When Johns Hopkins scientist Gregg Semenza, M.D., Ph.D., climbed to the podium in Stockholm last December to accept his Nobel Prize, Akrit Sodhi, M.D., Ph.D., sat in the audience, appreciative of the opportunity to witness the historic event. The two go back a long way. In 2017, they launched a company, HIF Therapeutics, that grew out of the work that earned Semenza his Nobel: the discovery of protein hypoxia-inducible factors, or HIFs, which guide how cells sense and respond to low oxygen levels.
Their collaboration began when Sodhi asked Semenza to serve as his primary mentor on a specialized grant from the National Institutes of Health (NIH) called a K12 award, given to newly trained clinicians to help launch their independent research programs.
In February, we sat down with Semenza, the C. Michael Armstrong Professor of Medicine at Johns Hopkins, and Sodhi, who holds the Branna and Irving Sisenwein Professorship in Ophthalmology at the Wilmer Eye Institute, to learn more about their work and working relationship.
How do HIFs work, and how are they related to cancer and eye diseases?
GREGG SEMENZA: HIFs allow the body to respond to changes in oxygen levels. For example, if you have a serious accident with blood loss, cells in the body will not receive enough oxygen. The low oxygen levels (hypoxia) will turn on (induce) proteins (factors) called HIFs. In the kidney, HIFs control the production of a protein called EPO that is secreted into the bloodstream and stimulates the bone marrow to make more red blood cells. It’s a beautiful physiological system that allows you to respond to changes in the amount of oxygen that is available to cells throughout the body. But in cancer, the disease process causes hypoxia, and HIFs are turned on in the cancer cells. This response helps keep the cancer cells alive and is good for the tumor, but not for the patient. Drugs that block HIFs may be a useful addition to anticancer therapies.
In the eye, when oxygen levels go down in the back of the eye due to diabetes or aging, the HIFs get turned on. In this case, the response is to make new blood vessels in order to bring more red blood cells carrying oxygen to the retina. But for reasons we don’t understand, the blood vessels don’t get made very well. These blood vessels have a tendency to leak or bleed, which can lead to swelling or scarring of the retina, which can lead to blindness. Again, a drug that interferes with HIFs may prevent the formation of these abnormal blood vessels.
What is the goal of HIF Therapeutics?
AKRIT SODHI: Most of the original inhibitors of HIF that many scientists are still using today were discovered by Gregg. Those are drugs that vision scientists have subsequently looked at — our lab in collaboration with Gregg’s and other labs in collaboration with Gregg. But there are limitations to those drugs, including toxicity. Those drugs have not yet translated to patients, and they may not be able to be translated to patients due to these limitations. What they did provide was a nice proof-of-principle that targeting HIF in many different animal models was a very effective way to treat many eye diseases and most cancers.
What we’re trying to do now is come up with other approaches to inhibit HIF that might be less toxic, more effective, longer lasting. The ultimate goal of the company is to identify those new therapies. “It’s important to have clinicians doing research because they understand the disease process.”
How are K awards beneficial to research in science and medicine?
AKRIT SODHI: K awards are grants that are designed to transition a clinician from learning to doing research to becoming an independently funded researcher. A very effective K award mentor is one who not only helps you to design a K award project that allows you to learn basic science or clinical research but also enables you to then transition to writing your own R01 grant to fund your own independent research program. You choose your mentor based on your interests, but the mentor shapes not just the project but the type of questions you ask, the rigor of your research and ultimately the impact of your work.
GREGG SEMENZA: It’s really important to have clinicians doing research because they understand the disease process. We really need people who are taking care of the patients also doing research, like Akrit does, because they’re the ones who best understand the clinical condition and are closest to the patients.
Dr. Semenza, is there specific advice you remember giving to guide Dr. Sodhi?
GREGG SEMENZA: My philosophy for research projects is that they begin and end with the patients. And so that means you start with a model of a human disease. You try to understand it, and then eventually, you hope to learn something that can be brought to the clinic to treat those diseases.
I thought that one of the disease models that Akrit was planning to use was not a clinically useful model. I suggested using a different model that was more representative of human eyes diseases and might provide information that could help develop new therapies.
AKRIT SODHI: That advice was exemplary of what ultimately resulted in one of the big shifts in the focus of my research program. Gregg instilled in me the importance as a clinician-scientist of understanding the endpoint, which is really translating what you are studying in the lab into therapies that can help patients.
Dr. Semenza, what was it like to win the Nobel Prize?
GREGG SEMENZA: It was quite an experience — a once-in-a-lifetime event, but quite hectic. I think Akrit had a more relaxed and enjoyable time in Stockholm than I did.
AKRIT SODHI: There was obviously much less pressure on me. But also a once-in-a- lifetime opportunity. When Gregg asked if my family and I wanted to go to the ceremony, I texted my wife, who is also a scientist, to let her know. I forwarded Silvia’s response to Gregg; I will spare you the details, but it was clear that Silvia was more excited about being asked to go to Stockholm than she was when I asked her to marry me.