Cell therapy—from bone repair to leukemia cure

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Carl Gregory, PhD, an associate professor in the Department of Molecular and Cellular Medicine at the Texas A&M College of Medicine, collaborates with Texas A&M engineers to bring his ideas to market—and to patients.

Episode Transcript

Christina Sumners: Welcome to Science Sound Off. I’m Christina Sumners.

Tim Schnettler: And I’m Tim Schnettler.

Christina Sumners: With us today is Dr. Carl Gregory, an associate professor in the Department of Molecular and Cellular Medicine at the Texas A&M College of Medicine. Welcome, Dr. Gregory.

Carl Gregory: Well, thank you for having me.

Christina Sumners: So you research bone regeneration with stem cells…is that a fair assessment and phrase?

Carl Gregory: Um, yeah, that would be fair. We’ve expanded our research considerably over the last few years. So we work on bone repair and of course at some point you’re gonna have to get out of the lab and start treating humans at some point and that got us into cell manufacturing. The challenges of generating enough cells, or biomaterial, to satisfy not just one human being but the millions that in the end are gonna need it.

Christina Sumners: Absolutely, why are some of the reasons that people might need this sort of treatment whether just a broken bone or—

Carl Gregory: About 90 percent of patients with a relatively normal level of trauma will heal themselves. I mean that healing process may be it may take a little bit of time, it may require a certain level of intervention, but for 90 percent of us, we heal. The other 10 and I’m talking about serious trauma, so surgeons would call this type of trauma a critical size defect which by definition is a defect that is just too large for the body to heal it. And then there are other at-risk segments of the population, the elderly, those of us that smoke, those of us with certain diseases such as diabetes, osteoporosis, so even a relatively shall we say non-noteworthy level of trauma can be a real challenge for these patients. So when that happens the orthopedic surgeon would evaluate certain treatment strategies. Usually that would involve fixation of some kind and then bridging of the gap with a bone mimic of some kind of which we have many it’s a billion- dollar industry. And then they would try to stimulate bone growth over the bone mimic to try and incorporate it into the body by maybe using your own bone marrow or autologous bone from your hip, or even very powerful bone morphogens, bone morphogenic proteins that you can get commercially. So you can apply those to the injury and it will stimulate your inherent ability to create bone. But of course these drugs are only as good as your ability to repair yourself. So where we come in, we’re trying to mimic autologous bone. So bio autologous bone, I mean, a fragment of bone that you would take from a distal site, a site that isn’t injured, and use it to repair a site that is injured. It doesn’t have to be the hip, but it generally is the hip. Your iliac crest is that big wing of bone in your hip and you can carve a square inch or two off, and then grind it up, and then incorporate that into the lesion. So naturally there are limitations there. We only have a certain amount of bone available for that process. Also again we’re limited by our inherent ability to heal ourselves. So we’ve decided that one way to address that issue is recognize a biological complexity of autologous bone. Recognize that that is the gold standard. And try and mimic autologous bone with stem cells from our bodies, from our bone marrow in fact.

Christina Sumners: So you mentioned stem cells. These aren’t the fetal stem cells that everyone is that has controversy around it? These are adult stem cells? How does that work?

Carl Gregory: The way I teach it, at the graduate and the medical school level, is that we always have stem cells in our bodies from the time our egg is fertilized all the way through to the point where we die. It’s just those stem cells have different properties at different times, and they have different levels of relevance at different times in our life. So in a fertilized egg we’ll form an embryo. That embryo will consist entirely of stem cells. Over time those stem cells will commit to tissues, and those tissues will lose their stemness, their ability to change into other cells, and they will function as tissues. So the stem cell for example would differentiate into a liver cell and then it’s a liver cell. So as a developing embryo you need a lot of stem cells, ’cause you need to develop a lot of tissues, and those stem cells have to be powerful. As we get older our bodies are established and they function, but we’re subjected to wear and tear. So there are little pockets of stem cells in our bodies that address that level of attrition and sometimes those stem cells will just maintain. For example, in our gut and in our skin we change our skin roughly every couple of months, our skin cells, in our gut it’s a couple of weeks.

Christina Sumners: Wow.

Carl Gregory: Bone tissue we change our skeleton roughly every 15 or so years. And these little pockets of stem cells that aren’t quite as powerful as embryonic stem cells, but they are certainly significant and can be harnessed as a therapeutic tool.

Tim Schnettler: You mentioned osteo arthritis. What are some of the diseases or some of the inflictions that these things can be used for?

