Dr. Ron McKay and Dr. Elias Zerhouni
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SUSAN DENTZER: You’ve been able to make embryonic stem cells in mice turn into dopamine-producing cells. How did you do that?
DR. McKAY: What you have to do is you have to make the cell believe that it’s going through its normal course of development. And so you set up conditions where the clearly present early cell that can turn into all the cells in the body generates the downstream cells in the right sequence, and if it turns out that, although this sounds incredibly complicated, it turns out for some cells it’s really easy to do. So in about four or five steps you can get high enriched populations of neurons that are of the type that are interesting to Parkinson’s patients.
SUSAN DENTZER: And what’s the secret of that? Is it the soup you cook them in, or what makes it go one way or another?
DR. McKAY: Well, the secret is you have to know–you know, you have to know what the intervening steps are like, and how to encourage those cells to stay alive and to grow and to change into the next step. And it is–it is a matter of knowing what’s in the soup, but it’s–it’s–it’s very important to know what the cells want. And we know a lot about that, actually, from our studies of development, so we’re not working completely blind. So one advantage of the ES-cell is it’s following fairly normal developmental signals.
DR. ZERHOUNI: But then in practice, when the cell culture evolves, you have at certain times specific molecules that signal the cell, hopefully, to go into one different direction or another. That’s really how it’s done. That’s what he’s referring to in terms of manipulation of the cells.
SUSAN DENTZER: Not to trivialize this, but, you know, back to the soup analogy, you’re going to add different ingredients at different stages along the way…
DR. McKAY: We’re controlling development. And, actually, it’s not to trivialize it. This is the problem now, in my view, and it’s a serious technical problem because to implement this approach or the potential of these cells we have to know exactly what should be in the soup. And that’s going to be–that’s going to be–that’s going to take quite a lot of work so that every time you do it you’ll see exactly the same cells you get out at the end.
SUSAN DENTZER: So what should be in the soup; when do you add it to the soup, because the cells are moving along at different stages…
DR. McKAY: Right, yes. But this is a remarkable thing. I mean this is the basis of all the interest in this is that the cells can do this, that you can trigger their development, and that you can control it adequately to get very specific cells out at the end and cells that work, not just something, rough approximation of what you need.
SUSAN DENTZER: And how did you know that you got these cells to produce dopamine?
DR. McKAY: You can measure. You can measure their production of dopamine. There are many tests that you can apply to the cell under different stages in its life, you know. You have the kindergarten test when it’s young and more sophisticated tests when it’s older. But, of course, the ultimate test that we’re interested in is what the cells will do in the context of disease. How will they teach us about disease? And one way of testing that is to put them into an animal which is a model for disease, and another way of doing it is to ask whether the cells tell you something that’s specifically interesting where we know about the genetics of human disease and whether the cells will now tell us why these genes are causing disease in the context of a human cell.
SUSAN DENTZER: And in the case of the work that you did, you took these neurons that were making measurable amounts of dopamine. You put them back into rats that had been given a kind of synthetic Parkinson’s.
DR. McKAY: Right.
SUSAN DENTZER: What did they do?
DR. McKAY: Well, they do something remarkable. They stay there for a long time to start with, and in very large numbers. And in the case of the cells that we’ve derived from the mouse embryonic stem cell, they’re functional. I mean they show beautiful physiology. They have, you know–the neurons fire these little currents in different patterns. They show all that, and the behavior of the animal is modified by the cells we’ve introduced.
In the case of the human cells, our best data are these shown here, which is this–here we’re looking at the detailed electrophysiology of the neurons, and this is very convincingly demonstrating that we have functional human dopamine neurons. And we’re interested to ask now how to get them to work in the animal models of the disease.
SUSAN DENTZER: And to be specific about what happened to these rats, as I say, you had engineered a kind of a chemical form of Parkinson’s; you put these dopamine neurons in them, and then the rats did what?
DR. McKAY: They changed. Their behavior is normalized, actually. I mean most of the behaviors we measured were really normalized. In one case we sort of pushed the animals too far. Their behavior was sort of too dominated now by the cells we put in. We actually made them move the other way, which is not the optimal outcome, but what it does tell us is that the cells are working extremely well. And now what we need to do is we need to try and understand how you make a graft like this interface appropriately with the host.
