Heart of Hearts: A Conversation with Pediatric Cardiologist Harold Bernstein
Did you realize that the muscle cells of your heart stopped dividing within weeks after you were born?
Think about that for a moment.
The heart of a newborn is about the size of a walnut. An adult heart is the size of a fist. If the heart is not adding new cells, how does it get bigger?
The answer, says pediatric cardiologist Harold Bernstein, MD, PhD, whose professional life spills from his research laboratory to patients’ rooms and back again, is that the individual cells simply get larger.
Unlike the hearts of amphibians, human hearts do not possess the innate ability to repair themselves. So when disease ravages this finite amount of heart muscle, the heart has to do more with less to keep us alive – or, in the worst cases, be replaced by a transplanted organ.
Harold Bernstein
It is this finality that makes Bernstein’s research on the developing heart so promising. You see, there is a brief window in the few weeks after birth when complicated heart surgery can be thoroughly successful. Why? The infant organ retains a degree of plasticity that allows it to remodel and rework itself. Perform the same operation a few months later, says Bernstein, and the infant might never fully recover.
Solving this profound mystery could be the key to an amazing array of new heart therapies. And while Bernstein celebrates the potential benefits to patients, you get the idea that finding out why hearts develop as they do will be just as exciting to him as figuring out how to make them whole again.
Alternative content
Related Links
Podcast transcript
Jeff Miller: Hello I’m Jeff Miller, and welcome to Science Café. Today I’m with Harold Bernstein, associate professor of pediatrics, in cardiology, a senior investigator in the Cardiovascular Research Institute, a member of the Institute for Regeneration Medicine, and a practicing pediatric cardiologist in the pediatric heart center. Welcome Harold.
Harold Bernstein: Thank you.
Miller: A lot of titles, when do you have time to breathe?
Bernstein: It’s interesting, it’s probably the most daunting aspect of the career of the physician-scientist, to try to blend all of these interests and responsibilities, but somehow it works.
Miller: So, MB PhD, a long training time– how long in your case?
Bernstein: I think my first faculty position happened when I was 37, so yeah, quite a protracted time for education.
Miller: And do you advise this career choice for others?
Bernstein: Well, I think it depends, I think in my case it took that long for me to achieve what I needed to to get here. I think certainly there are other routes to doing this. I think certainly if you want to take care of patients you need a medical degree, and I certainly have colleagues with medical degrees who do incredible research without having necessarily, formally gotten a PhD, but-
Miller: So you do you split your time between lab and seeing patients, and if you do, how do you split that up?
Bernstein: I probably spend 70 percent of my time in the lab doing research, and 30 percent of my time involved in both patient care and medical teaching activities.
Miller: So, let’s think back a little bit on your childhood, was this a career you could have imagined yourself doing? Maybe there was someone in your family who was a scientist, a doctor…
Bernstein: Actually, not. I grew up in a family where there weren’t any doctors of scientists, although I have to say my father was a closet physicist.
Miller: How so?
Bernstein: He had studied physics in college even though he did not have a career in science. When I was very young I remember us doing experiments in electricity and sound and light at home, because he was just interested in that, and even now at the age of 84 he still sends me articles to read and has this insatiable intellectual curiosity.
Miller: So how did you end up in the field that you’re currently in?
Bernstein: Certainly in college I had mentors or role models who really steered me towards biochemistry and molecular biology. I remember sitting in an introductory biology class and having Walter Gelbert give a lecture where he basically said ‘I’m not going to talk about what I had scheduled because there was a recent article suggesting that the DNA sequences of mammalian genes are interrupted by entrons and we have no idea what these are’. And he then went on to expound for about 90 minutes about this, and I thought this was incredible – I was watching something really important unfold and at that point I realized that’s what I wanted to do, I wanted to learn how things work, and I wanted to be a scientist.
Miller: I did look at your resume and I notice you spent some time as an intern in UCSF working with the legendary Abe Rudolph, so tell me about that experience.
Bernstein: By the time I started my clinical training I already knew that I wanted to practice pediatric cardiology, and in fact one of the reasons that I sought out doing residency training in pediatrics here in UCSF was because Dr. Rudolph was in care of pediatrics at the time, and this would be the best place to come.
I’ve been very fortunate to have an ongoing mentoring relationship with him, and in fact he’s still a professor emeritus and his office is right across the hall, and so -
Miller: You consult-
Bernstein: I happily get to see him couple of times during the week.
Miller: I know your field of research is the developing heart, and the role of stem cells and perhaps some therapeutic advances, so why don’t you give me some general ideas about the thrust and the direction at this point?
