Dr. Jerry Silver: Trailblazing Spinal Cord Research

Guy Kawasaki:
I'm Guy Kawasaki, and this is Remarkable People. We're on a mission to make you remarkable. Helping me in this episode is Jerry Silver. He's a professor in the Department of Neurosciences at the Case Western Reserve University School of Medicine. His work focuses on developing treatments for spinal cord injuries. His ultimate goal is to develop a way to overcome the lack of regeneration after a spinal cord injury. He has received numerous prestigious awards, including the Ameritec Prize, the Christopher Reeve-Joan Irvine Research Medal, and the Jacob Javits Neuroscience Investigator Award. In 2011, he was honored as a fellow of the American Association for the Advancement of Science.
Join us now as we delve into the excitement advances in nerve regeneration research with the potential for groundbreaking treatments for spinal cord injuries.
I'm Guy Kawasaki. This is Remarkable People, and now here's the remarkable Jerry Silver.
I'm not a doctor or a neurosurgeon or a neuroscientist, so go slow, okay?
Jerry Silver:
I will. I'll keep it simple. I'll keep it simple.
Guy Kawasaki:
Okay, first question. What does going into Phase 1b/2a of NVG-291 mean?
Jerry Silver:
It means everything for me, and it means hopefully, fingers crossed, everything for the people that are involved with that trial.
So the 2b means that the company, NervGen has had success in normal people, dosing them and they have tolerated it well and in very high concentrations, even much higher than we used in our animal models, and no appreciable side effects. So with that information that the drug is safe, it won't cause harm, the FDA has now allowed NervGen, the company that licensed our peptide, I'll tell you what a peptide is later, have licensed our peptide to use in spinal cord injured people, although the numbers of people are going to be fairly small. I think around twenty.
And this Phase 2b trial in human spinal cord injured patients is going to occur in the next few weeks. So our podcast, you and me, is happening exactly at the time when the company is just about ready to start in humans, patients with spinal cord injury. So that's very exciting for me, and it marks a culmination of forty years of my work going all the way to humans with spinal cord injury, and fingers crossed that it's going to help them. It helped our animals get a lot better after spinal cord injury, and now we have to see if this same peptide will help humans get better after their spinal cord injuries.
Guy Kawasaki:
These peptides are going to be injected into their spinal cords?
Jerry Silver:
No. So the way this peptide works is through the tissues of the body. You don't have to touch the spinal cord at all. That was our initial goal actually, to try not to touch the spinal cord. It's already injured and you really don't want to get in there and start putting needles into the spinal cord itself. That can cause even more damage. This peptide is given just subcutaneously, just under the skin, and they're going to target the subcutaneous fat area in the belly. So the injections are going to be given Sub-Q in the belly of these people. They'll probably get an injection once a day, like an insulin needle.
Nope, you don't touch the spinal cord. The peptide is designed to have a vehicle attached to it, so it takes the peptide from that area just under the skin into the brain and spinal cord. It just happens automatically.
Guy Kawasaki:
And when do you expect to see changes? How long does it take?
Jerry Silver:
In our animal models using this peptide, the changes occur actually relatively quickly. In our rat models of chronic spinal cord injury, when we give the peptide, we saw changes in our rat model of spinal cord injury within about a week or two. That's when the changes started to occur and then they continue to improve over time. So the answer to your question is if it's going to work, we're going to start to see changes right away, within weeks.
Guy Kawasaki:
Now, I listened to a podcast with you, and one of the points you made is that some of these results take weeks and months before they appear. How do you know that we got to keep giving these injections or it's not going to work? Where's the dividing line?
Jerry Silver:
The dividing line will be if there are no side effects of the continuing injections into these patients every day, so they don't get worse. You'll ask them, "How do you feel?" And then they're going to be tested for their ability to move, what they can feel. They'll get a neurological exam, and there's also going to be the use of physiology. So there'll be physiological recording equipment recording their muscle activity from outside the body.
And if there are no side effects and the patients report improvements, if they say, "Gee, I can move a muscle that I never moved before," or "I can feel my bladder. My spasms have changed. I can feel the bowels a little bit better, so I know when I need to do a rectal manipulation so I can poop." Anything that the patients start to report that seems to be an improvement. And, by testing the patients neurologically, if they continue to improve and no side effects, we could give the drug for as long as they wish.
I don't know the length of time. I don't know all the details of the Phase 2b trial, how long they're expecting to go. I think it's several months, but there's no reason that they couldn't go longer if there are no side effects. If the patients continue to improve and they report improvements, why stop? The company will have to stop at one point to report the data, but in the future you could just go on and keep on giving the drug as long as the patients improve. You could give the drug for years if it's safe. A year or more easily.
And, that's the key. Once the patients stabilize and they say, "I'm not getting any better. I've been taking the drug now for eight months. I seem to have plateaued," and there's nothing else that's happening, then you could stop. That would be a stopping point to see what else you might do. But there's no reason that a patient who is receiving the drug couldn't then start to do a rehab program, and there's going to be rehab all the way along during the injections. They might opt to get an epidural stimulation therapy at the end of this drug trial. So, they could do more.
There could be a waiting period between the end of the first delivery of drugs and maybe a second dose a little bit later. As long as there are no side effects, you can be as creative as you'd like.
I guess the answer to your question is the company is going to stop at a certain time. That's already planned. But, you don't have to. You can keep on going if you want to. I hope that's clear.
Guy Kawasaki:
And can you trace this all the way back to your work with nerve cells and pupils? Is it a continuous path from your days of ophthalmology through to spinal cord?
Jerry Silver:
You went really far back in my life. That's where it all started.
Guy Kawasaki:
I did.
Jerry Silver:
Oh my goodness. That's an interesting story. Yeah, just the way I have run my career is to start with an idea that I had many years ago, over forty years ago in the mid-eighties when I was studying the development of the eye all the way to now, to this moment in time talking with you. It's been a continuous path forward. It's been a long journey primarily because the questions I was asking were a bit outrageous, out of the box. Many people didn't believe what I was talking about.
But you bring up this issue about the eye. So in the mid-1980s, I was asking a question that really concerned developmental biology of the brain, and the eye is part of the brain, the retina. And the question that I asked way back then, that's a very long time ago, was whether there were boundaries or barrier molecules in the developing retina of the eye that would keep the nerve fibers from going in the wrong direction out of your pupil.
