Workshop 2016: A Rare Breed – the academic clinician

By Deborah Oakley

Moving between laboratory research and clinical medicine can be challenging, but offers an unparalleled opportunity to pursue a particular personal passion. This was the tone of the annual Chain-Florey Workshop, 2016, a celebration of the Chain-Florey scheme, which offers world-class research training to medical graduates.

“I think it becomes even more important that we have schemes like this so our extremely hard working clinicians are able to get research experience,” said Amanda Fisher, director of the MRC London Institute of Medical Sciences (LMS), which initiated the scheme. Introducing the keynote speaker, Sadaf Farooqi, Fisher said, “I think Sadaf really exemplifies what it is to be both a first rate clinician and a scientist. She’s also a woman and that’s important. I’m really excited to hear her talk.”

Like many Chain-Florey fellows, it was whilst working as a young doctor that Farooqi began to think more deeply about the biology behind the illnesses she saw in her patients. She said this fundamental drive to ask questions, and to search for the answers, led her into the science laboratory. But it was not a smooth transition. “I’d never been in a lab until I started my PhD. I set fire to things. I ran gels backwards. In a way, it was a disaster,” said Farooqi, now Professor of Metabolism and Medicine at the University of Cambridge.

Today, she’s known for discovering the first genetic mutations that cause severe obesity, and for translating these findings into treatments that help severely obese children return to a normal weight. But Farooqi said when she first began her research over two decades ago, other scientists struggled to understand her choice of specialism. At the time, in the 1990s, obesity was not as big a threat to public health as it is today, said Farooqi. Since then, there has been a surge of weight gain across Western nations. According to Farooqi, this has led to the popular but incorrect belief that obesity is a new phenomenon. She pointed to a textbook on obesity written in 1727, and said it must have been a concern even before modern Western diets evolved.

Current Chain-Florey Fellows, Lecturers and FY2 Trainees with Mark Ungless (far left), Director of Postgraduate Studies

Today, we’re surrounded by high calorie foods, which some think may explain why more people are overweight than ever before. But that’s not all. According to Farooqi, as the population’s weight has increased, it has also become skewed towards the heavy end of the spectrum.“Now, we have a higher proportion of people who are severely obese. And that can’t be explained by environmental factors alone. It suggests that individuals at the top end of the BMI spectrum have some susceptibility that isn’t down to environment.”

Farooqi’s research aims to understand why, when two people live in the same environment, one may become fat whilst the other remains thin. “There are people who are obesity resistant, who eat what they like and don’t gain weight. Some of you may have friends like this, though they may not remain friends for long,” she joked.

Her findings suggest that genes can predispose an individual to severe obesity. Addressing the audience, she said, if you take any two people in this room, at least 40% of the variation in body weight is determined by genetics.

In some people, the genetic and molecular regulation of food intake can go wrong. Farooqi has worked with children who were severely obese and constantly hungry. “Even NHS hospital food was really exciting for them. This was really a sign for me that something was abnormal.” She was the first to show that these children have abnormally low levels of the hormone leptin. “What’s given me great pleasure is seeing the kids go from having a miserable life to being completely normal after leptin injections.”

According to Farooqi, leptin also explains why “yo-yo” dieting typically fails. When people dramatically cut their food intake, their leptin levels fall and this acts as an in-built, biological drive to eat more. It’s intriguing to think that such complex eating behaviours have a biological basis, says Farooqi.

Harry Leitch, a graduate of the Chain-Florey Scheme, who first suggested inviting Farooqi to speak at the workshop, said: “She’s a great example of a clinician-scientist who started out with a clinical problem and, alongside her colleagues in Cambridge, has gone on to produce a molecular dissection of the appetite regulatory pathways. She has made a huge contribution both to basic science and to patient care.”

After Farooqi’s talk, Leitch and two Chain-Florey fellows discussed their research and experiences as clinician scientists. Leitch said, “Every one tells you that we really need medics who do basic science, but there didn’t seem to be many opportunities. The LMS was really looking for people interested in doing basic science – and that was a God send for me.”

Leitch was awarded an Academic Clinical Fellowship in 2016 and is continuing his research on how cells in an early embryo make the fundamental and irreversible decision to become either a normal body cell, with a complete set of DNA, or a reproductive cell, the sperm or eggs, with only half of the genetic information.

Next up was Amit Adlakha who said he moved into research after treating a transplant patient who died from a fungal infection. Adlakha said that almost four per cent of patients globally who have lung transplants die every year due to infections with the fungus Aspergillus. He wants to find out what makes some patients more susceptible than others, and how it could be treated. Finally Jennet Williams discussed her research on the possible links between fatty liver disease, cancer and an enzyme that plays a role in maintaining energy levels.

The workshop concluded with a lively debate about whether researchers should focus their efforts and limit funding to either common or rare diseases. Panel members suggested that the distinction may be artificial, and that seemingly unrelated conditions can be connected in unexpected ways.

“When I first started my research, I was studying how a fundamental part of the innate immune system (termed complement) was connected with very rare kidney diseases. It transpired that the findings are relevant not only to common kidney disease but also to diseases in other organs. For example, an eye disease called age-related macular degeneration” said Matthew Pickering, professor of rheumatology at Imperial College London, and a member of the panel. “So rare disease research can result in widespread benefits.”

Fisher added that more people study the rare developmental disorder Cornelia De Lange syndrome than have the condition. Much of this research focuses on a protein called cohesin, which is also mutated in many types of cancer.

Scientists are now collecting huge amounts of data on rare diseases, but young clinicians don’t have the skills to deal with this data, suggested one audience member. Farooqi said that she struggled with a lack of data because the equation commonly used to estimate basal metabolic rate was developed with information from one hundred healthy, male soldiers in Italy. “Intuitively it seemed ridiculous for me to use that equation to estimate the basal metabolic rate of severely obese children.”

Pickering added, “I think on the rare diseases I work on, it’s very collaborative and you meet amazing individuals in patient groups. That’s empowering.”

Panel members were Peter Campbell, Sadaf Farooqi, Helen Firth, Andre McMichael, Jeremy Pearson, Matthew Pickering, Michael Raff and Irene Roberts.

In 2017, Sadaf Farooqi joined the LMS scientific advisory board.

 

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