Kevin O’Byrne is Professor of Reproductive Neuroendocrinology in the Department of Women and Children’s Health at King’s College London. Here, he tells us about his career journey so far, his fascination with the mechanisms of pulsatile gonadotrophin release, and his advice for you if you are just starting out in endocrinology.

Tell us about the focus of your research

My passion in science is the gonadotrophin-releasing hormone (GnRH) pulse generator: the amazing neural oscillator in your hypothalamus that eventuates in the pulsatile release of GnRH, which, in turn, drives the pulsatile release of the gonadotrophic hormones, luteinising hormone (LH) and follicle-stimulating hormone (FSH), to control the gonads. 

This field was transformed by the discovery, 20 years ago, of kisspeptin, and the realisation that the kisspeptin neurones in the hypothalamus are the major component of this neural construct, diverting attention away from the GnRH neurones per se as the pacemaker. To be part of that was so much fun.

How has your career journey brought you to this point? 

As an undergraduate studying mostly respiratory physiology, my attention was captivated by Richard Dyball’s visit to Chelsea College, as part of a tiny reproductive physiology module, to demonstrate the milk ejection reflex in the rat model. Off I went to Bristol to do my PhD with Alastair Summerlee in the very department at the epicentre of that research. I was surrounded by all the main players – astonishing.

I was then invited to join Dennis Lincoln at the MRC Reproductive Sciences Unit in Edinburgh, to use my in vivo electrophysiology skills to study the multi-unit activity (MUA) volleys, the electrophysiological correlate of the GnRH pulse generator, in the exotic marmoset monkey. That was a complete failure, so I decided to join Ernst Knobil, in Houston, TX, USA, who discovered the MUA volleys in the rhesus monkey. 

After six amazing years in Texas, I decided to return to the UK, because I was concerned about how difficult it was to get a tenure track position in the USA. King’s College London seemed like an interesting place, so I joined the Anatomy Department in 1994 and have studied the GnRH pulse generator ever since.

How have technological advances shaped your research?

I have always felt that technology is absolutely key to advancement in science, so I have always wanted the latest ‘toys’ applicable to in vivo work in freely behaving animals. 

Naturally, the mouse, which we all take for granted, revolutionised our capabilities. The exquisite activation and deactivation of selective neuronal population using optogenetics and chemogenetics and all the intersectional strategies far exceeds neuropharmacological approaches, which were previously so important. I saw so many novel agonists and antagonists become available; getting access was key! 

The changes in in vivo electrophysiology, including the development of optrodes, which allows simultaneous optogenetics and multi-channel electrophysiological recording, are beyond belief. Of course, many researchers will not know what it was like to make your own electrodes for chronic implantation or, indeed, the equipment to make such recordings. The development of in vivo gradient-index (GRIN) lens microendoscopic systems to monitor, in real time, the neurone calcium dynamics (a proxy for neuronal activity) of selective GCaMP-expressing neurones is absolutely amazing, and provides opportunities to monitor neuronal activity at single cell resolution.

What have been your career highlights so far?

Working with Ernst Knobil opened my eyes and was so empowering, because it allowed me to compare a genius, a member of the cognitive elite, with others who profess or try to portray those attributes. Finally achieving my goal to engage with computational mathematical modellers was certainly a highlight. The opportunities they provide to expand your mind and research are immeasurable. I have enjoyed working with so many amazing people.

What do you consider your top three publications (Impact Factor/citation index aside)? 

It is very hard to select three papers, because I am fond of many for very different reasons. I also have a very bad attitude towards Impact Factors, which might be construed as political naivety, but I don’t care!

Publication 1: O’Byrne KT, Thalabard JC, Grosser PM, Wilson RC, Williams CL, Chen MD, Ladendorf D, Hotchkiss J & Knobil E 1991 Radiotelemetric monitoring of hypothalamic GnRH pulse generator activity throughout the menstrual cycle of the rhesus monkey Endocrinology 129 1207–1214.

The opportunity to conduct such research on a higher primate was an amazing privilege. It advanced our understanding of how the GnRH pulse generator operated across the menstrual cycle, especially at the time of the preovulatory LH surge, and challenged established dogma, which was rather amusing.

Publication 2: Comninos AN, Anastasovska J, Sahuri-Arisoylu M, Li X, Li S, Hu M, Jayasena CN, Ghatei MA, Bloom SR, Matthews PM, O’Byrne KT, Bell JD & Dhillo WS 2016 Kisspeptin signaling in the amygdala modulates reproductive hormone secretion Brain Structure & Function 221 2035–2047.

Serendipity played out here. The opportunity to collaborate with Waljit Dhillo and his amazing team at Imperial was and is such a pleasure. A casual conversation led to this study, and opened up a completely new avenue of research. It highlighted the importance of kisspeptin signalling in the amygdala, part of the emotional limbic brain, as an upstream regulator of the GnRH pulse generator, involved in pubertal timing and stress-related infertility. It led to many future studies and funding opportunities.

Publication 3: Voliotis M, Li XF, De Burgh R, Lass G, Lightman SL, O’Byrne KT & Tsaneva-Atanasova K 2019 Mathematical modelling elucidates core mechanisms underpinning GnRH pulse generation Journal of Neuroscience 39 9738–9747.

This was the first paper that came out of the collaboration with my Exeter computation modellers. This was mind-blowing. As experimentalists, we confirmed the modelling prediction that if you increase the basal activity of the arcuate nucleus kisspeptin neuronal network using optogenetics, you can initiate pulsatile release of LH. Increasing basal activity further increased GnRH pulse generator frequency, and if you continue to increase basal activity you cross an upper bifurcation point and switch off the oscillator. Again, the modelling has opened up so many opportunities to address the mechanism, which would not have been possible otherwise.

How important have the research environment and endocrine community been in shaping your research? 

For me, research has never been a job, but a way of life, and I have been paid to do precisely what I want to do, apart from a miniscule amount. I have had the privilege of being surrounded by remarkable colleagues from the endocrine community, and their contribution to my research is immeasurable. My collaborators have been the cornerstone of my research endeavours.

Finally, what is your advice for endocrine trainees who are forging a career in endocrinology? 

Have confidence in yourself; that is the most important thing in life. We are great at placing hurdles in our way, e.g. ‘I can’t put that technique in my fellowship or grant because I don’t have experience or preliminary data’! If the said technique puts you ahead of the game, then put it in. Don’t assume that your so-called superiors know what they are talking about. Take advice from as many sources as you can. Learn to say NO. Be highly selective in choosing your collaborators: any doubts, no matter how subtle, walk away. Our subconscious intuition is more powerful than we imagine. Science has got to be fun.