Reversing Severe Spinal Cord Injuries with Samuel Stupp, PhD
Regenerative nanomedicine is being used to develop new therapies for devastating conditions such as severe spinal cord injuries. Northwestern's Samuel Stupp, PhD, is a pioneer in the field of regenerative nanomedicine and recently published a paper in the journal Science that details how a new injectable therapy uses synthetic nanofibers to reverse severe spinal cord injuries in animals and how this therapy could soon be used in humans.
"The way we envision it now, at least in the initial stages, is that it could be used as a therapy after trauma has occurred. First, as a preventive therapy to avoid paralysis if possible, or at least to restore more functions after trauma has occurred. Moving forward, we will focus on the chronic injury, to see if we can impact patients that already have spinal cord injury."
- Board of Trustees Professor of Materials Science and Engineering, Chemistry, Medicine, and Biomedical Engineering
- Director of the Simpson Querrey Institute for BioNanotechnology
- Director of the Center for Regenerative Nanomedicine
- Professor at McCormick School of Engineering
- Professor of Medicine in the Division of Endocrinology
- Professor at Weinberg College of Arts and Sciences
- Member of Northwestern University Clinical and Translational Sciences Institute
- Member of Robert H. Lurie Comprehensive Cancer Center
In this episode, Samuel Stupp, PhD, discusses what he believes is one of the most important studies of his career. The reason for his belief is two-fold: the study gives hope to a lot of people who are afflicted with severe spinal cord injuries and it uses fundamental basic science research to tackle a critical human problem. According to the National Spinal Cord Injury Statistical Center, nearly 300,000 people are currently living with spinal cord injury in the U.S., and there's been no improvement in life expectancy since the 1980s.
- Since Stupp came to Northwestern over two decades ago, he set out to make an impact on regenerative medicine with supramolecular chemistry, an emerging area of chemistry that seeks to understand how molecules interact with each other.
- Stupp says the brain and the spinal cord are one of the most challenging targets in regenerative medicine, but he thought there could be success with the use of supramolecular systems.
- In 2008, Stupp published a paper with John Kessler, MD, the Ken and Ruth Davee Professor of Stem Cell Biology, applying a concept of use of supramolecular systems in a mouse model of spinal cord injury that laid the groundwork for the new paper in Science.
- In the new study, Stupp's team uses supramolecular systems to chemically tune the motion of molecules, so they can find and properly engage constantly moving cellular receptors in a mouse with a severe spinal cord injury and diminish damage by triggering cells to repair and regenerate.
- The treatment is injected as a liquid that turns into a network of filaments, which mimic the architecture of naturally existing filaments in the spinal cord.
- In the study, Stupp's team administered a single injection to tissues surrounding the spinal cords of paralyzed mice within 24 hours of their injury. Just four weeks later, the animals regained the ability to walk.
- Stupp says the next stop for this technology is FDA approval and, hopefully, an eventual human trial to use the therapy after trauma has occurred to avoid paralysis or to at least restore more functions after trauma. Moving forward, his team plans to determine whether the injection can impact patients who already have spinal cord injury.
Additional Reading & Resources:
- "Bioactive scaffolds with enhanced supramolecular motion promote recovery from spinal cord injury" in Science
- The 2008 paper in The Journal of Neuroscience: "Self-assembling nanofibers inhibit glial scar formation and promote axon elongation after spinal cord injury"
- Overview of supramolecular chemistry
- Explainer video about the study
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Recorded on Oct. 20, 2021
Erin Spain: Regenerative nanomedicine is being used to develop new therapies for devastating conditions such as severe spinal cord injuries. Northwestern's Dr. Samuel Stupp is a pioneer in the field of regenerative nanomedicine and recently published a paper in the journal Science that details how a new injectable therapy uses synthetic nanofibers to reverse severe spinal cord injuries in animals and how this therapy could soon be used in humans. Dr. Stupp is the Board of Trustees Professor of Materials Science and Engineering, Chemistry, Medicine and Biomedical Engineering here at Northwestern, and the director of the Simpson Querrey Institute for BioNanotechnology. Welcome to the show, Dr. Stupp.
Samuel Stupp: Thank you. Thank you very much, Erin.