Carl Gregory: The main market, so I’m talking, I’m trying to make the distinction between commercial relevance and health care, public health relevance. So the main market would be fusions. So spine fusions, that’s a billion dollar market, so you lose the ability of one of your vertebral discs to separate your vertebrae and they start rubbing together and they cause you pain. And one way to address that, you lose a bit of mobility, but if you fuse those vertebrae together, so you encourage bone to grow between the vertebrae. They can no longer move but you lose the pain, and that is a billion-dollar industry. The technology we have is either not as effective as one would like, or very effective to the point where it’s a bit dangerous. So we want to try and hit the middle ground with our stem cell-based technologies. Another population be of course those that are subject to the risk of high level trauma, so naturally I’m talking about the military, but there are certainly other occupations where that would be highly relevant. And then, I’m talking about the elderly, who have an inherently lower probability of healing from even relatively modest bone trauma. Taking together all of this is, again, is a multi-billion dollar industry affecting millions upon millions of people in the country today. So bone trauma really is an issue and it costs us money and it affects our lives in detrimental ways.

Christina Sumners: So what first got you interested in this field?

Carl Gregory: In the cytotherapy field or the bone field?

Christina Sumners: Which came first?

Carl Gregory: So ah, yeah, I was always interested in structural biology. I just like the form of complex molecules as often nerds like strange things. And that got me into appreciating the structures of collagens. So these are remarkable molecules when you look at the structures. A triple helix so it’s DNA’s a double helix where two strands are wound around one another. A collagen is a triple helix of course with three. It’s a remarkable structure. So I studied collagens in Manchester and the guy that taught me was taught by Darwin Prockop. And that’s when I moved to the states to work with Darwin Prockop. And of course at that point in time he had complete, well for the most part abandoned collagen work. So I said, “I want to come work on collagens.” And he said, “Well, there might be a snag there. “But here’s something that you might be interested in.” And these were mesenchymal stem cells that I work with now. And collagen and bone are very intimately linked, so I appreciated that these cells could generate bone tissue in the dish, and I wanted to improve that, and we did. So it was essentially following the pedigree, the training pedigree to its source, and that’s what got me into this.

Christina Sumners: Dr. Prockop, of course, is here at Texas A&M, so you ended up working with him here. That’s exciting.

Carl Gregory: Yep, yeah, yeah. Initially we were at Tulane all of us, and then we moved thereafter and were in Temple for awhile, and now we’re in College Station.

Christina Sumners: So how is your research about scaling up your research in order to be able to treat these millions of people? How does that work and what sort of obstacles are you encountering along the way?

Carl Gregory: Way back when I first started working in the lab, I was given some really useful advice that I completely ignored at the time. And that was even before you conceptualize a solution to a problem, think seriously about how that can be scaled up and given to the general public who ultimately are paying your salary in the end. And always have that as a monkey on your back as you do the work. And we didn’t do that. And in short we grew the cells that we use in experiments and in experimental models using lab scale methodologies. So we can make a few million cells and we can heal a few experimental defects. You scale that up to a human you’re looking at two or three orders of magnitude and your methodologies for growing cells, in this case it will be in flasks and dishes, is now obsolete. You just can’t produce enough flasks and dishes in an incubator to generate enough cells for one human, let alone a million or 100 million humans. So at that point we started to panic and in parallel start talking to engineers. The engineers we’re dealing with these very large bioreactors, we’re dealing with very large volumes of media, so the liquid nutrients that the cell is growing, and actually the liquids, chemicals, life forms, even physical phenomena that we consider to be quite intuitive like how heat travels, how things mix, how things foam, when you go up orders in magnitude that is a challenge and you need people with experience to help you. So in short, we joined forces with the guys over in biomedical engineering and we did two things. We identified the challenges. We characterized the current state of the art in industry. And then we started looking at ways to address these challenges that affect the industry. So we figured that if we could solve these problems for ourselves, then we could solve these problems for industry too. That is the philosophy at least in part, the philosophy behind the X-Grant that we recently had funded by the President’s Excellence Fund to address challenges with scale up, and how we can harness our current scope within the university and also the current expertise in technology we have.

Tim Schnettler: Has that been, what you just discussed, has that been the biggest obstacle for you in all of this is the scaling up of it and trying to get it on a larger scale?

