- Sir Peter Ratcliffe, was awarded the Nobel Prize in Medicine last year for his “discoveries of how cells sense and adapt to oxygen availability.”
- Some COVID-19 patients have low oxygen levels without being aware of it - so-called ‘silent hypoxia’ puzzles clinicians.
- Here, Professor Ratcliffe offers his perspective on hypoxia and the coronavirus crisis.
Some COVID-19 patients have low oxygen levels without being aware of it. This ‘silent hypoxia’ puzzles clinicians. We talked about this with Sir Peter Ratcliffe, who was awarded the Nobel Prize in Medicine last year for his “discoveries of how cells sense and adapt to oxygen availability.” Professor Ratcliffe is a Distinguished Scholar of the Ludwig Institute for Cancer Research and Director for the Target Discovery Institute at Oxford University, as well as Director of Clinical Research at the Francis Crick Institute in London. The European Research Council has supported the groundbreaking work of Professor Ratcliffe for five years from 2008 to 2013.
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When did you first hear about the new coronavirus and when did you realise that your scientific expertise could be useful to tackle it?
It was at the January Keystone meeting on hypoxia. My son who is working in Hong Kong called me to ask if this was anything he should worry about. He doesn’t usually worry about things, so I took it that the matter was serious and so it turned out. I spoke with my colleague Jeremy Farrar from the Wellcome Trust who is an infectious disease expert, and he warned then back in January this looked very serious. That's when we began to be concerned about the virus. I think it's fair to say that most people, in Europe at least, have been surprised that its impact has been even greater than was foreseen at that time.
As for my expertise, I know at present close to nothing about why the virus behaves as it does. We can talk about that lack of knowledge, but it will be wrong to pretend that I or anyone else understands in great detail how the virus causes serious morbidity and mortality, and quite what its relation to hypoxia signalling, if any, actually is.
COVID-19 silent hypoxia is puzzling doctors around the world. You are an expert on what happens in the body as a response to low oxygen. What do you make of it?
The process of matching lung perfusion [the rate at which blood is delivered to tissue] to ventilation fails in many lung diseases, but the failure in COVID-19 appears more severe, or disproportionate to the level of lung pathology. This is a process whereby the lung vessels constrict in order to limit the blood flow to hypoxic regions of the lung. By reducing the flow to those areas, the body avoids blood flowing through the lung that cannot oxygenate it. Now, why is this hypoxia “silent”? Curiously, given the importance of hypoxia, the brain does not respond to it with alarm signals. The patient experiences a feeling of euphoria or intoxication, rather than alarm. So it's unsurprising that profound hypoxia, without other features of lung disease, is not felt badly by the patient. Abnormal ventilation-perfusion matching and the failure to respond to hypoxia are what has led to this term ‘silent hypoxia’.
What can be done about it?
To improve ventilation-perfusion matching, the usual treatment is opening the lung mechanically with ventilation. Of course that has the penalty of potentially damaging the lung. This is what many physicians have argued about: what is the appropriate time to start mechanical ventilation? And what is the appropriate way to do it? This led some people to wonder if it will be possible to use drug treatments to better constrict the lung vessels when they are entering an “unoxygenated” lung.
We've been interested in an old drug called almitrine. It was initially made by Servier, a French pharmaceutical company, for this purpose, not for COVID but for other types of what is called respiratory distress syndrome. The question is could this drug be used in COVID-19 pneumonia? It is a matter of first sourcing the medication and then getting the protocols through the various ethical and quality control committees in order to assess that. But you might assess the effectiveness of his drug quite quickly: if a patient responds by increasing the arterial oxygen level, then that ought to be evident quite rapidly.
The hypoxia research you started working on a long time ago now seems very relevant. In the past you have stressed that it is important that scientists be allowed to derive knowledge for its own sake, and that you couldn’t have expected at the outset that your research would lead to breakthroughs and a Nobel Prize. What is your view now when we see that many scientists seem to focus on COVID? Are other research fields being neglected and, if so, does that worry you?
