“This is a textbook discovery”
Professor Randall Johnson, member of the Nobel committee, this year you are awarding the Nobel Prize to the discovery of how cells sense and adapt to oxygen availability. What does this mean?
Well basically it says that when you are a cell, if you are an animal cell, you have to always have some level of oxygen, almost all cells use it for their metabolic processes. It is just like a candle burning or any other kind of furnace or engine. You are burning things to in order to make heat, in order to make energy- that’s really what we do. Of course, we need oxygen in order to do those things. The problem is that cells inside a three dimensional structure, like the body, are always getting different amounts of oxygen. This can depend on different levels of blood flow, it can depend on the fact that the tissue itself might be using a lot of oxygen at any given time. My brain is probably using a fair amount right now, and my heart because it’s probably beating a bit faster and so that’s maybe using more oxygen than if I am lying down and sleeping. Because the cell has a very tightly regulated little furnace in it, it has to adjust to these different levels of oxygen in a very fine tuned way, and if it does this badly it can even be fatal for the cell. So, really it’s a sort of rheostat or a thermostat for oxygen levels, similar to a damper that you would have on a furnace to let in more or less oxygen at any given time... so that it's just bright, so the flame burns just right.
If we take a small step outside the cell, how does this discovery affect people's lives?
Well it affects people's lives because it really will help us and is already helping people to develop new medicines. Finding different ways to influence this fundamental process has already shown itself to be potentially very useful with clear medical applications. So as I mentioned in my presentation, for example, if you want to increase the levels of your red blood cells, this factor comes into play, and that of course makes sense, because if you are at high altitude you want more red blood cells to help you carry oxygen. If you have an accident and you lose a lot of blood, now there are not enough red blood cells to carry the oxygen, so you want a signal that tells your body to make more red blood cells. This is a fundamental part of that signal, it's the cellular aspect of it, so a drug that can raise the levels of this can trigger new red blood cell production. In fact, such a drug as I mentioned has already been approved in China and is under consideration in Western countries as well, including the EU and Sweden.
So in order to describe this in an accessible way, what kind of metaphor would you use?
I would, of course, go back to the candle or the furnace and say that this is a way for the cell to adjust its response to the amount of oxygen it gets, because the cell can't directly change how much oxygen it gets, oftentimes That's of course at the cellular level, but it also controls much more far ranging things. You can think of a cell having to change its metabolism. Okay, that's at a very basic level, but the cell also, when it senses it doesn't have enough oxygen, triggers, for example, the production of new red blood cells or new blood vessels. So, if I get a cut, those cells now don't get a good supply of oxygen, because I cut the blood vessels that were taking blood there. So the cells now release factors that induce new blood vessel formation, also through this factor. Or, again, if I go to high altitude, now I am not breathing in enough oxygen and now my body sends a signal saying ‘make more red blood cells’, so this signal level ranges from the cell all the way up to the body.
So if we turn to the laureates William G. Kaelin, Sir Peter J. Ratcliffe and Gregg L. Semenza, what have they done in this discovery?
Well I know them all. They are all very fine fellows and they all contributed very essential parts of this process. Gregg Semenza's initial and very important contribution was first to help define the region of a gene that is basically allowing this to happen, and then it was found that this region was found in lots and lots of other genes. Peter Ratcliffe also participated in that process of just defining that. Then Gregg actually was the one who cloned and isolated this factor called HIF, and he was the one who named it. That has really been the foundation for this discovery in many ways. Peter Ratcliffe came in and made an association between this tumor suppressor gene called von hippel-lindau or VHL and the regulation of the HIF gene and that's really an important part of how HIF senses oxygen. Bill Kaelin came in and also made that association and he and Ratcliffe helped to define the switch, the oxygen dependent switch, which really is the knob on the dial that ultimately helps you understand how all of this works. So, all three were necessary components or were actors in figuring out how this whole thing works. And although they haven't collaborated with each other, they have all been closely associated with the field through the course of all of this.
And why is it that the prize is being awarded now? I mean some of the findings were made in the mid-nineties, what has happened to make it such an active field.
I can't speak to you about real specifics because of course some of that is confidential in terms of the deliberations of the assembly. But it's very clear that we now understand this fundamental biologi- cal switch that really impacts all our lives as living creatures here on earth breathing oxygen. It's really one of the most important things we ourselves know how to do. In fact, if an embryo doesn't have this HIF gene, it won't survive past very early embryogenesis. So even in the womb, our bodies need this gene in order to do everything they do. So I guess you could say a direct answer to your question is that it now seems like a complete and clear story.
The laureates, I understand the Nobel Committee has been talking to them. What were their reactions?
Well of course Thomas, the secretary, is the one who calls them on the phone, but what I understood is that they were all very happy, as one should be, and very excited. And we are certainly looking forward to welcoming them to both Stockholm and Sweden in December.
And finally, if you had 30 seconds to explain the main impact of this discovery in an exciting way, what would you say?
I would say this is what Scientists often refer to when they toss around the phrase ‘textbook discovery’. This is really and essentially a textbook discovery. This is something that basic biology students will be learning about when they study at age 12 or 13 or younger and learn the fundamental ways in which cells work. This is a basic aspect of how a cell works and I think from that standpoint alone it's a very exciting thing.
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