Contagious Conversations / Episode 17: A Nobel Prize-Winning Career
The off-the-beaten-path journey to finding hepatitis C
Meet the man whose discovery has made it possible to save millions of lives. In this episode, Dr. Harvey Alter shares the story of his 50-plus year career and how his research led to the discovery of the hepatitis C virus.
Below: Dr. Harvey Alter in the NIH Clinical Center Department of Transfusion Medicine, 2004.
Transcript
Claire Stinson: Hello, and welcome to Contagious Conversations. I'm your host, Claire Stinson. Every episode we'll hear from inspiring leaders and innovators who make the world healthier and safer for us all. Contagious Conversations is brought to you by the CDC Foundation, an independent nonprofit that builds partnerships to help CDC save and improve more lives.
Joining me today is Dr. Harvey Alter, a medical researcher at the National Institutes of Health, who was just named a recipient of the Nobel Prize in Medicine for his work in discovering the hepatitis C virus. Dr. Alter's research focused on patients that developed chronic hepatitis from an unknown agent during blood transfusions. Dr. Alter is also the recipient of the 2015 CDC Foundation Fries Prize for Improving Health, an award that recognizes an individual who has made major accomplishments in health improvement, for his work on hepatitis C. In this episode, Dr. Alter discusses his 50-plus year career and how his research led to the discovery of the hepatitis C virus. Welcome Dr. Alter and congratulations on receiving the Nobel Prize in Medicine this year.
Harvey Alter: Thank you very much. It's been quite an honor.
Claire Stinson: We're so honored to speak with you today. So Dr. Alter you've had a long and distinguished career in public health. In fact, we should begin by again saying congratulations for being named co-winner of the 2020 Nobel Prize in Physiology or Medicine. You received the news, I hear, through a 4:00AM phone call from Stockholm. Is that right?
Harvey Alter: That's correct. Yes. It was quite an experience. I was fast asleep, the phone rang and first assumption was that it was a political solicitation call, or we also get calls to extend the warranty on our automobile.
Claire Stinson: Of course.
Harvey Alter: So I didn't answer it, and then it rang again about five minutes later and I still didn't answer, but was getting increasingly angry. And finally, the third ring I did answer it and before I could say anything they said, "This is Stockholm calling." And that kind of stopped me in my tracks. So it rapidly transformed into a great moment.
Claire Stinson: Absolutely. And I believe you called it the best alarm clock you ever had. Is that right?
Harvey Alter: That's true. That's true. Best one I've probably ever will have.
Claire Stinson: What a moment. Congratulations. Dr. Alter, you were trained in internal medicine and you have continued your career as a researcher with notable medical discoveries. Can you tell me what drew you to the field of health research?
Harvey Alter: Well, I wasn't really drawn to the field of health research truthfully, I was drawn to medicine. Training as you say, in internal medicine and hematology, wanted to be a practicing physician, had no thoughts about a career in research. But I did want to potentially be in academic medicine and therefore I had applied to NIH to the Department of Health Service, which would have been an alternative to the draft, which existed at that time.
However, before that happened, I got a letter from the draft board telling me to report to Fort Dix on November 30th, that was 1961. And then I had this frantic conversation with the chief of medicine and the chief of hematology and calls to the Public Health Service. And I found that if I got commissioned in the Public Health Service before my draft date, that would take precedence and somehow I got that accomplished with help.
Claire Stinson: Oh wow.
Harvey Alter: And so on November 27th I reported to NIH, three days before my draft and that changed my life, because I definitely would have been in clinical practice which would have been fine. But by coming in NIH I got involved in a... First research study I got involved in and it turned out to be finding this Australia antigen, which later turned out to be the hepatitis B virus and that kind of set my career into a more research mode.
But even then, I was still going to go into practice. Was at Georgetown University in hematology fellowship, and then on a faculty. Well, a hematology fellowship and then I applied for practice position, which I did not get, it's a very prestigious position in Washington. And my boss at Georgetown said, "Well, just to stay here, you can always go into practice." And I did. So I went on the faculty and then I got less enchanted with clinical practice and more attuned to academic medicine.
