Chet Cooper: How did you get involved with medical research?
Clive Svendsen, PhD: Growing up in Devon, England, I was exposed to science by my father. And then my love for it just grew. But the main thing that inspired me was studying Parkinson’s disease. When I was at the University of Cambridge getting my PhD in the 1990s and starting my lab, I was lucky enough to get involved with some of the fetal transplant work being done to treat Parkinson’s. Those studies have formed the premise for the study of nearly every other neurodegenerative disease. Researchers were trying to use aborted fetal tissue, taking out the immature cells that would have grown up to become the cells that are lost when one gets Parkinson’s. They would put those cells into the patient’s brain.
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Lia Martirosyan: How did they know where to put them?
Svendsen: They knew which part of the brain makes the dopamine neurons that are lost when a person has Parkinson’s. Now they’re making new dopamine neurons in the brain of the patient. That’s the foundation of Dr. Eva Feldman’s trial. Did you know that the very first human brain transplants were performed in Sweden? I was interested back then because I thought that using aborted fetal tissue wasn’t going to work. It’s ethically charged, and there are too many technical problems with getting the number of embryos you need.
Back then I thought, why not use stem cells? They were new on the block. We also figured that it might be possible to make neural stem cells by taking the tissue we were going to put into the patient, and putting them in a Petri dish to make those cells divide. Now instead of getting just enough for one patient, we may have enough for 10 or even 100. Or, if we keep expanding the cells, we could treat 1,000 patients from one fetal sample. That’s really what got me into the field in ‘92, and I haven’t stopped since. (laughs)
Cooper: So your focus now is?
Svendsen: I’ve diversified a bit. In 2002, after I moved from the University of Cambridge to the University of Wisconsin, I met a patient with amyotrophic lateral sclerosis (aka ALS or Lou Gehrig’s disease) and got introduced to the issues associated with that disease. Obviously I knew about ALS as a neurobiologist, but I’d never really met a patient with the disease. I really felt that this transplant technique could work for ALS patients as well, so now part of my lab is dedicated to ALS, and part focuses on Parkinson’s research.
Martirosyan: Dr. Eva Feldman spoke about trials and doing a surgical procedure to insert stem cells into the spine. Do you do something similar?
Svendsen: We found that the cells we grew to help Parkinson’s patients as well as to help other treatments could survive being transplanted into the spinal cord. So when I became more familiar with ALS, I thought, maybe these cells could also survive transplantation into the spinal cord at the place where the motor neurons that enable muscle movement are lost. When the motor neurons die, you become paralyzed. That’s the simple version of ALS.
Initially, stem cell work was based around the obvious, which was that we knew we could make stem cells into these motor neurons. The big goal in the late 1990s and early 2000s was to just replace these motor neurons in the spinal cord. The problem was that we couldn’t make the motor neurons grow to the muscle again. It’s very difficult in an adult to get a fiber to regrow all the way out to the muscle and have it reconnect. It’d be a bit like if a light switch short-circuited in your house because the connection from the switch completely melted away. In ALS, the light switch is in the spinal cord and the light is the muscle. If that whole pathway dissolves in your house, even if you just put a new switch in, it’s not going to do anything. You’ve got to rewire it to the light. So to put a new neuron in is not enough; we’ve got to make it connect back to the muscle again. That’s a huge challenge for the ALS field.
What people were finding is that the motor neuron in ALS may be okay, but in the spinal cord there are cells around that motor neuron that support it, and it’s those cells that die and leave the motor neuron very vulnerable. So the hypothesis that we have—and I think Eva’s technique is based around that as well—is let’s replace the support cells in ALS such that we maintain the connection between the motor neuron and the muscle. That’s the strategy we’re all following.
Cooper: Are you saying that what you’re inserting has the ability to grow the complete—
Svendsen: No. What we’re inserting will support and stop the degeneration of the existing fibers that attach to the motor neurons, which are already attached to the muscle. This is a preventive strategy. If all those fibers are completely dead and retracted, and you’re totally paralyzed then this strategy will not work. Our plan is to go into patients who have some connection left, and maybe some that are connected but dysfunctional, and put the new support cells in to maintain those connections. What’s really amazing in the muscle is that you can lose maybe 60 percent of your connections and still not have any symptoms. But when you lose those last few, you go off the cliff and it gets really bad quickly. So Eva’s trial and our trial are based on prevention. The stem cells, it turns out, can make support cells very efficiently in the spinal cord. So you’re replacing the sick support cells that are dying in the disease. In that way, you’re not making anything new in terms of the connections to the muscle, because they’re your original connections. You’re just maintaining them.
Cooper: How do you avoid disrupting the ones that
Svendsen: Good point. Based on the patients’ symptoms, we know what’s already gone. ALS usually goes from the legs up or from the breathing down and spreads. You don’t get ALS all at once. It moves slowly. If the right leg goes, within two or three months your left leg will go too. So you have an opportunity to put the cells in a location where the degeneration is just starting, has just finished or hasn’t even happened yet, because in a single patient, each limb will be affected differently.