That would be bad. It can happen in certain genetic mutations, but if your optic nerve fibers would grow out of the front end of your eye, they'd grow all over your cornea and that would be bad. So I just asked the simple question, "Why don't they turn in the wrong direction?" Might there be some kind of a barrier that mother nature has built on purpose to keep them from going out of your pupil? And, we discovered a family of molecules called proteoglycans in that area of the retina near the pupil, and they're very inhibitory. So the word proteoglycan may be a little bit foreign, but you've seen these molecules on the shelves of any grocery store or pharmacy that sells proteoglycans in a jar. They go by names such as Cosamin or glucosamine or Dr. Sholl’s anti-joint aging cream.
Guy Kawasaki:
What?
Jerry Silver:
Yeah, you'll find these, Cosamin or glucosamine or joint Osteo Bi-Flex is another one. There are a million of them. These are basically ground up proteoglycans, mostly taken from the hoofs of cattle or the cartilage of sharks.
Guy Kawasaki:
Geez.
Jerry Silver:
That's where the proteoglycans are in great abundance, and that's the source of these cartilaginous proteoglycans for you to eat. And the idea is that the cartilage of your body and your joints, which get worn down as you get older, are lined with proteoglycans. Proteoglycans are very inhibitory. That's why your cartilage doesn't have any nerves or blood vessels in it. You can bend your ears or wiggle your nose because that's mostly cartilage, and it doesn't hurt. There's no innervation in your cartilage for a reason. It has to be very flexible and bind a lot of water.
So the proteoglycans in your cartilage, in your ears and in your nose, does not have any blood vessel or nerve supply. And that's because it's just packed with inhibitory proteoglycans. They come by a special name, chondroitin sulfate proteoglycan, and if you go to the store, some of those bottles will be labeled chondroitin, or you'll see Cosamin or glucosamine.
Basically it's chondroitin sulfate proteoglycan is what you're buying and eating. By the way, it's a waste of money. It's already been shown that eating that stuff is not going to help your cartilage although some people swear by it. So basically everybody has heard about proteoglycans if you've shopped in any grocery store. They're very inhibitory and they're found in cartilage. Now here we are back in the early 1980s telling people that these cartilaginous molecules that are very inhibitory to nerve growth and blood vessel growth are present in the developing retina of the brain. And they keep your nerve fibers in your retina from going out of your pupil and turning them in the right direction so they exit through your optic nerve. That was the first time in history that anybody had ever said that or thought that or hypothesized that.
And, that paper was published in Science Magazine. It was quite an important paper. And we could show that if we got rid of the sugar, the glucosamine part with an enzyme that's called chondroitinase that's made by bacteria, and I'll tell you more about chondroitinase. It screwed up the retinal biology and then the nerves started leaving out of the pupil.
So if we got rid of the proteoglycans in the retina, your nerves took the wrong route. That was really interesting. When I say proteoglycan, so the proteo is the protein part of the molecule, and the sugars are like little chains. The molecules look like bottle brushes. Everybody has seen a bottle brush. There's the metal thing that runs in the center and holds the bristles of the bottle brush. That's what proteoglycans look like. They look like bottle brushes. It's the brushes, the sugars that are the bad guys.
They're the inhibitory ones and they're called chondroitin sulfate. So the chondroitin sulfate being inhibitory can be removed by an enzyme called chondroitinase, which means enzyme. And guess who figured out how to get through our defenses? Bacteria. So there's a kind of bacteria called Proteus vulgaris, don't get it. It's the worst. They live in swamps, and they have figured out how to eat through our barriers. They usually enter through the eyes or they enter through the mouth or nose if you go into a swamp. And, they can eat right through the basal lamina structures of our bodies. And the basal lamina of our bodies just underneath your skin, for instance, or underneath the surface of your cornea, that's full of proteoglycans, too.
So the basal lamina is another structure in addition to cartilage full of proteoglycans, and these bacteria have figured out how to get through them. They eat away the barrier with chondroitinase so we use that enzyme to our advantage. So that's where it all started forty years ago, looking at the retina showing that these barrier molecules play a very important role in telling nerves where to grow normally.
So, that's where it started. We can keep going for another decade if you'd like.
Guy Kawasaki:
So these people who doubted your discovery, how did they explain the fact that these nerve cells didn't grow the wrong direction, if not for something like what you were hypothesizing?
Jerry Silver:
Well, before I published that paper on the developing retina that you amazingly knew about, it was thought that such molecules like proteoglycans don't even exist in the developing brain. Period. It was thought, before I came around thinking about this, that there was no extracellular matrix in the brain at all. There was no such big molecules like proteoglycans in the brain. It was too tight. Everything was stuck very close to itself. There's no space to put these molecules, and it was thought that they do not exist in the developing brain, or ever.
And anyhow, what are these cartilaginous molecules doing in the brain? And many people, even people in my own department when I was a young assistant professor, said I was studying artifact, that what I was studying was ridiculous and totally wrong. But there it was. We had antibodies and there were these big spaces that I found near the pupil of the developing retina were these big openings. They looked like holes. I call them extracellular lakes.
And they were full of proteoglycan, because we could see the proteoglycans using antibodies that specifically bound to them and stained them. And I said, "Here they are. They're sitting there."
"No, can't be. It's impossible. The brain doesn't have these molecules. You're studying artifact." So, I was pretty much a voice in the wilderness for a very long time. So, I started my studies in the eighties. We published our first paper on the proteoglycan story in 1990. That was a paper on the spinal cord, which we didn't experiment with using the chondroitinase. And the 1991 paper you mentioned in Science was the paper on the retina. That really opened the eyes of the world to the possibility that this might be happening, because Science Magazine is a very high impact publication. There's a lot of scrutiny that goes into publishing in science. And, they loved it because it was a brand new idea.
But nonetheless, it took over a decade until 2002 for another group in England to reproduce our work. For ten years, I was just screaming about this story that this has got to be true, and doing everything I possibly could to convince people, but it was not easy. So I actually lost funding from the National Eye Institute while I was proposing this idea and publishing. People on study sections didn't believe it either, so I lost my funding to do my eye research. And so I had to come up with a new avenue of research, a new direction.