Claire Stinson: Well you never know where your life is going to lead you. Right? And it sounds like you had some twists and turns, but you weren't sure if you wanted to go into clinical practice because of those twists and turns. So it sounds like it all worked out.
Harvey Alter: Yeah, it worked out. And the biggest twist and turn was the alternative to the draft, that changed my life on a dime. But the other one was that I got the chance in 1970 to come back to NIH and I did, and that got me into these long perspective studies that transfused patients that really had the big payoffs. So just things kept working out for me.
Claire Stinson: Absolutely. And this leads me to my next question, which is in a recent National Institutes of Health telebriefing, you called your 50-plus year career “a tribute to non-directed research.” Which you defined as where you don't know where you're going, but you just keep moving. Can you talk a little more about the journey of your career?
Harvey Alter: Yes. That's I think a pretty accurate statement. You know you don't start out saying, "I want to discover a new virus," or "I want to cure the world of hepatitis C," which we didn't even know existed at the time.
Claire Stinson: Right.
Harvey Alter: So you start out saying, "This seems to be a problem in transfusion medicine, people are getting sick from the transfusions.” So we just set out to find out how many people were getting hepatitis, that was the biggest problem in those days. And if they were, why were they getting it and what can we do about it? And that just started the stepwise progression where one found that yes, a lot of people were getting it, about 30 percent of people who had open heart surgery.
They were multiply transfused, but they were very good population default because they were not immunosuppressed. They usually didn't have other diseases besides their cardiac disease. They got a lot of blood transfusions and we could follow them at NIH every one to two weeks after transfusion for six months. So we collected the samples. We collected donor samples where we could, and built up this repository which we dug back into many, many, many times as new technology came along. But first, we found that the incidence was about 30 percent. So a third of the patients were getting hepatitis after transfusion. Most of them were not aware of it because it was a relatively mild acute illness, but we were following their blood for liver enzyme elevations, and we found that 30 percent were getting these elevations that they didn't have before transfusion.
So we defined them as biochemical evidence of hepatitis. Some patients actually got sick and got jaundice, but the vast majority did not. But because we were doing this prospectively and collecting the samples, whether or not they were symptomatic, we found these very high rates. And then we traced the source of the blood and found that certain blood donors that were paid were very high-risk, so we switched from a partially paid donor system to an all-volunteer system in 1970, that made a dramatic difference.
Dropped the rates down to about 10 percent. By then we had also introduced the first test for hepatitis B, but found then that as better tests for B came along, that a lot of the cases were not due to B. And then hepatitis A virus was discovered by a group here at NIH. They were all collaborators and we then tested all the samples for A and not one of them was A, so then, we knew we had something new. We hadn't yet proven it was a virus, so we just non-specifically called it non-A non-B hepatitis.
And we're pretty sure we'd find what it was for the next year or so, but we did not. We could not pin down the actual agent, but we learned a lot about it. Because we transmitted this hepatitis from asymptomatic blood donors, from patients with acute hepatitis, from patients with chronic hepatitis, we were able to transmit this to the chimpanzee model.
Claire Stinson: What was your a-ha moment?
Harvey Alter: Yeah. Well, I guess a mini a-ha moment was to find that none of the cases were A, and then only about 25 percent were B, and therefore there was some new non-B entity. So we knew we had something that was non-A, non-B. And then we had this one patient, Mr. H, who we obtained a large volume of plasma from during his acute phase of hepatitis. We'd been looking for a patient that we could catch very early on in the disease, because that's when a virus would be most likely to be present.
So we did a 500 ml plasmapheresis unit on him. And then we were able to take that material, put it into a chimpanzee and show that it was infectious. Then Dr. Purcell here in NIH, my main collaborator, titered this material in the chimp model. So we had a chimp infectious dose that was defined.
Claire Stinson: Wow.
Harvey Alter: So now, when you have an infectious dose and you have the chimp model, and I might say these chimps got biochemical evidence in hepatitis, but they never got sick. So you can take this infectious inoculum and manipulate it. So Steve Feinstone, who is in Dr. Purcell's group, did a chloroform extraction study and showed that if you treated this plasma with chloroform, it was no longer infectious. If you just sham extraction, it was infectious.