Let’s say you have paralysis in your leg, then I know that’s lumbar region 3, 4 or 5 in the spinal cord that has the connections to that leg. So in our trial, which is a little bit different from Eva’s trial, we are targeting just the right leg and leaving the other one. So now we’re going to follow the progression of disease in the leg that we targeted in the spinal cord and compare it to the other side that didn’t get the transplant.
Cooper: And these people will be walking in circles eventually.
Svendsen: (laughs) If we’re lucky. We’d be enormously excited to see a patient walk in circles. It would be a good problem to have. Remember, these are very small trials. We’re talking about three to six patients going in, and then a delay, then another three to six patients.
ALS has a pattern. If you get it in this leg, two or three months later you’ll get it in the other leg. It’s almost never happened that an ALS patient has rapid progression over three months in one leg, and then it takes three years for the other leg to be affected. What that gives you is the enormous power of statistics, because you know that the other leg is a control for the leg you transplanted, so you can match progression rates. We can tease out the effects of the cells in a small number of patients, which is my main goal. The nice thing with our trial is that we only need 10 to 20 patients to get phase two data, which is significant clinical effect data.
Martirosyan: How is what you’re doing different from other trials currently taking place?
Svendsen: The difference is that part of my career is focused on growth factor treatments in gene therapy. There’s a growth factor called glial derived neurotrophic factor (GDNF), which is a powerful drug that stops motor neurons from dying. It’s been shown in hundreds of studies that this drug, if you can get it into the spinal cord, is protective of most neurons. The problem is, it doesn’t get across the blood-brain barrier. You can’t give it to patients. So we’ve engineered our stem cells using viruses to secrete GDNF so that now, like a Trojan horse, not only are they making these support cells, but once they get to their target they stop and pump out the GDNF right around where the motor neurons are dying. I think we’re the only group to show conclusively that it protects motor neurons. The strategy of the dual gene therapy/stem cell approach can protect motor neurons very robustly in every model we’ve looked at. The cells we’re putting into patients are combining the support with drug
delivery, which is very different.
In 2004, we were ready to do this, and the FDA liked the concept. We were about to raise megadollars to do it. My friend, Nick Boulis, MD, who’s a neurosurgeon, and I got together at the Cleveland Clinic and designed this trial with neurologists. We had everything written up. We were expanding the bank of cells secreting growth factor, but you need a lot of cells. They have to be manipulated a lot in the dish, and we found that they were creating a cell-abnormal phenotype called trisomy 7. One chromosome was triplicated in the cells that we wanted to put into patients, so we had to stop everything. Back in 2005, I told Nick, “We’ve got to sort this problem out.”
Cooper: It sounds like there’s good cooperation between you as scientists, as well as between your respective labs.
Svendson: Yes. Nick had done a PhD with Eva, and they went ahead and used the template that we’d written. I was perfectly happy with that because there was a company called Neuralstem that had a source of cells without this trisomy problem. It was from a different batch of fetal tissue that they’d generated and it looked healthy. The cells also survived in the spinal cord and seemed to have some positive effects. So that part of the story shifted as Nick went to Eva to get some funding to help move the same kind of idea forward but with neural stem cells. Nick and I wrote a number of papers where we did some of the preclinical work. Neuralstem took it on, and Eva took on a part of it, too.
The original trial was done at Emory University. Eighteen patients have already gone through. Nick and Jonathan Glass, MD, who is also a brilliant neurologist, pioneered the whole thing. Eva was the principal investigator on that trial, and I’ve collaborated with both Nick and John for years. Nick developed the device that enabled the trial to move forward.
Cooper: So what happened from there?
Svendsen: More recently, Eva got separate funding to take the trial to the University of Michigan, extend it, and start with the next set of patients. She’s focusing more on the cervical area of the spinal cord, the breathing area, which is important to patients because often the last thing to go in ALS patients is the ability to breathe. Eva’s strategy is to inject more cells into the upper spinal cord.
It took me a few years to sort out how to get rid of the problem with the cells. Then I moved labs from Wisconsin to LA because I really wanted to get some of the funding that was available in California.
Cooper: I thought it was to meet us.
Svendsen: Obviously meeting you guys was my major objective. Also, there’s the California Institute for Regenerative Medicine (CIRM). Have you heard of it? It’s one of the most astounding funding mechanisms for neurology. For stem cells, it’s the biggest. It was funded through the California Stem Cell Research and Cures Act—known as Proposition 71—which created $3 billion for research on spinal cord injury, cancer, or any problem that required human stem cells. It was funded in 2004 when President Bush was not allowing embryonic stem cells to be used. It was like, “In California, we’re going to do it anyway,” and $3 billion goes a long way. I moved to LA to try and get some of this funding because through the National Institutes of Health. You usually can get funding up to $3 million or $4 million, but it’s tough to get more than that. For a clinical trial you need $20 million. So I moved my lab here. Cedars-Sinai had this fantastic position starting up in regenerative medicine, so if you walk around the institute, you’ll see that we have 100 people here with 20 faculty members.
