Diabetes cure not just a dream
Interview: Professor Mirela Delibegovic (University of Aberdeen)…
Diabetes cure not just a dream
Professor Mirela Delibegovic leads a research team at the School of Medical Sciences, in the Institute of Medical Sciences (IMS), University of Aberdeen. Her research focuses on the role of tyrosine phosphatases in cell signalling and disease, with a specific emphasis on obesity, Type 2 diabetes, cardiovascular disease and non-alcoholic fatty liver disease (NAFLD).
“One day, a shell landed right on our school. But in Bosnia in those days, it was normal.”
Twenty years later, Professor Mirela Delibegovic has gone back to school in Scotland, as part of a project called Research the Headlines, set up by the Young Academy of Scotland (YAS), reaching out to schools to get students thinking more deeply about how “research is discussed and portrayed in the media.” The students talk about the latest news that ”chocolate is good for you” and review another article which says smoked salmon has more fat per gram than margherita pizza. For Delibegovic, this is one of the most enjoyable activities of the week, and she’s delighted that the students know so much about science and don't “swallow everything they read in the papers” without checking the facts.
As a mother, she also likes working with children, but she is also keen to get back to her lab in the Institute of Medical Sciences (IMS) at the University of Aberdeen, where she heads a research group seeking to “cure” diabetes.
The road to Aberdeen has been a long and sometimes very difficult journey via Tuzla (Bosnia's third-largest city), Edinburgh, Essex, Dundee and Harvard, but Delibegovic will never forget how the Bosnian War tore her family apart in the mid-1990s. Her elder sister Almira moved to Scotland soon after the start of the conflict, to study law. At first, her mother did not want her only other daughter to follow – until another shell came down, this time much closer to home. And reluctantly, she packed her off to Scotland.
In Edinburgh, the 17-year-old Delibegovic soon settled down to life as a student in exile, completing her secondary education in the capital city, thanks to a George Heriot's school studentship. Initially, she wanted to go on to study medicine, but finally completed a degree in pharmacology at the University of Edinburgh and moved north to Dundee to gain her PhD in Biochemistry, specialising in the study of obesity and diabetes, funded by a Royal Society Postgraduate Studentship.
Her family history also played a role in her choice of research. Several family members had developed Type 2 diabetes, while others seemed immune, and Delibegovic was interested in finding out why by studying the mechanisms of the disease.
During her time in Dundee, under the wing of Professor Patricia Cohen, Delibegovic developed an interest in special proteins called phosphatases, which she was researching as part of her PhD studies. She then became interested in a phosphatase called PTP1B (protein tyrosine phosphatase 1B) which seems to play a key role in the body's immune system, and went to a conference in Marburg (Germany) to find out more about the latest research into PTP1B, which suggested that it could prevent obesity and protect against diabetes development. Initially, researchers had suspected that the protein may also cause cancer, but this proved to be wrong. What fascinated Delibegovic was that this seemed to solve a conundrum: until then, it had seemed to be impossible to cure diabetes (obesity being a major risk factor) without causing cancer. Another complication with candidate treatments is that some may lead to terrible mood swings and even make some people feel suicidal. If PTP1B could cure or prevent diabetes, the next step was to study its effects on different parts of the body, including the brain. For example, isolating its effects on muscle, fat and liver cells while preventing it from crossing the “blood–brain barrier.”
Since then, Delibegovic has focused her attention on this potentially “game-changing” protein. But in the early days, her quest for a cure met with sceptical reactions. For example, at her Viva, when her examiners quizzed her in defence of her PhD Thesis, one of the interrogators asked her what she hoped to achieve in her future career. Without hesitation, she answered that she wanted to “cure diabetes,” and overheard one of the panel describing her wish as “naïve.” But ever since then, she has done her best to prove the sceptics wrong, and is already making significant progress.
The road to Aberdeen
Delibegovic has always been interested in diabetes and that was why she decided to do her final year undergraduate project at Smithkline Beecham Pharmaceuticals (now Glaxo- SmithKline) in Harlow in Essex, where she worked on a new class of anti-diabetic drugs which got approved for use in patients while she was working there. She then did her PhD in Dundee on a diabetes project, before she got a fellowship to continue her work on diabetes at Harvard Medical School, spending four years there from 2003 to 2007. Her husband, Dr Nimesh Mody, whom she met at Dundee, went with her to Harvard to pursue his own specialist interest in cancer and diabetes, and they both returned to Scotland in 2007 – with their newborn son, Seid.
