Life and Times of Leading Cardiologists: Joseph Hill

E. Magnus Ohman, MD: Hello, I'm Magnus Ohman, and I want to welcome you to another edition of Life and Times of Leading Cardiologists. We're very fortunate to have Dr Joe Hill here from Dallas, Texas, who is professor of medicine and molecular biology at the University of Texas Southwestern Medical Center. He is a well-known cardiologist, and probably best known to all of you as the editor-in-chief of Circulation, one of the premier journals in cardiovascular medicine. Welcome.

Joseph A. Hill, MD, PhD: Thank you, Magnus. It's my pleasure to be here.

It Started With 'The Bear'

Ohman: You have done a lot of things throughout your life that led to the editorship of Circulation. I think most of us would be interested in how you got into science. Where did it all start?

Hill: One of the joys of an academic career is the plasticity of the career path. I went to a high school in Burlington, North Carolina, which was a fine place. I told my sons that the high school they went to was 10 times better. But a chemistry teacher influenced me to such a level that I knew science was my future. I went to Wake Forest and majored in chemistry and math. I had a great time there. I came close to going to chemistry graduate school but decided that I really wanted to do research in something that was closer to the human condition. So I went down the road to Duke because the curriculum there allowed for a year of research in the third year. After about 6 months into it, I realized that it was not going to be enough. I was not going to be close to becoming a scientist at the end of that. So I matriculated into the MSTP (Medical Scientist Training Program), finished my PhD, finished medical school, and graduated from Duke.

Ohman: That is quite a unique story. For those people who don't live in North Carolina, this is Tobacco Road, a term for [rival] basketball country. You went to Wake Forest and Duke, so who do you root for? North Carolina because you lived in Burlington?

Hill: I don't pull for Carolina. I recognize that you have Carolina roots. I've moved around enough that my allegiances have sort of migrated with me to the different universities I've been in.

Ohman: Tell us a little bit more about this chemistry teacher. It's quite unique to get somebody who sparks you like that so early on.

Hill: We called him "The Bear," and a couple of others also really bonded with him. I was fascinated by the intricacies and the predictive capacity of chemical equations, and so forth. As I said, I majored in physical chemistry at Wake Forest. I ended up working with Harold Strauss, whom you knew well. I thought incorrectly that cardiac electrophysiology was the most "mathematizable" area of cardiovascular medicine. I still think we're not there yet—certainly we were not there 25 years ago.

Ohman: You were sort of right at the time. We used medications in those days to treat arrhythmias, which is pure chemistry. It turned out that that didn't work out so well. It's just fascinating how in the early part of scientific study you can hook onto something and then your career goes somewhere else.

Hill: The biophysics of ion channels and ionic currents is something we use equations a lot for, of course, but we're nowhere near using that to predict someone's risk for proarrhythmic events with an antiarrhythmic drug.

Family Life

Ohman: Tell us a little bit about your family. Are you an only child or do you have siblings?

Hill: I have a sister who still lives in Burlington. She is a certified public accountant (CPA). I had an older brother who was killed in an automobile accident when I was in college. I've lost both my parents, so my family roots in North Carolina are with my sister, Janet.

Ohman: Was anybody in the family in medicine?

Hill: I was the first one. My father was a CPA and my sister is a CPA. I did a lot of accounting spreadsheets in summers to earn a little money. Jumping into the future, I have two boys. Both of them are going to medical school in the future. Both want to do MD/PhDs, not because I tried to talk them into anything, but I'd be lying if I said I was disappointed. I think they came home to the dinner table and saw that their dad was exhilarated with what he does. The younger boy, who is at Vanderbilt, wants to do science—maybe neuroscience. The older son just graduated from Duke and spent a summer in Uganda working in an HIV orphanage. He came back a different young man. I remember him telling me, "Dad, I don't understand why it's like that there and this here, but I've got to figure it out." So he changed his major to public policy and he is focused now on understanding the interactions with the underserved. In fact, he is spending 2 years with Valentin Fuster working on his FAMILIA Project at Mount Sinai.

Choosing the PhD Route

Ohman: That is fascinating. We will come back to your children in a little bit. What made you decide to complete a PhD? Most people who say they need a little bit more science might do an extra year. It is a big commitment to do a PhD.

