Mysteries of the Heart: A Conversation with Cardiologist and Researcher Robin Shaw
When it comes to understanding the human heart, we think we’re pretty smart.
We know that the heart is basically a pump for what is literally our lifeblood. When the arteries carrying this blood clog up with residue, they can be cleaned out or repaired, or portions of them can be bypassed surgically.
Or we can swallow drugs that minimize the risk of clogs.
Whatever the method, the perspective is clear: Artery health is heart health.
UCSF’s Robin Shaw, MD, PhD, says, well, not exactly. From his perspective as both a doctor and a laboratory scientist, it is the heart cells themselves that should command at least equal attention. For starters, we don’t even know how many heart cells there are. It could be millions. It could be a billion. They assemble early in gestation and organize themselves into a complex, densely packed urban environment with elaborate communication networks.
Robin Shaw
Why? Heart cells must contract in an orderly fashion or we’re in trouble. They also must be able to react to changing circumstances – like aerobic exercise, for example. Or danger. In short, they need to be steady and supple, and to work in concert. Communication is essential.
Shaw studies this communication network – specifically, ion channels and what are called “gap junctions” between heart cells. These junctions are the bridges over which signals flow.
To his surprise, his research has now revealed that these bridges disappear in a sequential manner every hour. It’s a mystery, but one Shaw relishes – he’s a big fan of spy novels – and one that could someday redefine what heart failure really means.
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Podcast transcript
Miller: Hello I’m Jeff Miller and welcome to Science Café, today I’m here with Robin Shaw, assistant professor of medicine in the department of cardiology at UCSF, and also an investigator at the Cardiovascular research Institute. Welcome Robin.
Shaw: Thank you very much.
Miller: I noticed you’re an MD-PhD, and as people who regularly listen to these podcasts understands, you are in a class of people I truly admire. I wonder how long did it take you to acquire both degrees?
Shaw: Well, to save myself the math, I’m 39 right now, I’ve been on the clinical faculty for four years now, and I’ve been an independent investigator for one year.
Miller: So a lot of time, studying and learning, was all that time worth it?
Shaw: Absolutely.
Miller: Why do you say that?
Shaw: There’s a lot of time involved in the training, but the training essentially is the career. It’s a career of investigation. And I’ve been involved in investigation since my early twenties.
Miller: So I’m sure you’re aware that there is a decline in the number of MVPhDs, at least in the U.S., is that something you think about of worry about or discussed as you were acquiring both degrees?
Shaw: Absolutely. The landscape has changed write a bit since I started training. I entered medical school in 1990, so roughly 18 years ago. Two generations ago, it was sufficient for a doctor to do science, however, the practice of medicine has become so much more technical, that the training of physicians is more clinically oriented than it used to be, and what’s lost there is the basic science background for physicians. At the same time science has made remarkable advances in the past several decades, and so the training of science has left behind the general physiology, let alone path of physiology from which we derive a lot of our basic questions. And so there’s been a polarization between science and medicine. And guys like myself, MD-PhDs, try to fill that void.
Miller: Do you feel sometimes you’re not welcome in either camp? I know you’re early in your career, but I wonder…
Shaw: It is tough, because ultimately, for real practical reasons, it’s good to have a home in an institution, and increasingly, the clinical home is not a shelter for scientists and a scientific home is not a shelter for clinicians. And so we end up really, one foot in each. And again, for very practical reasons, it’s tough to exist in both worlds.
Miller: Well speaking of other worlds, I know that you were born in South Africa. Did you come from a family of scientists or medical people?
Shaw: My uncle and my aunt are physicians; my father is a veterinarian and my grandfather a pharmacist.
Miller: Did you say you wanted to be a doctor when you were growing up?
Shaw: No, never,
Miller: What was your first career aspiration?
Shaw: I was headed along the computer science engineering route.
Miller: What made you switch?
Shaw: It was late in college, I started to get involved in research, I quite enjoyed research, but I found the questions I could as an engineer were not as exciting as the questions I could as a biologist.
Miller: And where were you going to college at the time?
Shaw: Brown University.