Carl Gregory: Yeah, well for me the biology is complex, but if you’ve trained properly you can address that. It was a daunting challenge for me because I just didn’t have the expertise. So, for example, you think well I need to grow cells on a surface and I’ve calculated to heal one single human being I would need a surface area about the size of a small room. How can I address that? And the engineers will say, well you need microcarriers. How do these work? And then they would explain. And this insurmountable challenge suddenly becomes solvable. And then you say, “Well, how much media will we need?” And then they’ll say, “Well, probably 100 liters.” And then you pull out a napkin and you draw out a few calculations, and you find out that certain raw materials in your media would cost billions and there probably aren’t enough manufacturing facilities on the planet, or at least accessible, to cater to your needs let alone the industry. So then you go back to the engineers and say, “Well, this reagent that I need can’t be in the media, it’s too expensive.” And they’ll say, “Well, we can make these microcarriers with this reagent so when the call attaches to the microcarrier the reagent will be right there and not floating around in the media,” where 95 percent of the molecules in media never really see a cell. So instantly we’ve solved the problem of surface area and I’m making this sound easy. And it really isn’t. But also we’re reducing the cost of this process by orders and orders of magnitude, just by collaboration, simply by collaboration. We have a plan. And then the other issue which is currently affecting the field, the industry, is how to harvest these cells. So it’s been recognized for some time that using microcarriers, so by that I mean spheres of materials like sometimes plastic, sometimes gelatin, anything that a cell will like to stick to, these spheres will be added to a liquid media, and the cells will bind to the microcarriers and divide on the surface, and that’s how you increase your surface area. But how do you recover your cells from those microcarriers afterwards? And I often equate the problem to, well if you had a bag full of bowling balls and hamsters how would you separate the hamsters from the bowling balls? And the answer is carefully, right? So we looked at this problem and it’s been recognized by industry separating these heavy microcarriers from these very delicate cells and the answer is make the microcarriers disappear. Then the chemical engineers, or the chemists within engineering, say well we have molecules that very easily digestible by slightly altering the composition of the media. These microcarriers are very tough, and they work great, and they’re durable. We add a certain chemical and they dissolve. So this portfolio of technologies forms the basis of our platform technology. And again, it’s just through collaboration. These aren’t highly sophisticated, they’re not significantly high risk approaches, the innovation comes from combining two perspectives, or more, and coming up with a solution to a problem.

Christina Sumners: That’s amazing. So what’s next? If you have this grant money you mentioned and this collaboration going, what are your the next steps?

Carl Gregory: Well, we’ve set ourselves goals to use the bioreactors at the NCTM, the National Center for Therapeutics Manufacturing, and we’re gonna take our stem cells that we can culture in the lab and employ this microcarrier technology to grow large amounts. So we’re talking from 100 million or so to billions. The first step will be to validate the microcarriers using lab scale approaches. Make sure the cells behave in the way that we expect them to. And then over time very gradually increase the scale. Hopefully, by the end of the third year we’ll be generating billions of stem cells in the system. And by then we’ll have harnessed our connections with industry and they’ll hopefully be validating the technology on their sides too. And the overall goal is this platform technology, that solves a lot of problems, but also to harness the NCTM as a manufacturing facility, but also a facility for workforce development. So we have a shortage of reagents and technologies for scaling up cells, but we also have a shortage of people who can do this. The industry is growing. It’s growing rapidly. And it’s growing in Texas. So if we can setup a workforce development pipeline, from A&M and partner universities all the way through to training them at a technical, high level, using the NCTM as a base those guys can head off to Houston and fill up those manufacturing facilities. So Aggies and also kids from schools and colleges throughout Central Texas and beyond hopefully.

Christina Sumners: That’s exciting.

Tim Schnettler: Can you just talk a little bit more about the X-Grant that you guys are involved with now and how that’s gonna help your research, and what it can do for y’all?

Carl Gregory: The beauty of the X-Grant program is that it fosters collaboration, in fact it insists upon it. I think that’s important. So you think about Texas A&M, so I’m from Britain so I’m used to small universities, but I have a reasonable idea of the size of schools here in the U.S. And what you don’t have in a lot of places is the sheer scope. So on one side of the university you have a physics department with a nuclear reactor, on the other side of the university you have a vet school. And you have everything in between. And I haven’t even started on the humanities and all of those other essential components to the scope and the breadth of a good school. So the X-Grant encourages all of those entities to collaborate together. And we already talked about the power of that. So the idea is to fund collaboratively projects that wouldn’t traditionally be funded by conventional means, but could lead to extramural funding from say the NIH, or the DOD, the NSA. Our project, I believe, wouldn’t be readily funded by the NIH, because it’s basically an engineering and manufacturing problem. And the NIH are very much into hypothesis-driven science that increases our knowledge base. This is a means to develop an industry. And it’s slightly off from their goals. Now there are funding opportunities through the DOD that are slowly beginning to recognize that we need to jumpstart this manufacturing capability. But the caveat there is they ask for matching funds. So for every dollar you get from the DOD you have to match it. Well, we have X-Grant funding to do this work, can you imagine how much ground we could cover if the DOD matched those funds? With the funds as they are, we get to develop this manufacturing initiative. We get to develop in parallel, inevitably the workforce development, but also we are highly marketable to the DOD at thereafter. And I think that is very powerful, and we are writing proposals, and conceptualizing proposals right now. So we haven’t stopped, we’re not resting on our laurels. We haven’t stopped. We’re gonna continue writing.