So I thought, "All right, so let's ask another question. Let's see if these same barrier molecules, these chondroitin sulfate proteoglycans, let's call them CSPGs for short, maybe they reappear after injury to the brain or spinal cord. Or, they may appear in neurodegenerative diseases like ALS or Parkinson's disease or Alzheimer's disease where nerve cells are dying. Maybe these molecules that are normally playing a role as a barrier in the embryo, making a guardrail where you want one, reappear after injury but now these same molecules block regeneration."
So, we made lesions in the spinal cord, and here we are again just right around 1991. We started to make lesions with scalpel blades in the spinal cord, and by goodness, there they were again. They're in the embryo, in the places where you don't want nerves to grow. Then they disappear.
Guy Kawasaki:
Jerry? Just for clarification, you're talking about spinal cords of rats, right? Not people.
Jerry Silver:
Yeah, that part.
Guy Kawasaki:
Okay.
Jerry Silver:
That part. There's a movie, I can't remember its name right away, with Gene Hackman who plays a doctor who is cutting the spinal cords of people and curing them. What's the name of that movie? Anyhow, Gene Hackman played a bad guy. Hugh Grant was a young physician who found out about Gene Hackman and stopped him from doing this. Darn it, I can't remember the name of the movie, but it was with Gene Hackman and Hugh Grant.
But anyhow, no, this is rats with IRB approval and IACUC approval. You can operate. You have to have IRB approval to operate on humans. That's not what I did. The lesions that we make in the rats are not so terrible that they can't function at all. So, it was a small lesion in the spinal cord. And when we did that, these proteoglycan molecules that played a normal role as a guardrail in development reappeared after injury, and that was very exciting because now the idea was, "Oh, maybe Mother Nature is just using these molecules over again to form a wall, a barrier, around the injury."
And that's one of the roles of these molecules is to form a barrier, and that barrier around the injury site is called a scar, very much like the scar that you would get in your skin if you had a big enough injury. So if you cut yourself really badly and you have a scar that's observable and it's big enough, you'll notice that scar is numb. You won't have any feeling, and the reason is the scar in your skin, if it's big enough, is full of proteoglycans. So no nerve fibers will grow in there, and the blood vessels are underneath it so that's why it's numb. You're not bleeding anymore and you're not infected, but that happens.
The same thing happens in the brain and spinal cord. You get a scar, and that scar in the spinal cord if you stab it with a knife, is a wall that encompasses all the inflammatory cells. It makes a wall around all the debris that has accumulated and all the blood that has flowed into the spinal cord. And that scar serves an important function as a wall. However, the problem is in the presence of proteoglycans that are in the scar, there's no nerve regeneration. Even though they try, they try to regrow, but they can't and they get stuck in the scar, and they can't move forward at all. And one of the reasons they get stuck is because of the proteoglycan.
Guy Kawasaki:
And what I don't understand about this is all of this is happening at the molecular level and you're explaining it as if, "Oh, you can just see this."
Jerry Silver:
Oh yeah, you could see it. You cut sections.
Guy Kawasaki:
You can literally see it?
Jerry Silver:
With your eyes, yeah, if you're having a good imagination. In sections through the brain or spinal cord, you can stain the nerve fibers and you can stain the proteoglycans and you can see the interaction. And if you look at the cut ends of the nerve fibers, they get all balled up and swollen, and they're basically stuck. So in the adult, in the presence of proteoglycans, I just told you that the tips of the nerve fibers that have been cut don't die. The nerve cells are still alive. The nerve fibers are cut, and instead of turning like they do in the embryo, instead of turning away from the pupil in the adult, the nerves that are cut get stuck.
There's a difference, and I'll explain that, because of the receptor that NervGen is blocking. In the adult, the nerve fibers, when they're cut, upregulate a very important sticky receptor. And, let's call it PTPsigma. It's a very sticky receptor. You can think of it like Velcro. So, the proteoglycans in the scar would be the cloth, the loop, the fuzzy part of Velcro. So, that part would be the scar. And let's think about the cut end of the nerve fiber as the hook of Velcro. Hook and loop.
Now, in the embryo, the hook part is very small. Not very many hooks at all. And in the embryo, in the presence of proteoglycans, the nerve fibers turn away. They turn away. They go in the opposite direction. They have a different growth motor. They have more flexibility. So what the nerve fibers do in the embryo is basically to get stuck, but they can back branch. So as the nerve is going towards the pupil in the embryo, if it would try to do that, it gets stuck but then it can back branch. It forms a branch more towards the cell body and it goes in the right direction.
Adult neurons can't do that. They don't have the ability to back branch and turn away. They just go forward, and they go right into the proteoglycan. They cannot back branch, and now the hook, the receptor, is really big. And, there's a lot of them. So the adult nerve cell when it's cut has a lot of hooks and they're really big, and so now when they see the proteoglycan, just like Velcro, they get stuck right in it and you can't get free. Unless of course, you get rid of this hook and loop interaction, the bond. How can you do it?
One way you could do it is to get rid of the loops. The loops are the CSPGs. So, how do you do it? Guess what? You inject chondroitinase. That's the first thing we did early on in our career. So in the early 2000s, actually a group in England made a spinal cord injury. And that chondroitinase enzyme I told you about that those bacteria make to eat through our defenses, a group in England made a spinal cord injury and injected chondroitinase into the spinal cord. And, they showed nice regeneration and functional recovery.
So, they actually did the first experiment on a spinal cord injury model. In my lab, we were focusing on the retina and the visual system. It was very difficult because the optic nerve is so small. So a group in England in 2002, spinal cord injury, they removed the loops with chondroitinase. And when they did that by injecting the spinal cord, they saw regeneration and functional recovery. 2002.
So, I had discovered these molecules in 1990. We published, and it took 11 years until 2002, until a group in England actually published. And we did in our lab a lot of other studies. And, chondroitinase has been used to improve recovery after lots of different kinds of traumatic injuries to the spinal cord but also the brain. It's been used in models of Alzheimer's disease. It's been used in models of stroke. It's been, again, in models of spinal cord injury. It's been used in models of multiple sclerosis.
