Author: Society for Endocrinology

At SfE BES, Ashley Grossman, Professor of Endocrinology at the Oxford Centre for Diabetes, Endocrinology and Metabolism, gave a presentation entitled, ‘What killed Queen Mary’. In our latest interview, he tells us about his investigation into the unclassified illness that plagued Queen Mary and ultimately led to her premature death, and what we can learn from her tragic story.

Can you tell us why you think Queen Mary’s death was endocrine related?

Reading through Mary’s life history, which is quite a sad story, it seemed to me that something endocrine-related may have been going on and I came up with some interesting conclusions about her death. Mary was unfortunately plagued with illness throughout her life and her documented symptoms included her periods stopping, she starting to lactate, suffered from increasingly bad headaches and, just before Mary died, she began to go blind. All of these symptoms suggest she was suffering from an expanding prolactin-secreting pituitary tumour. Increased prolactin levels would explain her lactation and amenorrhoea. As the tumour expanded it would have compressed the brain, including the optic nerve leading to blindness. It may also have made her infertile explaining her failure to produce an heir. Ultimately, as the tumour expanded it likely placed pressure on vital areas within her brain  that may have been the cause of her early death in 1558 at age 42.

What sparked your interest in Queen Mary?

 I confess, initially I did not know much about history or Queen Mary. However, when my third daughter pursued history as an undergraduate and then as a Master’s degree student, it sparked my interest. I delved in and began reading books on the Tudors and Mary seemed quite fascinating. The fact that she died so young and childless was pivotal, as it completely altered the course of British History. If she had produced a child, then Britain would have remained catholic and Phillip II would have become King, dramatically changing history, with no future Elizabeth I on the throne.

Is there any way we could prove your theory?

Of course, the conclusion that Mary died from a pituitary tumour remains speculation. However, renowned Austrian physician – Victor Cornelius Medvei, whose passion for endocrinology led him to write the definitive textbook – A History of Endocrinology – also investigated the death of Queen Mary in some detail. To my delight his conclusions, discussed with Prof. Howard Jacobs, matched my own and reading his research really firmed up what I thought.

Mary’s buried in Westminster Abbey, so we could do a computerised tomography scan of her coffin to see whether or not her pituitary was indeed enlarged. However, I don’t think the monarchy would be very happy for anyone dig up her coffin and do that! To make a diagnosis on someone who lived hundreds of years ago is not hard science, but it is amazing to think that a pituitary tumour changed the course of British history.

What can we learn from your research?

Although historical, I think there certainly are things people can learn from Mary’s tragic story. I believe it’s important that people recognise how much life has been transformed by modern medicine, and how lucky we are to have treatments to disorders that just a few hundred years ago were highly debilitating or even lethal. For example, what destroyed the catholic British monarchy can now be treated simply with a few tablets and the disease might virtually disappear.

Ashley Grossman presented ‘What killed Queen Mary’ at the annual SfE BES conference in Glasgow on 20 December 2018. Discover more about the work of endocrinologists in our Meet the Endocrinologist series of blog interviews.

Meet Joseph Takahashi, Professor of Neuroscience at the Howard Hughes Medical Institute at UT Southwestern Medical Centre. His research focuses on the genetic and molecular basis of the circadian clock in mammals. He has been awarded the SfE Transatlantic Medal and will be delivering his Medal Lecture at SfE BES 2018, 19-21 November in Glasgow. In our latest interview, he tells us more about his career, research and what he is looking forward to at the SfE BES 2018 conference. 

Can you tell us a little about your current position and research?

I’m an Investigator in the Howard Hughes Medical Institute, and Professor and Chair of the Department of Neuroscience at the University of Texas Southwestern Medical Center in Dallas, Texas. My lab studies the genetic and molecular basis of the circadian clock in mammals. More broadly we are interested in the genetic basis of behavior. My lab is known for discovering the first circadian gene in mammals known as the Clock gene.

One of the initial surprises from cloning the mammalian clock genes was that they are ubiquitously expressed. This eventually led to the discovery that the circadian clock is cell autonomous and that virtually every cell in the body has the capacity for circadian oscillation. Thus, all of our major organ systems contain intrinsic circadian oscillators. This has led to a revolution in studies aimed at understanding the role of clocks in peripheral tissues as well as studies focused on understanding the systems level organisation of the multiple clocks in the body. The core circadian molecular pathway regulates thousands of genes in mammals, and this has led to the discovery of direct molecular links to a myriad of molecular, cellular and physiological pathways. These include direct links to endocrinology, metabolism, immune function, cell growth and cancer.

