Welcome: Elizabeth Haythorne

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Lizzie Haythorne’s research is all about diabetes – primarily type 2 diabetes (T2D). This is the form of diabetes that happens when insulin-producing cells in the pancreas, known as beta cells, produce too little insulin, or when other cells in the body become resistant to insulin’s effects. The result is high blood sugar, which can cause damage to various tissues, known as diabetic complications. Over time, the health of the beta cells declines, resulting in less insulin production and making the situation still worse.

Lizzie’s work has shown that this decline in beta cell function is due to a failure of the beta cell to completely break down – or metabolise – glucose. This means that some of the glucose breakdown products start to build up in the cell, triggering other processes that are harmful to the cell’s health. We have a good idea of what’s happening in outline, but there are many details that researchers like Lizzie would like to fill in. It’s only by getting this kind of detailed insight – understanding what’s going on at the level of individual molecules – that scientists can start developing new drugs to prevent the damage that happens to beta cells or even to reverse it.

Getting established

After six years at the University of Oxford, Lizzie will join CVS on a Chancellor’s Fellowship. These five-year fellowships are awarded to outstanding early-career researchers, aiming to support them on the path to scientific independence and to encourage interdisciplinary research and innovation.

“The Chancellor’s Fellowship really stood out to me as an opportunity to receive the support and mentorship that will keep me on the right track towards independence,” says Lizzie. She also highlights its importance in giving her the time and space to get established as a researcher. “As a postdoc you’re employed by someone else and you need to do a full-time job while also applying for your own independent funding, which is a full-time job on its own,” she says. “This fellowship will really help to protect my time as I apply for grants and work towards establishing my own research group.”

The recruitment of Chancellor’s Fellows also helps to drive CVS’s programme of interdisciplinary research. “The Chancellor’s Fellowships provide a fantastic opportunity for us to appoint talented scientists and broaden our areas of research and innovation,” says Head of CVS Andy Baker. “We’re thrilled to welcome Lizzie as our new Chancellor’s Fellow, and look forward to the ideas and collaborations that will follow.”

New connections

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Lizzie already has some potential collaborations in mind, for example with scientists in Shareen Forbes’ research group, who have expertise in islet transplantation. This is a process in which beta cells from a donor are transplanted into a patient with type 1 diabetes (T1D), helping to treat their condition by producing insulin and reducing or removing the need for insulin injections. In the long term, the aim would be to take stem cells from a patient – cells that have the potential to become any of various cell types in the body – and use them to create beta cells. Because these are made from the patient’s own cells, this would avoid issues of rejection that can arise when transplanting cells from a donor. It would also help to solve the current issue where there are too few donors for islet transplantation to meet the needs of T1D patients. “My research is really relevant to that,” explains Lizzie, “because when scientists try to make beta cells from stem cells, they often find that the reason they don’t work is because their metabolism isn’t quite right – not like that of a normal beta cell, so my experience in studying beta cell metabolism would mean there are opportunities for collaboration there.”

The close connection in CVS between fundamental science and clinical research is another motivating factor, along with the proximity of the Edinburgh Clinical Research Facility on the BioQuarter campus. “That makes it much easier for scientists like me to set up clinical studies,” says Lizzie. “I think that will really increase the translational impact of my work.”

Paradoxical approach

One class of drugs that have been investigated as a potential treatment for T2D are called glucokinase activators. They boost the activity of an enzyme called glucokinase, which is involved in the first step of glucose metabolism. They’ve been seen as a promising treatment because they make the beta cells produce more insulin, reducing the amount of glucose circulating in the blood. However, in the long term these drugs have been found to speed the decline in beta cell function and they can cause unwanted side-effects, such as increased fat storage in the liver. Lizzie’s research suggests why this might be happening. “The reason I think glucokinase activators don’t work is that they artificially increase metabolism and make the beta cell work harder,” she says. “Essentially they’re exhausting the beta cell, so if anything they’re making the problem worse.”

Lizzie is keen to try the opposite approach of partially inhibiting the activity of glucokinase to protect the beta cells. “It’s a really paradoxical approach, because if we reduce glucose metabolism in the beta cell, we know that on its own is going to reduce the level of insulin and increase blood glucose,” she explains. “So we’d probably need to combine that with other steps to maintain or reduce blood glucose. But it’s actually going to protect the beta cell by giving it time to recover.”

Providing further evidence of why this counter-intuitive approach could work, Lizzie describes other patients with a form of diabetes called MODY 2. MODY stands for maturity-onset diabetes of the young, and refers to several relatively rare forms of diabetes that are caused by mutations in single genes, unlike the better known type 1 and type 2 diabetes, which are caused by more complex combinations of factors. People with MODY 2 have a mutation that reduces the activity of glucokinase. As expected, this causes lower levels of insulin and higher blood glucose. “But they don’t experience any diabetic complications, and they don’t require drug therapy,” says Lizzie. “In fact they seem to manage quite well, so that suggests our approach of inhibiting glucokinase might be a good one.”

Finding the way

Despite her success as a researcher, it wasn’t always clear that this was the path Lizzie would take. She went to a school where there wasn’t a strong expectation that pupils would go on to university. She thought about becoming a doctor and ended up studying for a degree in biomedical science, but still didn’t feel it was exactly the right fit. “I didn’t really enjoy it initially because it was just a lot of learning and not much practical stuff,” she explains. “I’d always been really interested in nutrition and metabolism, and I kept thinking I would leave to go and be a dietitian.” Job shadowing with dietitians, however, left her feeling like she wasn’t getting to do enough science day to day. “I think it wasn’t until my final year of undergrad, when I sat in a lecture about diabetes, that I realised how my interest in medical things and science and nutrition could marry together in one condition,” she says. “I decided that diabetes was the thing I wanted to do a PhD on. It was that or nothing, and I’ve been addicted ever since.”

That was always the plan, to come back to Scotland and establish my own research group, and I’m so happy that I’m now getting to do that.

One of the scientists Lizzie particularly admired was Professor Dame Frances Ashcroft, in whose group she has just spent six years at the University of Oxford. “Frances was somebody I always looked up to when I was a PhD student. She was really the only female lead scientist that I was seeing in the literature and I was impressed by all the things she’s discovered, like the mutation that causes neonatal diabetes. That meant the lives of those patients were totally transformed by only needing to take a pill, rather than making regular insulin injections. When you’re translating basic science into the clinic, that’s the best outcome you can hope for.”

When she finished her PhD, Lizzie initially joined a group studying beta cell biology at Imperial College London. “But I always had this niggling feeling that I wanted to work with Frances, so after a few years in London I just contacted her out of the blue!” she says, with a smile. “I ended up moving to Oxford and I’ve been there for six years and it’s been brilliant.”

Originally from Fife, Lizzie is glad that the move to CVS will allow her to make a long-awaited return to Scotland. “I always thought I would come back a lot sooner, but almost nine years later I finally am,” she says. “That was always the plan, to come back to Scotland and establish my own research group, and I’m so happy that I’m now getting to do that.”