I think that the threat from this type of virus is sufficient, and justifies some refocusing. However, the base consideration remains the same, that knowledge can be assembled with other knowledge to create knowledge which is of use in quite unexpected ways. The challenge now, amongst other things, is to draw on the body of knowledge for a different purpose that is tackling viral infections of this type. The principle, nevertheless, holds that this knowledge may be derived from research that was never intended to have that outcome.
The work on hypoxia had no means of anticipating the current problem. So, I still believe it is important to gain knowledge in an unbiased way, in the confidence that it will be of use to society in the future.
If we wanted to be alarmist for a moment, this epidemic looks as if it has been quite a close shave for humanity. It has surely upset the entire world, caused misery, caused the sad death of hundreds of thousands of people.
However, the case fatality rate is probably more than ten-fold less than it has been for other recorded coronaviruses that caused the original SARS and MERS epidemics. It's a matter of good fortune that this virus, which is much more infectious, is substantially less dangerous. Otherwise the world really would face a huge crisis.
As we emerge from this, there will be a need to consider more carefully what preparedness we can make for other infectious threats. The viruses are difficult to manage and dangerous, because they co-op normal human cellular components to cause disease.
When you talk to your students or young people from the new generation of researchers, what is your advice? Should they still follow their passion?
I believe in the harnessing of human passion. I still believe that's important. Now, people’s passions may change.
People get motivated to do things for all sorts of reasons. People may become passionate about the treatment of viral disease. Nevertheless, I don't think it will help in discovery research to be too regimented and too closed about what we think will be a value to society in future or indeed what we believe will be of ultimate value in managing this epidemic. There are so many unknowns. The problem with being prescriptive, as we have seen in so many political and high-level announcements, is that the assumptions guiding our approach to COVID are almost certainly oversimplified.
The majority of facts about this virus and the disease that it causes are almost certainly not known. Therefore, trying to anticipate them and control research to what is believed by some powerful people to be most relevant is likely to fail to catch all of the things that might be relevant.
There is an unprecedented scientific effort worldwide to fight this pandemic but some voices have been raised for a more coordinated approach. What is your take on this?
I think scientists have not been any less coordinated than any other group of human beings. We can criticise any group for lack of coordination. Yes, if people could agree to explore different aspects of the problem and not to look at similar ones that would be a good thing. We've seen that it's not that easy to organise human behaviour on a world scale in very short order.
Sadly, one of the things that this epidemic demonstrates is that there is a mismatch between economic dependency, human dependency and political dependency. We have vast social networks of people travelling rapidly all over the world for one reason or another or no reason at all, and we have massive economic dependency on production and manufacturing in different parts of the world, but we don't have political coherence. That problem was evident before but it's clearly evident now.
What would be your argument to convince policymakers and politicians to support what you call discovery research or frontier science?
I’ve certainly given a lot of advice to policymakers over the last couple of months, particularly to people in the UK government and civil service. Should this epidemic presage a different attitude to the funding of research? I don't really think it should. When we are having a clear prospect of what we want to do - which is to control an epidemic caused by the transmission of an agent from one human being to another close to each other, where the diagnosis can be made by testing for that virus - then I feel we can give pretty clear instructions what should be done. But the discovery base which underlies that type of advice is another matter. Just think about it. We are in a better place than we were in 1918 during the Spanish flu epidemic. We know what this virus is and the sequence of nucleic acids. We know how to make a diagnosis using the polymerase chain reaction. We know all sorts of derivations of different types of polymerase that could do that more efficiently. We know how to measure antibodies. We know how to do that in a test tube. We know how to test whether those antibodies work on the viral system. We know broadly the life cycle of the virus. We know all the enzymes that it needs to use and how to make drugs to work against those enzymes, at least in theory.
So, all those pieces of scientific information have been accrued over the last hundred years without any clear idea as to how they would be used or how they would be used in this epidemic. The challenge we now face is a coordinated response of bringing that knowledge together on a particular problem on a rapid timescale. Let's be clear: the ability to research this virus is dependent on a massive infrastructure of knowledge which has accrued since that disastrous 1918 epidemic. We hope that this one will be less serious to mankind, but that’s the hope at the moment rather than certainty.