Dr. David Crouse on Stem Cells: What’s Real, What’s Hype, What’s Next?

Transcribed automatically and lightly corrected.
 Michael Lyon: This is Heartbeat, conversations about medical science, research, and the discoveries that touch all of our lives in collaboration with the University of Nebraska Medical Center. We are exploring how science works, why it matters, and how today's research could shape tomorrow's care. My guest today is David Crouse, PhD, board president of Nebraska CURES, a nonprofit that supports, promotes, and advocates for health science research and education. He is a retired emeritus professor, a cell biologist, in the Department of Genetics, Cell Biology, and Anatomy at the University of Nebraska Medical Center. Welcome.
David Crouse: Thank you.
Michael Lyon: You've had a fascinating career at the intersection of science, ethics, public policy, and public education. To begin with, could you tell us about your academic training and research background and what originally drew you into the field of stem science?
David Crouse: Well, I started out actually in physics, a bachelor's degree in that area, and then moved into a bit of genetics for a master's degree. Got drafted, came back, and thought, "What am I going to do?" So, I went to graduate school in a different area, in radiation biology, and that's what my degree was in. During that study, I was working with stem cells and how stem cells act in recovery of radiation injury. How do stem cells work, and how do they fail in some cases? And so that's where I got into stem cells. That's been 40, 50, almost 50 years ago, so a long time ago.
Michael Lyon: I know this may have been a few years ago, and stem cells, to a lot of people, seems to be a very modern science. But it’s obviously been going on for decades. What was the state of stem cell research at that time?
David Crouse: Well, actually, the definition goes back 100 years. So, the definition's an old one. But at that time, they were talking about stem cells in restricted systems, so there were stem cells in the skin, stem cells in the liver, stem cells in the bone marrow, each functioning in those compartments. That reigned for 50 or more years. And in the late '50s, people began to experiment with bone marrow transplantation, which is basically a stem cell transplant, for treatment of various cancers, and that's where it began. So, the use of stem cells restricted mostly to hematopoietic, blood and bone marrow forming cells, lymphoid forming cells, started about in the '50s. But it really didn't ramp up until the '80s when the, they understood how to prevent rejection and treat patients better and get, have more success.
Michael Lyon: What were the other drivers? Obviously, access to the systems, scientifically, would have been one thing. But what were the other drivers of the expansion in stem cell research back then?
David Crouse: Well, back then, trying to treat more diseases. I mean, originally, it was just to treat bone marrow related diseases, lymphoma, leukemia, and the like. But people began to say, "Can we treat other cancers by transplantation of bone marrow cells?" In other words, if we irradiate a breast cancer patient with a high dose of radiation and then transplant them with stem cells from the bone marrow, can we effect a cure that way? And, actually, most of those trials didn't work out very well. So, that's the way research works. You go down avenues that look promising. Some of them work, and some of them don't.
Michael Lyon: What didn't they understand back then that made those things less than successful?
David Crouse: Well, there were a lot of side effects from the treatment, of course, that were hard to manage. And, although it looked early on like it was going to be successful, what happened was the doses were not high enough to cure the cancer, and therefore it came back. So, it had high relapse rates. Plus, treating those patients using that kind of therapy, um, even when it's a bone marrow transplant for leukemia or lymphoma, you give high doses of radiation or high doses of drugs to knock down their own system so that you can replace it with a new system, okay? And so that's the basic premise in that. And that's worked for a long time. UNMC's had a bone marrow transplant unit since the early '80s. They've done probably thousands by now. I don't know the exact number, but it's a large, large number, very successfully. And, it's turned out to be an absolute cure for some children's, leukemias. It basically works almost every time, and it's been very effective in many others for adults.
Michael Lyon: Stem cell research has e-evolved, as you say, enormously over the past few decades. When did you first become involved in advocacy and public education surrounding these issues, and what convinced you that scientists needed to engage more directly with the public and policymakers?
David Crouse: Stem cells became controversial with the emergence of embryonic stem cells in 1998, the exact year.
Michael Lyon: Stem cells derived from fetuses?
David Crouse:From, well, from the embryo, which is even earlier.
Michael Lyon: Okay?
