during his time as a research associate at Stanford University with the state-of-the-art proteomics facility at the Institute. He also collaborates with the Institute’s world-leading experts in autophagy – another crucial cellular process for clearing up misfolded proteins.

It’s work that could reshape our understanding healthy ageing and disease, identifying new therapeutic targets and allowing us to treat neurodegenerative diseases and cancer much earlier. But only, Samant concludes, if we go back to basics. “We don’t yet understand how ageing affects the prevalence of misfolded proteins – and understanding these processes at a fundamental level is really important before we can start addressing the disease aspects.”

This feature was written by Becky Allen for the Annual Research Report 2019-2020.