So the chondroitinase enzyme has been used hundreds of times in many labs and published. And people now surely believe it's now a major part of the story. After all this time, finally, people are understanding the importance of proteoglycans in the brain. They're real. It's not artifact.
Then we move forward another few years, because chondroitinase is not the best therapeutic for a spinal cord injury and the reason is it's bacterial. It's not stable at thirty-seven degrees, which is body temperature. This is a bacterial enzyme. You put it into the body, or into the spinal cord, and it doesn't last very long. It likes to be cold, like the swamp. And so, when you warm it up, it loses its potency. So, it doesn't last very long.
Also, it has to be injected right where you want it to get rid of the hooks. So you have to inject it into the lesion of the spinal cord and elsewhere to get it to work, and you don't want to put needles into the spinal cord or brain to get rid of the hook, the proteoglycan. There might be a better way.
So now if you have any questions, ask now because I'll tell you about how to get rid of the hooks.
Guy Kawasaki:
Okay, so the NVG-291 is not that theory of direct injection, obviously. You're saying subcutaneous in the stomach. So what's the theory of NVG-291?
Jerry Silver:
All right, now we're going to talk about the hooks. So you can ruin Velcro attachments two ways: get rid of the hooks or get rid of the loops. If you get rid of either one, Velcro is not going to work. So I told you about how do you get rid of the hooks using chondroitinase. That's the CSPG part. That's the loop.
So what about the hook? Who is the hook? So, the hook is the so-called receptor. It binds to the proteoglycans. People didn't know what the receptor for the inhibitory actions of CSPGs was for many years. So we discovered that proteoglycans, the CSPGs were barrier molecules in the mid-1980s and we published our first paper in 1990. But this sticky phenomena is mediated by some kind of interaction between the proteoglycan, which is the loop, and some receptor that the nerve cell or other cells make.
But we didn't discover what that receptor was until 2009, so you're talking almost twenty years. Searching all over the world, what's the receptor? Who is the hook? And it turns out to be this family of very sticky receptors called the LAR family. And one of the members of the LAR family is PTPsigma. Let's just call it sigma. Sigma is a very sticky receptor. It causes adhesion, stickiness when it binds to CSPGs, just like the hook binds to the loop. Sigma is the hook. Another way to screw up Velcro attachments is to get rid of the hook. That's sigma. How do we do it? We could find some enzyme that dissolves it or we can find some drug that blocks it or modulates it, gets rid of it. Block the hook, or cut it off in a sense. And since we now discovered what the hook was, it's PTPsigma. Let's call it sigma, a very sticky receptor.
Its function normally is what's called a synapse in the developing brain. The synapse, which is I think Greek or Latin for the word kiss, K-I-S-S, a kiss, is a nice attachment, a pleasant one. It's a nice kiss. So the synapse, the kiss between two cells makes a connection between an axon, a nerve fiber, and a dendrite of another cell. This receptor sigma is involved with normal synaptogenesis. It's a very sticky receptor. But this same sticky receptor is appearing in great abundance on the cut nerve fiber.
So when the nerve is cut in a spinal cord injury or a stroke, or in a degenerative disease, it upregulates, it increases the amount of hooks. It changes the type and the amount of the hooks. They make way more. Now there are zillions of hooks around on the cut nerve fibers. And don't forget, the proteoglycans are present in the scar, so they make lots more of the receptor.
So how do we get rid of it? And in my lab, we decided to block the receptor by using what's called a peptide. And that peptide would bind to the hook and it would block it. It would make it non-functional. It's like taking the part of Velcro that has the hooks and smearing it with molasses or glue. Just cover up all the hooks. So now they can't hook onto the proteoglycans. So, that peptide we call intracellular sigma peptide, or ISP. And in our Nature paper in 2015, we described this peptide for the very first time. The peptide has a shuttle attached to it. It's called TAT, T-A-T. It's a sequence of amino acids that helps the peptide get across membranes. It's based on HIV infectability. HIV can get into your body easily, mostly through sexual contact, and that T-A-T part is a shuttle that allows that virus to go through your tissues.
So we used tat, T-A-T, and attached it to our peptide which blocks the receptor. It's called the wedge domain. So the part of the receptor that causes its activity is called the wedge. That's not so critical. Our peptide blocks the receptor and gets through the tissue even if you just inject it just subcutaneously under the skin of the stomach. So it's a TAT/peptide. T-A-T/peptide. And that, you can put anywhere because TAT, like HIV, takes that peptide all the way into the brain and spinal cord, it takes it all over your body. So, you don't have to touch the spinal cord.
You just inject it subcutaneously under the skin of your stomach or your back skin. So then it gets into the brain and spinal cord and it blocks the hook, so now the receptor is blind. They can't see the proteoglycans and the nerves regenerate, and they sprout like crazy because they no longer see the loops. They just grow right past them.
Guy Kawasaki:
I have some dumb questions.
Jerry Silver:
Please. The dumber, the better.
Guy Kawasaki:
Okay, dumb question number one is if you're blocking this process, how come now all of a sudden you give this to patients and things aren't growing into their pupil? Haven't you stopped that process?
Jerry Silver:
Very good question. So remember what I said just a few minutes ago? Let's stress it. When the nerve fibers are damaged by a spinal cord injury or a stroke, or by a neurodegenerative process, those nerve fibers upregulate, increase dramatically the number of those hooks. They increase dramatically the number and packing density of that receptor. So they make lots more for some unknown reason.
So now if you give the peptide, those are the first cell types that are affected because they have so much receptor. So you can play around with the concentration, how long you give it, and those are the first ones that are targeted because they make so much.
Now that's not to say that your question is dumb at all. Your question was actually brilliant because one wonders if you give this peptide for such a long period of time that it changes the way the connections in the brain are hooked up. Or, when the nerves regenerate when you give the peptide, are they going to be able to make connections? Or, are they going to just keep growing wildly?
The answer to that question is in the animals, we give the peptide for seven weeks, not forever, and then we stop. And then the animals continue to get better after we stop giving the treatment. It's conceivable that in the presence of the peptide for very long periods of time, those regenerating nerve fibers don't make very good connections because we need the receptor to make the kiss, the synapse.