Cooper: But the building’s so old and decrepit.
Svendsen: Yeah, I’ve complained about that. (laughter) They obviously don’t update anything here. We have an institute here that works on liver regeneration, diabetes, pancreatic cells and osteoporosis. We have five major programs in neuroscience. It’s been a lot of fun setting all this up. The reason I came here was for the CIRM money, and my ALS project was key for me. So we put an application into CIRM for $20 million to do GDNF-secreting stem cells for ALS. It’s a complete continuation of what I’ve been doing for 10 years, of what I started in Wisconsin, and it’s similar to the Neuralstem trial. Luckily, we got the funding and started nine months ago. We have $20 million in the bank to do all the preclinical studies. To get to the clinic, you first have to grow your cells. Behind where you’re standing, we’ve got cells growing in these incubators.
We’re still using fetal tissue at this point, but we’re expanding beyond that, and we’ve learned how to get rid of this trisomy.
Cooper: Because I would have said, just take it and trim off those extra two chromosomes.
Svendsen: Be nice if we could, but of course it’s far more technical than that. Under sterile conditions we dissect the fetal tissue, and then we grow it, expanding it in the dish. You can just keep growing these things for up to 40 population doublings. So we can go to the equivalent of 40 billion cells very rapidly. Then we bank them. We’ve done this now in a facility that’s FDA-approved. We bank the cell lines such that we have 1,000 tubes, and the cell lines are also being engineered to make GDNF. Then the FDA wants you to try it on animals. So you have to take those cells that you’re going to put into humans, take, say 150 vials, and put them into animals to show that they don’t make tumors, and that they’re safe.
Cooper: How long are you required to do those trials?
Svendsen: Nine months. You have to show that your cells can survive nine months in animals. When you tell an ALS patient this, their heart drops, because trying it on the ALS patient is still at least a year away. But this is the way it’s done. I’m supportive of the FDA, because we know our cells are safe, and we’re pretty sure they don’t make tumors. But there are 100 cowboys out there who’d love to go ahead and put the cells into patients, even though those cells could create a tumor. In the case of ALS, which is terminal, some might argue, who cares? You’re going to die from the disease anyway. But I care because a tumor could cause excruciating pain. I can’t say to a patient, “You know what, the trial didn’t work, and now you’ll be in pain for the last two years of your life, sorry.” I wouldn’t be happy with that.
Yes, ALS is a fatal disease, but you can’t just try anything on a whim. So we’re doing it properly. By the end of this process, next year this time, we’ll be done with all of our preclinical work, and we’ll start recruiting patients. The patient trial should start towards the end of 2014, and then we have this jump forward to the trial. We’ll have 18 patients who get unilateral injections, and from those 18 unilateral injections and progression in both leg data, we should establish whether it’s effective. And remember, what we’re trying to do is take patients who show very mild symptoms in one leg, and put the cells in to stop the condition from progressing. This is to protect the circuits that are already functional because normally they would just die. We want to maintain that level of function, and maybe by strengthening what you’ve got left and stopping it from dying, they’ll sprout a bit, and you’ll get an improvement. That’s the rosecolored glasses version. I had Stephen Hawking in our old lab three months ago, and we almost got him excited enough to give a biopsy, but not quite.
Cooper: He’s a professor at Cambridge University?
Svendsen: Yes. He’s 72 now, and still a physics professor who supervises three graduate students a year. We brought him into my lab and a few other labs. Bob Baylor, a neurologist, and I had given a lecture, 10 minutes each, and Dr. Hawking wanted to ask a question, so everybody was excited, and his voice comes out through this machine, the Hawking voice, that he’s had patented-he’s actually copyrighted his voice. He said, “I do not think I have ALS. I think I have a Vitamin B disorder.”
Cooper: Interesting theory. Back to what you were saying, what if there was a genetic deficit?
Svendsen: We can now engineer cells pretty well, so even if what we were doing had a genetic deficit, I could do gene engineering and take the deficit out, with gene targeting and other procedures.
Cooper: It sounds like a very promising scenario.
Svendsen: The guy who developed it won the Nobel Prize for medicine six months ago. It’s because it’s so mindshifting. This new technique of induced pluripotent stem cells means I can take a skin cell from you or any adult, put the core in a dish and reprogram it back in time to an embryonic state. Once you’ve got that embryonic state, it’s now an embryonic stem cell. The other thing of relevance, and why we’re pushing it so hard, is it’s the opportunity for autologous transplants, which means, if you had your own tissue bank, an exhaustible pluripotent stem cell line could be created. I could then push it forward to be spinal cord tissue and put it back in you, and it’s your own cells, so I don’t have to use immune suppression so your body won’t reject it, which is what has caused a lot of problems for the Neuralstem trial. I think five of the patients couldn’t tolerate the immune suppression, so they had to come off of it. I also want to get away from fetal tissue. Aborted fetal tissue is not what people want to use.
Cooper: Where does the other part of your research stand right now?
Svendsen: Everything is moving forward. As a matter of fact, I’ve got to get back to two papers that I’ve been writing.