Meet Heike Heuer the 2021 Pitt-Rivers Lecturer

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.

Meet Mark Febbraio the Society’s 2021 International Medal winner

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.

Meet Greet Van den Berghe the Society’s 2021 European Medal winner

Professor Greet Van den Berghe is the head of the clinical department and laboratory of Intensive Care Medicine at KU Leuven University and its University Hospitals in Belgium. The Leuven Clinical Intensive Care department is a large, tertiary referral centre treating over 3,100 patients per year. She is also Professor of Medicine at KU Leuven and actively researches the endocrinology and metabolism of critical illness. Here she tells about her career, research and how important it is to break boundaries and challenge classical ideas in the pursuit of better patient care.

Tell us a little about your career path
After obtaining my medical degree, I trained in anesthesiology and intensive care, then in biostatistics and later completed a PhD in endocrinology. I followed this path so that I could work at the boundaries of several disciplines, which provided an excellent opportunity to build a multidisciplinary research team and to expand on translational research in endocrinology and metabolism of critical illness, from bed to bench and back.

What inspired you into research?
When I was a junior attending physician in the intensive care unit (ICU), I observed that long-stay ICU patients, both children and adults, quickly began to look much older than their chronological age. At the same time they showed endocrine and metabolic abnormalities that mimicked certain characteristic of ‘ageing’. I hypothesised that maybe this ‘accelerated ageing’ phenotype of ICU patients could in part be iatrogenic, and if so, may be preventable. These thoughts formed the basis for my PhD research, in which I demonstrated that dopamine infusion, a drug commonly used at the time for haemodynamic and renal support, was causing an iatrogenic suppression of the anterior pituitary with harmful consequences. Based on these findings the practice of infusing dopamine in the ICU was abandoned.

“Together we have made exciting discoveries and we were able to repeatedly close the loop from an original idea triggered by patient care, to basic research in the lab and back to randomised-controlled trials in patients.”

In my postdoctoral research, we went a step further and identified biphasic neuroendocrine and metabolic responses to acute and prolonged critical illness in both patients and animal models. This research clarified many earlier, apparent paradoxes and provided the basis for our later work that focused on the acute and long-term harmful impact of hyperglycemia, the early use of parenteral nutrition and the pathophysiology of the HPA axis response to the stress of critical illness.

What are you proudest of in your career, so far?
In 2002, I inherited a very large and well organised clinical intensive care department to chair, upon which I have built research from bed to bench and back again. There was no research in the department when I started, so I had to build everything from scratch. Over the years, this growing symbiosis, between high-level patient care and research, has proved to be very successful. This also allowed me to recruit the best clinicians and scientists who now work effectively together as a very close team.

“I enjoy thinking outside the box, creating new ideas by crossing boundaries between classical disciplines”

Together we have made exciting discoveries and we were able to repeatedly close the loop from an original idea triggered by patient care, to basic research in the lab and back to randomized-controlled trials in patients. That is such great fun! So, I am most proud of my team, and grateful to them for making me happy every day!

What do you enjoy most about your work?
I enjoy thinking outside the box, creating new ideas by crossing boundaries between classical disciplines, and working with young, enthusiastic physicians and scientists, to generate new knowledge that forms a solid basis for better patient care.

What will you be presenting in your lecture at SfE BES 2021?
In my talk, entitled “Re-thinking critical illness induced corticosteroid insufficiency”, I will present novel insights from our recent research on HPA axis changes that occur in response to acute and prolonged critical illness. I will challenge the classical paradigm of stress-induced increased ACTH-driven cortisol production as the basis for increased systemic cortisol availability in severely ill patients. I will also challenge the idea that a short ACTH stimulation test can diagnose failure of this stress response.

To say it with a metaphor: “What you see is not always what you get”.

Any words of wisdom for aspiring endocrinologists?
Look further than the boundaries of your own discipline, there is much to be learnt and innovated when you go beyond them!

You can attend Professor Van den Berghe’s Medal Lecture, Re-thinking critical illness induced corticosteroid insufficiency on Tuesday 9 November at 18:45.

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