So now you stop giving the peptide and you ask me how long do you give it? That was one of the first questions you asked me, how long? And we really don't know what's the optimal time. Or, should you give it every other day? Then the nerves that grow can make a connection. Or, do you stop after two months and the nerves that have regenerated, they can make connections? Or, do you give it for a year and then stop? See, we really just don't know the optimal timing and position for the best route of administration yet. That's something the company has to work out, and the best way to work it out for people is going to be in patients.
So, the very first patients, if they report that they are still improving when NervGen wishes to stop, in that trial, they'll have to stop when they said they would. But they can do another trial where they give the peptide for much longer, or in much higher concentrations, or deliver the peptide in a different place. That could be better.
Guy Kawasaki:
Okay, dumb question number two.
Jerry Silver:
Please.
Guy Kawasaki:
Are you essentially saying that this treatment doesn't fix the problem, it enables the human body to fix the problem because the process was being blocked?
Jerry Silver:
That's right. Very good. Again, a brilliant hypothesis. Basically what we're doing is helping the body, and in this instance the spinal cord, fix itself. The nerves have the capacity to grow, not as fast as their embryonic counterparts but they can grow. They can grow towards proper connections. We have seen that in our animals. The animals get better, not worse. So the nerves that are regenerating and sprouting seem to be able to find the proper partners to connect with. The animals don't throw themselves off the table. They don't do strange things.
There's no unbelievable spasticity or weird dystonic type of postures. The animals get better. They can walk better. And, we just had a paper accepted for publication. They can actually use their fingers better depending on where you put the lesion. And if you give the peptide then, they can use their hands better, their fingers better, and they can walk better, not worse.
So somehow, Mother Nature is allowing the connections to be functional rather than non-functional. Now I can say one thing, there's another paper that you might know about that has been published where we studied the use of chondroitinase, not the peptide, the chondroitinase enzyme in a breathing recovery model. And in that paper, we report two very important things. One, the longer you wait after the injury to give the enzyme or the peptide, the better the result.
Guy Kawasaki:
What?
Jerry Silver:
The longer you wait after injury, the more chronic the condition, the better the results are when we get rid of the hook and loop interaction. There's some kind of reconnections that are forming very slowly, we think, that are being smothered by the proteoglycans. So, that's very important. So people who have very long, chronic spinal cord injury should not be depressed. As a matter of fact, they should be quite happy. There's no reason that twenty to thirty to forty years after your accident, the cause of paralysis, there's a lot of new connections that have been formed in the spinal cord, in the area of the lesion and elsewhere that are being smothered by the hook and loop interaction.
Now when we give the peptide or the enzyme, those connections that are smothered wake up very rapidly. Do you remember when you asked me how long it would take for people to get better? And I said it would happen very quickly within weeks. That's what we've seen. Actually using the peptide or the enzyme, an acute injury was not nearly as good as chronic.
Guy Kawasaki:
Okay.
Jerry Silver:
That's a good point.
Guy Kawasaki:
I was going to ask you for clarification on this, and I think you just explained. This interview I listened to of you said that there was a very fortunate accident where your research assistants went down and looked at rats that were treated 18 months ago.
Jerry Silver:
That's right.
Guy Kawasaki:
And lo and behold, the rats that had this for 18 months had great progress. Is this what you're alluding to?
Jerry Silver:
That's exactly right. Most people in our business, spinal cord injury business, the field, don't study chronic injury. But, they're very high risk although a high reward experiments. They're extremely expensive because you have to keep the animals around so long, and animal care is expensive. But my student who was an expert in the area of spinal cord injury that affects breathing and the spinal cord, so this is a very high cervical injury, which by the way, most people get. Most people are injured in the spinal cord in the cervical area, the neck because it's so flexible and it tends to get hurt.
He had made lesions in our rats at a high cervical level that paralyzed their diaphragm on one side. You can't make the lesion all the way because the animals can't breathe. So, it's a partial lesion that paralyzes half the diaphragm. And we were injecting the chondroitinase enzyme and using our peptide acutely after that injury and seeing very poor recovery. I was actually very depressed when my student, his name was Warren Alilain, first arrived in the lab.
I said, "Warren, let's do something else." And, we did. But he had lesioned 12 animals, 12 rats, in the high cervical spinal cord there in the animal facility and he had forgotten about them, that they were even there. And he forgot about them for over a year. And he discovered them one afternoon and came up to my lab. I will never forget the day he came into my office and said, "Jerry, guess what? I'm sorry, but I lesioned a dozen animals over a year ago and forgot about them. And, they're in the basement. What are we going to do with them?"
I said, "I don't know. We can't throw them away." It cost me about $5,000 just to keep them down in the basement in the animal facility. So I said, "Let's inject chondroitinase and see what happens." Now, this is before the peptide. So he did and he came running back in the next few days and said, "Jerry, the animals are breathing. It's incredible." So then, we needed more help so another six months passed, and we hired a postdoctoral student who's from England. Her name was Pippa Warren. So Warren Alilain and Pippa Warren, and when Pippa came, she did this study really well.
The recovery of the diaphragm on the side that had the lesion, so the animal had been paralyzed essentially all of its life, and within one week after an injection of the chondroitinase enzyme into the spinal cord near where the motor nerve cells are that move the diaphragm, within one week, they started to breathe and within two weeks, after injecting the enzyme, the breathing, the amount and the depth, the quality of the breath was equal to that of the other side. It was completely normal. Complete recovery of diaphragm function.
And, we also saw improvements in the ability of the same animal to use the fore paw, which is also paralyzed from that lesion on the same side. Now, here's the other part of the story I was going to tell you. So from those experiments we learned that longer is better. We found that an optimal time after the injury to get recovery is you have to wait at least three months. And almost nobody in my field waits three months. They wait one week, or they wait one day, and then they treat and then they report their results. Minimum of three months but the longer you wait, the better. And the quality of the breath, and the amount of unusual changes is very small.
Now, let me add the second part. In some of the animals, if we gave the enzyme to the animals that were about three months after their injury and we pushed the animals too hard with their respiratory therapy, and that therapy was called intermittent hypoxia. So, we basically forced the animals to go to Denver for five minutes and then come back to Cleveland for five minutes. So they'd go up to Denver and breathe low oxygen air. Then they'd come back to Cleveland for five minutes, they'd breathe normal oxygen air and back to Denver, and then back to Cleveland. And, you alternate that. That's called intermittent hypoxia. That's respiratory rehab.