Miller: When did you come to the U.S.?
Shaw: I grew up in Florida; I was really only 7 years old when I came from South Africa.
Miller: Oddball question, but I’m curious: Do you have time to read novels or books that are about science, or mysteries – do you have a particular gene that you like?
Shaw: It’s a great question, and frankly, no. My time at home is spent on age-appropriate books for a 6-year-old and a 9-year-old and a toddler. Although my interest in reading, at least in the past, was spy novels. That’s my secret little pleasure.
Miller: So you like the term investigator I guess, the CVRI-
Shaw: I suppose so.
Miller: OK. Ion channel regulation, I know that’s the focus of your research, but before we really get into the details of that I’m curious if there are any common misconceptions the average person might have about the heart, the role of the heart, how it functions that you see or you hear or learn about in your interactions with patients or with others?
Shaw: I think we all understand the heart to be a complicated organ, but one misperception that I try to change is that the heart has many different gradations of working. It’s not as if the heart stops working, or works well. And the reason for that is that the heart, when you break it down to its elements, is composed of millions of individual cells.
Miller: So how many millions?
Shaw: Somewhere between a million and a billion.
Miller: No precise number?
Shaw: (laughter) No. I would guess roughly 200 – 400 million cells.
Miller: And these are largely cells that we’re born with in the infant heart, correct?
Shaw: That’s correct; once we’re born we generate very few new cells.
Miller: So the cells increase in size but not in number…
Shaw: Exactly.
Miller: So you mentioned the fact that people think of the heart as working or not working, but there are many gradations. What would be an example of something that’s percentage function that they don’t understand?
Shaw: When the heart pumps it can eject blood at its peak efficiency which is about 60% of the blood with each squeeze of the main pumping chamber, or it can inject 30% of the blood with each squeeze of the main pumping chamber.
Miller: There must have been something about heart function that attracted you in your research pursuits, and there must have been a lot of avenues you could’ve chosen so why this field?
Shaw: There is something fundamental about the heart. It has to work every second for us to live. When it stops functioning, we don’t have blood flow, and unless it’s restarted, we die. And so that fundamental aspect of the heart as a requirement for our existence, which is such a delicate balance -- that was the attraction.
Miller: Sudden cardiac death, something we hear about often when it’s a young athlete who dies in the practice field, or soon after a contest, how does that condition relate to the work you do?
Shaw: Sudden cardiac death is a misunderstood concept. The technical definition of sudden cardiac death is the heart stopping. That does not mean the heart can’t be restarted. And so when someone experiences sudden cardiac death, the heart no longer works as a pump, hence, there’s no blood flow. Now many of us are familiar with defibrillation, when people get shocks, either by an implantable defibrillator or the pedals on the chest that we’ve all seen on TV. The reason defibrillation works, say after a heart attack, is that the rhythm of the heart is restored. So going back to the millions of individual heart cells, these heart cells need to work in synchrony for the heart to work as an organ, for it to beat as a pump.
When there is sudden cardiac death, the synchronicity of cells no longer exists, so the individual cells might be contracting, but they don’t contract in coordination and therefore, the heart as a pump doesn’t work. When we apply electricity, we reset the synchrony. So for example in a heart attack, a small part of the heart is actually damaged, however, that small part of the heart can set off a generalized electrical disturbance to ruin the synchrony. When we shock, the small part of the heart is still not working, but the synchrony of most of the muscle is restored.
Sudden cardiac death really is an electrical issue, it’s an issue of synchrony of the heart, and it’s fatal unless reversed.
Miller: So how does the ion channel regulation of this process relate to that description you just gave?
Shaw: The electrical system of the heart coordinates the mechanical system. So the heart has a timer if you will, like a Quartz crystal -- the old watches, every second sets off a signal “hey, contract!” – and that signal passes throughout these millions of cells, which in each individual cell causes a contraction, and when that contraction happens together the heart works as a pump.
It’s the ion channels that carry these signals to contract throughout these millions of cells. So every second, ion channels are telling each individual heart cell to contract, and telling the next cell, their neighbor, “hey we’re going to contract, and you better contract as well”.