Bernstein: Well, I guess we became interested -- a big part of our endeavor is to use human embryonic stem cells to both model the development of heart muscle, and to explore these cells as a potential therapy for damaged cardiac muscle. And I think we were led down this path when a few years ago we were doing studies in muscle repair in the mouse, and we realized that the way muscle is repaired in rodents actually is different than the way in which it’s repaired in humans, and that in humans, the stem cell repertoire in humans may actually be much broader, and there may be much more opportunity in humans to take advantage of different stem cell populations which is much more restricted in the mouse.
Miller: It’s true that the cardiac muscle cells stop dividing soon after birth, correct?
Bernstein: That’s correct in both cases, but it was at that point we realized that if we really wanted to explore something that would be valuable to humans, we needed to work in a human system.
And that’s when we started to make the transition to really work with human embryonic stem cells as a tool, both the study the development of heart muscle as well as how we might manipulate that to treat disease.
Miller: So, what happens when a heart gets damaged, and what might this potential therapy do to alleviate it?
Bernstein: What we find is that the adult heart, and by adult I mean patients who are everything from several months old, an infant, to an adult like you and I, when cardiac muscle is damaged, there really is no inherent repair process that can replace the damaged muscle, and so the heart is left with whatever living tissue has not been damaged.
In some cases if that damage has been very small, the heart does a good job of compensating. But in many cases where the damage is severe, the heart can’t compensate, and as a result it puts stress on the rest of the heart, to work in a way it’s not meant to, and over time that results in heart failure. And currently, aside from medications that can help relieve some of the symptoms of heart failure, really the only definitive treatment we have is cardiac transplant.
As a pediatric cardiologist, we know that as limited as adults are for adult heart transplant recipients, they’re even more limited in children, which makes this an even more pressing issue in children who have sustained injury to their heart muscle.
Miller: And that injury might be as the result of some genetic defect, or physical injury?
Bernstein: Probably the majority of pediatric patients that we see have had some damage to the heart due to either a viral infection that has caused inflammation and then resulting cardiac injury, or someone who is born with defective muscle proteins and so they’re more prone to damage-
Miller: So it takes time for that to show-
Bernstein: But there is also a growing number of patients who had been born with abnormally structured hearts – they have a congenital heart defect, and they have undergone surgery to help palliate, or improve their heart’s function with that defect, but they still don’t have normal hearts, and we find that those patients as they get older, their hearts began to fail.
Miller: You said a growing number, so I don’t want to let that slip by – why would the numbers be growing at this point?
Bernstein: It’s interesting because it’s not growing because more patients are being born with these defects, it’s growing because we’re getting better at saving them early in life. So 30 years ago these patients would have died as infants, but over the past 30 years as surgical and interventional techniques have improved, we’ve been able to save these infants, who have gone on to grow up to become children and young adults.
And this is the population of patients with congenital heart disease that we’re now facing who have developing heart failure.
Miller: So when a heart is damaged, is there a percentage of functionality that determines whether or not the heart can manage on its own or whether it’s severely compromised – so is it 50 percent, or if you have 60 to 70 percent function that’s going to be OK?
Bernstein: I think that in the adult population who start off with essentially normal hearts there are parameters that suggest when your heart is functioning at least at 30 or 40 percent of its capacity, it can function fairly normally, although it may be starting to trend towards failing. In pediatrics it becomes much more complicated, especially because these patients don’t start off with normal pumping chambers, and in some cases patients are born with a pumping chamber that really wasn’t meant to do the job that we ask of it, and so it’s hard to put a number on that.
And so instead we really assess these patients in terms of what they’re able to do, and whether their heart in particular is able to meet the demand that’s placed on it by their activities.
Miller: How does a heart actually grow from a child to an adult size if their heart cells cannot regenerate or add. How is it actually increasing in size?
Bernstein: What we know from studies mostly in mice and rats, and then subsequently in some human studies, is that somewhere midway through gestation – so when you’re about a 20 week old fetus – the cells comprising the heart muscles stop dividing. They continue to divide to a certain extent – but by the time you’re born, less than 10 percent of those heart muscle cells are dividing, and within about three weeks, really an imperceptible number of dividing heart cells can be seen.
When the average human baby is born, its heart is about the size of a walnut, and yet it has to grow into adulthood to the size of a fist. And it does that predominately by each individual cell growing in size. So the cell number doesn’t increase, but each cell itself grows in size -
Miller: Muscle up – they all muscle up--
Bernstein: That’s essentially how the heart grows.
Miller: Why do you suppose, in evolutionary terms, heart cells were not given the capacity to regenerate?
Bernstein: Hmmm, so what’s the teleology…I would venture that, heart cells are asked to do a lot of very specialized traits. They need to conduct electricity, and convert that electrical activity to mechanical activity in a synchronized fashion, so that each cell together forms a functioning pump. And so I suspect that because of that, it would not be an easy matter for any of those highly specialized cells to de-differentiate into a cell that could then expend a lot of energy dividing.
