Meet the 2020 Society for Endocrinology Dale Medal winner, Professor Frances Ashcroft

Our 2020 Society for Endocrinology Dale Medal winner, Frances Ashcroft, is Professor of Physiology at the University of Oxford and a Fellow of Trinity College Oxford. She will be talking about her fascinating research on ion channels and their role in insulin secretion during SfE BES 2020 Online. Find out more about her career and research and get some invaluable words of advice in this interview article.

Tell us a little about your current research

My research interests are ion channels and the metabolic regulation of insulin secretion. These two fields come together in our studies of the role of ATP-sensitive potassium channels in insulin release. I am excited to understand how the metabolism of beta cells works, and how high blood glucose levels in diabetic patients change these beta cells, so that they don’t secrete insulin anymore.

Can you tell us about your career path and what you are most proud of?

I did my undergraduate and graduate studies at the University of Cambridge in zoology. I then did post-docs in Leicester with Peter Stanfield and Los Angeles with Susumu Hagiwara, where I worked on calcium and potassium currents in muscle. After this I set up my own lab in Oxford and chose to study beta cells. I used a technology called patch clamping to look for ion channels closed by glucose. I was a total novice at patch clamping and I was fortunate that others helped me get started and that I got a grant to do it. I have always been led by the science and followed what I am interested in, which in my case is ion channels. I have written a popular book on this subject called the Spark of Life.

I’m most proud of the success of all the brilliant students and post-docs who have worked in my lab. It’s also been wonderful to meet some of the neonatal diabetes patients who have been helped by our work.  Andrew Hattersley and his team found that 50% of neonatal diabetes cases are due to mutations on the ion channel I had been working on for 20 years, and we were able to show that these mutations impaired the ability of ATP to close the channels and thus prevented insulin secretion. However they could still be closed by sulphonylurea drugs. This was very exciting because it enabled the patients to transfer from insulin injections to oral tablets.

What inspired you to choose endocrinology as a career?

When I was an undergraduate it was thought that electrical activity was mainly confined to muscle and nerve cells, so I remember being fascinated at finding that it also occurred in endocrine cells, like pancreatic beta-cells. When I took up an independent position at the University of Oxford, I decided to work in a field that was different from my previous one and where there were people at Oxford with whom I could collaborate. I picked beta-cells because of their interesting electrical activity and because I met Stephen Ashcroft, who was working on the biochemistry of insulin secretion. It was the start of a long and happy collaboration.

What do you enjoy most about your work?

There are three main things I enjoy most about my work. Firstly, making discoveries – there is nothing quite like the exhilaration of finding out something new. Secondly, seeing the people who have worked in my lab flourish is a constant joy.  And finally, the wonderful long-term collaborations I have had with some outstanding scientists, such as Steve Ashcroft, Patrik Rorsman, and Andrew Hattersley.

How has the COVID-19 pandemic affected your research?

Lockdown was a twofold problem because it prevented us from working in the labs. It was also impossible to keep all of our animal colonies going because of reduced staff in the animal house. We are back in the labs now, but social distancing means that we cannot work at the same intensity as normal. There’s also a constant low level of anxiety about the virus that affects everyone.

What will you be presenting during your lecture at SfE BES online 2020?

I’ll be talking about our work on the role of the ATP-sensitive potassium (KATP) channel in glucose-stimulated insulin secretion. Glucose has to be metabolised by the beta-cells for it to stimulate insulin release. This is because metabolically generated ATP closes the KATP channel, thereby triggering electrical activity, calcium influx and insulin exocytosis. I’m going to show how mutations in the KATP channel that impair ATP inhibition cause neonatal diabetes and increase the risk of type 2 diabetes. I’ll also talk about how chronic hyperglycaemia impairs the metabolic generation of ATP, reducing insulin secretion and speeding the progression of impaired glucose tolerance to full-blown diabetes, and what this means for diabetes therapy.

What do you think about the move to virtual meetings?

