“It is not easy to convey, unless one has experienced it, the dramatic feeling of sudden enlightenment that floods the mind when the right idea finally clicks into place,” wrote Nobel Prize-winning molecular biologist Francis Crick – co-discoverer of the DNA molecule’s double helix structure – in his 1988 book What Mad Pursuit: A Personal View of Scientific Discovery. “One immediately sees how many previously puzzling facts are neatly explained by the new hypothesis. One could kick oneself for not having the idea earlier, it now seems so obvious. Yet before, everything was in a fog.”
Recipients of the Nobel Prize in Physiology or Medicine tend to be those, like Crick, who clear away the fog surrounding basic physiological mysteries, paving the way for a rush of progress based on their findings.
It’s a pattern that certainly holds true for the 2019 Nobel Laureates in physiology and medicine. In October, the Nobel Assembly at Karolinska Institutet in Sweden announced that William G. Kaelin Jr (Harvard University), Sir Peter Ratcliffe (Oxford University) and Gregg L. Semenza (Johns Hopkins University) had been jointly awarded the 2019 Nobel Prize in Physiology or Medicine.
The three academics won the prize “for their discoveries of how cells interact and adapt to oxygen availability”. The award recognises decades of investigational work by Kaelin, Ratcliffe and Semenza, and their findings have already underpinned the development of new therapies for conditions like anaemia and cancer, and will almost certainly exert an influence on drugmakers – not to mention biology textbooks – in years to come.
Oxygen regulation: untangling the inner machinery of cells
For centuries, the scientific community has been aware of the cellular importance of oxygen, which fuels the conversion of food into energy and is transported to tissues by red blood cells. The enduring mystery has been exactly how cells can sense and adapt to differing levels of oxygen, and the three scientists’ work over the years appears to have solved it, illuminating the molecular machinery that regulates gene activity in response to oxygen levels as they rise or fall.
The steps taken to reach this point have a history in previous Nobel Prize winners. In 1931, Otto Warburg received the prize for his discovery of the enzymatic process, by which cells use oxygen to break down nutrients for the construction of new cells. And in 1938, Corneille Heymans was awarded for his working describing how the carotid body in the neck plays an important role in sensing blood oxygen levels via specialised cells and controlling the respiratory rate by sending signals to the brain.
The work of Semenza, Kaelin and Ratcliffe – in various capacities and at various stages – put together the remaining puzzle pieces to get a clearer picture of how blood O2 levels control the cellular response. The starting point was a hormone called erythropoietin (EPO), the release of which stimulates increased production of red blood cells in response to low oxygen levels (hypoxia).
EPO’s role as a hormonal reaction to hypoxia has been known since the early 20th century, but separate studies by Semenza and Ratcliffe went deeper, discovering that specific DNA segments located next to the EPO gene mediate the response to hypoxia. They also found that this oxygen-sensing capability is not limited to the kidney cells that normally produce EPO; it is present in many different cells types across virtually all tissues in the body.
“It’s sort of a fundamental discovery in the field of cell biology, and it shows that all cells have the ability to respond to changes in oxygen retention,” University of California, San Francisco developmental biologist Emin Maltepe told Popular Mechanics in October.
VHL discovery completes the picture
Semenza named the protein complex in cells that binds to the DNA segment based on O2 levels, describing it as the hypoxia-inducible factor (HIF). If the body’s oxygen levels are low, HIF produces a transcription factor called HIF-1α, which binds to the EPO gene and raises red blood cell production, while at normal oxygen levels, the HIF-1α is degraded and removed by the cells’ proteasomes.
Meanwhile, research into an inherited disorder called von Hippel-Lindau’s (VHL) disease being undertaken by Kaelin at the Dana-Farber Cancer Institute shed more light on the process. Kaelin’s work demonstrated that the VHL gene restored normal levels of hypoxia-regulated genes when introduced to cancer cells, and Ratcliffe’s group confirmed that VHL is required for the degradation of HIF-1α at normal oxygen levels.
