Robert W Hunter, Centre for Cardiovascular Science, Queen’s Medical Research Institute, University of Edinburgh, UK

https://doi.org/10.36866/pn.113.49

In physiology – as in life – words matter. One of the things that attracted me to physiology was that it is a discipline that is very careful with its words. In our first undergraduate physiology lecture as medical students, we learned from Roger Carpenter that physiology was the study of “whys” and “wherefores”.

Why does the kidney reabsorb more salt after we vomit? Because aldosterone activates sodium channels in the collecting ducts. Wherefore? Because this will restore circulating volume. I found the wherefores more engaging: understanding how systems operate to defend homeostasis at the level of the whole organism is a fascinating pursuit, and one to be highly valued in the era of molecular biology (Lemoine & Pradeu, 2018).

Fast-forward 20 years and I’m now an academic nephrologist studying the molecular determinants of renal tubular function. Recently, I have been wrestling with a subtle semantic distinction. Am I an academic clinician or a clinical academic? Do I see myself as a doctor who sometimes does science or a scientist who sometimes treats patients? As a medic, am I even allowed to call myself a scientist? Why on earth should a medic do experiments in a wet-lab when a “proper scientist” could do the same work more rigorously? I love academic medicine but I – and many others – find it a hard career to pursue because it is so easy to succumb to the imposter syndrome.

I was awarded an Undergraduate Prize for my degree project (“Depolarisation-induced pH gradients in patch-clamped snail neurones” with Christof Schwiening in Cambridge). I had really enjoyed my time in the department and had definitely caught the physiology bug. I loved that reproducible data could emerge from a combination of the sophisticated (the hideously complicated patch-clamping apparatus) and the unsophisticated (the snails were foraged from the wild and we dissociated the ganglia at ~37 °C by shoving Eppendorfs down our socks). I loved that simple models could explain current traces in terms of pump and channel activity. I loved that these models could be refined by iteratively testing predictions in the lab. However, I don’t think I believed that I could make a career from studying physiology. Wouldn’t it be better to leave all that to the proper scientists?

The Undergraduate Prize validated what we had been doing; it allowed me to think that perhaps I could become a physiologist. And of course when, some years later having completed my medical degree, I decided that I would like a career in physiology it was a very useful thing to have on my CV as I applied for PhD funding.

I have since completed a PhD as part of the Edinburgh Clinical Academic Track (ECAT) scheme for trainee clinical academics. I studied renal tubular physiology in a model of apparent mineralocorticoid excess with John Mullins, Linda Mullins and Matt Bailey. I spent three happy years studying ion fluxes again – not in the snail neurone this time but in the mammalian nephron (Hunter et al., 2018). I recently started as a Wellcome-funded Career Development Fellow and now spend most of my time studying communication between renal glomerular and tubular cells via extracellular RNA. (We are trying to define why and wherefore the renal tubules respond to RNA signals from the glomerulus.)

When I’m not in the lab I work as a nephrologist. It is difficult to think of any other medical specialty in which the interplay between basic physiology and clinical medicine is so immediate. Many of the problems faced by patients with kidney disease are a direct consequence of deranged fluid-electrolyte physiology: oedema, hyperkalaemia, hypertension, acidosis. Not only can we understand exactly why our patients are unwell, but we can also make them better using therapies that specifically subvert basic renal physiological processes. Clinical practice evolves, driven by basic physiological research. For example, over the past decade we have learnt how oedema in nephrotic syndrome is caused by the activation of sodium channels in the collecting ducts (Svenningsen, 2009). We can treat this using sodium channel blockers, such as amiloride. Or to take another example: decades of research into the molecular mechanisms of renal tubular glucose transport are now culminating in the introduction of sodium-glucose co-transporter inhibitors into widespread clinical practice, with the potential to prevent death and disability in millions of patients with diabetes and kidney disease.

It is this potential to be truly transformative that attracts me to basic physiology research. Despite the huge advances that we have made, there are still clinical problems that we cannot solve. Many patients with glomerular disease will progress inexorably towards kidney failure and a life of dialysis treatment or kidney transplants. We don’t understand why this should be. That is the problem that our lab is trying to address, by first understanding how glomerular disease spreads to involve other kidney compartments.

I am extremely grateful to The Physiological Society for encouraging me at an early stage to pursue a career in basic physiology research. They helped me to consider myself as much a physiologist as a clinician: a clinical academic. Medical students often say that they chose medicine in order to “make a difference” or “help others”. I would encourage any student – so motivated – to consider a career in fundamental physiology research. Basic scientists have had a pervasive influence on modern medicine (think Banting & Best, Cesar Milstein, Bob Edwards, Dorothy Hodgkin, Peter Medawar, Marie Curie). Why should a medical student today wish to become a clinical academic physiologist? Because is it a fun, rewarding and stimulating career. Wherefore? Because he or she could advance our understanding of physiology in a way that opens up new ways to treat disease, and so help people around the globe.

References

Lemoine M & Pradeu T (2018). Dissecting the meanings of “physiology” to assess the vitality of the discipline. Physiology 33, 236–245.

