Professor Mark McCarthy is Executive Director of Human Genetics, and a Principal Fellow at Genentech, where he leads research in human genetics to advance molecular understanding of health and disease. In this interview he tells us about his career, the people who have shaped his experience in endocrinology and what we can expect from his SfE BES lecture.
Tell us a little about your career so far
I trained in medicine at the University of Cambridge, then St Thomas’, working through medical SHO and Registrar rotations at Barts and the London School of Medicine and Dentistry (the London). One of which was endocrinology, and that became my chosen specialty. I fell into the research program that Graham Hitman was leading at the London on the genetics of type 2 diabetes. The first couple of years of research were difficult, but by the third year, I felt I was making progress. To test my research confidence a bit further, I secured an MRC Fellowship in Boston with Eric Lander, which was pivotal. I came back to a position in the UK after that which was half clinical and half research, but as the years went by, I found myself doing more research and less clinical work. I moved to Oxford in 2002 as the Robert Turner Professor of Diabetic Medicine, where I led a global research group that focused on the genetics of type 2 diabetes, obesity and related conditions. In 2019, I moved to Genentech, to lead up their efforts in human genetics (across multiple disease areas), putting what I had learned in Oxford to support target and biomarker discovery.
What attracted you to endocrinology?
It was pretty clear from my time as a student that I was going to be a physician, not a surgeon. So I rotated through a series of medical SHO positions before ending up in endocrinology. Two things about that rotation convinced me that this was the direction I wanted to go in. First, I was fortunate enough to work for John Monson, the endocrinologist at the London, who was just the most fantastic mentor and paragon of medical excellence – I owe him a huge debt of gratitude. Second was the practice of endocrinology itself – endlessly fascinating, (mostly) logical, and, for many patients, transformative.
What is your career highlight so far?
I had the opportunity to be part of the team leading the Wellcome Trust Case Control Consortium, which in the mid-2000s performed the first large-scale, genome-wide association studies. It was thrilling to be part of such a seminal study. We didn’t know if it was going to work out, and there were huge technical and computational hurdles that the team had to overcome, but the study really transformed the field of common disease genetics and set in motion the explosion in our understanding of these conditions over the past 15 years. During the project I was particularly involved in type 2 diabetes, which revealed the first common variant influencing the risk of obesity.
Who have been your mentors?
There were three people who had a significant impact on my career. John Monson, who instilled in me a passion for endocrinology and a commitment to the ethical aspects to practising medicine and science. Graham Hitman, who guided me through my first few traumatic years in the lab, and pushed me towards more computational and analytical research (which was a good thing since I was much safer with a keyboard than a pipette). And Eric Lander who welcomed me into his lab in Boston, and gave me the belief that I could thrive in research.
What do you think are the most exciting breakthroughs in your field?
We are going through a revolution in research that brings together three complementary advances. Increasingly we are able to gather genetic and genomic data with both massive scale and high resolution. This started with human genetics and the ability to do genome wide association scans (rather than having to look one gene at a time), but we see the same now in genomics, for example through the power of single-cell and spatial genomics. We are also now able to gather data in humans, rather than animal models, which to state the obvious is the species we are most interested in. That’s in part down to genetics, but also through developments in the research of cellular and organoid models from human sources. Finally, we have these awesome advances in computational methods (most obviously in machine learning and AI) which allows us to make sense of vast, complex and diverse data sets.
What are the biggest challenges your field faces?
Too much of the data we have comes from European populations, so there’s much more that needs to be done to ensure that we embrace diversity in research and translation. Also we still have some way to go to ensure that we make use of these rich and diverse data sets to guide us to safe and effective ways of improving patient care.
Tell us what’s coming up in your SfE BES 2022 Medal Lecture
One of the most exciting developments in human genetic research relates to the use of polygenic risk scores. These aggregate data across multiple small genetic effects, and are becoming increasingly powerful at identifying those at extreme (whether high or low) risk of disease; and in some cases, in dissecting some of the clinical heterogeneity that we see in many of these conditions (with regard to progression, complications, and therapeutic response). I am going to describe three examples from my own research that I hope will give some sense of the translational potential of these approaches.
Do you have any advice for aspiring endocrinologists?
Follow your passion.
You can attend Professor Mark McCarthy’s Dale Medal Lecture “Mining the genome for gold“ on Monday 14 November at 5:45 – 6:15pm.
Take a look at the full scientific programme for SfE BES 2022.