Tim Schnettler: I can see it in your face as you talk about this, I mean you light up. I mean you’re obviously very passionate about this.

Carl Gregory: It’s been, so you work in the lab for years, and you get to the point where you develop something. You get to a level of self-evaluation where if you can’t get that thing, if you can’t get that technology to the general public, then at some point you have to say, well do I stop? So this grant, this opportunity, as well as others that are in the pipeline are helping to bridge that gap, okay? So the technology is now freed to go to the next level. And again, these technologies are notoriously abandoned because we don’t have the capacity, they call it the Valley of Death, in terms of technology development. You get this excellent, elegant technology, and for all sorts of reasons you’re unlucky, you haven’t properly evaluated whether the technology can be scaled, or maybe a combination of those, or maybe something else, but this technology just falls by the wayside. This is make or break right now. This is put your money where your mouth is and move forward or stop, and we’ve decided to move forward. With the grace of the X-Grant initiative.

Christina Sumners: That’s wonderful. So once you do get this technology through the Valley of Death, so to speak, how do you envision it changing health care and people’s lives?

Carl Gregory: Well, so the short answer is up until recently medical care has relied on molecules, medicines, and more recently very complex molecules like the biologics so from aspirin through to antibodies that say block RANK ligand and protect you from bone loss. What we haven’t really addressed is the level up, the level up, and that is living tools. So these cells respond, they change, they change by the day. And there are challenges associated with that. In manufacture we talked about that, but also regulation as well. So in doing this and providing cells, and also providing cells cheaply—inexpensively, there’s nothing cheap about this—we can provide avenues for investigators to and setup more clinical trials and take this idea of, not just stem cell therapy, but cytotherapy, cell therapy, to the next level and get to patients. And in doing that we’ll help influence the FDA hopefully in a positive way to generate an understanding of how these cells are gonna be regulated. Now, in other countries this happens faster because they are a little bit more permissive when it comes to safety and different philosophies, different mechanisms, but here we to do it right and within the scope of how we’re regulated we’ve gotta get these cells manufactured and out in a safe manner into patients. And that will change health care because these drugs will be tested and some invariably will reach the patients and be cheap enough for patients to afford.

Christina Sumners: What is your ultimate goal with this research to accomplish?

Carl Gregory: Two goals, so disclaimer I have an ulterior motive, I have a technology that I would like to get to the clinic, so that is not my most important goal, but that’s one goal. The other goal is to provide a platform that is hopefully based at A&M that facilitates the next era of cytotherapeutics. So when we, when I say level up, we level up from inanimate objects that are the drugs, to live tools for repairing injuries that up until now just can’t be, because they’re just too severe.

Christina Sumners: So when you say live tools what do you mean by that?

Carl Gregory: Well, it’s really just a euphemism for cells. So a living cell can adapt to their surroundings, a living cell can recognize deficits in those surroundings, will work to achieve homeostasis with a host, and in doing that cure disease tissue or regenerate tissue. One great example is CAR T therapy where cell biologists and clinicians are taking blood cells from cancer patients, reprogramming those cells genetically to kill cancer cells, and then readministering back to the patient. This is the next generation of cancer therapy. There are challenges with solid tumors but the CAR T therapy could in the future represent quite literally a cure for some blood malignancies.

Christina Sumners: Like leukemia or similar cancers?

Carl Gregory: And it’s been approved by the FDA and why? Because it was pushed forward. It was pushed forward by initiatives very similar to this one.

Christina Sumners: Well, wonderful…we’re really glad to have you here, and thank you so much for joining us today. It’s been fascinating.

Carl Gregory: You’re most welcome, it’s been fun.

Christina Sumners: And thank you for joining us on Science Sound Off, and we’ll see you next time.