Month: October 2021

Professor Shalet is an Honorary Consultant Endocrinologist at the Christie Hospital, Manchester and Emeritus Professor of Endocrinology at the University of Manchester. His main research interests are late endocrine effects following treatment of cancers, pituitary disorders and in particular abnormalities of growth hormone secretion. In our latest interview, he talks about his career, the importance of keeping patient care at the forefront, complemented with an anecdote or two.

Tell us a little about your career path

I completed a BSc in Physiology at London University and qualified in medicine at the Royal London Hospital. My medical training posts in London and Bristol were followed by an appointment as Research Fellow in Endocrinology at the Christie Hospital, Manchester. I formally retired in 2005 but carried on seeing patients until around 2010. Now all I really do is I teach, I like the subject, so it’s not really work, it’s enjoyable. Occasionally, I referee a paper and participate in data safety monitoring boards. I still do a moderate amount of that work, which keeps me in the loop in terms of what’s going on in the field.

“Although I’d never done any research, the focus there was on childhood cancers. The survival figures for kids with cancer had massively increased but now these patients were having growth and puberty problems. That’s why an endocrinologist was needed there.”

What inspired you into research?

I always liked endocrinology, the science is very attractive. At first it makes logical sense, the pituitary controls the thyroid, the thyroid sends a message, the pituitary changes, but then hold on there’s the hypothalamus and it’s that complexity that makes the science really attractive. Clinically, you can have long-term relationships with patients. When qualified, I knew I wanted to do endocrinology but I was then doing a medical registrar job in Bristol and after attending a course on endocrinology, I realised I knew nothing. So I decided if that’s what I wanted to do, I had better learn some and then a Research Fellow position came up in Manchester – and that’s how I got started.

Although I’d never done any research, the focus there was on childhood cancers. The survival figures for kids with cancer had massively increased but now these patients were having growth and puberty problems. That’s why an endocrinologist was needed there.

What do you enjoy most about your work?

Clinical practice is what matters, I care about the patients. I’ve always cared about their outcomes. I also enjoy teaching and research. Those are the three components that I need and enjoy and of course they interact. At the end of the clinic, we all used to have discussions where you’d bring the rest of the team up to date, think about what we don’t know, why we don’t know it and how could we know it? That’s all part of the teaching training and research, thinking as well as doing the best for patients.

Has anyone particularly influenced your career?

I can’t tell you that I had a specific mentor but Colin Beardwell was a very good role model. He cared about patient outcome, was intelligent and an excellent teacher. He didn’t have an ego problem and was happy to see a younger colleague develop.

I’d also seen bad guys along the way, really unimpressive, and that showed me who I didn’t wish to become. I tried to feed off the bad guys and I knew I never wanted to be like that.

“At one point in Manchester, we published the worst surgical results for acromegaly in the world. At that time six surgeons did the operating instead of one. You need one because the number of cases isn’t high enough for six to obtain the volume of experience.”

What are you looking forward to at SfE BES 2021 in Edinburgh?

My lecture will look back over my career and research, and include an anecdote or two! When you get to my age, you have friends to catch up with, you may have known them 30 or 40 years and only have that once a year chat but I look forward to it.

I have a funny Edinburgh story from years ago. I flew from Manchester to Edinburgh and was waiting for a taxi outside the airport. A taxi driver approached me and asked something that sounded like ‘do you want sex’? The whole queue could hear as I replied, as reasonably as I could, that I did not want sex, it was November and very cold, but I thanked him very much for the offer. At that point the taxi driver clarified the taxi was a six seater and he wanted to know whether there was six people in my party! That was one of my most memorable Edinburgh conversations.

What do you think are the main challenges in your field right now?

Late effects of cancer treatment is still a challenge. You’re always catching up as these can occur up to 10 years after treatment. There needs to be expert resource available to treat the problems as they arise. Another issue is transition to adult life. Bridging the gap between paediatric and adult care can be very difficult. New more targeted treatments such as proton beam therapy will still cause endocrine damage, which may need to be tackled differently.

What do you think will be the next major changes for endocrinology?

More centralisation of key procedures. You need real expertise for these procedures, which may not come up very often around the country, centralisation means that volume of experience is contained in a centre of excellence. Although this means fewer endocrinologists get that experience, we need to make sure that patients are getting the best care.

At one point in Manchester, we published the worst surgical results for acromegaly in the world. At that time six surgeons did the operating instead of one. You need one because the number of cases isn’t high enough for six to obtain the volume of experience. Now Manchester has one surgeon and the results are as good as anywhere else. That’s why I think centralisation of certain key procedures will be better for patient care.

Any words of wisdom for aspiring endocrinologists?

Try to get a reasonable understanding of yourself. I think that’s the journey. Not everybody is destined to do lots of research, just as some people are better suited to clinical practice whilst others are destined, particularly in a subject like endocrinology, to be lab-based. You should try to work out what combination of clinical work, teaching and research works best for you. 

You can attend Professor Stephen Shalet’s Medal Lecture, “Cancer treatment endocrinopathies and growth hormone status throughout life” on Wednesday 10 November at 4:40pm.