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

I have been incredibly fortunate to have had great mentors and colleagues as well as research institutions and funding agencies that have supported me throughout my career.  In college, I was interested in biology, but did not know what careers one could pursue except for med school. Later I had the good fortune to do an independent research project and learned that one could go to graduate school in biology(!). That was the beginning of my research career.  I took a post-baccalaureate year to work with Patricia DeCoursey, one of the pioneers in mammalian circadian rhythms, and then went to work with Michael Menaker for graduate studies. Menaker was the perfect mentor for me. He had a free and open lab environment that encouraged creativity, independence and scale and automation. We pioneered long-term ex vivo culture of tissues that contained and expressed circadian rhythms in the late 1970’s. These initial forays continue to pay off decades later as the entire circadian field uses large-scale data collection, automation and long-term in vitro circadian models.

After graduate school, I did a 2-year post doc with Martin Zatz at the NIH where we worked on the pharmacology circadian rhythms in the chick pineal in vitro.  I was then recruited to Northwestern University by Fred Turek. As an independent faculty member at Northwestern, my lab focused on reductionist dissection of the circadian oscillator in the chick pineal.  In addition to pharmacology, we worked on the biochemistry of various circadian pathways in the pineal.  However, eventually we were stymied, and my interest in the molecular biology and genetics of circadian rhythms was growing.  We knew that molecules and genes had to be important for mammalian circadian rhythms, but how to get there?  That was the beginning of my ‘second career’ as a geneticist.  Ironically as an undergraduate, I was not very interested in molecular biology or genetics (I was interested in animal behavior), but luckily I ‘had’ to take these courses.

In 1990, Larry Pinto, Fred Turek and I decided to use mouse genetics to try to find circadian rhythm mutants. We collaborated with William Dove at the University of Wisconsin-Madison, and Martha Vitaterna conducted our first screen of mice that were ENU mutagenised in the Dove lab.  In our first screen, we isolated the Clock mutant mouse which has a 28-hour period length and a loss-of-rhythm phenotype in circadian activity.  This mutant mouse then provided the means to identify the Clock gene by positional cloning. The isolation of the Clock mutant and the positional cloning of gene was the crowning achievement of my lab.

What are you presenting in your Medal Lecture at SfE BES 2018?

I plan on giving an historical account of our forward genetic approach to finding clock genes in mammals. The effort to clone Clock was massive.  Ten members of my lab worked together as a team for three years to complete the project. In the 1990’s there was no genome sequence. The Clock gene turned out to be huge: it had 24 exons and covered over 90 kB of genomic DNA. Then I will discuss more recent molecular and genomic analyses of the circadian clock gene network. Finally, I will describe our new work on the importance of time and caloric restriction for aging and longevity.

What are you looking forward to at this year’s conference?

I am very much looking forward to seeing all the advances in the field of endocrinology as well as the plenary lectures.

What do you think are the biggest challenges in research right now?

It is of paramount importance to support research in basic science. It is very important to translate these basic science discoveries, but one must remember where these advances had their beginnings.  It is impossible to predict new discoveries and how they will impact medicine in the future.

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

Many important breakthroughs in the circadian field will be their connections to all aspects of cell biology, cancer and metabolism. New views of metabolism and longevity are already being linked to circadian biology.

What do you enjoy most about your work?

I love the fact that we are supported to pursue knowledge and discovery of biological systems.  Making scientific discoveries is like a treasure hunt for adults.  It never gets old, and one discovery always opens the door to countless new questions.  Also, as an academic, we have intellectual freedom that is rare in other professions.

Who do you most admire professionally?

My role models have been: Seymour Benzer at CalTech, who pioneered genetic approaches to complex behaviors; Eric Kandel at Columbia, whose systematic and scholarly approach to understanding learning and memory in simple model systems was fundamental; and Denis Baylor at Stanford, whose biophysical analysis of phototransduction was a thing of beauty.

Any words of wisdom for aspiring researchers out there?

My mantra is:  Always begin with first principles. What I mean by this is that you must understand what you are doing. To an electrophysiologist or biophysicist this is self-evident. But in today’s world of molecular biology and informatics, the kits that you use in the lab and the computer programs that you employ are frequently applied without a fundamental understanding what they are doing and how they work.

You can hear Professor Takahashi’s SfE Transatlantic Medal Lecture, “Circadian Clock Genes and the Transcriptional Architecture of the Clock Mechanism” on Monday 19 November, in the Lomond Auditorium at 18:00. Find out more about the scientific programme for SfE BES 2018.