Hill: I figured out early on that 1 year was nowhere close enough. An analogy that I use sometimes is that learning to be a scientist is like learning to swim. The first thing you do is get in a pool and splash around and see if you like being in a pool. That is a 1-month lab experience. The next is to say, "I'm going to take some swimming lessons to see if I like this." That is a year. That is what the first year at Duke provides. You do some science and decide, "I kind of like to swim so I could be a competitive swimmer." But if you want to be a competitive swimmer who wins races and gets his grants funded and papers published, then you have to train. That is where the extended PhD and post-doc comes in. I see a lot of people who try to shortchange that and that is a real problem. You don't want to start that tenure clock unless your engine is already in third gear. You don't want to still be climbing that learning curve toward the bottom end when the clock starts ticking.

Ohman: You finished your PhD and MD. Where did you go from there?

Unexpected Detour to Paris

Hill: The plan was to do my internship and residency. But I married this woman who told me that we were going to Europe because she was going to do a PhD at the Sorbonne on the history of science. She studied the 17th century emergence of the mechanical worldview in France when there were two competing schools: one in Paris allied with the king and one in Montpellier aligned with the pope. What the patron said influenced what the science was. A mechanical worldview was emerging in Paris but a Paracelsusean view with humors and vapors was held in Montpellier. Over the course of the 17th century the mechanical world view of atoms bumping into each other came to the fore.

I worked hard to get a post-doc in Paris and I managed to secure one with a very famous scientist named Jean-Pierre Changeux, who was the first person to clone an ion channel. The plan was that [my wife] Beverly and I would go there for a couple of years and then I'd get on with my internship before I forgot the doses of Lasix [and other medical information]. But, after 2 years, we said, "This is changing our lives." We traveled, learned another language, and saw our homeland through the eyes of another culture. We stayed 5 years, and it was one postdoctoral fellowship after another. We actually ran out of money twice. Finally, we were done and headed back.

Ohman: It's a quite a culture shock to go from Burlington, North Carolina, to Paris. How did you assimilate to that culture shock?

Hill: It was a shock. I'll never forget getting out of the airplane at Charles de Gaulle Airport thinking, "This has to be a big mistake."

Ohman: It's not just that there is no basketball, it is a whole change.

Hill: Everything. In Changeux’s lab, we had 3-hour lab meetings in French. That is an incentive to learn French quickly, right? I never really studied French but sort of learned it in the lab. Even today, I can speak French in a colloquial manner. I can go to a movie and understand the colloquial language but I don't write it very well. Whereas my wife, who studied French, is the other way around. She writes this beautiful French from the 19th century but she has trouble with slang.

Sommelier Scientist

Ohman: You are a perfect experiment of how immersion works. Did you pick up any other French cultural aspects while you were there?

Hill: I was interested in wine before I went there and became more interested in it. I ultimately studied to be a sommelier on the side because I'm fascinated by wine. It is art for the mouth. I wanted to fill in the holes in my knowledge base and, frankly, I wanted to find the good wines that cost $20 or less. I managed to do that; I rarely drink a bottle that is more than $25.

Ohman: It was really financial preservation more than anything else. I think you told me in the past that sommelier is a French word meaning "wine mule." How long did the process of learning to taste wine take?

Hill: There are three levels. The first level was 6 weeks, the second level was 3 or 4 months, and the third level was 9 months. There are two schools. I went from 9:00 AM to 6:00 PM two Sundays out of three for 9 months and did a lot of reading on the side. It was intense—probably more than I wanted. I really don't care about the rainfall in southern Chile—those parts didn't fascinate me. But it's a fascinating world. If you think of the equator, just north and just south is where you grow money crops like corn, wheat, and soybeans. But just north of that in the northern hemisphere and just south of that [in the southern hemisphere] where it's too cold to grow money crops is where wine is made. The circle in the northern hemisphere and the one in the southern hemisphere have been completely filled in and there is wine all around those zones.

Ohman: This chemistry major from Burlington, North Carolina, becomes knowledgeable in both France and French wine. Have you used this knowledge in your life besides for buying the $20 wine?