When we did that in our animals, and these are mostly three months after injury, when we pushed too hard, when we gave the enzyme and lots of intermittent hypoxia, then we saw some problems in the diaphragm. It was too much of a good thing. It was bad. The side of the diaphragm that had recovered was now spazzing and not breathing properly. Now, that would go away. It would fix itself in about two weeks but you don't want your patients to have a spastic diaphragm or a spastic arm for any time at all. So we found that you can't push too hard, so the amount of rehab you give has to be the right amount, not too much. At least for the diaphragm.
And, that's a warning. I can explain that. So what happens is when you give the enzyme, and you give intermittent hypoxia, one of the nerve fiber tracts that regenerates and sprouts like crazy makes a nerve transmitter called serotonin. Some of you may have heard about serotonin. You may have, because serotonin is really critical for anxiety, and SSRIs like Prozac increase the amount of serotonin that's interacting with its receptor in the brain. So, more serotonin is good if you're anxious, but too much serotonin, way too much, is bad. That's the way Mother Nature is. It's got to be the right balance. Too little is bad, too much is bad. And we found out that in the animals that had this bizarre spastic diaphragms, there was too much serotonin. We had to back down.
Guy Kawasaki:
Okay.
Jerry Silver:
So people can overdose on SSRIs and they get horrible spasms and they get crazy hallucinations. So, you can take too much. That's one of the drawbacks. You can't push too hard.
Guy Kawasaki:
Okay. Now, it seems to me the way you describe all these discoveries over the course of thirty, forty years, it's pretty exciting and has major ramifications. And yet, I read that if it wasn't for some dentist whose daughter became a paraplegic, we might not be having this conversation.
Jerry Silver:
That's right.
Guy Kawasaki:
So I don't understand why was it necessary for this dentist to rekindle this interest?
Jerry Silver:
That's a very important question. Let me tell you a little bit about the story that led to the licensing of our peptide and the establishment of NervGen. We had published our Nature paper on the discovery of our peptide in 2015. The receptor itself, sigma, the hook, was discovered in 2009. So between 2009 and 2015, we were trying to figure out a way to smother or cut off the hook, and we had made some advancements that were unpublished before 2015.
The work was being done, but it hadn't been published yet. Our story was pretty ripe already around 2012, 2013, and fortunately our university has some connections with big pharma and actually invited big pharma, and this one happened to be GlaxoSmithKline, to Case Western Reserve to hear the good stuff that was happening at the university. One of the tech transfer people at Case Western was from GSK and knew some of the big shots in that company, invited them to come and they said, "Okay."
And so we had a GSK day at Case Western and they marched a couple of dozen labs in front of these guys. I was the last roadshow of the day. It was around 4:00pm , 4:30pm in the afternoon. Everyone was tired. And I presented our story about our peptide and our walking rats and the chondroitin sulfate receptor interaction, and they loved it. They absolutely loved it. And we talked more and we actually formed a partnership.
This was around 2010, 2011. We were rolling along really well. Actually, GlaxoSmithKline gave us some money to do some very critical dosing experiment. They assigned a group of people at GSK to us. They had a program at GSK at that time to fund basic research in different universities for promising translational science. And, we were rolling along and now finally comes time to ratchet up the funding to bring this in-house and do it right and mass produce the peptide, do all the important control experiments, and move to people.
Unfortunately, I will never forget this day, I was sitting in the office with the person who is the friend of the person at GSK. We were sitting in the office waiting for the phone call, is it a go or no go? And the answer was no go. Why? Oh, it was so depressing. And the reason was spinal cord injury is a small market and GlaxoSmithKline likes to make a lot of money, and we were studying mostly acute injury at that time. We hadn't made our animals in the basement mistake yet.
So, the number of people who are paralyzed in the United States each year is around 16,000, and that's an orphan market. It's very small compared to Alzheimer's disease or multiple sclerosis where the numbers of patients are in the millions, and the amount of money to be made obviously in Alzheimer's disease or MS is huge compared to spinal cord injury. And so the upper level management made a decision to abandon the program.
They then suggested the possibility. I think at that time the company called AbbVie who makes Humira, makes a fortune from Humira, AbbVie, and they have a lot of new drugs on the market these days. So AbbVie, I think it's A-B-B-V-I-E, they suggested we talk to AbbVie. And so, they loved us too. And AbbVie got very interested in the possibility of licensing our peptide and doing a clinical trial, and we spent another year doing experiments, and then they had a special team appointed to us and upper level management again, "No go. No, too small a market."
They wanted us to study multiple sclerosis, and we hadn't done our research using an MS model until later. Actually, the peptide NVG-291 and our peptide that we use in rats called ISP has beautiful effects in MS models. So spinal cord injury is not the only target of NVG-291. The cells that make new myelin also have the same receptor, and in the MS plaque, you see the same proteoglycans all over again. It's repeated.
AbbVie wanted us to already have data on multiple sclerosis, which we did not so the project got killed, and now we have nothing. Nobody. And time is passing and the clock is ticking, and I'm getting older and nothing is happening because Case Western does not have unlimited contacts with big pharma. And we were dormant until Harold Punnett. I can't remember exactly what year. It's been seven years so is this around 2016? Yeah, around 2016 I started talking to Harold Punnett. Harold is a dentist. He's in Canada. He is a wonderful guy, and unfortunately his daughter-in-law was paralyzed in an accident.
She fell and broke her back and became a paraplegic. And Harold, the dentist who has some knowledge about biology and science, was searching the world for something that could help. It's his daughter-in-law. And, he couldn't find anything until he happened upon our paper, which was published in 2015 and he got really excited about it. He's also an angel investor. He's done this before. It's one of his, I guess, hobbies to invest in startup biotech companies. And he knew some investors in Canada who might come along with him. And, Harold and I talked and talked and we got along beautifully. He's a wonderful guy. He's just a nice guy, brilliant, and he wanted to start a company. And so, we brought in a few other people and NervGen was born. It took a while for Case Western to negotiate the deal. It took years actually.
Guy Kawasaki:
Wow. What a story.