“Scientists are always asking themselves ‘am I doing the right thing?’” says Delibegovic. “I had started work on a new pathway, linking the immune system with diabetes, and my preliminary studies suggested that PTP1B could be important, but the step up from researcher to leader of my own research group was a big move to make. Suddenly I would be responsible for other people’s careers, and would have to ensure that we had enough funding in place. It was like running a small business.”
In terms of research, the big question was, why do we gain weight and what is the link between obesity and insulin resistance? What is the link between cardiovascular problems, weight gain and diabetes? And what is the link between diabetes and Alzheimer’s disease? A high percentage of Alzheimer’s patients also have diabetes (for example, a study of the Mayo Clinic Alzheimer Disease Patient Registry revealed that 80% of patients with Alzheimer’s exhibited either impairments in glucose tolerance or diabetes), but researchers still have to establish if diabetes is a consequence or a risk factor in developing Alzheimer’s.
At Harvard, Delibegovic was funded by the American Heart Foundation, but back in Scotland, the big question was where the funding would come from – and the answer was Diabetes UK and the British Heart Foundation. “I sat at my computer and surveyed the empty lab,” says Delibegovic. “The project was starting from scratch, and it was not until the next year that I got my first grant and was able to hire my first post-doc assistant, then my first PhD student.”
Researchers have established that the PTP1B protein has the potential to protect us from infections by “turning on” our immune system in response to particular triggers. The protein also acts in the opposite way by switching off the immune system when it becomes overactive; for example, it may help to reduce inflammation or treat conditions such as septic shock or rheumatoid arthritis. What makes PTP1B so special for Delibegovic is that it may enable us to develop pharmaceutical solutions which cure diabetes without complications.
Delibegovic is also interested in using PTP1B to target specific locations, without any damaging side effects. “We wanted to know if it had global effects,” she explains, “or could be used to lose weight, for example, without affecting the brain. And we found that we can use it to target the liver or muscles or fat cells, to protect the body against diabetes, without any weight loss.”
Some of the research involves working with mice. Because it is important to find out if the protein works in adults, and monitor progress from early life onwards, mice are useful because they are “middle-aged” after a year and can be fed special diets; so researchers can study the effects of changes in nutrition in mice, then try to reproduce the same results in humans. Delibegovic uses a range of molecular biology, biochemical, pharmacological, cellular and gene knock-out mouse models as well as tissue biopsies and plasma samples from human volunteers. “This allows us to create a truly integrative physiology approach to understanding the aetiology of these diseases, as well as possible therapeutic intervention points,” she explains.
While focusing on diabetes, Delibegovic inevitably starts to see other connections and wants to investigate other diseases. And her next “dream” is to understand why we get old – and hopefully slow down the process of ageing. The same mechanisms that lead to disease are connected with ageing and even though Delibegovic continues – for the time being – to focus on obesity and diabetes, and related issues such as nutrition, ageing will inevitably be a hot topic in future.
Anti-ageing and cognition have enormous potential for treatments based on proteins such as PTP1B, she says. “If we can treat diabetes and other diseases like cancer,” she says, “why not ageing?” This means finding out why we age in the first place and studying the role of nutrition in much greater detail. As societies get older, finding cures for age-related conditions such as senile dementia are also becoming more urgent, and scientists have recently established something called ‘Type 3 diabetes’ to describe the form of Alzheimer’s disease which results from resistance to insulin in the brain.
In fact, says Delibegovic, researchers are beginning to establish a lot of new things about insulin and diabetes, in the search for more effective and economical treatments, aimed at individual forms of the disease such as late-onset Type 1 diabetes, as well as early detection and prevention.
Will the research at IMS lead to commercialisation of patented treatments? Delibegovic says you can “never say never” and believes that PTP1B has huge potential for a breakthrough in the treatment of different conditions and, ultimately, the development of a new class of drugs. “I am always looking out for something new,” she adds.
What is diabetes?
Diabetes is a group of metabolic diseases in which there are high blood-sugar levels over a prolonged period. Symptoms include frequent urination, increased thirst and increased hunger. Diabetes can cause many complications such as cardiovascular disease, stroke, chronic kidney failure, foot ulcers and eye damage. The disease results from the pancreas not producing enough insulin, or the cells of the body not responding properly to the insulin produced.
There are two main types of diabetes:
Type 1 results from the pancreas failing to produce enough insulin. The cause is unknown and it is usually diagnosed at a young age.
Type 2 is a condition in which cells fail to respond to insulin properly. As the disease progresses, a lack of insulin may also develop. The primary cause is excessive body weight and lack of exercise.