On the other hand, we know that in other eukaryotes--
Miller: Eukaryotes being?
Bernstein: Animals with more than one cell. For example, amphibians. They have hearts as well that pump similar to ours, however they are capable of regeneration. Some fascinating studies were done in the 1970s, where amphibians were subjected to amputation of part of the pumping chamber. They would observe those animals over time and see that they were able to completely regenerate that heart muscle, over a period of about a week.
And there are many investigators who are trying to understand what it is about the amphibian heart that allows it to do what the mammalian heart, or the hearts of humans, cats, dogs, mice and rats, cannot do.
Miller: Does that information inform at all your work with stem cells, when you think about how that might work in overcoming heart disease?
Bernstein: It’s a little bit removed from the kind of work we’re doing with stem cells, but I can tell you that what does inform our work with stem cells is what we observed in new born infants versus what we see in adults. This is where insights into development and insights that those of us who are pediatric cardiologists have really come into play.
We know that patients who are born with congenital heart defects, when we do surgery to repair hearts within the first two to three weeks of life, the ability of their heart muscle to repair and remodel and assume normal function as best as we can measure, is really quite incredible. Those patients do phenomenally well.
On the other hand, when patients with very similar defects, are missed (in terms of diagnosis) until they are older, even just a matter of several months, and they have similar surgeries for these defects, they have a much rockier post-operative course. In some cases, their heart muscle may never actually come up to the level of functioning that we see in infants.
Miller: So what’s going on there?
Bernstein: That’s where the idea that there’s some plasticity that remains very early in life as a remnant of in utero development - before you’re born – that is quickly lost after you’re born, and it’s one of the reasons why we think we may be able to find the answer by looking at development of a cardiac muscle cell from an embryonic stem cell. Because that’s effectively the same developmental pathway that we’re seeing in infants.
Miller: And in working with those cells you have to be able to determine what signals help them differentiate, correct?
Bernstein: Yes.
Miller: And how close are you to that?
Bernstein: That, I think is one of the essential questions, at least in the field of human embryonic stem cell derived cardiac muscle cells. We know that using fairly straight forward techniques we can take pluri potent human ES cells, and they will differentiate into cardiac muscle cells. And we’ll find that up to about 20 percent of those ES cells will become cardiac muscle cells. However, in a dish, when we differentiate them, we see that they become all different types of cardiac muscle cells.
And without getting too detailed about the different types of cells you find in the heart, some of the cells act like the muscle cells in the pumping chambers, some act like the cells in the muscle collecting chambers, some act like the electrical cells, but it’s a very varied group of cells, without any kind of organization.
So we know that there’s an inherent genetic programming that allows these cells to become one of these types of cells, but we know that in real life, this is not a random process, and that in the majority of cases, cells develop appropriately depending on where they are in the heart. So I think one of the key questions is ‘what guides that.’
Miller: They migrate to a spot and then differentiate?
Bernstein: We don’t know. So one of the questions we’re trying to answer, which I think is fundamental to understanding myocardial development, is, ‘what is the contribution of inherent genetic programming, and what is the contribution to the tissue environment, in determining what kind of heart muscle cell you’re going to become.
Miller: What’s your guess?
Bernstein: My guess is that it’s both a question of tissue environment and the time during development that the cell is exposed to the tissue environment that will predict what kind of cell it becomes. And I think this is where it becomes not only an essential question to the biology of understanding development, but also an essential question if we’re going to develop therapy.
Because if we want to take human cardiomyocites derived from stem cells, and we want to use them to repair damaged myocardium, we have to pick them at a time when they’re at that point in development when they’re still susceptible to environmental cues – we have to find the right way to deliver them to the damaged area, we have to find the right way to have the tissue environment be able to communicate to the cell, in order to incorporate it into the heart, and to have it help.
So they’re a lot of issues that need to be solved. The piece we’re looking at is at what point in development is the cell still susceptible to those tissue cues. We collaborate with a number of other groups here in UCSF who are looking at other aspects of those questions that need to be answered before we’re able to really provide cell based therapy for heart disease.
Miller: You mentioned delivery systems. What would you imagine might actually work?
Bernstein: Well, right now, and again this is work being done by some of our collaborators-- right now most of the delivery systems that are being used are direct injection. And whether that means opening up the chest and directly injecting cells into the damaged heart area, or using ultrasound to guide a needle to go through the chest without opening it, to the correct area, are the main ways that people are using to deliver cells that they hope will become cardiomyocytes.
Another very promising approach has been to use bone marrow derived stem cells, which can be delivered basically through a blood transfusion, and then looking to them to ‘home’ towards areas that have been damaged and repair them.