Further investigation by Kaelin and Ratcliffe filled in the final details, identifying the exact protein modification that allows VHL to recognise and bind to HIF-1α to remove it when oxygen levels normalise, with the help of certain oxygen-sensitive enzymes. It was for the discovery of this as yet unknown dance of proteins – the type of asymmetrical perfection that makes all life possible – that led to Semenza, Ratcliffe and Kaelin being awarded this year’s Nobel Prize, after decades of research.
“The field really coalesced around this discovery, which was dependent on each one of their findings,” said Oxford University physiologist and Nobel Assembly member Randall Johnson in an interview with Nature. “This really was a three-legged stool.”
Clinical potential: next-gen anaemia drugs hit the market
Having described three lifetimes’ worth of revolutionary experimental biology into a few scant paragraphs, there is a natural question from the pharmaceutical perspective: what are the implications of the trio’s discovery for new medicines and therapies? For such a fundamental shift in our understanding of the cellular mechanics around oxygen, it’s too early to give a full account of the potential applications, but the oxygen-sensing mechanism is pervasive enough that the benefits of this discovery are likely to be felt for years to come.
“You could argue that some aspect of this is going to be germane to all diseases you can think of,” University of Pennsylvania cancer biologist Celeste Simon told Nature.
Potential applications include for oxygen-regulating treatments include therapeutic areas such as cancer, stroke, infection and heart disease, as well as our understanding of the physiological processes surrounding embryonic development, respiration, immune response and more.
One of the most obvious applications for drugs targeting cells’ oxygen-sensing mechanism is in anaemia, which is caused by a reduced red blood cell count, impairing the blood’s ability to transport oxygen around the body. Already two potential blockbuster drugs have emerged for the treatment of anaemia caused by chronic kidney disease (CKD).
Astellas’s roxadustat – co-developed with AstraZeneca and FibroGen and GlaxoSmithKline/Kyowa Kirin’s daprodustat both target the EPO-driven red blood cell production response described by this year’s Nobel Laureates. The oral drugs work, according to Kaelin during a Nobel Prize press conference, by “trick[ing] the body into thinking you’ve gone to the top of Mt Everest”, thereby kick-starting the production of red blood cells in the bone marrow.
Roxadustat has taken the first-to-market advantage by being the first to win Chinese approval in December 2018 for patients on dialysis with anaemia caused by CKD, while in August the drug’s label was expanded to include CKD patients who are not on dialysis. In September the drug was approved for CKD patients on dialysis in Japan, where it will be marketed by Astellas under the brand name Evrenzo and will find a large pool of potential patients in the CKD-prone country, where there are around 3.5 million people with anaemia linked to CKD. AstraZeneca holds commercial rights to the drug in China and the rest of the world, and marketing applications are underway in the US and Europe.
GlaxoSmithKline and Kyowa Kirin, meanwhile, filed their first application for daprodustat in Japan in August, based on positive Phase III trial data generated in the country. The drugs could improve the standard of care in CKD-related anaemia when compared to current erythropoiesis-stimulating agents by having a more convenient oral formulation and sidestepping the risk of tumours and blood clots associated with current treatments.
Starving oxygen-hungry tumour cells
Cancer is another disease area in which Ratcliffe, Kaelin and Semenza’s work has already borne fruit in the clinic, albeit via a very different pathway. Broadly speaking, when cancer cells are hypoxic, they co-opt the body’s oxygen-sensing mechanism to increase oxygen supply and build new nutrition-carrying blood vessels to tumour sites through a process called angiogenesis. This co-opting of the body’s natural defences is what makes some tumours so hard to kill.
“What we’ve learned is that when [cancer cells] become hypoxic, they turn on genes that enable them to invade, metastasise and spread throughout the body,” Semenza said at the Nobel Prize press conference. “We believe it’s these cells that survive the therapy and come back to kill the patient.”
Partly stemming from the trio’s revelations around oxygen sensing, a wave of angiogenesis inhibitors have been developed to help starve hypoxic tumours when they issue the call for the oxygen they need to survive and grow. These include Genentech’s Avastin (bevacizumab) for colorectal, kidney and lung cancers and Celgene’s Revlimid (lenalidomide) for multiple myeloma and mantle cell lymphoma, among others.