Recipe For Turning Skin Cells Into Heart Cells
IRA FLATOW, host:
This is SCIENCE FRIDAY from NPR. I'm Ira Flatow.
There's no mistaking a skin cell for a heart cell. Skin cells are circular; heart cells are spindly. Heart cells beat spontaneously; skin cells just, well, they just sit there.
But according to a new study, if you take a few genes and a cocktail of chemicals, add them to a mouse skin cell, it will transform them into beating heart cells.
So far this is nothing new, but researchers have done, of course, this in the past. But in the past, those skin cells first had to be turned into stem cells. Then the stem cells could be converted into a new cell type. This new recipe skips the stem cell step.
The skin cells go directly to becoming heart cells, beating heart cells. How is that done? What might that mean for treatment? And what about other types of cells? That's what we're going to be talking about this hour, 800-989-8255, our number. And you can also tweet us @scifri, @-S-C-I-F-R-I. Or go to our website at sciencefriday.com.
Leonard Zon is an investigator at Howard Hughes Medical Institute, director of the Stem Cell Program at Children's Hospital in Boston and a professor of pediatrics Harvard Med School. He joins us by phone from his office. Welcome to the program.
Dr. LEONARD ZON (Harvard Medical School): Hi, Ira. Thank you very much. It's a pleasure to be here.
FLATOW: Thank you. I know you were not involved in this study, but you're certainly aware of what's going on. What is the main difference here? Is the main difference you don't have to go through that intermediate step?
Dr. ZON: Yeah, that's exactly right. So you know, in your body you organs, and inside the organs there are small numbers of stem cells that have the ability to remake the organs. And those cells are very precious, and it would be great to capture them.
There are studies on embryonic stem cells, which can make all the tissues of your body, and people over the past couple years have been able to take a set of genes and put them in and reprogram the skin cells to think they're an embryonic cell and therefore being able to make all the tissues of your body.
And as that work started to come up, the question is: Do you really have to back up and go back to an embryonic state, or could you just take a cocktail of cells and put them - a cocktail of factors, put them in and actually direct them to the tissue that you want?
And so in several studies recently - there's been on in the blood system and one for and two for the heart system - you can literally take a cell from a skin biopsy and then reprogram it with a set of factors that will make it think it's a heart, and then it'll start beating in a dish and being able to use those tissues to study biology, and also to put them into patients would be interesting.
FLATOW: There have to be some drawbacks and advantages to this. Give us the advantage first.
Dr. ZON: Well, the advantage of this is that you don't really know exactly what paths you are taking when you back the cell up all the way to an embryonic state. And during that period of time, changes might happen.
The way I like to think of this is picture yourself at the top of a ski slope, and you have many paths to take to ultimately get down to one of the ski lodges. And so what you want to do is eventually get down to the heart or to the blood.
And so this directly puts the paths in place to get you to the lodge as quickly as possible, and in the case of reprogramming all the way back to an embryonic state, it may still work fine to go back up to the top of the hill and eventually find yourself to the lodge, but it's probably much more efficient to do this directly, and a lot less changes will happen along the way.
FLATOW: And you can do it quicker.
Dr. ZON: Exactly, exactly. So the speed, the efficiency, these are things that become important as you think about stem cells being therapeutically useful. So it's definitely a step forward.
FLATOW: And are there any disadvantages to this?
Dr. ZON: Well, the only disadvantage right now is that you have to put a gene into a cell. And this is true both in converting the skin cell back to an embryonic-like state or to this tissue. With these genes inserted into the genome of a cell, you might cause mutations to occur. This could lead to some type of cancer. And so this is something that needs to be done safely and reproducibly before it would actually get into the clinic.
And I do think that the efficiency arguments for these - how efficiently can you make an entire dish of cells beat and be useful, these are issues that need to be considered.
FLATOW: So you have to actually examine what the cells do over a period of time.
Dr. ZON: That's right, exactly. So you know, some of the things that we want to use these for is to study disease. So for instance, at Children's Hospital Boston we see a number of children who have heart problems, and it might be possible to take these cells directly from a skin biopsy and then in a dish turn them into heart cells.
And presumably you would see the disease in a dish, and that might allow you to actually look for medicines or drugs that you could treat the dish and cure the disease in a dish, and that might lead to new therapies for those patients.
And then therapeutically, you would like to take those cells and implant them into a diseased heart and then be able to, again, cure that disease.
FLATOW: And so then might you be able to do the same trick with other cells besides making them into heart cells?
Dr. ZON: That's right. So there was a paper recently by Mickie Bhatia's lab, in which he was able to take cells that were skin cells and reprogram to think they're blood cells. And so this might be used, let's say, in a transplantation setting, similar to a bone marrow transplant.
And so in each organ you'll need research to be able to drive these cells to a particular lineage, and then they might become therapeutically useful.
It's actually interesting that the genes that they're putting in are the genes that affect the embryo, and so how embryos make tissues are being transferred, that knowledge is being transferred to the dish. And in a certain case by Deepak Srivastava, where he could take skin cells and put them into a - make them into a heart, he actually took the master regulators of the heart cells themselves, these cell-specific regulators that tell a gene to turn on in a heart cell, and that turned these cells into a beating tissue. And so again, kind of using what the embryo normally does to develop but transferring that into an adult fibroblast and making that tissue - and it's very, very fascinating research.