So now we knew that it had lipid... The virus had lipid, usually that would mean it was in the envelope. So we knew it was a lipid envelope virus. And then we were able to do filtration studies and take different filtrates through different filters, inoculate those into the chimp, and show the agent was very small and it was lipid-encapsulated. This greatly narrowed the possibilities down. It made it look like it was probably going to be a small flavi-like virus, small RNA virus, or some entirely new virus. So the next step was we knew a little bit about the agent. What about the patients? Was this really a serious disease? A lot of people thought this was just called transaminitis, a rise in liver enzymes, but not much clinical significance.
Claire Stinson: Oh, okay.
Harvey Alter: But working with the liver service here at NIH or the NIDDK, Jay Hoofnagle, Adrian Di Bisceglie and others, and all the fellows, so many great fellows would help me. Because I really wasn't a hepatologist. I got thrown into liver disease, but I wasn't a trained hepatologist. I couldn't do liver biopsies, but the liver service did the biopsies and collaborated all through. And we started to show that these patients, most of them had mild disease, but some had already had cirrhosis and others when we re-biopsy them years later, went from fairly severe fibrosis into cirrhosis. So, in the end we showed that 20 percent of the patients developed cirrhosis and several of them died of their cirrhosis and others had cirrhosis when they died of their own cardiac disease. So we now knew it was a severe disease from a small virus in 1987 possibly '88.
I was contacted by Michael Houghton's group, the Chiron. They thought they had cloned a non-A, non-B agent. They were doing this for about... Experimenting for about six years, very quietly. Nobody knew what they were doing. And suddenly they thought they had it and to confirm that, they asked for a panel that I had established, it was a little panel, but very tricky and had duplicate samples and random order. And it had a lot of negative controls and samples that were proven to be infectious in the chimp. And 19 other laboratories had tested that panel and never had broken the code correctly. And so, when Chiron tested it, and then they asked me to break the code, I didn't kind of jump into it. I was expecting another failure. So they kept calling me and finally I broke the code and they had broken it perfectly.
Claire Stinson: Oh, wow. And Dr. Alter at this point, did you know you were on the cusp of something big?
Harvey Alter: Well, at that point, yes. I mean, the cloning was a Eureka moment for Chiron and indirectly for me, because we showed that every case that we had called non-A, non-B was negative for this antibody to see before the transfusion and positive afterwards, that was 15 straight cases. And then we looked at 25 cases and looked at the blood donors to those cases and we found a positive donor first in 80 percent and then a near 90 percent, when this assay got more sensitive.
So we then knew that we could probably prevent 90 percent of post transfusion hepatitis if we screen donors with this antibody assay, which we started doing in 1990. And rates had already come down considerably from other interventions along the way and less use of blood. But nonetheless it was this test that brought it down first to one percent incidence and by 1997 to virtual zero, and we're still following cases, we haven't seen any more cases of hepatitis A or B in the next decade after we introduced this test. Yeah, the moment that all our cases became C, I guess you could call it a ‘Eureka moment.’
Claire Stinson: That's quite a story and thank you for sharing that with us. So Dr. Alter let's shift to COVID-19 if we can. Given the current climate with the COVID-19 pandemic, there's a lot of attention focused on the work of virology. As a scientist who has spent your career in this field, what are some of the lessons learned that you hope others can gain insight from?
Harvey Alter: I remember Dr. Fauci telling me years ago, after AIDS was under control with medication not cure, but under control with medications. He said his greatest fear was a new respiratory virus for which we did not have a treatment or a vaccine. And that's what has played out with COVID. A easily transmissible agent with potential dire consequences for which we do not as yet have a good treatment or a vaccine.
Claire Stinson: Right.
Harvey Alter: We're in a much better place than we were with hepatitis C, however, because now molecular biology is incredible. Technology is so advanced. So we actually knew then within weeks of the Wuhan epidemic, the Chinese had sequenced the virus and I'm surprised that nobody has yet come up with a designer drug for COVID or SARS-CoV-2, similar to what they have done for HCV. You have to crystallize the structure and see where the sequences fall and determine which is the critical replicative sequences. But they're very close to that.
