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Oxygen sensing mechanisms, first discovered as a result of studies on the production of the kidney hormone erythropoietin, regulate about 1000 different genes that control all sorts of processes including metabolism, blood vessel growth and blood flow. A better understanding of the oxygen sensing pathway might help us design better therapies for disorders that involve oxygenation problems, such as angina and cancer.

Q: What is the contribution of genetics in renal disease?

A: The kidney is a very complicated organ; we might think of it as simply making urine but in fact it controls all sorts of parts of the internal environment. It controls blood pressure, it controls salt and water metabolism, it controls calcium and prophase balance and intriguingly it also controls the number of red blood cells we have in our bodies. So genetics has had impacts in all sorts of ways in renal disease because gene defects can lead to malfunction in all sorts of different parts of that system. A while back when Peter Harris was working here, he identified the genes involved in polycystic kidney disease by genetic approaches; that is the commonest inherited cause of kidney failure. Raj Thakker's group in Oxford have extensively worked on calcium and prophase metabolism and they've identified all sorts of genes involved by that mechanism. My own work with Peter Ratcliffe has concentrated on the oxygen sensing functions of the kidney and its ability to produce this hormone erythropoietin.

Q: Can you tell us about the link between oxygen sensing and renal disease?

A: The kidney is the primary source of this hormone erythropoietin in adult human beings. In kidney failure it fails to make that hormone and patients become anaemic. The question Peter asked right back in 1989 was how does the kidney sense changes in oxygen levels. I joined him in the lab shortly after that and the first thing we did was to identify a bit of DNA flanking the erythropoietin gene that was responsible for its oxygen regulation. That itself was quite interesting but the thing that made it really important was the discovery that parallel oxygen sensing mechanisms worked in every cell in the body and controlled a whole variety of different genes. Since that first step we've gone on to work out how this all works: these fragments of DNA work because proteins bind to them. Gregg Semenza at Johns Hopkins identified the proteins that bind to this bit of DNA and called the complex HIF - hypoxia inducible factor. The work that Peter and I have done along with probably over one hundred people in the lab and people in other labs around Oxford has been to work out how HIF is regulated. One component of the hif complex is regulated both in terms of protein stability and in terms of how active it is by oxygen availability. The key finding which we made along with Chris Schofield's group in the Chemistry Department and help from Johns Hopkins' group in Genetics was to identify the enzymes that modify the HIF protein when oxygen is present and determine its function. We first found one of these enzymes in C. elegans worm and we then from that enzyme were able to identify the equivalent enzymes in human beings. These enzymes actually use oxygen itself in the modification of the hif protein so they themselves sense the availability of oxygen: when oxygen is present they work well, modify the hif protein and inactivate it; when oxygen is lacking, the enzymes work less efficiently, the hif protein remains stable, remains active and can drive the expression of a variety of genes. And those are genes that control all sorts of processes: energy, metabolism, blood vessel growth, as well as erythropoietin, the original paradigm gene.

Q: What are the most important lines of research that have developed in the past five or ten years?

A: I think following on from the identification of those enzymes we've been very interested in working out what they do in biology. It would have been very simple if there was one enzyme that did everything but in fact we've found three enzymes that affect hif protein stability and one enzyme that affects its activity; they're expressed in different amounts and different tissues, and the amounts vary with different stimuli as well. Taking that biology apart is really important for any application that might follow. The other thing that's interesting is these enzymes are part of a super family of genes, and there are probably 70 or 80 similar enzymes in the human genome; it's opened the door to beginning to explore what all these other genes might do, that themselves might be regulated by oxygen level, or indeed iron level or metabolic level in the body.

Q: Why does your line of research matter, why should we put money into it?

A: Oxygen is a pretty fundamental requirement for human life and very important that our bodies control the delivery of oxygen to every cell at an appropriate level. We all know what happens if there isn't enough oxygen around, but actually it can also be toxic if there's too much oxygen around; this very fine balance that makes sure that oxygen reaches every cell in the body at just the right level is really important. A whole spectrum of diseases depends on problems with oxygenation. If there's narrowing in a blood vessel to the heart, patients experience angina because the heart muscle cells are not getting enough oxygen, enough nutrients for their metabolic demands; this system is triggered under those circumstances, and want we wonder is whether if we can increase the triggering of this system, we can actually help the body adapt to that low oxygen stage. As another example, as cancers grow they outgrow the oxygen supply that would normally be present, in fact they would only get to one or two millimetres across if they didn't grow new blood vessels into the core of the tumour; the way in which they do that involves hijacking this normal physiological mechanism, so if we can understand how they hijack the mechanism - and there are several ways in which they do that - maybe we could interfere with that and slow the growth of tumours, or limit them so they couldn't get beyond one or two millimetres in size. That's a sort of broad overview. In fact the work over the last five years has shown that the system is very complicated, there are many feedback loops within it and we'll need to be very careful in designing interventions to maximise the potential benefit. But that's part of the interest, part of the fun and part of the excitement working out how to make it really work.

Q: How does your research fit into Translational Medicine within the department?

A: I think it provides one example of dissecting a physiological pathway that then has led on to a lot of interest by international pharmaceutical companies in finding drugs that target the particular enzymes that we've identified. There are many such programmes going on. The links to these other enzymes actually link with a number of other groups around the department, and one of the exciting things of the last 20 years has been our ability to collaborate with a large number of other groups in Oxford and outside to move the science forward as effectively as possible.

Chris Pugh

Genetics of Renal Disease

The kidney plays a central role in our metabolism, by controlling various physiological balances. Genetics plays an important role in renal disease since gene defects lead to all sorts of malfunctions. Prof. Chris Pugh is working on the oxygen sensing functions of the body; whilst these were discovered in the context of erythropoietin production the underlying system controls about 1000 genes.

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