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Gregg Semenza

Gregg Semenza on how doping in endurance sports and treating cardiovascular disease are interrelated:

Gregg Semenza

When you started your career, did you intend to make such big contributions to health or were you purely driven by curiosity?

SEMENZA: There was clinical relevance initially when I was studying the erythropoietin gene since it was being used to treat patients with kidney failure. Of course we had no idea that we would stumble on something like HIF-1 that had a much broader impact in medicine.  That is the serendipity of research. You never really know where it is going to lead and if you are lucky it will lead you to something clinically relevant.

You are credited with discovering HIF-1, which is now being tested as a therapeutic target against cancer and heart disease. What is HIF-1 and why is it important?

SEMENZA: HIF-1 helps cells survive in low oxygen by making more red blood cells and developing new blood vessels. HIF-1 also controls how cells use oxygen, so when oxygen levels are low, cells can switch to a different type of metabolism that doesn’t require oxygen.

Interestingly, cardiovascular disease and cancer, two major causes of death, are affected by HIF-1 in two different ways. In cardiovascular disease, cells do not get enough oxygen because of blood vessel narrowing. We want to increase HIF-1 in these patients as a therapeutic treatment to increase the blood supply. In cancer, the tumor cells use HIF-1 to make new blood vessels that bring in a fresh supply of oxygen and nutrients to fuel growth of the tumor. We are developing molecules that decrease the amount of HIF-1 in this case.

How did you discover HIF-1? 

SEMENZA: We were studying the gene that codes for the protein erythropoietin, which controls red blood cell production.  We identified a part of the DNA sequence in the erythropoietin gene that was needed for the gene to be turned on in response to low oxygen conditions. We identified a protein, which bound to that DNA sequence and helped turn on the erythropoietin gene. We named the protein Hypoxia-Inducible Factor 1 (meaning a factor that is active in low oxygen conditions) or HIF-1.

What are the effects of chronic low oxygen on the body?

SEMENZA: In the case of sleep apnea, people have problems breathing during sleep and low oxygen levels in the blood cause the person to wake up and breathe again. These people have cycles of low oxygen followed by normal oxygen conditions many times during the night. We’ve found that this creates high levels of HIF-1, which causes many of the pathological consequences associated with sleep apnea, such as increase in blood pressure. Sleep apnea may be another case where inhibiting HIF1 may be a beneficial therapy.

Recently, several studies of Tibetans who live at very high altitudes and have adapted to life at low oxygen conditions have been published reporting differences in their DNA that account for their adaptation to low oxygen levels. The genes that seem to show the greatest changes for survival at high altitude are genes that either regulate HIF-1 levels or make up the components of HIF-1.

Is there evidence of similar types of DNA changes in HIF-1 that could make one better at endurance sports, where athletes are gasping for air over long periods of time?

One of the ways you can have higher endurance is if you have an increased number of circulating red blood cells. This condition can occur if the receptor that senses erythropoietin on the immature red blood cells is hyperactive. It turns out that the first family in which this DNA change in the gene for the erythropoietin receptor was found included a member of the Finnish Olympic cross-country skiing team. 

One of the problems in cycling and cross-country skiing has been the illegal use of erythropoietin to increase red blood cell counts and artificially increase endurance. It’s possible that someone could stimulate the production of HIF-1 to produce more red blood cells to increase endurance and hopefully the new drugs being developed as treatments for cardiovascular disease won’t be used for doping.

In the case of the Finnish cross-country skiing team member, it was a natural benefit of this DNA change that may have improved this person’s endurance and allowed them to compete at the Olympic level for which of course they can’t be penalized.

--Interviewed by Vanessa McMains

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