Stem cells hold the potential to change the landscape of medicine and bring patient care and well-being into a new era. Neurosurgeon Robert Hariri, MD, PhD, talks about the possibilities and promise of using placental stem cells to target cancer cells, control diseases like HIV, restore brain function, and extend life expectancy.
Dr. Stieg: I'm extremely pleased to have Dr. Robert Hariri as our guest today. He's not only a visionary in the STEM cell industry, but also a neurosurgeon, biomedical scientist, and a highly successful entrepreneur, i.e., the Renaissance man. Bob is the founder and former CEO of Celgene cellular therapeutics, one of the world's largest human cellular therapeutics companies. He has pioneered the use of STEM cells to treat a range of life threatening diseases and has made significant contributions in the field of tissue engineering. Bob, I'm delighted to have you here today to talk about your specialty STEM cells.
Dr. Hariri: Well, Phil, I'm sure you know that any time I get to spend with you is always a big treat, so thank you for having me.
Dr. Stieg: Let's start explaining to us what is a STEM cell?
Dr. Hariri: So, you know, it's interesting, but we all learn early in our medical careers about how every human being is derived from a single cell that's created during the fertilization process. When the egg and the sperm meet and then that single cell gives rise to the complex organs and tissues that make up our body. Those cells that take that job on are called STEM cells from that original totipotent STEM cell created by fertilization.
Dr. Stieg: And by totipotent you mean that — can develop into anything.
Dr. Hariri: Exactly. Totipotent — and we'll talk about the different definitions because the nomenclature, that is important. The language of STEM cells is important. So we'll spend a little bit of time talking about that and I have my own pet peeves about it, but totipotent simply means that that single cell has the ability to give rise to a fully complex organism, a whole human being. Pluripotent, which is another term, refers to the ability of a single cell to give rise to all the different tissue types of the body hair, brain, nails, liver. Multipotent is a STEM cell which can give rise to multiple tissue types, but not all of them. And unipotent means that that STEM cell can give rise to cells of a specific lineage. Ectoderm, endoderm, mesoderm . What that simply means is those categories of cells give rise to the different body types.
Dr. Stieg: Let's speak specifically about how this all works. So you get a STEM cell transplantation or implantation, they become the tissue. They incorporate some of their genetic material into the tissue. They also have some anti-inflammatory effects so that it really the spectrum of diseases. Can you go into a little bit of detail about how they work?
Dr. Hariri: So know you probably remember Phil, 25 years ago when STEM cells were first hitting the airwaves. Most of us thought that these were going to be like miniature organ transplants. That you're going to use a cell, a STEM cell to plug a hole, a hole in the brain after a stroke, a hole in the heart after heart attack, a hole in the cartilage after a degenerative joint problem. The reality is the way STEM cells work therapeutically, we now know, is to orchestrate a complex cascade of events which stimulate the person — the patient's own system to repair itself. Now—.
Dr. Stieg: And the STEM cells don't necessarily live for the entire cycle.
Dr. Hariri: That's right. They don't have to stick around that. In many cases, they take on a transient role of... kind of controlling, and modulating, and stimulating the immune system and the repair system in order to get the end result. I often say every STEM cell thinks it's in a fetus, okay? And every STEM cell is attempting to drive the system back to that remarkable regenerative potential that exists in a developing fetus. Well, that's really good for guys like us who want our knees to work, we want our brains to work, we want our skin to look well. So that's really a remarkable fundamental principle of what STEM cells can do. But you hit on another important part, which is that they naturally control the immune system and keep it in check. They can augment the immune system and help combat things like cancer and they can, they can stimulate a patient's own tissues to repair themselves at a much higher effectiveness than those tissues repair on their own.
Dr. Stieg: I think when people talk about genetic engineering of STEM cells, they get a little bit alarmed, a little bit worried that— I mean that's an old science. We've been doing it for years. What's the process and where do you envision that taking the STEM cell industry?