And in this case we are setting up an animal model, but one valuable thing to think about as one’s thinking about using cells like this in people, is that we have to have a detailed understanding of how the cells interact with the diseased patient. Because it’s not going to be a simple matter of putting the cells in there and just, you know, crossing your fingers. We’ll need to know precisely how the cells interact with the disease, and that’s going to be very, very interesting. It’s also going to take a lot of work and a lot of resource.
DR. McKAY: So what happens in Parkinson’s disease is that the particular group of neurons which are deep in the brain and there are a very few of them that make a transmitter called dopamine, that they die. And it takes a long time for them to die, but when almost all of them are dead, Parkinson’s patients have serious problem controlling their movement.
Now, these neurons have actions all over the brain, so there’s no really effective treatment for the patient once a lot of the cells have died. And out of this has grown the idea that we need to put in new cells. So–and that seems to work, and it seems to work in patients when you get the cells directly from the developing human brain. But that’s a very difficult source, so in our group we’ve been interested in asking, can we make cells in the lab rv Parkinson’s patients? And right now, the best place that we can get them from is this embryonic stem cell which is this pluripotent, very early cell. And by a very few simple steps where we control signals that come into the cell at the right stage in their development, we can get large numbers of these neurons in the lab.
And, quite remarkably, if you take these cells and you put them into an animal model of the disease, they have very clear effects on the behaviors of the animal. But not all of the effects are correct. You can quite easily push the behavior too far, at least in some of our tests. And so now we’re interested in taking this technique and applying it to human embryonic stem cells and dissecting out the different functions that the cell needs to have. These cells have many different functions, actually, so we need to understand them in detail.
SUSAN DENTZER: Then what you did, specifically, is you took mouse embryonic stem cells.
DR. McKAY: Right.
SUSAN DENTZER: Let’s go from there.
DR. McKAY: So we take them, the first step is that you need to differentiate them into the very earliest cells of the body. And the way we do that is we allow the cells to aggregate. And then these aggregates we can control them enough so that they can be dominated by the cells, the early cells of the brain. And when that’s true, we can grow out the early cells of the brain from the aggregates highly efficiently. And then we can trigger the differentiation of these early brain cells into neurons, and if we have the conditions right, most of the neurons make dopamine.
SUSAN DENTZER: And again, getting there is all a question of what soup you cook these in that–
DR. McKAY: Right, yes. It’s a question of knowing the thing, the right conditions, and it’s a question of having the right people over a decade or so working them out. So that’s essentially what we’ve done here. We’ve worked out that you could do this.
SUSAN DENTZER: And once you deduce that you had dopamine-producing neurons from mice, you then put them back into rats that had been given a chemically-induced form of Parkinson’s.
DR. McKAY: Right.
SUSAN DENTZER: What happened?
DR. McKAY: Well, the rats, as it were, get better. I mean they don’t become perfect, but they get better. A lot of their behaviors get much better. So, for example, one of the–the animals are given the disease in one half of their brain. And if you make the animal a little hungry, then–then it will reach out for a pellet of food. And if you put it in a condition where it can use either pole, then you can ask whether the injured side is recovered after you do the graft.
And, in fact quite remarkably, our data show that the injured side recovers. And this is a complicated task. It’s called an integrated sensory motor task because the animal has to use its sensory input to know that the food is there and to detect it, and then has to use its motor system correctly to eat it. So it’s a sophisticated task.
But in some of the tasks that we measure, the animals actually overcompensate. It’s as if the grafted cells are much better than they should, that they’re–they’re not–perhaps a better way of putting is they’re not appropriately regulated. So now we’re very interested in asking why do the cells do some things correctly, apparently, but some things are not quite correctly controlled. Obviously, to use this in the clinical context, we’d want to know that.
SUSAN DENTZER: So would you say you have cured a rat of Parkinson’s?
DR. McKAY: Well, no. I wouldn’t really. I mean I think–but, you know, I think that–I think that it’s–I’m always asked this question, and I think it’s not really a fair one. You know, I tore my tendon about a year ago, and the surgeon came in and stitched it up. And now I can walk, and I can run across the road if a car is coming fast. But I’m not longer going to pursue my NFL career, you know.