Erin Spain: Your research group is focused on the development of self-assembling organic materials, focusing on functions relevant to both the fields of energy and medicine. Now, you've had many important discoveries in your lab over the past several decades. Tell me specifically the work you've been doing in regenerative nanomedicine.
Samuel Stupp: We are living longer. We have the expectation of living a very high quality of life. We want a long health span. We want to be able to move and think and create and enjoy life for a long time. So the ability to regenerate tissues in adults is a very attractive technology. It is a very important technology that would impact healthspan, quality of life. In the year 2000, approximately when I first came to Northwestern, I set out to use supramolecular chemistry to have an impact on regenerative medicine. Supramolecular chemistry is an emerging part of chemistry that seeks to understand how molecules interact with each other. The genesis of this type of chemistry goes back to the 1980s. In the late 1980s, there was a Nobel Prize awarded for the very beginnings of our journey in learning how molecules interact with each other to form stable structures. So of course, when you have molecules, you always have atoms and you have typically covalent bonds between them, and those are very strong bonds. But in supramolecular chemistry, the intent is to understand the interaction among many molecules and the bonds that they form to interact are much weaker than covalent bonds. So we call them secondary bonds in chemistry. And interestingly, they are tunable bonds, meaning that we can bury the strength of those bonds and therefore modify the nature of the structures that form when molecules interact. And my idea was that if we could figure out how we could design molecules with signals, that would signal cells, then in the context of supramolecular chemistry, we could create ensembles of many molecules interacting with each other that present those signals to cells. So the idea was that possibly the collective behavior of thousands of molecules in an an ensemble could have a huge impact on their ability to signal cells.
Erin Spain: Well, that leads us to the paper that we're here to talk about today. You've said this paper, just published in Science, is one of your most important papers. In it you explain a new therapy made up of what you call these dancing molecules and synthetic nanofibers and how, after just a single injection, paralyzed animals regained full ability to walk within just four to six weeks. Explain this therapy and the findings to me, which are detailed in Science.
Samuel Stupp: Cells themselves are constantly moving. So if you think about a cell, a cell is like a tiny hydrogel, maybe measuring 10-20 microns in diameter and everything is moving in the cell, particularly on its membrane, where they have receptors. And those receptors are moving very rapidly, exploring. They're walking, they're dancing. And the idea here was that if we could rationally think about the motions of the molecules that are signaling the cells, recognizing that the cells are also moving so much, that if we recognize that we need to match those motions, we could be much more effective at signaling. So just imagine a group of molecules in our filaments, let's say, 10, 12, 15 molecules, trying to activate a receptor on a cell. That receptor is moving. The cell is also moving. The cell is changing shape constantly. It's migrating or it's extending, perhaps projections in different directions. And so the receptors are going everywhere. If that group of 20 molecules is able to move and jump out, in and out, and probe those receptors as they're moving, there is a much higher probability that those molecules will be able to activate the receptor by touching the receptor in the right place. So if they move, they succeed. So the dancing of the molecules helps the molecules succeed at talking to the receptors in cells. This is, of course, something that will no doubt be of universal value in many aspects of medicine, in many therapies. We tried to apply the principle to regenerative medicine, and we chose one of the things that I care most about, which is the regeneration of the central nervous system. This is probably the most challenging target in regenerative medicine because the central nervous system, which is effectively the brain and the spinal cord, have very limited capacity to regenerate, very limited. So it is one of the greatest challenges that we face in regenerative medicine.
Erin Spain: And so that's why you decided to take on this challenge and actually try this therapy in animals who have severe spinal cord injuries. Tell me about that.
Samuel Stupp: So what we did is we decided to apply the concept to a model, to an in vivo model of spinal cord injury. This is a murine model. It's a mouse model. And we had earlier, in 2008, I published a paper with Professor John Kessler from our Neurology Department. We published a paper on the use of supramolecular systems, you know, these filaments with a signal to restore function after spinal cord injury, and that paper showed that we could use a specific signal and get some recovery from the injury. So that's the background. But then at that time, of course, the technology, it was an early technology. It was at that time, maybe 8-, 10-years-old. Now we know a lot more about the supramolecular chemistry, these filaments, and we were now prepared not only to explore this concept of the motion that I alluded to earlier but also to explore the possibility of using more than one signal to restore function. So in this new paper, not only do we tune the motion, we demonstrate that the motion is absolutely critical. So you keep the signals the same, the shape the same, everything the same, but you go in and chemically tune the motion and you get remarkable differences in the outcome after spinal cord injury. So this is indeed very, very exciting, and we would like the scientific community to appreciate the value that it could have for many other biomedical therapies.