Dr. Hariri: If you think about STEM cells as a platform, a platform of technology that, in their native form, their unmanipulated form, they have valuable clinical utility. So let's look at an example. STEM cells have been used for decades as a way to rebuild the bone marrow in patients who have cancer or a patient who have inherited diseases or patients whose bone marrow fails because of things like a bad viral infection. You know, it's been shown that if you take STEM cells from a healthy donor and put them into a patient after that condition, you literally rebuild their bone marrow. So, so STEM cells as a, as a tool for restoring bone marrow function. Basically the system that builds our blood and immune system, it's an established standard of care. STEM cells are also being used to stimulate the patient's own system to repair itself after things like serious wounds, burns, et cetera.
Dr. Hariri: But where we're actually really excited about the potential future is if you think of this platform as the, as the native cell, all the other tools that are being developed around us to turn that cell into a targeted effector is what's really transforming the field. So let's talk about a couple of things. Okay. STEM cells give rise to the immune system. We talked about that. They give rise to the cells that can combat any infectious or malignant disease. A revolution that's occurred in healthcare and specifically in cancer care is that if you can take an immune cell and engineer it to specifically target a cancer cell, that becomes your, your heat seeking guided missile against cancer, and we're just at the, at the dawn of this, but to take it even further. We're soon going to be able to look at STEM cells and pick them based upon biological properties that are, that are resident inside the DNA of those cells.
Dr. Hariri: Think about this— there are patients out there who just happened because of the genetic lottery. Be lucky enough to be resistant to certain diseases. I'll give you a classic example. There are patients who are naturally resistant to HIV, okay? The human immunodeficiency virus, the cause of AIDS, the cause of these serious immunologic problems. If I take STEM cells from those patients and put them into a patient with HIV, it's now been shown you can convert that patient to HIV negative. So in that example of HIV, you take an HIV resistant patient, use those cells to treat an HIV disease patient and you can control the disease. Listen, that's the future.
Dr. Stieg: Just for the listeners, I mean, how common, how prevalent is that therapy? Is that—
Dr. Hariri: It's brand new—
Dr. Stieg: Brand new.
Dr. Hariri: It's brand-spanking new, and, and some very heroic clinical scientists are beginning to show that that's an approach that has a lot of merit. That's where the future's leading.
Dr. Stieg: There's this whole anti-aging movement going on. What's going to be the role of STEM cells in that process?
Dr. Hariri: Well, Phil, you know that I made it my mission to keep you around long enough so that we can enjoy more and more time together. So, you know, the reality is that many years ago I had made the observation along with some other really great colleagues that we, as we age, we, we actually begin to use up and exhaust the population of STEM cells that are resident in all of our tissues and responsible for their renewal and renovation of our organs and tissues. I call those cells the regenerative engine. Okay? So if you think about it this way, our regenerative engine is fueled by STEM cells. Those STEM cells are an exhaustible resource and they're exhaustible not just quantitatively. It's not that you just use up a limited supply. Those STEM cells in your tissues and organs actually get damaged over time. And so as we age, a combination of using them up and using up ever declining quality of cells, I think is the reason why we age. And there's a lot of evidence to support that. So many years ago we embarked on studying this and found out that first and foremost, the number of STEM cells in your organs and tissues decline with age. There's no doubt about that.
Dr. Stieg: And even the ones that you have aren't as potent, shall we say, as when you're 12 years old.
Dr. Hariri: Exactly. They're just not as good at doing their job. And so the reality is, you know, even even a surgeon can figure this out, Phil, you know, that if you're running out—
Dr. Stieg: I'll take that as a compliment.
Dr. Hariri: I think we both, we stand unified in that right. But the reality is we, we recognize that, that one of the easiest strategies is, okay, as we age, if we're using up STEM cells and the STEM cells we have left behind aren't as good, why not just replace them with young STEM cells? So just to give you a little hint on where this has the potential to lead, many years ago, based on a hunch, we collected the placental STEM cells from experimental animals at birth, processed and stored them away, and then gave these animals back doses of their own STEM cells as they aged. We were shocked by what we saw. The animals who got back doses of their own STEM cells as they aged, lived 40% longer than their litter mates. Think about what that would translate to in a human being. You know, 120 140 years of age would be realistic. Now we're along—
Dr. Stieg: Do you have a phone number that you want me to publicize? *laughs*
Dr. Hariri: I mean, look, you know, I'm not the only guy interested in this. I think that everybody, everybody over the age of 50 is saying to themselves, you know, there's no reason why I can't maintain my high performance mobility, my high performance cognitive function, my thinking, and my youthful aesthetics well into my 80s, 90s, early 100s. I think we're on the threshold of, of STEM cells being being used as a tool to do that, but here's the problem: In order to do this in today's conventional healthcare environment, you've got to go through the same clinical trials you would to get a product approved for treating cancer.