They really know exactly now where the antibody fits in under the spike protein. And I think we'll come up with a drug that might prevent the attachment or another drug that might prevent the replication. So I think that's going to come this coming year.
Claire Stinson: We'll be right back with Dr. Harvey Alter.
During this season of Contagious Conversations, we want to recognize all of the public health heroes who are working behind the scenes and on the front lines during the COVID-19 pandemic and protecting us from many other health threats. Thank you for all that you do every day to keep us healthy and safe.
And now, back to our conversation with Dr. Alter.
Well, it's been an interesting year for all of us. Dr. Alter, you've worked at the National Institutes of Health for several decades. People who are just now starting to understand the role health sciences and public health plays in everyday life, can you talk about the importance of organizations like NIH and CDC, for example?
Harvey Alter: Yeah. Critically important. I mean, this work could not have been done anywhere else besides NIH. I was given the freedom to keep pursuing this. Our department was given a research budget and my department chiefs provided the funds for some of the research. I collaborated with other institutes that provided the chimpanzees, that provided the liver biopsies.
Claire Stinson: Do you see a shift in people's awareness about the importance of public health?
Harvey Alter: Well, we're a divided country and I think the recognition is also divided. I mean, it's just a tremendously split country where some people believe science and some don't, where some people wear masks and some don't. I hope that will change. Denial has never worked and science has almost always worked. So that's where I hope we don't play out that way.
Claire Stinson: Right. And it certainly seems like a lot of people that never thought about public health are now thinking about it.
Harvey Alter: That's true. That's true. I think Dr. Fauci has been such a model of fortitude and integrity, and he's given science a good name.
Claire Stinson: Absolutely.
Harvey Alter: And I think he resonates with much of the country. I think we have Fauci donuts and Fauci bobbleheads, Fauci this and that and he deserves it. He's done an amazing job in a very, very difficult time.
Claire Stinson: Well, you've contributed so much to the field of public health and we're indebted to you for that. In the press conference for your Nobel Prize win, you mentioned that eradication of viruses like hepatitis C hinge not on further research or therapeutics, but on political will and making drugs available to everyone through insurance or low cost. What do you see as some of those main barriers or challenges?
Harvey Alter: Yeah. As I alluded to, because the drugs for hepatitis C are so efficacious and so easy to administer and so free of side effects that you don't even need to have better drugs. Maybe there will be better drugs coming along, but right now you can cure people in 8-12 weeks with a single tablet a day a and these are cures. These are not just controls. These are cures. So a single tablet a day for 12 weeks with virtually no side effects, it's just amazing.
Claire Stinson: Right.
Harvey Alter: So we don't have the vaccine because it just like HIV. It's a very highly mutable virus. And it's very difficult to get a vaccine that would hit all the variants that exist in any given person any time or that any new person might be infected by. So you might have to have a vaccine that gets changed every year, like flu, and that's not a very good situation. So the vaccine story is still on hold, but to eradicate without a vaccine... There are a 170 million people, I think, infected throughout the world and only a small fraction have been treated.
So you have to have national testing, not only in the developed world, but in the developing world. That's how a lot of testing, you have to have the resources to do the testing. And then to link that to these treatments. The treatments are much more affordable in the developing world, the companies gear their pricing to what people can afford and there's been a lot of help. I think there will be programs like for HIV, like PEPFAR, like Gates Foundation, the CDC global initiative.
So if there was the will to do it, to set up massive testing program, to link that to affordable treatment, it could be done. And it requires an investment of the public health services of all the nations, or the World Health Organization, of philanthropic groups, of governments. Everybody's got to combine to say, "This is something we want to do. It's important to do." And when you have that will, which John Ward from the CDC, or former CDC, has with his group of global eradication of hepatitis C.
If you get enough people behind it, the amount of money is large but it's been shown that treatment is cost-effective for hepatitis C, if you prevent cirrhosis and liver cancer. So it's a good deal for everybody and I think it'll happen. I really do think it will happen.