FLATOW: Does that mean you wind up with, let's say, heart tissue that's younger than you are?
Dr. ZON: It could, actually. You know, these cells have an embryonic character to them. And so we're just at the beginning of learning what type of tissue they really are.
For instance, as you know, you have an atrium, which is the top part of the heart that collects the blood, and then the ventricle, which will pump it through to your circulation, and we don't know directly whether these cells represent the atrial type of heart cell or the ventricular type of heart cell.
And in a similar way you have heart tissue that's embryonic, fetal and adult, and we don't really know which type of tissue is being developed, and that needs to be worked on more specifically.
And each of those will have an interesting biology and also an interesting therapy that could be used to apply.
FLATOW: There's another study out this week showing epigenetic differences between induced stem cells and embryonic stem cells, that induced stem cells had a memory, basically. Is this the concern there?
Dr. ZON: Well, it turns out that when you're making these tissues, and we make many of these cells, skin cells, that are reprogrammed to think that they're embryonic cells, we make many of them here at Children's, they have a certain propensity to differentiate. And they will remember where they came from.
So if you start with a blood cell and reprogram it, it may be different than starting from a skin cell. So either experimentally in a dish, you have to figure out how to overcome those biases, or you may want to start with the tissue that was diseased in the first place and reprogram that particular tissue.
So far it hasn't made a major difference, but it's theoretically something to watch out for, and again, now we can make these reprogrammed cells from both skin cells and blood cells, and you may want to choose one or the other.
FLATOW: And so what's the next logical step in this proof of concept?
Dr. ZON: Well, I think that what you'd like to see is these cells become therapeutically useful. And so you would need to raise the efficiency here. So you'd want many more cells in a dish that are beating and with the right cell type.
So understanding what chemicals you could add to make them differentiate exactly to the diseased type of cell type so that you could fix that disease. And then I think for the heart you obviously have a three-dimensional structure that's very, very important to the beating of the heart, and so you might need to put these into certain matrices or other types of tissues so that those cells would engraft and stay there for the lifetime of that human.
FLATOW: Could you create a complete heart?
Dr. ZON: I think you could. You know, there's tremendous advances in bioengineering, and it's possible to seed these cells into a certain matrix, and they would adopt a three-dimensional structure. It may or may not look exactly like a human heart, but it's possible.
And so, you know, we're very interested, as you think about organ transplantation, there's a deficit of donors, and we really rely heavily on patients and trying to get those organs so that we can transplant them into the patients who need them.
And so really for us to have an unlimited supply of tissues and also tissues that come from you - in other words, if you have a skin biopsy, you could turn that into a heart, those tissues won't be rejected, because they're yours.
And so again, I think that's a great advantage of this type of a system, and hopefully as people need more organ donors, this will be another set of tissues that could be used.
FLATOW: Would the heart make its own valves, or would you have to bioengineer that?
Dr. ZON: I think you would have to bioengineer that. And it's very interesting. There are people taking these types of stem cells, and they're actually stretching them. And they will form different types of tissues upon stretching.
You know, there's friends of mine who are working on making ligaments and cartilage, and so again, there the stretching response is actually critical for that fate to be determined in a dish.
FLATOW: Oh, you mean if you actually change, physically yourself, the shape, it turns into something else?
Dr. ZON: Yes, exactly. So part of how you make the tissues as an embryo develops is exactly those type of mechanical stresses. And then on top of that, of course, you have this cell-specific program with these master-regulator genes that are making a blood cell different from an eye cell different from a skin cell.
FLATOW: Wow, this is like a brave new frontier.
Dr. ZON: Well, you know, the stem cell field is really one of the most fascinating at the time, and if you think about the great possibilities that we have, it's really wonderful. But there's a lot of very detailed work.
Every single organ needs its own set of scientists to work on it, to be able to differentiate to that lineage. And it's going to take a while before we're successful clinically, but if you think about how you could change biomedicine, this is one area where instead of necessarily taking a drug, you might actually be able to take cells for that particular disease.
FLATOW: Does this work with skin cells, take away the need to still work on embryonic stem cells?
Dr. ZON: No, I think it's important to continue to work on embryonic stem cells. They are the gold standard, and they definitely make all tissues. And what we're finding is when we take these reprogrammed skin cells, we need to compare it to a gold standard.
And so it's really great that embryonic stem cell research was there for us, and also that most of these leads that we're talking about today came from embryonic stem cell research.
So I think they'll continue to be around and be useful, and these new reprogrammed cells are very interesting and have great opportunities also.
FLATOW: Well, thank you very much, Dr. Zon, for talking with us today.
Dr. ZON: Great, it's been a real pleasure.
FLATOW: Good luck to you. Leonard Zon is an investigator at the Howard Hughes Medical Institute and director of the Stem Cell Program at Children's Hospital in Boston and professor of pediatrics at Harvard Med.
We're going to take a break. Stick around because up next, we're going to talk about what you can do - to move to another part of your body -to keep your brain healthy. It might involve walking around the block a couple of times or other things. And we'll talk about things that won't work. Hmm. Stay with us. We'll be right back.
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