Hill: I don't like to pontificate about it. When I'm at a table where people are ordering everything from spicy meat to a simple fish I'm able to pick something that generally will match all. That is a useful social skill. I find it absolutely fascinating. It's a merging of science and art and it is evolving. The science behind viticulture and viniculture is evolving rapidly.

To Boston and Brigham

Ohman: You finished your PhD and spent 5 years in France. Did you have some children while you were there?

Hill: No, we waited and had our first son when I was in Boston. I trained at the Brigham and he was born there.

Ohman: You finally got to your internship. How was the first week after that long of hiatus?

Hill: I was terrified. I actually came back a month early and functioned as a medical student for a month so I could pick up some of the numbers again and because it was a new hospital and institution for me. They allowed me to carry one or two patients for a little bit and that worked out just fine.

Ohman: You finished your residency and then went into cardiology fellowship also at the Brigham. You have a very strong science profile. How were you able to maintain your science? Was some accommodation made in your fellowship to allow you to build on what you were working on?

Hill: There was. One of the things that attracted me to the Brigham was their so-called Braunwald residency, colloquially termed the "Hemi-Doc" program, where they would pair up somebody like me with another person. I did 6 months of internship, 6 months of second year, and a full third year. Rather than doing a lot of H and P's in internship year, it was weighted back toward the more cognitive elements in third year. I worked in a lab with Bernardo Nadal-Ginard during that period where I had 6-month blocks. I actually wrote a grant, got a little money, hired a technician, and had my own little lab when I was a fellow. That sounds more bark than bite. It was hard to get much done when I was talking to my technician at 6 PM after being in the cath lab all day, but I did knock out a gene during that period of time. I kept things going on a little bit.

Getting a 'Real Job'

Ohman: That is great. You finished fellowship. Now you had to get a real job. What was the selection path?

Hill: At that point, we didn't have any geographic constraints whatsoever, so I sent out letters all across the country. Thomas W. Smith had just died and they were recruiting a new chief (ultimately Peter Libby), so the Brigham was not an option at that point. I got a callback from a man named Don Heistad at the University of Iowa. I pulled out a map because I was not exactly sure which side of the Mississippi Iowa was on. I flew out for a visit, and when you fly to Cedar Rapids you think you are going to land in a cornfield. I thought, "Wow, this isn't going to work for me." I had dinner that night with Don, the chief of cardiology, and two Howard Hughes investigators, Kevin Campbell and Mike Welsch. That impressed me. Don said, "Joe, what are you looking for?" I said, "Dr Heistad, I don't have geographic constraints but I want to go to a place that will mentor me because I feel as though I'm standing in front of a dark wood. I don't know what the rules are. I don't know what tenure is. I don't know if I need one grant or four grants. I don't know if I should go this path or that path. I want to go to a place that is as invested in me as I am in my own success because I don't know these rules." And the three of them started laughing. I thought, "OK, this is probably not good." Don said, "I bet you're wondering why we're laughing." I said, "Well, honestly I am." He said, "Because Joe, that's a Harvard question. That question doesn't make sense at Iowa. Of course, we would do that if you came here." I thought, "I'm coming." I picked up and moved my family down to Iowa City.

Shifting Research Interests

Ohman: Wow, that is a big change. The research started going really well for you. It shifted away from ion channels to being more about diabetes and obesity. How did that transition come about? I think a lot of people start out on a path but science takes them elsewhere.

Hill: To be a good scientist you have to have "intellectual fortitude," as Joe Goldstein calls it. You go where the data lead you. I read a paper by Eric Olson, whom I didn't know at the time, describing a molecule called calcineurin that when activated would lead to dramatic hypertrophy and failure of the myocardium. At that time, we were banding the aorta in these animals because we were looking at action potential repolarization. Eric had shown that that pathway was sufficient to grow the heart in a pathological way. I wondered if it occurred in the context of a disease-related model like elevated afterload. So we took mice, banded the aorta, and randomized them to get a calcineurin inhibitor or a vehicle injection. I went in every single morning and injected those mice for 3 weeks. At the end, we echoed and sacrificed them. The heart was either huge, as you'd expect from transverse aortic constriction (TAC)-induced afterload, or it was normal in size. And, of course, the ones that were normal in size were the ones where we had delivered cyclosporine, a calcineurin inhibitor. It was completely a binary response.^[1]