Meet Maria-Christina Zennaro, a professor in the Paris Cardiovascular Research Center at the French National Institute of Health and Medical Research (Inserm).  She specialises in genetic mechanisms of aldosterone-related disorders. She has been awarded the SfE European Medal and will be delivering her Medal Lecture at SfE BES 2018, 19-21 November in Glasgow. In our latest interview, she tells us more about her work and what she is looking forward to at the SfE BES 2018 conference.

Can you tell us a little about your current position and research?

I am a research professor heading the team exploring the genetic mechanisms of aldosterone-related disorders at the Paris Cardiovascular Research Centre at the French National Institute of Health and Medical Research (Inserm). My team is interested in unravelling the genetic and genomic mechanisms of aldosterone-related disorders, particularly primary aldosteronism, by combining clinical work with genome-wide strategies and mechanistic studies in cell and animal models. I am also an associated investigator at the Genetics Department of the European Hospital Georges Pompidou (HEGP) in Paris, where I coordinate the genetic diagnosis of pseudohypoaldosteronism type 1 and primary aldosteronism at the genetics laboratory, which is the French referral centre for the genetic diagnosis of these diseases.

What inspired you into endocrinology?

I received my MD and board certification in endocrinology at the University of Padova (Italy) and completed a PhD in molecular endocrinology at the University Pierre et Marie Curie in Paris. I had the chance to have great mentors, in particular Decio Armanini, who shared his passion for research with me, and John W Funder, who has supported my career ever since. In Paris, I had the chance to work with major players in the field of arterial hypertension and aldosterone, setting the basis for my future research.

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

After obtaining a tenured position as an Inserm researcher twenty years ago, I developed my own research group, which is now benefitting from the outstanding environment of the Paris Cardiovascular Research Centre and HEGP. I am particularly proud of having been able to create our research group, with the successive recruitment of two great researchers, with whom I have taken pleasure in sharing my working career with for many years.

What are you presenting in your Medal Lecture at SfE BES 2018?

I will present an update on the genetic and molecular mechanisms involved in the development of primary aldosteronism. In particular, I will summarise our current knowledge on the genetics of primary aldosteronism, notably our recent paper identifying a new gene in early onset primary aldosteronism, and discuss the pathogenic mechanisms leading to increased aldosterone production and cell proliferation. I will also discuss perspectives for clinical management of patients and open questions to be addressed by future research.

What are you looking forward to at this year’s conference?

There are many great sessions on the adrenal gland, featuring world-leading experts in the field, which I highly recommend. There are exciting plenary lectures and I am looking forward to hearing about the influence of the microbiome in endocrine disease on Tuesday afternoon.

What do you think are the biggest challenges in endocrinology right now?

I think the challenges are threefold. First, the scientific challenge of improving our understanding of common and rare endocrinological disorders. Second, to be able to efficiently transfer this knowledge to patient care, in particular the knowledge generated from large-scale ‘omics’ studies. Improving diagnosis, management and implementation of precision medicine in clinical practice is really important, and should be affordable and available for everyone anywhere. Lastly, but not least, a major challenge is gathering funding for research in endocrinology.

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

I hope it will be the development of new diagnostic procedures for endocrine hypertension, which will have a major impact on treatment of those patients and prevention of cardiovascular and metabolic complications, improving their quality of life.

What do you enjoy most about your work?

Most certainly it is the scientific exchanges with my colleagues all over the world and mentoring young people to transmit my knowledge with passion to future generations.

Who do you most admire professionally?

I have had the chance to meet many extraordinary colleagues, many of whom I admire for different reasons. I particularly admire a few of my senior colleagues and mentors: I consider it a great opportunity to meet them every year at different meetings around the world, to have discussions with them and benefit from their profound scientific knowledge and incredible experience, especially when they talk about experiments they did 30 years ago!

Any words of wisdom for aspiring researchers out there?

Endocrinology requires a deep understanding of the complexity of endocrine feedbacks and interactions throughout the body. Research in the field of endocrinology is exciting, as it addresses the many questions we have on the mechanisms regulating endocrine physiology and hormone action. In this sense, it is also very diverse, ranging from genetics to cellular and molecular mechanisms, not only in hormone-producing organs but also in the multitude of target organs.

You can hear Professor Zennaro’s European Medal Lecture, “Molecular mechanisms in primary aldosteronism” on Wednesday 21 November, in the Lomond Auditorium at 15:30-16:00. Find out more about the scientific programme for SfE BES 2018.