The biggest benefit is that you don’t have to travel – which is both good for the planet and saves a great deal of time.  Another benefit is that if the talks are posted online, you can listen to bits you’re particularly interested in again at your own convenience. This means you don’t run the risk of missing a talk because another you want to hear is scheduled at the same time. The drawback is that you don’t get to meet your colleagues in person and you miss out on those unexpected and stimulating conversations that lead to new collaborations.

What do you think will be the next major breakthrough in your field?

I think this year has taught us that making any predictions about the future is very unwise, because we never know what’s going to come around the corner!

Any words of advice for aspiring endocrinologists?

My best advice is to ‘find a friend’ – a good person to collaborate with who you not only admire scientifically, but whose company you enjoy. My collaborators have supported me through the inevitable difficulties a scientific life throws at us, have celebrated with me when things went well, and are endlessly and wonderfully stimulating to interact with.

I also think it is important to do what makes you excited and follow what you are interested in. As science is a hard field, unless you love what you are doing, it is perhaps not the best career for you. I’d also recommend you remember Churchill’s advice – never, ever, give in. Perseverance gets you a long way in science.

You can hear Prof Frances Ashcroft’s medal lecture “Metabolic regulation of insulin secretion in health and disease” during SfE BES 2020 Online on Wednesday, 18 November, at 13:05-13:35 GMT. If you haven’t already, register for SfE BES Online now!

Meet our 2020 International Medal winner, David Mangelsdorf

David Mangelsdorf is Professor and Chair of the Department of Pharmacology at UT Southwestern and an Investigator of the Howard Hughes Medical Institute. His research focuses on nuclear receptor regulation of metabolism. Dr Mangelsdorf will present his Medal Lecture at SfE BES Online 2020, on Monday 16 November. Learn more about his research, upcoming presentation and career in our interview.

Tell us a little about your career

I became Chair of Pharmacology in 2006, which I inherited from Alfred Gilman, who discovered G proteins and won the Nobel Prize for it. At first I was reluctant to become Chair but then I realised that the role isn’t just about holding together a department but also mentorship and recruiting great, young talent. Here the Chair is given quite a bit of latitude, you keep the Chair as long as you want it and are doing a good job – really you are a benevolent dictator, where you make the rules but they are for the benefit of everyone.

I wanted to be able to juggle three balls, the department, my research lab and my family. Our department has a great administrative team to support me in managing the department and I run a joint lab with Steve Kliewer. We did our PhDs together and have now been working together since 2002.

What inspired you in to endocrinology?

As a graduate student I was in Mark Haussler’s lab, which discovered the hormonal form of vitamin D and its receptor. Mark Haussler was a great scientist and mentor who supported and inspired my work. I then went on to investigate orphan nuclear receptors.

What are you most proud of in your career so far?

The accomplishment of understanding the role of orphan nuclear receptors. I was involved in deorphanising several nuclear receptors.

I am most proud of the discovery of the farnesoid X receptor (FXR), as it has become an important therapeutic target for biliary cholangitis and more recently nonalcoholic steatohepatitis, a type of fatty liver disease. Our work showed how FXR affected liver and lipid biology and to see it now being developed into a therapeutic target is one of my most significant accomplishments.

Steve Kliewer and I are a team, we worked on FGF hormones together, to establish what they do. We worked out the FGF signaling pathway and showed the important role of FGF19 and FGF21 in liver function and metabolism.

Please tell us a little more about what you will be presenting during your Medal Lecture at SfE BES online 2020?

I will be focusing on how FGF21 signals from the liver to the brain to regulate metabolism and nutrient stress, which has implications for obesity, diabetes and the response to alcohol. You can think of FGF21 as a stress hormone, it responds to nutrient stress and two of its most common inducers in people are sweets and alcohol. FGF21 signals to the brain to trigger an anhedonic response – intended to tell you to stop consuming it.

If you give animals a choice between water and water with something sweet or alcoholic added, they will choose the sweet or alcohol up to a point but when FGF21 is administered they stop and return to only drink the water. However, if you knock out the FGF21 signal entirely, they not only keep drinking the sweet or alcoholic water but they drink it even more. FGF21 also encourages more water drinking, presumably to encourage hydration when consuming sugar or alcohol.