Erin Spain: There's five key ways that this therapy triggers cells to repair and regenerate and drastically improve severely injured spinal cords. Walk me through those five different ways.
Samuel Stupp: First, we found that we could regenerate axons after the injury. So we localize the injury. The injury is also a very important difference. This time the injury is a severe spinal cord injury, not a mild injury, so that's an important point. Secondly, we observed that we could get enhanced vascular growth, so we saw the new blood vessels growing. Very excitingly, very interestingly, we also saw that we could myelinate the axons. So myelin, which is sort of a coating, you can think of it as a coating around axons that is very important in the ability of neurons to transmit their signals through electrical phenomena and you can think of it as an insulator, insulating membrane around the axons, which you could think of as electrical cables. And so you have this installation. And many neurodegenerative diseases are connected with demyelination, so neurons lose their myelin and this affects their ability to fire well, to transmit signals. So we saw greater myelination of the of the axons as well. So that was the third observation. The fourth observation was that we diminished the glial cells that form after spinal cord injury. We saw something similar in the 2008 paper, and this time we again saw that the glial scar that forms after spinal cord injury is diminished. I mean, we reduced the size of the scar. Now, the importance of reducing the scar is that then if that scar is not there, you know, think of the scar as a physical barrier so that even though the axons might be still alive and could regenerate to reestablish the proper connections with muscles in the brain, they can't because they face this physical barrier, which is the scar. So we saw a diminished level of scarring, and that was effect number four. And effect number five is that we proved that we saved a lot more motor neurons as a result of the therapy. So there you have five critical observations at the biological level. The most exciting one, of course, is we observed that the animals regained their ability to walk freely after three or four weeks from the injection as a result of these biological phenomena that our therapy was able to induce.
Erin Spain: Tell me about the injection and how it's administered.
Samuel Stupp: Basically, this would be a simple injection. I mean, so the therapy, if you were looking at it, it looks like water. So you would see a bottle and you think, "It's water, what's in there?" But of course, the filaments, the nano filaments, are in that water. And as soon as they touch living tissue, this solution that's based on water, mostly water, turns into a hydrogel. It just gels and stays right there where you inject it. So now the questions are going to be: Exactly where are we going to put it? If we're going to put it through a covering that the spinal cord has called the dura? Are we going to inject into the cord itself? I mean, there are some open questions, and we will no doubt have to engage our neurosurgeons in giving us ideas on how would be best to administer it. But it's essentially an injection of a liquid that then turns into a network of filaments and those filaments actually mimic, interestingly, the architecture of filaments that naturally exist in the spinal cord.
Erin Spain: I'm curious, when it came time to do those experiments, how did that work? How soon after the injury were they given the injection?
Samuel Stupp: In this particular paper, we did it 24 hours after the injury to attempt to simulate what a therapy might be like in humans, right? So you may have an injury, you know, which come from an explosion, a sports injury, a car accident, et cetera, a gunshot wound. Whatever it is, you may not be able to get help in a hospital right away. So we administer the therapy 24 hours after the injury. But of course, in future experiments, this is something that we will explore further and to make sure that the timing is optimized.
Erin Spain: You mentioned some of the ways that people develop spinal cord injuries, and according to the National Spinal Cord Injury Statistical Center, nearly 300,000 people are currently living with spinal cord injury in the U.S. and life can be very difficult for these people, just basic functions, and they may face multiple hospitalizations, and there's been no improvement in life expectancy since the 1980s. So how big of an impact could this therapy make on this group of people, their caregivers, the healthcare system.