Miller: So this is the communication system among all the cells -
Shaw: That’s right. So there are ion channels that exist not only for individual cell, but between each cell. These ion channels are known as gap junctions.
Miller: So we’re not talking – a river way channel, but a communications system and pathway.
Shaw: That’s just it. I think of it as a passageway. But a highly regulated passageway.
Miller: What exactly do you study about these ion channels and what tools and techniques do you use?
Shaw: What I study is how these ion channels, these regulations of the electricity of the heart are formed, how they get where they need to go, and how this process is affected by a blocked artery.
Let me give you a metaphor. An individual heart is cell is roughly the width of an individual hair. That’s about 40 to a hundred microns across. And Think of that individual heart cell as being a city. One heart cell is San Francisco and the other is Oakland. Between SF and Oakland is the Bay Bridge, the Bay Bridge is essential for the Bay Area to function as a whole.
Now to carry that metaphor, the Bay Bridge is our gap junction, our communication between our two cities, or in the case of the gap junction, between the two heart cells. However, gap junctions are removed every hour. And so, going back to our metaphor, it’s as if the Bay Bridge disappeared every hour.
Miller: Why is that?
Shaw: We don’t know. That’s relatively recent knowledge. We used to think these channels were so important that they were there forever. They disappear and now ones replace it.
Miller: Every hour?
Shaw: Every hour.
Miller: What do you suppose is the evolutionary reason for that I wonder?
Shaw: It’s a fascinating question. And it speaks to the dynamic nature of the individual cells in the heart, and how they probably have to respond to stress. And so when, say, the heart gets an extra stimulus, or the heart gets an insult, how does it overcome those environmental factors, because again, the heart needs to beat for the organism to live.
How is it that the heart can respond so dynamically to many different kinds of stress…?
Miller: But doesn’t an hour seem like a long time?
Shaw: The overall turnover rate is an hour – so that’s where, honestly, the metaphor does fall apart, because it’s not just one Bay Bridge, there are many thousands of small bridges, that the overall turnover rate for each individual one lasts about an hour.
Miller: So we’re not without bridges completely, there’s one disappearing, but eh system continues, and the one at the back --
Shaw: And that’s exactly what we study. How is it that on average, there is always the same bridges…? How is it that there’s always communication between SF and Oakland… How is it in the heart, that there’s always communication between the heart cells… Despite the fact that it’s so dynamic.
Miller: So what do you think?
Shaw: And so what exists in individual heart cells are highways call it the cyber skeleton. Which helps set up the structure of the cells, but what we’re learning is these structural elements of the cells are not just there for structure, but there to bring channels to where they need to go. And so they’re not just structural components but they’re transport components of the cell. And this system breaks down when an artery’s blocked.
And so just to tie it into an earlier question of yours, ‘how does sudden cardiac death occur?’ It occurs when a blocked artery causes the heart cells to stop generating these proteins, to block these proteins. These proteins, which are channels don’t go where they need to go. That causes a decrease in communication between the cells which sets off an arrhythmia which upsets to coordination of the heart.
Miller: So, looking at it from the individual point of view, what can a person do when we talk about measures they can take to heart health. Does this information at all inform prevention methods that people can employ to maintain their own heart health?
Shaw: That’s a good question. The best of our knowledge today addresses not so much the muscle of the heart, but the arteries that feed the heart. And what I’m talking about is cholesterol. Atherosclerosis, coronary artery disease. How do we prevent blockages from developing in our arteries?
In time, what I hope this research will lead to is a new kind of therapy for the heart. If we accept that we’re going to have coronary heart disease and we’re not going to wipe it out, there are millions of Americans walking around with damaged hearts, who would love to restore health to their damaged hearts, and one of the ways we hope to do that is by improving the way the individual heart cells function. And by learning more about the biology of the heart cells, learning more about how they regulate the proteins which are essential for their function, we hope to understand how to improve function, when compromised by blocked arteries.
Miller: So this is where the fusion of the MD-PhD comes into play, you have a unique perspective on this problem.