Find out more about the scientific programme for SfE BES 2021.

Professor Heike Heuer is Professor for Molecular Thyroidology at the Department of Endocrinology, Diabetes and Metabolism at University Hospital Essen – University Duisburg-Essen in Germany. She is interested in thyroid hormone actions in the central nervous system (CNS) and uses mouse models to investigate the function of thyroid hormone transporters and to develop treatment strategies for patients with Allan-Herndon-Dudley syndrome. As the 2021 British Thyroid Association Pitt-Rivers Lecturer, she will present a plenary at SfE BES 2021. In our interview, she talks about her research and highlights how preclinical animal studies can lead to important and useful clinical advances.

Tell us about your career so far

I studied biochemistry at the Leibniz University in Hanover, followed by a PhD in neuroendocrinology at the Max-Planck Institute for Experimental Endocrinology. As a postdoctoral fellow I joined Carol Mason’s lab in the Center for Neurobiology and Behavior at Columbia University, New York, where I extended my neurobiology training. I was appointed as an independent, junior group leader at the Leibniz Institute on Aging/Fritz Lipmann Institute in Jena, where I headed a neuroendocrinology group working on thyroid hormone transporters. Later I became a tenured group leader at the Leibniz Research Institute for Environmental Medicine in Düsseldorf and in 2018, I was appointed as a University Professor for Molecular Thyroidology in Essen.

What inspired you into research?

“I’m pleased that our findings contributed to the rapid establishment of a treatment option for patients with a rare and devastating disease.”

I became interested in neuroendocrinology during my undergraduate degree, as I found it fascinating how peripheral organs communicated with the brain and vice versa. Encouraged by my mentors, Karl Bauer and Theo Visser, I started my research career by examining the thyrotropin-releasing hormone (TRH) signaling system in the rodent CNS. I then became intrigued by the profound effects that thyroid hormones exerted on brain development and function. The breakthrough discovery of the highly specific thyroid hormone transporter MCT8 by Theo Visser and colleagues strongly influenced my research. It became unequivocally clear that thyroid hormones need transporters for transmembrane passage and, consequently, for reaching their receptors. The profound neurological phenotype of patients with inactivating MCT8 mutations (also known as Allan-Herndon-Dudley syndrome) encouraged us to develop mouse models in order to understand the underlying pathogenic mechanisms and also to investigate treatment strategies.

Now, a major focus of my group is to analyse cell-specific TH transporter mouse mutants as we aim to understand which proteins act as critical ‘gate-keepers’ for TH in the CNS, as well as in peripheral organs and how their transport activity is affected under pathophysiological conditions.

“Endocrinology is, in my opinion, a very attractive and exciting research field that offers many interdisciplinary interactions and cross-links with other disciplines.”

What are you proudest of in your career, so far?

With the generation of mice lacking both thyroid hormone transporter Mct8 and Oatp1c1, we successfully established a mouse model that replicates many clinical features of patients with Allan-Herndon-Dudley syndrome, a severe form of psychomotor retardation. Using this animal model, we were able to test therapeutic strategies including the application of the thyroid hormone analog, Triac. This treatment improved many neural impairments and based on our preclinical data, a first Triac Trial was successfully conducted, and a second Triac Trial is in progress. This highlights the importance of preclinical animal studies and I’m pleased that our findings contributed to the rapid establishment of a treatment option for patients with a rare and devastating disease.

What do you enjoy most about your work?

I mostly enjoy lively discussions with colleagues, coworkers and students about scientific studies and novel results.

What will you be presenting in your lecture at SfE BES 2021?

It is indeed a great honor for me to present the Pitt-Rivers lecture at the SfE BES 2021 as Rosalind Pitt-Rivers not only discovered T3 in her pioneering work, but was also the first to establish that the thyroid hormone metabolite, Triac, exerts T3-like effects in animals. To acknowledge her seminal achievements, I will highlight not only the impact of thyroid hormone transporter deficiency on brain development but also discuss how Triac application can improve neural differentiation, and may be a promising treatment option for patients with Allan-Herndon-Dudley syndrome.

What do you think are the main challenges in your field right now?

According to the classical view, TH action is largely determined by circulating TH levels that are mainly regulated by negative feedback loops within the hypothalamus-pituitary-thyroid axis. However, with the recent discovery of patients harboring defects in local TH signaling, e.g. due to genetic TH transporter or receptor mutations, this classical concept of TH action has been challenged. These patients clearly display a discordance between serum TH and TSH concentrations on the one hand, and tissue-specific TH deficiency and/or excess on the other hand. In other words, patients with TH and TSH concentrations within the normal range may still have a “hypothyroid” brain despite a “euthyroid” liver and may benefit from a CNS-specific TH supply. A major challenge is now to identify suitable biomarkers that indicate a tissue-specific change in TH status and to develop clinical strategies to modulate TH status in a cell/organ-specific manner. Certainly, a change in perspective from systemic towards local, tissue-oriented TH action will be needed for comprehensive understanding of TH effects in the body and will ultimately pave the way for the development of novel approaches for modulating cell-specific TH signaling under certain pathophysiological conditions.