That suggested very strongly that this pathway was clinically relevant in that model. I'll never forget when I was on the 10th floor of the VA doing echoes with a colleague. We both said to ourselves, "If you raise blood pressure 80 points and prevent the heart from responding with compensatory hypertrophy, it's going to dilate and fail." Not at all. That was the shocking part. We published that in the year 2000 in Circulation and that observation has been replicated way over a hundred times but only in mice. We're finally testing that hypothesis in monkeys in China, where we have developed a TAC model with a collaborator in monkeys. It takes about 4 months rather than 3 weeks, but it grows and plateaus off. Its contractile function remains normal for several months. We are currently randomizing these animals into three groups: vehicle injection, cyclosporine, or an HDAC [histone deacetylase] inhibitor. We'll ask two questions: do either of those two block hypertrophy or not, and if so, how does the left ventricle respond to that suppression?

Ohman: You went to Southwestern in Dallas mainly because Eric Olson was there, I presume?

Hill: That was part of it. They offered me the chief of cardiology position at the time.

Ohman: That's a job good to have.

Becoming Editor-in-Chief of Circulation

Ohman: You have published a lot yourself, but how did you become interested in publishing? This is now what you are working very hard on. How did you get to the next level where you're managing a whole journal?

Hill: I stumbled into that. Eugene Braunwald has been a mentor and sponsor. He thinks about his trainees and proactively reaches out to them. He called me on the phone and said, "Joe, you should think about the job." It had not crossed my mind. I gave it some thought, became increasingly excited, and threw my name in the hat. I did a lot of research and prepared for it, and here I am.

Ohman: You've done a great job with that journal. What is next for Joe Hill? Is it going back to France and trying out wines or is it some other part of science?

Hill: There is an apartment at the base of the Rue Mouffetard that I would like to own, and I'm waiting for the current occupants to get out of it. I'm having the most fun in my science now and I would not do anything to give that up. And I really love working with Circulation. It's a lot of work and an everyday thing but I love it. I don't really know what is next. But many times these turns are unanticipated. I surely didn't think I'd live in Paris. I surely didn't think I would be in Iowa City for only 5 years and then in Dallas. I surely didn't think I'd ever edit a journal. Who knows what lies ahead?

PhD vs MD Debate

Ohman: It's wide open for you. I think it's interesting that not many physicians in the United States do PhDs but it is more common in Europe. What is your opinion about the PhD level of science versus the MD and basic science?

Hill: I think that one of the major limitations in our world is that the PhDs and the MDs don't talk to each other. I have many smart PhD people—smarter than me—who don't understand what heart disease looks like. They never worked with it. I know many practicing cardiologists who can tell you everything there is about what disease looks like but they don't have the tools to address it. I've tried many times in my institution to bring those worlds together. We're starting something in Circulation that was just released this week called "Ventricular Phenotyping Reviews."^[2] By that I mean I have many friends who are way more expert than I am in signaling and transcription and metabolism and so forth but they have never been in an echo lab. They don't know how to evaluate the ventricular dimensions and contractile performance—asystole and diastole—in a heart. Not in a human heart, not in a large animal, not a mouse. We can help them there. When ventricular phenotyping in a study in Circulation comes in we have identified some reviewers who will spend just 2 days to help them on whatever they're using—M-mode, B-mode, MRI, invasive hemodynamics, etc—and help them know what to do to make their observations compelling. That is an example of how clinicians who know all about echo and evaluating contractile performance can help the PhD optimize their science.

Ohman: Your vision is a wonderful one of bringing people together and making the science go forward. It's tremendous for me to hear your story because, as you said, it wasn't like you went A, B, C, D. You went A, A5, B6, and around. I want to thank you for sharing all these observations with us. It's been wonderful. Thank you, Joe.

Hill: Magnus, you have been a friend for a long time. Thank you for giving me the opportunity.

Ohman: Thank you. And thank you, the audience, for participating with us.