David Crouse: So, embryonic stem cells, there's no fetus involved, although fetal tissue and fetal stem cells are another issue. We'll talk about the regular stem cells today. embryonic stem cells truly were controversial because an embryo is destroyed in the process of obtaining embryonic stem cells, and that raised an enormous controversy. Could we use those cells at all? The nice thing about embryonic stem cells, if I can say nice, I'm putting air quotes up, is that you can convince those cells to become almost any cell of the body By proper manipulation of its environment. You can push them to be cardiac cells, you can push them to be liver cells, to pancreas cells, and . We know that you can do that with embryonic stem cells. The idea was then if you had embryonic stem cells, you could tailor them to treat certain diseases like diabetes, like Parkinson's, where you have errors in systems that, need to be, have single cell types replaced, for the most part, single cell types. And so that was the hope. And actually, it was very effective in animal systems. But the controversy was so high in using them in human systems that embryonic stem cells, I won't say fell by the wayside because they have still been used, but they became superseded by new systems because people were so interested in how can we make something like an embryonic stem cell without destroying an embryo? And so that came to a pinnacle, in 2007, a Japanese group headed by Yamanaka, that produced what are called induced embryonic stem cells or induced pluripotential stem cells.
Michael Lyon: Would you define that?
David Crouse: Yeah. Yeah. What it means is we can make stem cells that look just like an embryonic stem cell in terms of their characteristics, what they can do, how they can be cultured, how they can be transplanted, how they can be used, but you can make them in an artificial system. Now I'll explain it real simply. You can take, for example, skin cells, fibroblasts, the most common cell in your body probably, and you can take those cells and culture them for a little while. And then if you add the right ingredients, they're called transcription factors, biochemical term. But you add the right ingredients in the right quantities in the right way, they revert to an embryonic state. So, you can take an adult cell and make it flip back to an embryonic state and look like an embryonic stem cell. For all intents and purposes, it looks just like an embryonic stem cell. What that means is you can take a patient's skin, flip it back to an embryonic form, and then make whatever you need and those are called iPSC, induced pluripotent, that means can make anything, stem cells. So induced pluripotent stem cells. So that has been quite successful.
Michael Lyon: There seems to be still some controversy about the use of stem cells. Is that because of lingering concerns about embryonic stem cells? People just don't know about these pluripotent stem cells. What's the gap here?
David Crouse: Part of that is public understanding. Yes, embryonic stem cells also gave stem cells a bad name . I hate to say it that way, but t hat's what happened. I mean, people thought everything was embryonic stem cells that were going on in research, even in potential clinical therapy, and they didn't want to hear about that. It's actually the literature, when I say the literature, the controversial literature has cooled off tremendously in the past ten years. The organization I work with, Nebraska Cures, was formed to advocate for stem cell research. That's what we actually started out with, defending the university's position on doing stem cell research. And not necessarily the embryonic stem cell research, but all stem cell research, 'cause it all got a bad name for a while. And that's how we started. But as that time has gone on, and these new approaches that don't use embryonic stem cells have emerged, so there are others, I'm only mentioning one, but there are others, then there's less attention being paid to embryonic stem cells, and the controversy has died down greatly. It's still there, and there are advocates strongly saying there should never be an embryonic stem cell used anywhere for anything.
Michael Lyon: I want to ask you, given my very, very basic understanding of these matters , whether there is a third aspect to this and what this means exactly in regenerative medicine.
David Crouse: Well, this is part of regenerative medicine. Part of it is, and this is where hype got into stem cells. Many people will have noticed, they've probably received mailers, in their mailbox, saying, "You need to have regenerative medicine to cure your back pain or cure your arthritis or to cure your Parkinson's or whatever. And we can offer you stem cells at this clinic, and you can come in, and we'll treat you with stem cells that come from your fat or from your bone marrow or wherever we can get them. And we'll treat you, and it'll be successful 'cause everybody knows that stem cells can cure everything." Mm-hmm. And so that has becomeunfortunate because there are a lot of these pop-up clinics. There have been many in Omaha. Some of them have come and gone. I just got a mailer last week for another one that's here. So, they’re still here. They're still promoting these cures, and I call them cures, for a wide variety of diseases and disorders, ailments also. Just back pain, can we take care of that? That's a huge problem in this country. And, as it turns out, there's a scant amount of evidence that that works. this is something that has not gone through, clinical trials where you actually test things against, different procedures, to make sure which is best. It's never gone through a controlled clinical trial. So, there's no clinical trial-based, evidentiary-based, reason to be using these cells to treat something like back pain.
Michael Lyon: Are there no federal or state restrictions on these types of pop-up clinics?