So it’s not perfect, right, but it’s better, right. You’ve made a difference. And, hopefully, these cells will make a big enough difference for Parkinson’s patients to benefit.
SUSAN DENTZER: How long do you think it would be before you would be trying the cells on human patients?
DR. McKAY: Well, we have very interesting data with human ES-cells turning into dopamine neurons, so I think it’s going to be a very short time. This technology is going to matter to Parkinson’s patients very soon, but how quickly it will make a big difference to Parkinson’s patients, that depends on how the experiments turn out. But within several years it’s certain this technology will be important. And one other point I think is worth stressing is that it’s a general technology. This is not just a Parkinson’s-oriented kind of approach. This approach is going to matter in many, many areas of medicine. So the technique will matter to the whole biomedical research community.
SUSAN DENTZER: What about the technique, the fact that you can make the embryonic stem cells differentiate and then put them into the body, generally, or more specifically than that?
DR. McKAY: No. Well, I think that’s the way most people kind of understand it like it’s the simplest way, really, to kind of see that it’s important to make cells of a specific type is to say that we’re going to use them, directly, to cure disease. That’s very, very straightforward.
But it’s also probably obvious to people that if you can make specific human cells, and you can make them reach a stage where you can look at their functions, then, actually, that’s very interesting so that we can understand why you get disease.
So, for example, in the case of the Parkinson’s patient, what the Parkinson’s patient really wants from us is when the Parkinson’s first goes to the doctor and says, “Doc, you know, I’ve got this tremor. I don’t know what’s wrong with me,” the doctor says, “Oh,you’ve got Parkinson’s disease.” And then you immediately do something simple which stops the progression of the disease, which stops the cells dying. And in our case, if we have these neurons and we can look at their function and look at why they live or die, that might be as important as actually directly grafting the cells into the brain.
And from the point of view of biotechnology and pharmaceutical development, that’s really very exciting, because these are complicated cells. And so if you can have the human cell in front of you, you can, quite specifically, ask, why does this human cell live or die? And that’s what I think we really need to know. And I’m–you know, one–it’s a guess, of course, but my guess is that within the next 10 years we will know why this human cell lives or dies.
SUSAN DENTZER: Ron Reagan, Jr., spoke the other night and he, specifically, used this Parkinson’s example. He described a whole chain of events and at the end of it he said, “You’re cured.”
DR. McKAY: Right.
SUSAN DENTZER: How soon would we really be able to say without reservations, “You’re cured”?
DR. McKAY: You know, everybody gets old, and everybody gets sick. So all of us have to face the reality of ill health. And, of course, all of us want to be able to turn to a doctor or to a pharmacist at a given point and say, you know, “Give me something that cures me.” And it’s possible that in the case of Parkinson’s patients that the patients with a given type of disease, one might be able to go and say to them within the next decade, “You know, you’re very lucky. You have this form of Parkinson’s disease. It turns out we understand it better than the others, and we can really slow down the disease.”
Most Parkinson’s patients would be very, very delighted if that’s what you told them, right. It’s one of the reasons that the disease is so interesting. I don’t know if you’ve talked with Parkinson’s patients. They’re often very successful people and, certainly, the ones that are coming to talk to me, and very active and very lucid. They know. And what they want is they want help. They want understanding, and they want progress to be as fast as possible. And I think what they want, me and what the National Institute of Health say to them is we will move as fast as we possibly can to help you. And I’m afraid most of us at some point in our lives will have to come to terms with the fact that that not be fast enough. But we will move as fast as we can.
SUSAN DENTZER: And do you think that this embryonic stem cell research is going to move as fast as it can?
DR. McKAY: Well, what I can say is that I believe this is absolutely critical to understanding the disease, and that work on human ES-cells over the next three, four, five years will become necessary to study all aspects of the disease, and that there will be an absolutely overwhelming moral case for developing new policies as the technology demands different types of cell, different types of manipulation of the cell.
Currently, the exciting results are that the human ES-cells that we’ve have been using here at NIH differentiate into really beautiful dopamine neurons, and that’s very, very interesting. The issue is really how do you have a conversation with a Parkinson’s patient? This is complicated stuff, and, but my view is that it’s absolutely critical. This technology is critical, and it is extremely important that that’s recognized very, very widely. I mean it is completely unnecessary for us to paint ourselves into some box here.