Why do you think people eat and drink to excess then?

This is more of an addictive or conditioned behavior but there is no evidence, yet, that FGF21 can affect this in people. We know FGF21 is active in the human brain and perhaps even in areas that control addictive behavior. It is possible that the human FGF21 pathway evolved to compensate for the intake of very sweet or alcoholic foods. We know that people who enjoy drinking, and who drink more, have more of a certain genetic marker in their β-klotho gene than teetotalers. β-klotho is a co-receptor for FGF21. This may have evolutionary significance as alcohol is a natural preservative and there was an evolutionary advantage to having a little alcohol in things like water, to prevent disease. When you start drinking, you might like a sip of beer or wine but would hate stronger alcohol like vodka. People condition themselves to drink more as they get a buzz from it.

Could the FGF21 pathway have therapeutic applications for obesity and alcoholism?

There are very few things known to limit the intake of sugar and alcohol in humans, so there is potential therapeutic value in FGF21 but this needs much more investigation. However, human genetics do point towards a role for FGF21 in overdoing alcohol and sugar consumption.

How has the COVID-19 pandemic affected your research?

Significantly, I think like everyone else it has set us back. We thought it would be just 2 weeks lockdown back in March but even now we are not back to full working capacity. We do a lot of animal work, so we couldn’t do anything. Our long-term studies using animal models had to be stopped and that meant we had to cull colonies. So when we came back we needed to restart everything – in some studies it has set us back as much as 6 months to a year.

The other problem is the inability to interact directly with other people, either in a laboratory or at conferences.

What do you think about the move to virtual meetings?

Doing virtual talks is a terrible experience in my view, it is so artificial and the technology isn’t quite up to par yet. You really miss the human interaction.

The only benefit is saving money on travel and being able to be present at meetings you might not have been able to attend. I’ve enjoyed being at home with my family but do miss interacting with colleagues directly.

What do you enjoy most about your work?

Well, before COVID-19, I enjoyed interacting with the lab – I have an open door policy. I enjoy the element of discovery, I like to be inspired, to take bold steps, not to be afraid to ask a big question, and to go in new directions. I love learning about new areas, we have just started working in neurobiology.

What do you think are the biggest challenges in your field?

Specifically in my work it is the complexity of the central nervous system. It takes a long time to do thorough and careful investigation in the brain.

More generally, the lack of funding makes it difficult to take risks and move the field forward. Investigating new areas, defining new pathways and developing new models needs a lot of funding and a lot of time.

What do you think will be the next major breakthrough in your field?

To demonstrate whether FGF21 and FGF19 are viable therapeutic targets. When looking at treatments that are given long-term, there will always be problems. All drugs have side effects but the longer you are exposed to them the more likely adverse effects may occur. We need to establish if these targets are good for designing new treatments. Deciphering the neuroendocrine circuits of metabolism and behaviour is ongoing and will be key to establishing new therapeutic targets.

Any words of advice for aspiring endocrinologists?

You have to ask a big question to answer a big question. Don’t be afraid, if you want to make a difference, you have to take risks. As long as you are asking an important question, you are going to learn something – you shouldn’t spend time trying to put a round peg in a square hole, whilst losing sight of what the science is telling you.

For example, we were trying to find the ligand for a different nuclear receptor when we discovered the one for LXR. The graduate student had used a negative control that came up positive in her experiment. She was distressed that her experiment had failed but in fact she had inadvertently found the LXR ligand.

In the spirit of the times, my advice is that you should practice safely masking your face, but not your science!

You can hear David Mangelsdorf‘s Medal Lecture “FGF21 and Nutrient Stress: Eat and Drink, But Don’t Get Too Merry” on Monday 16 November at 13:40 GMT. If you haven’t already, register for SfE BES Online now!

