Inside a Nobel Prize winning lab
Dr Tammie Bishop (1995) discusses her work in the lab of 2019 Nobel Laureate Professor Sir Peter Ratcliffe.
Dr Tammie Bishop (far left) and Professor Sir Peter Ratcliffe (second right) celebrating the Nobel Prize announcement
Q. This year’s Nobel Prize for Physiology or Medicine was awarded to Professor Sir Peter Ratcliffe and others for their discovery of the molecular mechanisms by which cells sense oxygen. In simple terms, how do these oxygen sensors work?
A. The fundamental importance of oxygen has been understood for centuries, but until now it has been unknown how cells adapt to changes in levels of oxygen. The Nobel was awarded for identifying the molecular machinery known as the Hypoxia-inducible factor (HIF) pathway that regulates the activity of genes in response to varying levels of oxygen. In particular, the research established the basis for our understanding of how oxygen levels affect cellular metabolism and physiological function. In hypoxia – as opposed to normal air – the mechanism activates the expression of hundreds of genes controlling a range of processes from new blood vessel growth to increased red blood cell production in order to help cells adapt to hypoxia.
Q. Why is it important that cells can sense and respond to oxygen in this way?
A. An adequate oxygen supply is essential for efficient cellular metabolism, particularly to fuel energetic processes like cell growth and division. Oxygen is also very chemically reactive and too much (or too little) can cause widespread damage to molecular functions. In this context, the initiation of controlled cell death may be preferable to continuing with such disruption to cellular physiology. Detecting and responding/adapting to oxygen availability is therefore a key determinant of cell survival and proliferation.
Q. So how does this relate to situations where people are short of oxygen? Mountaineers at high altitude spring to mind.
A. Certainly, mountaineers at altitude would be exposed to low oxygen or hypoxia, resulting in an activation of HIF pathways. In the short-term this is beneficial/adaptive, with an increase in oxygen delivery to cells via increased red blood cell production and ventilation as well as decreased oxygen consumption via a switch from aerobic to anaerobic respiration. With sustained hypoxia, however, HIF over-activation can result in excessive red blood cell production and pulmonary hypertension, or mountain sickness. Interestingly, high altitude human populations, such as Tibetans (and as far back as the Denisovans), carry genetic variants of HIF that may help them survive in this environment while avoiding such complications.
Hypoxia gradients are also present in the body even at low altitude (like the fens of Cambridgeshire!). This means that there is tonic/basal HIF activity in many tissues and this plays a role in maintaining normal vasculature and red blood cell population, continuously coupling oxygen delivery to demand.
Q. Are similar mechanisms at play in any diseases? Might this work lead to new treatments for any of these conditions?
Pulmonary hypertension (high blood pressure in the lungs) is a recognised complication of high-altitude exposure but can also develop in the context of other heart and lung diseases. HIF inhibitors are being tested in clinical trials to treat this condition, which carries a high level of morbidity and mortality but currently has limited treatment options.
HIF also plays an important role in localised hypoxia or ischaemia (not just changes in systemic or whole-body hypoxia experienced at altitude), which may arise as a result of a blood clot occluding a vessel. Activation of HIF may be particularly helpful in treating treating ischaemic pathologies, such as heart attacks and other forms of vascular disease.
However, probably the most interesting example of pathological hypoxia signaling is in cancer, where unregulated growth of cells with a disordered vasculature means that the centre of tumours are frequently hypoxic. The HIF signaling pathway is co-opted or hi-jacked by tumours to drive new blood vessel growth, supporting further growth and metastatic spread. In certain tumours (for example a type of kidney cancer), the HIF pathway also initiates the onset of cancer formation and mutations in the HIF pathway, which may be inherited, are common in these tumours. HIF inhibitors are currently in clinical trials to treat kidney and other cancers, with promising results.
Q. Why were you initially attracted to this area of research?
A. It may be obvious in retrospect but when I joined the lab straight after my PhD – even though the research at the time was not necessarily in the highest impact journals – there was already a story unfolding with each paper gaining yet more traction and building on the last. It was like a jigsaw puzzle where you only have some of the pieces, but the overall sense was that this was a new signalling pathway and I knew I would be part of an incredibly exciting journey. And one that is still going on!
Q. When we last spoke, during our 40th anniversary of co-education, you said your greatest career achievement to date was discovering part of a new signalling pathway that allows for sensing and responding to a drop in oxygen levels. How does it feel for your field of research to be recognised on a global scale?
A. Humbling! At the end of the day, though, it is still the same people in the same lab, and no one is resting on their laurels. We are already on to the next thing.
Q. You’ve worked alongside Professor Ratcliffe for many years. Can you give us any personal insight into what it is like to work with a Nobel Prize winning scientist?
A. As with any job, when you are in the day-to-day just trying to get results and trouble-shooting the inevitable setbacks, you don’t realise you are part of anything bigger. It is only when you step back you realise the enormity of it all. The one insight I would give about Peter is that he is only focused on the discovery of the truth, regardless of the whether the research is in vogue i.e. whether the work is published in high impact journals, attractive to funding bodies or leads to career progression. Perhaps easier said than done when your livelihood as an academic depends on these things! Professors come and go, the only meaningful way to leave a legacy is to make a discovery, or, in Peter’s own words: “Oxygen sensing is something true: it will be true in 10 years’ time, and it will be true in a million years’ time. That, for me, is very satisfying”.
Q. What were you doing when you heard the news and how did you celebrate?
A. We were all together in a normal lab meeting. His PA interrupted the meeting looking slightly ashen to say that he had an urgent phone call to take – I realised then that he had probably won the Nobel Prize and started taking bets with my colleagues. He came back into the lab meeting after taking the call and carried on as normal without saying anything (as requested by the Nobel committee); we only found out an hour later when the official announcement came through!