Dr. Stieg: So, access to this right now is basically for the person that can afford it and they go either to Bermuda or Europe or something...
Dr. Hariri: Or Panama, or the Bahamas...
Dr. Stieg: All these places. Or you are fortunate enough to get into a clinical trial and that's where I'd like to go is with where are you in regard to clinical trials and the specific diseases with STEM cell therapy.
Dr. Hariri: So the company that I currently run, which is a spinoff of Celgene Corporation, Cell Therapy Division, is going after the big ticket clinical applications because as a company, our mandate is to be a sustainable, profitable business, and we're going to use that sustainability and profitability to invest in all the other really cool and interesting areas. So we're going after cancer, we're using STEM cells to give rise to immune cells that target cancer. We're giving rise to cells that are used to modulate the immune system to treat autoimmune disease. And we're giving rise to cells that can stimulate repair in treating things like diabetic foot ulcers and peripheral artery disease. All of that is clinically meaningful. But the long game here is to first and foremost continue to populate a dataset that says that cell therapy is safe and then use that as a basis to be more creative and risk tolerant to take these cells into treating things like age related degenerative diseases and ultimately to use them to enhance lifespan.
Dr. Stieg: But for the listeners, I want to make it clear that Dr. Hariri has better STEM cells than me because he looks younger every time I see him.
Dr. Hariri: Well, I don't know about that. You know, I think it has a lot to do with, um, uh, where we dine? *laughs*
Dr. Stieg: So why did you pick placental cells?
Dr. Hariri: Back in the laboratory when we were looking at, at, uh, mechanisms behind brain injury, the ultimate objective of guys like you taking care of patients after trauma or after a brain tumor or any type of acquired injury to the brain is to restore functionality. We were really good at keeping people alive after those brain injuries, we weren't good at restoring their function. So when STEM cells hit the airwaves, I was convinced that had the potential to transform what we did to return them to function. The problem was I was also convinced that unless somebody turned a living cell into a medicine, it wasn't going to be deployed. So around that same time I was, I was here as a, as a resident in the surgical ICU, my wife was pregnant with our first child. I ran down to the L and D suite to look at the ultrasound and for the first time it dawned on me that my unborn daughter, who was the size of a peanut, was encased in a placenta that was already a big organ.
Dr. Hariri: And as a guy who was trained as an engineer and in medical school, I was led to believe that the placenta was just a vascular interface between the mother and the developing fetus. If that was the case, they would have developed the same pace. The fact that the placenta was already this large organ suggested to me it was the governor. It was the rate limiter on that development and if I put two and two together, STEM cells are important. You need STEM cells. Maybe the placenta was a place where STEM cells were, were basically propagated and expanded and trafficked into the developing fetus and that gave rise to the all of the incentive to explore that leftover tissue, the product of a full term healthy pregnancy as a source of STEM cells.
Dr. Stieg: One of the things we worry about in this is really transplantation or implantation is the rejection phenomena and that is particularly not very pertinent in placental STEM cells. Can you explain that?
Dr. Hariri: There is a unique immunologic relationship that exists between the developing fetus and the maternal host that doesn't exist anywhere else during our lifetime, and that relationship permits the placenta to exist in that maternal host, even though it only carries half of the genetic material from that mother and one would say that they're mismatched, they're imperfectly matched. So why would the mother carry that developing fetus without rejecting it? Because that would happen if I was to use any other tissue. Well, it turns out that the placenta is nature's professional allograft. And what I mean by that is that it's designed to coexist in an unmatched recipient without inducing rejection or without stimulating its own rejection phenomena. Think about this. In a conventional pregnancy, mom, mom delivers half the genetic material to that developing fetus. But in surrogate pregnancy, she's not even related to the fetus yet. She carries it and doesn't reject it. You know, from our, from our surgical experience, I couldn't do that with a kidney, couldn't do it with the liver, et cetera. So the fact that the placenta is nature's professional allograft meant that it was the one size fits all solution to the cell therapy debate.