Jerry Silver:
That's just the way Case Western works, but there were several points during the negotiations that were very tense. The university wanted more, the company wanted more. You know how it is. So the negotiations took a while, but they were successful. I am told by the people at NervGen they would have never walked out, ever. They were prepared to negotiate for as long as it took. But eventually, thank God, NervGen was born and in a few weeks, the culmination of forty years of my work is going to happen and the first patients with spinal cord injury are going to be injected with the peptides. So, fingers crossed.
Guy Kawasaki:
Mazel tov.
Jerry Silver:
Thank you. It's not a slam dunk. You never know. Rats are small, people are big. Rats are all the same size, the same weight, the same genetic background. Everything about white rats is pretty much shared from one animal to another. Humans are all different. We don't look alike, our genetics are different. We're different sizes, shapes. It's just the way it works.
Guy Kawasaki:
So I hope this story is true, but you know what WD-40 is?
Jerry Silver:
Sure. It's one of my favorite. I spray it on everything.
Guy Kawasaki:
Okay. So the story goes that WD-40, it represents the fortieth attempt at the formula.
Jerry Silver:
Really?
Guy Kawasaki:
So NVG-291 basically the 291st attempt at creating this peptide?
Jerry Silver:
No. I don't even like that name. I wanted to name it something sexy like Regenavid, or something like that. NVG is NervGen. I don't know why. It's the first iteration. It's a humanized version of the rat peptide. It's designed to work the best in people. I have no idea. You'll have to ask somebody at NervGen why did they pick 291. I have no idea. It's actually NVG-1. Hopefully there'll be a two, three and four but I don't know.
Guy Kawasaki:
Okay. This is my last question. First, pardon my scientific ignorance but I think that what the glia does is it makes these physical barriers and inhibitors that protect neurons, right?
Jerry Silver:
Correct.
Guy Kawasaki:
Okay, so now I read or heard someplace that you have license plates that say GliaMan.
Jerry Silver:
Oh no.
Guy Kawasaki:
Now, it would seem to me that by making license plates that say GliaMan, you are in fact highlighting something you're trying to undo because you're trying to end the protection of neurons and stimulate regeneration. Right? So, why GliaMan?
Jerry Silver:
In the first place, I wouldn't call myself a pioneer but in the modern age of science that goes back to earning my PhD, most people in the neurosciences studied neurons. And, I guess it's just the way I am. I just like to do stuff that other people don't do, and I have a weird stubborn streak so if I see something that I'm sure is right, because I see it in front of my own eyes, I become very persistent. I'm unflappable.
And so, I believe that the glia were important. They must be doing something other than being nurses to the neurons. That's what people thought. Glia just support the neurons, but I believed that the glia impart important information to the nerve cells. They help them work better, we now know, but also they get in the way sometimes. And one of the jobs of a glial cell called the astrocyte which means star shaped, astro. Cyte means cell, which are the most abundant glial cell types in the brain. It's not a nerve cell. It doesn't fire an action potentially. It's a glial cell. It looks like a star. They're everywhere.
The astrocytes have another job, and one of their jobs is to make a scar. Just like fibroblasts in your skin make a scar. You want to stop the bleeding and you don't want the infection that could occur in that site to spread all over your body, you make a scar. But we don't have fibroblasts normally in the brain so the astrocyte plays a role in building so-called glial scar, which surrounds the area of inflammation that you might get after a small hemorrhage or a bump on the head. And that scar that the glia makes serves an important purpose.
It walls off the area of injury, so it doesn't spread all over your brain. Sometimes the scar actually responds to tumor cells that have invaded your brain, and if they trigger the scar, the tumor in your brain will be round like a golf ball. Unfortunately, a glioblastoma, which is a tumor cell that's very clever and have fooled the astrocyte into not knowing it's even there, does not create scar. And unfortunately, glioblastoma migrates all over the brain.
So, the glial scar plays an important role. Unfortunately, it also blocks nerve regeneration. Now, can you get rid of the proteoglycans or get rid of the receptor on the nerve cells and not do damage to the scar so much that it allows the inflammation to spread all over your brain? And apparently, you can get rid of the proteoglycans with chondroitinase, but the wall building ability of the scar still remains, because Mother Nature has not built a scar just using proteoglycans. She also makes the cells, the astrocytes, very interconnected, what are called adhesion junctions.
So, the astrocytes that make a scar are all welded to each other with I call it adherence junctions. See, Mother Nature's smart. She doesn't use just one mechanism to build a wall. She also takes the astrocytes and makes them really big, and she makes them really convoluted shapes. No longer are they parallel or nicely shaped. They are bizarre, like spaghetti. Bigger, shaped like spaghetti, all welded together in a wall, and they make proteoglycans. One, two, three, four different, so you can get rid of the proteoglycans and still have a wall, so you don't have this expanding lesion.
So that's what Mother Nature does. Thank God we can get rid of the proteoglycans, but the wall building function is still partly there, but the nerve cells can now get through or across the wall.
Guy Kawasaki:
Okay, this is truly my last question. You've been at this for forty years.
Jerry Silver:
That's right.
Guy Kawasaki:
Luckily, a student left some rats in the basement and luckily a dentist made contact with you. So as you look back on these forty years, what's the lesson here? What's the lesson of Jerry Silver?
Jerry Silver:
That's a good question. I don't know why I am the way I am. It probably has something to do with the way I was raised by my parents. I don't know. Maybe it's having a Jewish mother who used to tell me crazy things that I thought were wrong, and I had to base the way I am on my own beliefs because my mother was telling me crazy things. You know how Jewish mothers are. If you don't eat enough, or you could go blind if you do the wrong thing, and all kinds of crazy things about who you can date, who you can't date. And so, I had to make up my own mind about what I see, and I've always believed if I see something in front of me with my own eyes, it's true. So, that's how I started.
If I would see something that everyone said was wrong, even my mother, I said, "I'm sorry. It's wrong. I'm right." And I have carried that with me all my career. And if there's anything to say about who Jerry Silver is, it's that I'm stubborn, I believe in myself, and if I see something that I think is true, even if the rest of the world says I'm wrong, I stick with it. I've been doing that for forty years, and the proteoglycan story, don't forget, people in my own department said I was studying artifact.