Hunter RW, Craigie E et al. (2014). Acute inhibition of NCC does not activate distal electrogenic Na+ reabsorption or kaliuresis. American Journal of Physiology – Renal Physiology 306, F457-467

Svenningsen P, Bistrup C et al. (2009). Plasmin in nephrotic urine activates the epithelial sodium channel. Journal of the American Society of Nephrology 20, 299-310.In physiology – as in life – words matter. One of the things that attracted me to physiology was that it is a discipline that is very careful with its words. In our first undergraduate physiology lecture as medical students, we learned from Roger Carpenter that physiology was the study of “whys” and “wherefores”.

Why does the kidney reabsorb more salt after we vomit? Because aldosterone activates sodium channels in the collecting ducts. Wherefore? Because this will restore circulating volume. I found the wherefores more engaging: understanding how systems operate to defend homeostasis at the level of the whole organism is a fascinating pursuit, and one to be highly valued in the era of molecular biology (Lemoine & Pradeu, 2018).

Fast-forward 20 years and I’m now an academic nephrologist studying the molecular determinants of renal tubular function. Recently, I have been wrestling with a subtle semantic distinction. Am I an academic clinician or a clinical academic? Do I see myself as a doctor who sometimes does science or a scientist who sometimes treats patients? As a medic, am I even allowed to call myself a scientist? Why on earth should a medic do experiments in a wet-lab when a “proper scientist” could do the same work more rigorously? I love academic medicine but I – and many others – find it a hard career to pursue because it is so easy to succumb to the imposter syndrome.

I was awarded an Undergraduate Prize for my degree project (“Depolarisation-induced pH gradients in patch-clamped snail neurones” with Christof Schwiening in Cambridge). I had really enjoyed my time in the department and had definitely caught the physiology bug. I loved that reproducible data could emerge from a combination of the sophisticated (the hideously complicated patch-clamping apparatus) and the unsophisticated (the snails were foraged from the wild and we dissociated the ganglia at ~37 °C by shoving Eppendorfs down our socks). I loved that simple models could explain current traces in terms of pump and channel activity. I loved that these models could be refined by iteratively testing predictions in the lab. However, I don’t think I believed that I could make a career from studying physiology. Wouldn’t it be better to leave all that to the proper scientists?

The Undergraduate Prize validated what we had been doing; it allowed me to think that perhaps I could become a physiologist. And of course when, some years later having completed my medical degree, I decided thatI would like a career in physiology it was a very useful thing to have on my CV as I applied for PhD funding.

I have since completed a PhD as part of the Edinburgh Clinical Academic Track (ECAT) scheme for trainee clinical academics. I studied renal tubular physiology in a model of apparent mineralocorticoid excess with John Mullins, Linda Mullins and Matt Bailey. I spent three happy years studying ion fluxes again – not in the snail neurone this time but in the mammalian nephron (Hunter et al., 2018). I recently started as a Wellcome-funded Career Development Fellow and now spend most of my time studying communication between renal glomerular and tubular cells via extracellular RNA. (We are trying to define why and wherefore the renal tubules respond to RNA signals from the glomerulus.)

When I’m not in the lab I work as a nephrologist. It is difficult to think of any other medical specialty in which the interplay between basic physiology and clinical medicine is so immediate. Many of the problems faced by patients with kidney disease are a direct consequence of deranged fluid-electrolyte physiology: oedema, hyperkalaemia, hypertension, acidosis. Not only can we understand exactly why our patients are unwell, but we can also make them better using therapies that specifically subvert basic renal physiological processes. Clinical practice evolves, driven by basic physiological research. For example, over the past decade we have learnt how oedema in nephrotic syndrome is caused by the activation of sodium channels in the collecting ducts (Svenningsen, 2009). We can treat this using sodium channel blockers, such as amiloride. Or to take another example: decades of research into the molecular mechanisms of renal tubular glucose transport are now culminating in the introduction of sodium-glucose co-transporter inhibitors into widespread clinical practice, with the potential to prevent death and disability in millions of patients with diabetes and kidney disease.

It is this potential to be truly transformative that attracts me to basic physiology research. Despite the huge advances that we have made, there are still clinical problems that we cannot solve. Many patients with glomerular disease will progress inexorably towards kidney failure and a life of dialysis treatment or kidney transplants. We don’t understand why this should be. That is the problem that our lab is trying to address, by first understanding how glomerular disease spreads to involve other kidney compartments.

I am extremely grateful to The Physiological Society for encouraging me at an early stage to pursue a career in basic physiology research. They helped me to consider myself as much a physiologist as a clinician: a clinical academic. Medical students often say that they chose medicine in order to “make a difference” or “help others”. I would encourage any student – so motivated – to consider a career in fundamental physiology research. Basic scientists have had a pervasive influence on modern medicine (think Banting & Best, Cesar Milstein, Bob Edwards, Dorothy Hodgkin, Peter Medawar, Marie Curie). Why should a medical student today wish to become a clinical academic physiologist? Because is it a fun, rewarding and stimulating career. Wherefore? Because he or she could advance our understanding of physiology in a way that opens up new ways to treat disease, and so help people around the globe.

References

Lemoine M & Pradeu T (2018). Dissecting the meanings of “physiology” to assess the vitality of the discipline. Physiology 33, 236–245.

Hunter RW, Craigie E et al. (2014). Acute inhibition of NCC does not activate distal electrogenic Na+ reabsorption or kaliuresis. American Journal of Physiology – Renal Physiology 306, F457-467

Svenningsen P, Bistrup C et al. (2009). Plasmin in nephrotic urine activates the epithelial sodium channel. Journal of the American Society of Nephrology 20, 299-310.