Some of the clinical trials that are being done elsewhere have shown that there is some effect to using bone marrow derived cells – the exact component of bone marrow derived stem cells is not known, – whether these cells actually become new muscle cells, or merely create an environment conducive to new blood vessel growth, and just sort of a ‘beefing up’ of the area, or whether these cells participate in decreasing scar formation is really not known, but other groups are studying this.
Miller: As you know there’s been a lot of hype about stem cells, so again I’m curious, when we talk about, let’s move from pediatrics to adult for a second, adult heart disease, heart attacks – do you foresee a day when this type of therapy might actually be able to regenerate and repair large areas of a damaged heart?
Bernstein: I think so. I’m very optimistic that the kinds of work being done both in basic research as well as in the clinical trials are leading us there. I would say that on a near-term horizon, the use of stem cells, especially human embryonic stem cells, is really the first chance we’ve had to have a system we can study in a culture dish that really mimics cardiac development in humans, so in the near-term I suspect these cells will be very useful for screening drugs, for example.
But I do believe that within the next 10 to 15 years we will really see cell based therapy using stem cells in the treatment of heart disease.
Miller: And how long might it take – again, in the fantasy world we’re talking about right now – for a therapy like that to work. Let’s say someone has a massive heart attack, and a large percentage of the heart is damaged. Let’s say there was a therapy available – I know I’m putting you on the spot, but would this work in a matter of days, weeks, months, or what do you suspect?
Bernstein: Let me first challenge the way you pose the question, because I think someone who’s had a massive heart attack where the majority of the heart is damaged, I don’t think we’re going to be able to treat that with cell based therapy, and so I don’t think we’re going to see cardiac transplant completely disappear. But I think in places where people have sustained enough damage so that their heart is still functioning but they start to deteriorate due to heart failure, I think those are the patients we’re going to have the biggest impact on.
As far as how long it will take, boy, that’s a really hard question to know. I think that in the studies that are being done now, people are really looking at improvements in function after several months. And generally looking at the six-month horizon as a time point to see whether a therapy has had any effect.
Miller: Fair enough. Do you think the public over emphasizes the ability of stem cells to fix a lot of problems?
Bernstein: I can only talk to heart disease, and I don’t think that the public enthusiasm for the use of stem cells in the treatment of heart diseases is unwarranted. I think the public is correct in being very optimistic there. It has been suggested that stem cells are going to cure many things, I can’t really comment on those.
Miller: What do you think the public gets most confused by in the whole stem cell question – we can confine it to heart disease. We’ve established that it can be done; you’re hopeful about that, we know that they’re a lot of people around the country doing research similar to yours; there’s funding; so maybe on a more technical side, is it the belief that this can happen quickly – because more money’s being thrown at it? Would that be one example?
Bernstein: One of what I think is a misconception is that there is a population of adult stem cells that reside in the heart, that can be used to repair the heart. And the reason that I think that’s a misconception is not that those cells don’t exist; I think that’s been demonstrated. But there’s a lot of emphasis from groups who do not believe we should be doing work with human embryonic stem cells, on the use of adult stem cells for this kind of disease.
And unfortunately, while adult stem-like cells have been identified in hearts of adults, the question of whether they could really be used in therapy, or rather they’re a remnant of development much like our appendix is in the gastrointestinal tract, really is unknown.
And certainly one would suspect that if they were capable of any kind of repair, we would see that process, and we really don’t. So I think it is somewhat of a misconception that there are significant enough advances made with adult stem cells to treat heart disease, such that we don’t need to use embryonic stem cells.
On the other hand, there’s been some very recent, exciting data suggesting that we may be able to use skin cells, and reprogram these cells to become heart cells. However, as exciting as that data is, that work still is in fairly early stages, and methods will need to be developed to insure that enough of those cells can be turned into heart muscle cells, and that those heart muscle cells are normal, and would function and be able to integrate into the heart before we put all other research into other cell types aside.
Miller: Last question: the term regeneration, is that really an accurate term to use regarding all the stem cell research?
Bernstein: I think that when people think about this term of medicine, they think about organs that have a native capacity to regenerate, like the liver, or they think about animal studies as we mentioned before with amphibians. I think what we’re really looking at is therapy.
Because it may turn out that our ability to use cells to improve heart function, may not come down to actually regenerating muscle, it may come down to using cells to create an environment that helps the heart handle the stress of the damage that’s been done to it in a better way. And frankly, whether we create cell therapy that replaces muscle, or we create adult therapy that improves heart function by another means, really doesn’t matter. The bottom line is we want to use cells to try to improve the lives of patients who have heart failure.
Miller: Harold thank you for joining me on Science Café, we wish you great success.
Bernstein: Thank you, my pleasure.