Meet our 2020 Clinical Early Career Prize Lecture winner, Dr Steve Millership

Dr Steve Millership, Research Fellow at Imperial College London, is one of our 2020 Early Career Prize Lecture winners. His research focusses on the beta cell epigenome and the impact of diet on beta cells and he will be giving his lecture “Tracking of imprinted gene hypervariability and diet-induced deregulation in pancreatic beta cells” at SfE BES 2020 Online on Tuesday, 17 November. Read this interview to find out more about his talk and get some expert advice on how to become a successful scientist.

Can you tell us a little about your career, research and an achievement you are proud of?

I started my career in metabolic energy homeostasis and cell biology and have always been fascinated with it. I did my PhD in Cardiff University and moved to the London Institute of Medical Sciences to complete a post-doc on imprinted genes and modelling diabetes in mice. In the last year or two I have been writing grants and fellowships, as well as doing a short term fellowship with the Welcome Trust at Imperial College London to continue exploring the modulation of the beta cell epigenome and the effect of diet on beta cells in diabetes. I had been in this position for about 2 months and in the transition phase of getting set up on my own, before the pandemic started.  

A proud moment for me was winning the Early Career Prize Lecture – very exciting and unexpected! I would have originally said my proudest moment was when my first paper was accepted, but that has now been overshadowed by winning this award.

Can you tell us a little more about what you will be presenting at SfE BES Online 2020?

There are two main angles to my talk. The first is that beta cells are not all equal and a small percentage are doing different jobs to the rest. This is important to help understand how they secrete insulin as a whole islet. The model I created has the ability to image imprinted gene expression longitudinally and you can look at individual cells and analyse them. The second part to my talk is about how the diet can deregulate and alter expression of beta cell genes, which could explain why diet is so essential to beta cell function.

How has the COVID-19 pandemic affected your research?

I didn’t go in to the lab for six weeks and have mostly been grant and application writing at home, so it has been good to have the opportunity to do that and make lockdown feel more productive. In our lab we have had restricted occupancy so there is only ever 5 people in the lab at a time. This means you don’t get the same lab environment, as everyone just gets on with their own thing and as everyone is so spread out, there is little socialising. However one benefit I have noticed is that my efficiency and organisation levels gone through the roof, as you have to make the most of limited time in the lab. I’m not usually an organised person so that is one thing that has changed for the better!

What do you enjoy most about your work?

I’ve always really enjoyed having hypothesis driven conversations and not knowing what is to come is exciting. I find it really interesting solving mysteries and working on something that has a high impact on human health.

What do you think about the move to virtual conferences?

I went to two conferences in the last month and I found having everything laid out in front of you provides an opportunity to focus on certain bits that are beneficial to you in more detail, and you can go to more talks than in person. Another benefit is having access to conferences you wouldn’t usually go to as there is no need to travel, which can be expensive.  However a major drawback of online meetings is not having as much opportunity to network with other attendees. Sometimes talking with other people you can find out valuable bits of information or find better opportunities to collaborate.

What do you think are the biggest challenges in your field?

One of the biggest challenges in beta cell biology is determining what the best method to treat diabetes is – there is always the divide between advancing beta cell function, or reducing insulin resistance. We always had the belief that efficiently functioning pancreatic beta cells is better for diabetic patients and saving beta cell function is a better option, but it is hard to decide which pathway is most effective as there are still things we don’t fully understand.

What advice would you give to aspiring endocrinologists?

One piece of advice I would suggest is, when you are writing grant or fellowship applications, give yourself time and let your ideas develop. You ideally need to give yourself between 6-12 months and write them as you go along, getting feedback from talks and people from the field.

My PhD mentor gave me a couple great pieces of advice which I didn’t expect to be so helpful.  She said to make sure you have got at least one main paper coming out of your post-doc which you can call your own, and also to get on with people! It’s difficult to achieve anything if you aren’t collaborative and you don’t get anywhere by keeping your experiments to yourself and not getting help or feedback. You need to be open to ideas and having your work critiqued and then take that feedback on board.

You can hear Dr Steve Millership’s lecture “Tracking of imprinted gene hypervariability and diet-induced deregulation in pancreatic beta cells” on Tuesday, 17 November at 15:55 GMT. If you haven’t already, register for SfE BES Online now!