Stem Cell Research Reverses Paralysis in Rats
IRA FLATOW, host:
I want to bring on another scientist with sort of a related topic on neurological problems and a paper that's been also published this week that comes out of Johns Hopkins Medical School. It showed, for the first time, a team of scientists have used embryonic stem cells to allow paralyzed rats to move their limbs again. And neurologist researcher Dr. Douglas Kerr treats people with Transverse Myelitis or TM. He calls TM a cousin of MS or Multiple Sclerosis.
And Dr. Kerr and his team used stem cells from rat embryos to grow knew motor neurons. They implanted these neurons into the spinal cords of paralyzed rats. And after three months, the motor neurons in the rats had re-grown and actually jumped the gap of this severed spinal cord and connected with the paralyzed animal's muscles so the rats could be - get to move around again.
Dr. Kerr is associate professor of neurology, molecular microbiology and Immunology at Johns Hopkins, also Director of the Transverse Myelitis Center. Welcome to SCIENCE FRIDAY, Dr. Kerr.
Dr. DOUGLAS KERR (Professor of Neurology, Molecular Microbiology and Immunology, Director of the Transverse Myelitis Center, Johns Hopkins University): Thanks for having me.
FLATOW: So this is - these neurons actually bridged a gap and found the muscle and that's the first time it's ever happened?
Dr. KERR: That's right.
FLATOW: And how excited are you by this?
Dr. KERR: This was an amazing journey to get to that point. I mean, we've been trying to do this, this re-bridging between spinal cord and muscle, for about six years and have failed up until very recently. And so it's taken a complex array of factors and stem cells and differentiation paradigms to get that to occur. But it's really been an amazing work for us.
FLATOW: What was the - talk a bit about this array. What was the magic that you had to find to make this work this time?
Dr. KERR: Well, so paralysis in humans, in the patients I see, but also in the rats that we study is really - it's a disconnection between the spinal cord and the muscle. And so the way we think of movement is there's an electrical impulse that starts in the brain and it travels down a wire, or an axon, in the spinal cord and then hands off that electrical signal to a second neuron, which is called a spinal motor neuron. And that neuron then has to extend its wire, or axon, out and make connections with the muscle. And if that all occurs appropriately, the muscle moves. And the absence of that is paralysis.
And so in many forms of paralysis, it's that second neuron that has gone away, in ALS or Lou Gehrig's Disease or Transverse Myelitis or even traumatic spinal cord injury. So we set about reforming that electrical bridge. And the first step was to take an embryonic stem cell, which has the potential to be any cell type in the body, and to specifically and efficiently differentiate it to become that neuron, a spinal motor neuron.
So a few chemicals and growth factors called retinoic acid and sonic hedgehog did that trick. And this was taught to us by Tom Jessel and his colleagues Hynek Wichterle at Colombia. So that was the first step, we have to generate that cell type.
The next step then, is we have to transplant those cells into the spinal cord of the paralyzed rat. And we have to get them to first survive. And it's very rocky at first, whether or not they will survive. So certain growth factors have to be applied at the time of transplantation so that they make it through this rocky period.
The next step is then, the host nervous system has to recognize these transplanted cells as friends. So they have to form connections onto the transplanted cells or they won't form part of an electrical neural circuit. So some growth factors were applied to do that. And for many years, we got stuck there because we could not get the transplanted motor neurons their axons out toward muscle.
And we had to overcome some various developmental - some problems there and gave growth factors and chemicals to allow the axons to migrate out of the spinal cord. And then, finally, we applied a certain growth factor called GDNF at or near the muscle. And we knew that this was a growth factor which would attract motor axons toward them.
And so we reasoned that this would be a source that would act as a bait to bring the axons further out toward the region that we wanted them to go, which was skeletal muscle. And when we did that, they took the bait. And they made it all the way out to muscle. And once they got near muscle, they did what they would appropriately do, which is to form neuromuscular junctions and the muscles became functionally active. We know that because of electrical studies we did in these rats. And the animals regained some movement.
FLATOW: How much functioning did they regain?
Dr. KERR: They got back about 35 to 40 percent of their pre-treatment strength.
FLATOW: That's a lot isn't it?
Dr. KERR: It was really amazing how much strength they got back. Interestingly, if we watch these animals longer, they didn't get more strength than that. So that's kind of the ceiling effect right now. And you might then think that we probably recreated 40 percent of the connections, but we didn't. In fact, we only regained about maybe five or six percent of the connections.
But they were working very, very well and so they did a lot of the work. And that's exciting, because it tells you that we don't have to redo what was all there. We don't have to recreate this amazing complexity of the nervous system in repair. We can do it pretty inefficiently and still get a modest to pretty good recovery.
And I think the key of the study was that we knew that in the developing nervous system there are specific cues or signposts that tell these axons where to go. After development, when the nervous system is already set in place, they're gone. They don't need them anymore, so they're taken away.
And we thought that now in the adult animal we would try to replace them. We would try to put these signposts back so that we could kind of recreate development, in a way. And it seemed that that has worked.
FLATOW: So can you get better results, or is that asking too much?
Dr. KERR: No, I think we can. I think we can do a better job. We can get more specific signposts. And, you know, each of those steps that I mentioned to you was really a hurdle that took a year or two to overcome.
But we could be better at each one and more specific with each one. So there's still an awful lot of room to go, even in rats. But we've also got to, you know, extend these studies, for example, using larger animals, such as pigs, and also using human embryonic stem cells, as well, if we ever hope to consider this as a therapy for paralysis.
FLATOW: And so human studies are way, way down the road.
Dr. KERR: Way down the road. We have to - we have to do those things. We have to do human embryonic stem cells. We have to do the larger animals. And really, most importantly, we have to show that this approach is safe, because the worst outcome would be to rush this into a human trial too early and to harm somebody.
And there are several ways that that could happen. These cells could turn into something that we don't want them to be in the spinal cord, which could cause a worse function.
Now, we've looked at several hundred animals and haven't seen that, but that's not enough. And so we've got to be very, very careful as we go forward to make sure that we've done all the safety studies before we even then package up all of that information and enter into formal discussions with the FDA to say, is this justified to go ahead and do a clinical trial. So that'll take some time.
FLATOW: One last question, why human embryonic stem cells and not adult stem cells?
Dr. KERR: You know, we have tried adult stem cells. We have tried umbilical vein stem cells and a variety of other sources and we have not been able to get these very specialized cell types, the spinal motor neurons, very effectively.
We do get them occasionally, but not nearly as much. And so we have not been able to see these results. And I think that kind of intuitively makes sense, because all of the adult stem cells that we've mentioned have already been programmed towards a particular fate.
Now, what this would require is to deprogram them and then shunt them towards another fate, which does occur but inefficiently. And the embryonic stem cell is really a blank slate. So it has never been primed toward a particular fate. And therefore, it very efficiently, if directed, can go toward a fate such as a spinal motor neuron.
FLATOW: Dr. Kerr, Dr. Lindquist, I want to thank you both for taking time to be with us today. And good luck to you. We'll check in...
Dr. KERR: Thanks so much.
FLATOW: ...as you make progress. You're welcome.
Dr. LINDQUIST: Thank you. Delightful to be here.
FLATOW: Dr. Douglas Kerr, associate professor of neurology, molecular microbiology, and immunology and Johns Hopkins School of Medicine. Dr. Susan Lindquist at the Whitehead Institute for Biomedical Research, where she is also professor of biology at MIT.
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