Claire Stinson: Well, I appreciate the optimism. It sounds like it's going to take collaboration though.
Harvey Alter: Definitely collaboration. It has got to be a global effort. And you also have to change some other things. Nowadays the only way you get hepatitis C in the U.S. is through drug injection, drug use, sharing of needles.
Claire Stinson: Right.
Harvey Alter: So you need to approach that population as well. And in the developing world you need to change medical practices. You’ve got to make sure there's no reusable needles, reusable medicinal vials, scarification procedures, tattooing with unsterilized needles, all that would have to change as well. So it's a big deal and it's going to take a decade maybe, or more, but could happen.
Claire Stinson: Absolutely. So, Dr. Alter, you've had an incredible career. What's next for you in the work to try to eradicate hepatitis C?
Harvey Alter: Well for me, not a lot. I'm near the end of the line.
Claire Stinson: No.
Harvey Alter: Yeah. I've been lucky to be healthy and to not perhaps show my age as much as it is, but there comes a time you have to stop. I already retired and then came back emeritus and now I've come back for another year as a part-time employee. But the work goes on. There's always young people to take over. There'll be people fighting for hepatitis C and now a lot for hepatitis B, that's become a big player. So there's enormous effort going on and it doesn't require me anymore.
Claire Stinson: But you provided the foundation for that work, that must make you feel so proud.
Harvey Alter: That does. I acknowledge that and I'm happy. I couldn't have done it by myself, there's been so many people who've helped me and I've found that my collaborators have been my mentors as well. I've learned so much from the people I work with here. So I'm in a place I never expected to be, very grateful for that. I personally, I've gotten much more than I ever expected out of my career, I've loved it. I love books. I love research. I love clinical research. I love being at NIH. It's hard to give up, but there comes a point where you got to give it up and you just go back to your family and enjoy the fruits of your labor.
Claire Stinson: Well sure. And you've had such an incredible career, it's well-deserved time. So Dr. Alter, here's a question I often like to ask guests on this podcast. What advice do you have for the future health and public health leaders of America that may be listening today?
Harvey Alter: You know, I've been asked a lot to give advice to young researchers and I guess what I say for young researchers would apply to public health people in general. You need to have a passion for what you're doing. You need to be in a good place, a place that is dedicated to research, to delivering healthcare, to improving the safety of the world from medical diseases. If you're lucky, you'll be at CDC or NIH, but there's many academic institutions who have the same goals.
So if you're really young, I advise find not only a good place but a good mentor. Find somebody who doesn't just want your hands, they want your mind, and they want to advance your career. Get into an established laboratory where you can find a niche and then expand your own niche. I tell people to try to become an expert in one area and not to jump around too much but get to an area where you know a lot and you become an expert other people seek out.
Or collect samples in a well done study where the samples or your patient population becomes valuable and induces collaborations. Mainly be collaborative, don't be possessive. You can't do it on your own anymore and just try to work with others to whatever goal you have in mind, that'd be my main advice. Oh, and be persistent. All of this, both hepatitis B and hepatitis C, the results are kind of dogged persistence, first by Dr. Blumberg on hepatitis B.
But I learned that from him, the hepatitis non-A, non-B, C story took 30 years to completely unfold, maybe 40 years. So if you're onto something stick with it, and sometimes you got to take some risks and go off the beaten path to find something. But just know that you may find something you don't expect to find, as happened in my case.
Claire Stinson: That's great advice. And we appreciate you sharing it with us as you are a recipient of the Nobel Prize in Medicine this year. Thank you so much for your time today Dr. Alter and for sharing so much about your research. It was an honor to speak with you.
Harvey Alter: Thank you very much. I enjoyed it.
Claire Stinson: Thanks for listening to Contagious Conversations produced by the CDC Foundation and available wherever you get your podcasts. Be sure to visit cdcfoundation.org/conversations for show notes and bonus content. And if you like what you just heard, please pass it along to your colleagues and friends, rate the show, leave a review and tell others. It helps us get the word out. Thanks again for tuning in and join us next time for another episode of Contagious Conversations.