David Crouse: That is really controversial because the FDA has kind of got caught in a pickle here. the language is very clear that if you manipulate cells from your body, take them out and put them someplace where they d-didn't originate, in other words, move them to a different site, you have to have our approval But the makers that are doing these stem cells are saying, "Well, there's no problem. These are coming from the same person. They're going back into the same person, and it's none of your business," essentially is what they're saying. Um, and some of them have even stopped. there's just been a legal case settled in Iowa, if you've read the papers recently, that the, attorney general in Iowa got a very nice settlement on a, a clinic that was running in both Iowa and Nebraska, for treating these kinds of ailments, and that there was no basis for their treatment.
Michael Lyon: How can patients, someone like me, understand, or distinguish between legitimate clinical science and questionable claims?
David Crouse: Well, the first thing I would do would be work with my personal physician. Your own physicians are knowledgeable enough in this area to know what not to do and what to do. Um, and that's the first suggestion. The other is pay attention to something other than social, social media. Social media carries so much misinformation; it's kind of scary. Even at that, a Google search can lead you astray- 'Cause it will bring up stem cell clinics left and right. There's no question about it. So, you've got to be very careful, but your personal physician is your very best bet. And, if you have a particular ailment like a back pain and you go to an orthopedic doc, talk to them 'cause they could give you more advice in that area. So, personal physicians or bonafide establishments like the medical center, like Creighton, those can give you good advice.
Michael Lyon: You've worked extensively in Nebraska, where public policy and biomedical research sometimes intersect in very visible ways. What legislation or regulatory actions here in Nebraska have had the greatest impact on stem cell research and related biomedical work?
David Crouse: Well, as I said, there was a great battle that went on in early 1920 or 28, a- thereabouts. And lots of bills went up before the legislature to ban stem cell research of one type or another, cloning, all kinds of things. great arguments. We worked ... When I say we, a number of people in the private sector have worked with some legislators to say, "We need to find a way to make this controversy go away." So, they came up with what was called the Stem Cell Act, LB606, in 1998, I think it was. Or, 2008, excuse me. And the act, I mean, after great effort, the act said you can do anything in Nebraska that is permitted by federal law. Now what that meant was that since federal law did not restrict embryonic stem cell research in, in many ways, it did in some ways. You couldn't do cloning and things like that. Well, nobody here ever planned to do cloning, but as long as we adhere to what the federal law said, we're okay in Nebraska. So that's LB606, 2008. A great accomplishment by our legislature. So, it solved the controversy pretty much. At least the battling that went on publicly between people in the legislature. That's why there's been almost no bills that have addressed this at all since then.
Michael Lyon: Some applications regarding stem cell research are experimental, and we've just sort of covered that broadly. But there are applications that are already standard medical practice. Are stem cells currently being used clinically at UNMC? And if so, how are they helping patients today?
David Crouse: Well, I'll, I'll, not go back to the hematopoietic stem cells. Stem cell transplants for bone marrow, lymphoma, leukemia, widely done for 40 years almost. So aside from that, yes, there are some things going on. Now, there, there are modifications of stem cells that, um, you may have actually heard about. I mean, I'm sure the public has heard about CAR T cells. Those are chimeric antigen receptor. Boy, that's a bunch of big words. Chimeric means blended really, and it could be blended into two animal genomes. It could be blended into two genes. But chimeric means you've joined two things together. And antigen is what is on the surface of cells that identifies them as what they are. So, tumor cells have antigens on their surface that are unique to most tumors. So, a chimeric antigen receptor, what they did is they take T cells Which are in a stem-like situation. They can proliferate hugely and make many more cells just like themselves. That's a stem-like activity. So, they take T cells, which come from your blood, it's a lymphocyte. They take it from your blood, separate it out, culture it with magic chemicals that inserts a new receptor into the T cell. So, the T cell now has a chimeric antigen receptor, which means it can identify whatever that antigen, receptor was that you put in there. So, what the most common use now is to put in a chimeric antigen receptor that identifies lymphomas and leukemias of the B cell, of the one type of lymphoma that char- characterized by B cells. that's one type of lymphocyte. So, CAR T cell therapy utilizes a stem cell-like technique to generate huge numbers of T cells that are ready to go after that tumor, injects them back into the patient, and by golly, some of these people are cured in weeks. I mean, it's a miraculous treatment. UNMC started this almost 10 years ago, I think nine years ago now. And they are one of the places here in the Midwest that's gotten quite good at it. So that's, that's one application that is, that is really coming on strong. There are research applications that are highly directed at, using stem cells to treat retinal diseases. Now, these are not yet in clinical trials at our institution. They are in other institutions. I would not be surprised to see them as a clinical trial here sometime in the future, because we have the researchers who are doing some of the work that backs it up. But, the clinicians that might want to get on board.It's a big thing to do. So, ocular diseases of various types, mostly involving your retina, are being treated now with stem cells, induced pluripotent stem cells in some cases. So, they've taken, these induced cells that came from their skin, diddled with them with chemicals in the culture to convert them to a particular type of cell that's important in your eye, like your retina. So, they can make them so they will replace parts of the retina, and animal models show that works very well. It's been very successful in the clinical trials in people that have been run mostly in Japan and China, and these are widely known now. I just did literature research before I came on board here to see, because I didn't know how many have been done. I'll give you just a couple numbers. This is impressive stuff. in a 2024 survey, worldwide survey, there are 83 different products, types of products being used for stem cell transplants. That's not including the bone marrow transplants. In 115 clinical trials worldwide with 1,200 patients with 34 different diseases, and almost in all cases in the clinical trial, they've been proved to be safe and effective. That's the bottom line for a clinical trial, is it safe and effective? Then they move on from a stage I, II or phase I, II trial into a later trial where they have to work with doses and things like that. So, the first trials of these are being quite effective. This being treatments for all kinds of ocular diseases, treatments for Parkinson's disease, treatments for diabetes—Type 2 diabetes. All of these have been in clinical trials already.The only ones at the Med Center have been the CAR T-cells, which are a type of stem cell.