Samuel Stupp: The way we envision it now, at least in the initial stages, is that it could be used as a therapy after trauma has occurred, first as a preventive therapy to avoid paralysis if possible, or at least to restore more functions after trauma has occurred. Moving forward, we will focus on the chronic injury, that is, to see if we can impact patients that already have spinal cord injury. And then through some procedure in a slightly different form of our materials and nanostructures, we could then have impact on those patients that are already paralyzed and have very substantial reduction in their normal functions relative to the population at large. This not only would impact patients greatly, but it would also impact the burden on caregivers, right, on families, and not to mention the economic burden that spinal cord injuries and our government have to face to take care of those patients. So we want to reduce the economic burden. We want to, most importantly, raise the quality of life for those that unfortunately have experienced traumatic injury and give them a better life and a longer health span, which is something that hasn't changed, as you mentioned earlier.
Erin Spain: You want to see this therapy move into to human trials soon.
Samuel Stupp: Absolutely.
Erin Spain: What needs to happen to make this a reality?
Samuel Stupp: We are headed for the FDA. We are determined to do this. Northwestern has been extremely supportive in this process. INVO, which is the organization that looks at technology transfer that concerns itself with technology transfer at the university, has been extremely useful. So from INVO we have been able to access consulting and funding to accelerate the process of translation. And so we are right now getting ready for that. We are already planning the experiments. We're planning the tests that are going to be important in gaining FDA approval for a clinical trial in humans. And we are going to try to go through this journey as fast as we can, and we hope that the FDA will be open because this is a new type of therapy. It is, first of all, a supramolecular therapy, a therapy that operates with an ensemble of molecules, not with individual molecules. As you know, in the pharmacological world, all therapies are based, you know, most of them on small molecules -- small, strange looking, organic molecules that people, that chemists make and screen so they can inhibit an enzyme or activator a receptor and or inhibit a receptor. But here the therapy is an ensemble of molecules, it's a thousand molecules working together, right? And they all have signals that are basically trying to signal receptors in cells. And I should say that biology uses this supramolecular strategy in the way it signals receptors, and this is something that people outside of my field, you know, don't think a lot about, but proteins, for example, signal cells oftentimes bonded to each other into filaments, oftentimes bonded to macromolecules that are present in the extracellular space. So this is a very biomimetic therapy. We hope that the FDA will be open to the importance of this type of therapy because it could impact many other biomedical therapies universally, not just spinal cord injury, not just regenerative medicine, but any other biomedical therapies. It is sort of us trying to begin the era of supramolecular medicine, and this is going to be very exciting to see how it plays out, how it develops, how the regulatory agencies are going to approach it.
Erin Spain: For anyone who is listening, anyone who is a biomedical scientist, any young students listening, any patients or family members, what is the one thing that you want them to take away from this research that's just been published?
Samuel Stupp: This paper should give hope to a lot of people that are afflicted with degeneration or trauma and require the restoration of function through regenerative processes. It should give them hope. But the other message that I would like to make clear is for people to recognize the importance of basic science research. We designed the paper so that it would show that we can use fundamental basic science to tackle a critical human problem. I mean, the paper has that combination, and this is why I am so excited about the paper. I think it's a very important message of how basic science is so critical in all of our medical advances.
Erin Spain: Well, thank you so much, Dr. Samuel Stupp, for joining me today, sharing details of this paper. We're excited to see what happens next.
Samuel Stupp: Thank you, Erin. Thanks for having me, and I enjoyed the conversation with you very much.
Erin Spain: Thanks for listening. And be sure to subscribe to this show on Apple Podcasts or wherever you listen to podcasts and rate and review us. Also for medical professionals: this episode of Breakthroughs is available for CMA credit. Go to our website feinberg.northwestern.edu and search "CME."
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Samuel Stupp, PhD, is an independent contractor for Nanyang Technological University-Singapore and the University of Hong Kong, advises (i.e., advisory committee, review panels, or board member, etc.) the Institute for Bioengineering of Catalonia, and is the co-founder of Amphix Bio and NeuronGrow. Content reviewer John Kessler, MD, has nothing to disclose. Course director Robert Rosa, MD, has nothing to disclose. Planning committee member, Erin Spain, has nothing to disclose. Feinberg School of Medicine's CME Leadership and Staff have nothing to disclose: Clara J. Schroedl, MD, Medical Director of CME, Sheryl Corey, Manager of CME, Allison McCollum, Senior Program Coordinator, Katie Daley, Senior Program Coordinator, and Rhea Alexis Banks, Administrative Assistant 2.