Shaw: Perhaps not unique, but at least informed. I do both clinical care and basic science research. If you walk into my laboratory, it’s a basic science laboratory, no different than any other scientist’s laboratory at the University. The difference if you will in our approach is that the clinical insight informs the questions we’re asking in the laboratory.
Miller: Is there a specific example other than the more general one on ion channel regulation, something that maybe was a question triggered in your mind by a patient that you treated?
Shaw: Absolutely. I take care of a lot of patients who have heart failure, by definition that’s decreased pumping of the heart... Most of these patients have suffered damage to the heart as a result of blocked arteries, however a good subset of these patients have decreased pump function who have no more arteries. And the question is, why?
We term this kind of heart failure idiopathic cardiomyopathy – and I like to joke that when we as clinicians call something idiopathic it’s because we feel like idiots. We don’t know what causes it.
Miller: Can you give me a percentage?
Shaw: It would be 5 to ten percent of heart failure patients, and that depends with age group.
Miller: So the kind of work you’re now doing might help to explain this mystery.
Shaw: Absolutely. The reason I raise that example is that the basis of heart failure is that the cells don’t work well with each other. And the individual cells don’t work well enough.
And that’s a long ways away from how we traditionally thought about heart failure which is, well, blocked arteries don’t give enough blood supply to the heart, therefore if we improve the blood supply the heart’s going to come back to its normal function. What I’m focusing on is not so much the insult, but the actual heart cells themselveShaw: what causes them to be damaged, what is this process of damage at a sub cellular level, and when we understand that, we can understand how to improve how the individual cells work.
Miller: Clearly this must have implications for congestive heart failure patients as well, of which there are millions I believe, in the U.S.
Shaw: There are at least 5 million patients in the U.S. who have heart failure, there are half-a-million new heart failure patients that are added to that number per year in the U.S., --there’s a growing epidemic. Part of that is good news,
Miller: How so?
Shaw: (laughter) Sorry, I should explain. When patients suffer heart attacks as a result of what we do in the Cath lab, as a result of bypass surgery, as a result of stents, more patients survive their heart attacks. But as a result, they do suffer heart damage, they do suffer heart failure.
Miller: So part of this increase in number is a result of successful other procedures, but they do consequences -
Shaw: That’s exactly it. So for good reasons and bad, heart failure is an increasing health problem in the U.S.
Miller: You mentioned earlier about a new type of therapeutic medications – describe to me how that might actually work.
Shaw: This would be in the form of a drug, and when I think about the heart, I’m thinking about individual cells, and when I think about individual cells I don’t think about them as amorphous single units, I’m thinking about them as complex cities, going back to that SF and Oakland analogy. And so, what drugs are out there that can improve the way transportation works in this city? And what I mean about transportation, I mean how proteins are moved around in the cell. To go where they need to go. To not go where they shouldn’t go. And the more we understand of the biology of how these cells work, we will therefore be able to use drugs that affect these processes.
Miller: I can’t let you go without asking about the potential of stem cells in your work. Do you foresee any benefits?
Shaw: Stem cells are obviously a very exciting topic and our investigators are hot on the trail. Where the work I do fits into stem cell therapy is that any cells that are injected into the heart will need to communicate with the rest of the heart. For example, one of the earliest forms of stem cell therapy in humans was taking skeletal muscle precursor cells and injecting them into the heart to improve the heart’s ability to contract. And what happened from earlier trials that occurred in France is that patients died from arrhythmias, and the reason was the cells that were injected did not communicate – they may work individually as muscle cells, but they couldn’t work in concert with thee rest of the heart.
It was shown as recently as a few months’ ago in a very exciting study, if the skeletal muscle cells are modified to include these communication proteins, these gap junctions we were talking about earlier, the arrhythmias can be resolved.
So where my work comes in, is how the cells injected into the heart communicate with the rest of the myocardium. And that’s going to be, I think, a very exciting area of research in the next decade.
Miller: Robin thank you for that glimpse into the future and thanks for joining me on Science Café.
Shaw: Thank you Jeff.