Dr. Stieg: Well, let's ask this question first. The reason you chose placenta versus harvesting bone marrow or harvesting stromal vascular fraction cells from your, at your fat tissue in your abdomen is, is why?
Dr. Hariri: Well, first and foremost, you can collect it without any risk to the donor, right? I mean, it's a, it's a waste material. So these things wind up in the red biohazard bag after a full term pregnancy and it's just abundantly available. Secondly, there was no objection to using this source of cells compared to using embryonic material. And then the bottom line is if you really want to develop a therapeutic that's going to reach the masses, you've got to have a resource, you have to a source material that is limitless in supply, limitless and supply and economical. And when you think about it, there really is no comparative to the placenta.
Dr. Stieg: Do you have this resource, the placental cells that you can put in a jar sterilely and put on a shelf or manipulate that you can't do very effectively with these other sources? Can you go into that a little bit?
Dr. Hariri: You know, I think guys like us tend to look at things in a very practical way, right? Great science often is never reduced to practice, never reduced to a tool that physicians can incorporate in the management of their patients. That would have been tragic for this emerging field of cellular medicine. And to be honest with you, it was kind of heading down that way when everyone thought that we're going to basically be using discarded embryos as a source of STEM cells. So, so first and foremost, I was troubled by the fact that that this potentially transformative technology might be sidelined by those limitations. And then, and then more importantly, I was convinced that what was harbored inside this placenta, the natural biological attributes could take it far beyond what was originally envisioned for STEM cells and STEM cells in medicine. Now you hit on the real key here.
Dr. Hariri: How do you do that as a, as a physician or a surgeon effectively and put and bring the right resources to bear to put these tools in the hands of our colleagues. And that really required an industry effort. Great science that often develops or emerges from academic centers actually has to translate into a program to develop that will ultimately meet the current conventional therapeutic environment, which is doctors have to write an order for these things and deploy them like they do pharmaceuticals. And so when, when, when you looked at all of the alternative approaches, placenta, because you could collect it under controlled circumstances, productize it and inventory it and you could, you could deliver it one size fits all to any patient was the solution that I, I felt the industry needed.
Dr. Stieg: I'd like to talk with you a little bit about the applicability of STEM cells in the brain. There's been some recent data published about STEM cell implantation's in post-stroke patients, which I found amazing. The patients that have been the only done 18 patients, they've gotten better. Some of them have gone from being unable to talk, unable to use one side of their body to walking. And then when they followed those patients, they found that the cells were dead, but the patient had recovered. How does work and where should we take this?
Dr. Hariri: So stroke is a really interesting example of a, an acute brain injury that evolves over time. And part of the process of a recovery from stroke in the traditional way leads to changes in the brain that result in functional deficits that are permanent or semi-permanent. What we've learned with cell therapy and with STEM cells in particular is that STEM cells have the ability, just like we talked about before, to orchestrate biological processes that are either detrimental to the injured brain or inhibit the full recovery that's possible. So it's interesting, right? We know that in certain species, right in, in certain, um, reptilian species, infinite regenerative potential, you know, he cut a salamander arm off and it grows back not just the muscles of the arm, not just the bone, but the nerves too, right? So we know that STEM cells can in fact orchestrate turning back on some of the regenerative processes that can help the brain recover.
Dr. Hariri: Now, the complex thing I brought brain recovery is you've got a couple of things you have to deal with. You want to deal with the post-injury inflammatory processes, which changed the nature of how the brain can recover over a long period of time. It's a process of scarring, if you will. Scars don't make for good neurologic circuits. And then you have the need to turn back on. What we'd like to think of as the, um, the plasticity of the brain so that it can rewire again. What's true is true — in a damaged brain, that circuitry is gone forever. But if you can lay down brain tissue that can reestablish circuits, you can restore functionality. And we know that what STEM cells do is they turn back on those regenerative processes in things like neurons and supporting cells of the brain that can lay down a fresh area that can be rewired.
Dr. Stieg: Dr. Robert Hariri, you make all of us, I think extremely hopeful about the impact that STEM cells are going to have on our lives. And I look forward to living to be 150 years old. *laughs*
Dr. Hariri: Yeah, right, right. Thanks Phil.
Dr. Stieg: Thanks for being here.