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

I envision that the discoveries of novel mechanisms underlying local control of thyroid hormone action (e.g. identification of additional TH specific transporters or novel modes of TH action) will open new avenues to modulate TH signaling in a tissue- or even cell-specific manner (by applying e.g. novel TH receptor agonists, specific TH transporter inhibitors or novel trojan-horse hormone compounds).

Any words of wisdom for aspiring endocrinologists?

Endocrinology is, in my opinion, a very attractive and exciting research field that offers many interdisciplinary interactions and cross-links with other disciplines. Therefore, I can only strongly encourage young researchers or clinicians to become “endocrinologists”.

And for some words of wisdom, ‘Endocrine systems and their regulatory mechanisms and modes of action are complex – thus do not rely on selected serum values only. Always aim for the complete picture or you might miss important (and maybe yet unknown) local effects.’

You can attend Professor Heike Heuer’s Medal Lecture, “Role of thyroid hormone transporters in brain development and function” on Monday 8 November at 14:00 GMT.

Find out more about the scientific programme for SfE BES 2021.

Professor Mark Febbraio is a Senior Principal Research Fellow and Investigator of the NHMRC and Head of the Cellular and Molecular Metabolism Laboratory within the Drug Discovery Program at Monash Institute of Pharmaceutical Sciences, at Monash University, Australia. He is also the CSO of N-Gene Research Laboratories Inc., a USA-based Biotechnology Company. His research focusses on understanding mechanisms associated with exercise, obesity, type 2 diabetes and cancer, with the aim of developing novel drugs to treat lifestyle-related diseases. Here he tells us about his unconventional route into research and how he helped start a new subfield of endocrinology!

Tell us about your career path so far

“Being a scientist is a balancing act between small wins and frequent disappointment. Experiments often don’t work out, papers are frequently rejected and grant applications are often not funded. The key is to savour the small wins.”

I didn’t take the conventional scientific path. After completing my undergraduate degree in exercise science, I became a full-time (semi-professional) triathlete. During a race in Japan, I become extremely heat stressed and dehydrated, so I decided to go back to do a PhD looking at the effect of environmental temperature on muscle metabolism during exercise. For the next 6 years, I worked as an exercise physiologist and undergraduate lecturer until I met Professor Bente Pedersen, a clinician from the University of Copenhagen, which got me into research. Since then, approximately 20 years ago, I’ve devoted 100% of my time to research as an NHMRC Research Fellow and Investigator in the area of tissue crosstalk, exercise and metabolic disease.

What inspired you into research?

Professor Bente Pedersen and I shared data that we had independently gathered showing that during exercise, muscle produces and releases IL-6, a cytokine previously thought to be made predominantly by immune cells in response to inflammation. We coined the term “myokine” (muscle-producing cytokine).

Muscle then became known as an endocrine organ. About 15 years earlier my friends and colleagues, Jeff Flier and Bruce Spiegleman, discovered that adipsin, a serine protease homolog, was synthesised and secreted by adipose tissue, and the field of adipokines was created. Muscle was a little late to the party but we got there eventually!

What are you proudest of in your career, so far?

Of course the IL-6 story was a proud moment, but our work on heat shock protein 70 as a therapeutic target for treating metabolic disease, as well as our recent work on extracellular vesicles and the synthesis of the chimeric protein IC7Fc to treat metabolic disease also make me proud.

What do you enjoy most about your work?

By far, training and interacting with my mentees. It has been wonderful to see so many great people transition through the laboratory and go on to be highly successful independent scientists.

What will you be presenting in your lecture at SfE BES 2021?

Basically, I will be presenting the historical story of how we came to discover that IC7Fc could be a viable treatment for metabolic disease. The story has many twists and turns!

“My feelings are that the next breakthrough will come from the global push towards artificial intelligence in drug discovery.”

I think the main challenge is that a complex problem like metabolic disease can’t be cured by simple solutions. Whilst “the molecular age” produced so much important knowledge, it become clear that there is no single molecule that, if targeted, will produce the magic bullet to treat or cure a disease that is so complex.

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

My feelings are that the next breakthrough will come from the global push towards artificial intelligence (AI) in drug discovery. I’m not saying that we will get the “slam dunk” from AI, but I’m sure we will learn so much via the big data revolution.

Any words of wisdom for aspiring endocrinologists?

Being a scientist is a balancing act between small wins and frequent disappointment. Experiments often don’t work out, papers are frequently rejected and grant applications are often not funded. The key is to savour the small wins and understand that the failures are part of building success. I often tell my trainees “in order to be successful you must be prepared to fail”. It’s OK, in fact it’s normal. Above all enjoy the process and don’t focus on the outcome.

You can attend Professor Mark Febbraio’s Medal Lecture, “Activation of the gp130 receptor: a panacea for the treatment of metabolic diseases?” on Tuesday 9 November at 09:00.

Find out more about the scientific programme for SfE BES 2021.