Michael Lyon: Are there still unresolved issues in translating stem cell research into safe and clinical treatments? What are the biggest ones in your mind?
David Crouse: It's probably going to be cost. It's not a simple procedure to make induced pluripotent stem cells. It takes time. So, it's not an emergency procedure where you can have a patient and say, "I'll treat him next week." It takes weeks to produce these cells. there are lots and lots of technological steps that have to-- done to produce them, so not every clinic is going to be able to offer them. there'll be a very limited number of places that will have these treatments for a long time. Right now, none of these can be handled quite like a drug, which is in a bottle, which you can distribute and inject. Hmm. It's not quite like that. You've got to build it, and it has to pretty much build on-site. Although there are some companies that are offering products that they will make it custom for you, not on your site, because they've got the equipment and takes all kinds of technical FDA equipment to be able to make these products. So not many places have that. So that's going to be limiting. And when you have something that's that limited and that technologically driven, it's going to be expensive. And so those two are going to make it, uh, difficult to move in a mass movement. But I think it may come because it's been becoming more and more sophisticated all the time.
Michael Lyon: And finally, I'm going to ask you to look ahead 10 or 20 years and give me your thoughts on what developments in stem cell science or regenerative medicine are you most excited or perhaps more cautious about. You've already spoken obviously to the things that are happening now, but where's the horizon? You know, if there could be a point that we could reach in 20 years' time, what would that be?
David Crouse: You know, it's an interesting question, first of all. If I look back to myself 20 years ago, and if I would've tried to project where we are now, I would've missed by a long shot. So, for me to be presumptuous and predict 20 years from now, I'd like to think we can overcome some of these issues in terms of cost and distribution, and ability to make a product that's almost off the shelf. I think we can get there for some of these products. For some in particular, it looks like it might work. The cells that they produce to treat, and hopefully cure diabetes, type 2 diabetes in adults, is working really well, and it's an interesting way of delivering it too. So, it's not an injection. It's an encapsulated product that is protected from your own body’s defenses, so it can't be thrown away by your own im- immune system. Hmm. so Th-those have come a long way in a short period of time. So, I would expect that to continue to change. I would've never predicted induced pluripotent stem cells. I was an old stem cell guy. I thought, I thought they were all fixed in their discipline. That's not true. Mm-hmm. You can diddle with them and make them do all kinds of things. I'd be surprised to see it stop. I think it will continue to advance maybe a bit more slowly. The past 10 years have been rocket science in stem cell world. It's gone very, very fast.
Michael Lyon: Concerns, cautions, ethical issues?
The ethical issues will always be there. I think one of the ethical issues is why can't we treat everybody? Is it going to be a treatment that's only available to the rich and famous or the people who could get to it? No, that's not the way we want to deliver medicine. You'd like to have a product, a process that you can handle large numbers of patients in an effective way. So, we may never quite get there. I'd like to see that change. I'd like to see some of these stem cell treatments, I'll call them that, move to a position that they're more widely available and they're still as effective.
Michael Lyon: I've been speaking with David Crouse, PhD, board president of Nebraska Cures, a nonprofit that supports, promotes, and advocates for health science research and education. I'm Michael Lyon, and this is Heartbeat.