I can tell you a very interesting phase of my life where my story came to fruition in another company, which it's a rags to riches to rags again story that you might be interested in. I was studying proteoglycans for a long time, since the mid-1980s and late 1980s, and we published the first paper 1990.
So right about the end of the 1990s, another company came to Cleveland that I founded, and the company's name was Glia Tech. Glia Tech was the very first biotech company in northeastern Ohio, and there was a fellow at Case Western who was just looking around for technology that could be promising and translational. And, I told him the proteoglycan story. I said, "They make barriers." But back then, Glia Tech had a different story that actually went all the way to an FDA-approved product and was used in hundreds of thousands of patients.
My idea back then was to build a barrier where you would actually want one and use proteoglycans to do this. Where do you want a normal barrier? If you know about nerve entrapments, for instance you know about carpal tunnel syndrome? You've seen people with carpal tunnel, the median nerve and tendon get entrapped in scar. So, scarring in the body is very bad. You can get scarring in the uterus or around the uterus. It causes infertility. You can get scarring in your abdomen that binds to your GI system, and that's bad. Scarring after burns of the face or an operation that's gone wrong, like a tracheotomy, a big scar.
So the scarring is bad. I thought, "Wouldn't it be interesting if we could get rid of scars inside the body?" And Glia Tech was born on a completely different patent that I had generated. It's not important, but I told them about my idea. And what Glia Tech did was to say, "Let's put a barrier where we want one." So if you damage a peripheral nerve, say in your elbow, say you damage your ulnar nerve, and that nerve gets entrapped in scar tissue, or if it gets entrapped in your wrist in scar tissue, that's extremely painful. Nerve entrapments in the body are very common. If you cut your wrist with glass and you get scar tissue around the nerve, the median nerve, oh, it's terribly painful. It's called nerve entrapment. That scarring that tethers the nerve causes unbelievable pain.
It turns out that proteoglycans inhibit not just nerve cells, they inhibit all kinds of cell types, even fibroblasts. So my idea was to make a barrier out of proteoglycans and make it into a gel so could be squirted into the area with the nerve damage and cover up everything. And Glia Tech invented a product called ADCON, A-D-C-O-N. They were going to use it in surgery on the back after you get a discectomy and people who have ruptured discs. One of the horrible things that can happen after a discectomy is nerve entrapment of the dorsal roots, which is unbelievably painful. It's called failed back syndrome.
So that's what they were going to target first, and other nerve entrapments. So they called this product ADCON-L. You can Google it and find out. Basically ADCON-L was gel foam powder, which is a collagenase powder, a glycosaminoglycan that was synthetic called dextran sulfate, not chondroitin sulfate, and water buffer. That was it. It made this beautiful antifibrotic gel.
And if you have a nerve entrapment, you could go in as a surgeon, cut away the adhesions, but unfortunately the patient would get better because you cut away the scar, loosen up the nerve, but many people develop scar again. And if you go back and cut away the scar around the nerve, they get relief, pain goes away and in six months or a year, the scar comes back always worse than the time before. And after four or five surgeries, it's called neurolysis, to free up the nerve from the scar, you can't operate anymore.
And ADCON-L was invented for those patients. Amazingly, one of the first patients in the United States was named Mr. Smith right around 1998 with FDA compassionate approval. Mr. Smith had five surgeries on his wrist because he had cut his median nerve, not completely, but he had terrible scar in his wrist. He had so much pain, he couldn't sleep. He wanted to have his arm amputated, and he was the first American patient to receive ADCON-L. After his fifth neurolysis surgery, he was cured. And ADCON-L was used in all kinds of interesting other types of areas where there were scarring. Tracheotomies gone bad with scarring around the trachea and the larynx, scarring in the face because of dog bites. ADCON-L was fantastic.
Glia Tech was rolling along. They were on the NASDAQ Exchange. The stock price was soaring. That's my riches part. Rags first, riches and then the company screwed up. The company had very greedy, selfish people. You hear about these kinds of people from time to time in the United States and elsewhere, where they take a perfectly good product and ruin it because of greed. And, unfortunately that happened. It's a longer story and you can read about it. The FDA blackballed, but that was my first successful biotech company. ADCON had been used in over a half of a million operations around the world. So, lots of people got better.
So that was my first experience, ADCON-L, Glia Tech, and an FDA approved product within just a few years, and the company went bad and fell apart. After Glia Tech fell apart, I was very down on forming yet another company because of the bad experience that I had with Glia Tech who killed my baby. So now, my attitude, I was very scared, fearful, of forming another company where the same thing could happen to me all over again. That is greed at the level of the company management. Now, I am convinced and extremely happy with the upper level management at NervGen. I'm not afraid anymore. I believe that now instead of putting a barrier where we want one, we're going to get rid of a barrier where we don't want one.
It's very similar, in a sense, to Glia Tech, which was quite a remarkable success. They were predicting billion dollar market until they screwed it all up and the company went broke. You can read all about it. There are lots of essays about it and the history of Glia Tech. And when NervGen came along, I had to convince myself that everybody was honest. They're not in it just for the money. They're in it because they want to really help people. Of course, helping people can be profitable. I don't have any problems with the company making a great profit. That means they're successful and people will be getting better. But I believe that NervGen is really meaningful and they are going to target spinal cord injury first.
So I'm so happy finally after all these years, they're going to target, and with the failure of GSK, the failure of AbbVie, finally with a startup biotech company in Vancouver, I have hope they're not going to screw it up.
Guy Kawasaki:
Now your mother will be proud.
Jerry Silver:
Yeah, right. May she rest in peace.
Guy Kawasaki:
I hope you enjoyed learning about the advanced work of Jerry Silver, truly a pioneer in the field of spinal cord injuries. His discoveries and explorations have shed new light on possible treatments for conditions that are life-changing. This makes him truly a remarkable person.
I'm Guy Kawasaki. This is Remarkable People. My thanks to MERGE4, the coolest sock company, for sponsoring this episode. Remember, use the promo code “FRIENDOFGUY” to get 30 percent off. My thanks to the incredible Remarkable People team, Jeff Sieh, Shannon Hernandez, Tessa Nuismer, her sister Madisun Nuismer, the Drop-in Queen of Santa Cruz, Fallon Yates, Luis Magaña, and Alexis Nishimura. Until next week, Mahalo and Aloha.