When asked, the ultimate goal or dream of any budding scientist, myself included, is the Nobel Prize. In April last year, while tediously revising for my preliminary exams over the Easter break, I thought it would be funny (my sense of humour failing me once again) to post one of the molecules I was studying on Instagram. This was, as I described it then, the “humble erythropoietin,” a hormone that regulates the number of red blood cells we produce. It is able to respond to the amount of oxygen in our cells so that more is produced in conditions of hypoxia, or lack of oxygen, and yet my out of date, rather elementary textbook did not describe how. Six months later, the Nobel Prize association announced the 2019 Nobel Prize in Physiology or Medicine had been awarded jointly to Gregg Semenza, William Kaelin and Sir Peter Ratcliffe for their work on “how cells sense and adapt to oxygen availability”, the regulation of the very molecule I had thought was cool enough for the gram half a year prior. You can therefore guess my excitement when two of the three laureates, Kaelin and Ratcliffe, the latter based in Oxford, visited the Oxford Union to deliver a speech, and I was lucky enough to discuss their work with them beforehand.
Sitting in a rather grand room in the Union building, Kaelin and Ratcliffe described the processes and paths they took that led them to their discovery. Sir Peter Ratcliffe, who led the hypoxia laboratory in Oxford for over 20 years and remains a supernumerary fellow at Magdalen College, had intended to be a physician from the off. Both Kaelin and Ratcliffe have extensive clinical training, Kaelin currently serves as a professor of medicine at Harvard University, and both believe this aided their research. Yet, when asked their motivations for the research they gave responses that were initially surprising. While, as clinicians, they knew and hoped there was always the chance of finding clinical applications to their work, it was not the prospect of bettering treatments and finding novel ones that drove them. Instead it was pure “curiosity” and wanting to know and understand this process that spurred them on. Kaelin described the mechanism of oxygen regulation as a “puzzle” and Ratcliffe elaborated on the ease at which you could become obsessed and consumed with solving it.
The body’s ability to adapt to the availability of oxygen had been well documented since the 1880s when the French physiologist Paul Bert showed that the red blood cell count increases at altitude. In 1986-87, a variety of scientists then showed that it was erythropoietin (Epo) responsible for this. Despite the biological problem on why cells respond to oxygen being established so long ago, way before the discovery of DNA, there was very little work being done on how. Ratcliffe described this paradox by stating “the failure of solution and [failure] to understand this topic [was because it was] deeply unfashionable.”
Kaelin and Ratcliffe initially worked independently but began collaborating when, as described by Kaelin, “their two lines of investigation collided.” This was after Kaelin made the rather vital link of spotting the connection between VHL and HIF. When probed on their working relationship and collaboration throughout the years they laughed, and said they saw each other as “friendly competition”, emphasising that this was essential to drive good scientific work and human society forward.
What did they win the prize for?
Within the body, the level of oxygen changes in response to events in the environment, such as moving to a higher altitude, or within the cell such as when we consume more oxygen during exercise. Erythropoietin is a hormone that causes cells in the body to specialise into red blood cells- the oxygen carrying cells in our blood. It was known that in conditions of low O2, more erythropoietin is made so that we have more red blood cells around, yet how Epo was regulated by oxygen remained unclear. Semenza found a protein named hypoxia-inducible factor (HIF) that causes more Epo to be made by switching the gene on. HIF itself was found to itself be sensitive to oxygen and the work of Kaelin and Ratcliffe showed that VHL, another protein found from cancer studies, regulates the activity of HIF by destroying it in normal oxygen conditions but failing to do so during hypoxia. Kaelin described that, once discovered, “[the] mechanism struck them as simple, beautiful and elegant”. The ability of HIF only to be present to induce large amounts of Epo when the cell is struggling for O2 once again shows the remarkable sophistication of our cellular machinery.
What comes next?
Since the discovery of the oxygen sensing mechanism there have been obvious clinical applications. Two examples are fighting kidney cancers by tricking certain cells into hypoxia and relieving symptoms of anaemia by reversing this effect. Current drugs based on their mechanism have been developed and are expecting to be approved very shortly, over ten years since their findings were published. I asked the two laureates how they believed their careers would change after winning the prize, particularly on their research flexibility; their responses were pleasantly refreshing. They acknowledged the propensity to be swept up in the prize, since the number of invitations to discuss their work and to accept honorary positions are seemingly endless. Kaelin even joked they had roughly calculated the carbon footprint that could be linked to the win as invitations come from all over the world. Instead, they hoped that since winning the prize they could use their influence for good. Ratcliffe announced that we would like to “speak up for education” and possibly focus on teaching, discussing his disdain at how, he believes, society and this university “seriously undervalue education.”
One recurring theme was that, while both scientists agreed their experiments were performed well and rigorously, they denied that any stage of their research was genius. Ratcliffe mused it “wasn’t necessary to be clever to solve biological problems” so long as one was methodical and Kaelin, rather poetically, said that “if a discovery is beautiful, it is a tribute to nature-not the discovery.”
I will leave you with those concluding remarks and the belief that, with Kaelin and Ratcliffe’s curiosity to explore the risky unknown, maybe a Nobel Prize win for you or I might not be such an impossibility after all.