Dr. Robert Hariri, a surgeon and stem cell entrepreneur, explains how a temporary product of pregnancy, often discarded as waste, is actually an example of evolution at its best, a veritable “nature’s supermarket” for cells with amazing regenerative properties.
Phil Stieg: Hello. Today, our guest is Dr. Robert Hariri, jet aviator, physician, surgeon, biomedical scientist, and business executive. He is CEO of Celularity, a stem cell company that promises to bring stem cell therapies to address anti-aging and multiple diseases. He and his wife are also philanthropists, and I am honored to be the first Margaret and Robert J. Hariri: Professor of Neurological Surgery here at Weill Cornell Medicine.
Dr. Hariri, welcome and thank you for being with us today.
Robert Hariri: Well, Dr. Stieg, it’s always a pleasure to be with you. And I appreciate you inviting me.
Phil Stieg: So Bob, you founded a company called “Celularity.” Can you define for us what cellular medicine is?
Robert Hariri: Cellular medicine, broadly defined, is the use of living cells to exert a biological effect that has therapeutic value. So let’s look at the simplest cellular therapy. People will understand; transfusion medicine, OK?
A blood transfusion is collecting whole blood from donors, in some cases separating red cells from other cells and then giving it back in order to treat a condition. What’s blood transfusion most commonly used for? To treat anemia? It’s real simple. You have a red blood cell count that should be about 45 to 50 percent of your total blood volume. If it drops to below twenty-five and patients begin to develop symptoms, the easiest thing to do is give them some cells back and those cells go in through a vein, circulate and become part of your system.
Phil Stieg: Bob, you trained as a surgeon and then as a neurosurgeon. How on earth did you get interested in stem cells? And more specifically, what serendipity had to be involved in you getting involved with placental stem cells?
Robert Hariri: So, you know, Phil, not too far from where you are upstairs in the surgical ICU. About 30 some odd years ago, I was called down to look at the first ultrasound of my unborn child. And while I was sitting there looking at the ultrasound and for the first time recognizing that the placenta was already kind of a large structure, even though she was a peanut-sized embryo, it dawned on me as an engineer that some of the things I learned in medical school might not be correct.
One of the things that I was taught was that the placenta was an interface. It was a connection between the maternal system and the developing fetus system. But if that was true, the placenta should grow at the same pace as the developing embryo and fetus. The fact that it had been this large organ already suggested to me that it played a role in controlling the rate of embryogenesis and fetal genesis, creating that newborn.
And so it just was a hypothesis that maybe the placenta was the site where stem cells proliferated, expanded, increased in number, and differentiated into different forms that trafficked into the developing fetus and participated in creating that newborn. And if that was the case, could that be an alternative to other sources of stem cells?
Phil Stieg: Where do you where do you get the placentas from?
Robert Hariri: Over the last 20 some odd years, our company and the predecessor companies have established procurement relationships with hospitals, birthing centers, obstetric practices. And we procure under a very rigorously controlled program where we are under full informed consent with deep medical history of the parental lineage and so on. We collect these organs. They’re transported under very tight controls to our laboratory for processing. We’ve been doing this for 20 years. We have procured cells and biological materials from more than fifty thousand newborn donors in our history, and we have over 100,000 cryopreserved cell lines from these various donors. So we’ve been doing this a long time.
Phil Stieg: As a matter of fact, if you weren’t taking these placenta, they would just be discarded as biological waste, correct?
Robert Hariri: That’s right. And you guys would have to pay to have this stuff incinerated, right? I mean I mean, there’s a cost to getting rid of this biological waste. So by recycling it and by making it useful, we’re doing a service for the patients who receive the therapies and for the birthing centers that are trying to get rid of this material. There’s no risk to the donor. There’s no added expense to the birthing center. It is a no-harm, no-foul method of getting the raw material.
Phil Stieg: What ailments have you treated and where do you see the most promise currently with these stem cells?
Robert Hariri: So cellular medicine has taken a very interesting series of turns from the origins where we thought that stem cells were going to be, in essence, a kind of a mini replacement part. That we were going to use stem cells to plug holes. You’re going to use them to plug holes that occur after a stroke. We’re going to plug holes in the heart after a heart attack. We were going to plug holes in your cartilage when you get degenerative joint disease. That was our original thought. And placental cells, because of the unique immunologic features, were an ideal place to start off. And so the origins where we began to use these cells to control two things: regeneration – We wanted to stimulate repair and we wanted to turn off inflammation. And it turns out that many stem cells are good at this. Placental stem cells are really good at it. But the really, really neat thing is that the field has now evolved that from stem cells where we’re giving rise to mature cell types, including immune cells. And some of those immune cells can be used in the treatment of things like cancer and other immunologic diseases.
So that’s some of the really important focal work we’re doing at Celularity now, is to take cells from the placenta, turn them into mature, specialized immune cells in some cases, engineer them to have certain characteristics and then give them back to patients to help combat their cancer. Because just like many other diseases, cancer occurs when your immune system fails to do its job. So if we can augment or boost it with cells from a source like the placenta, you have an enhanced way to battle that disease.
So you’ve got a patient with terrible spine pain because they’ve got a degenerative disc or whatnot. By injecting cells or byproducts of cells into that space, you turn down the inflammation, you stimulate repair and you get rid of the pain. That’s the obvious easy way. In things like treating stroke or treating traumatic brain injury. It’s giving back cells that can turn back on some of the natural renovation process that every organ goes through during your lifetime. And then obviously in brain cancer, we want to use stem cell derived immune cells to go in, hunt down the cancer and kill it better than the patient’s own immune system. So those are some of the ways it’s applicable to the field you and I know and love.
Phil Stieg: We’re using the word immune a lot. And everybody, I’m sure, is thinking I’m a little bit worried about getting stem cells from somebody else’s placenta.?
Robert Hariri: That’s such a great question. So, you know, most people remember and recognize that organ transplantation, transplanting a kidney or a heart or a liver requires you to find a suitable donor. Right. You have to match the donor to the recipient or else the recipient will reject the organ. Right. People know that. People also know that when someone needs a bone marrow transplant, they have to find a suitable match, someone whose tissue type is compatible with the tissue type of the recipient.
Now, that’s what happens when cells mature in an individual, they take on their own identity. They have their own biological fingerprint. And if the fingerprint doesn’t match, it won’t work. But what’s unique about the placenta is that it’s nature’s professional universal donor tissue. Every pregnant uterus that carries a fetus is, in essence, accepting a foreign body for nine months without rejecting it.
It turns out that it’s the placenta that drives that immunologic tolerance. The placenta actually makes the maternal host comfortable with its unique identity, its unique immunity. And in fact, we know today that mothers who carry multiple babies over their lifetime will actually carry some of those cells from those individuals for the rest of their life. They accept them and tolerate them. They wouldn’t accept a kidney from a different donor. But the placenta induces that state of immunologic tolerance, which makes it the ideal place to create a therapeutic.
And so that’s why we are as excited about our technology as anyone else. We’re the guys who discover that the placenta was the source of all of these rich stem cells. And now we’ve taken them into treating things like autoimmune disease, degenerative disease. We’ve taken them into treating cancer. And we want to create a way to preserve human performance in the aging population.
And it turns out I’m a very, very strong believer. One of the reasons we age is that we deplete or we damage the pool of stem cells in our bodies, which are necessary to constantly renovate and renew us and keep us in a youthful form. So if you have stem cells that can be given to anybody and you can augment that regenerative engine, you should be able to preserve some of that biological performance as we age.
Phil Stieg: One of the interesting things I read is that these stem cells have, as you said, different functions. And one of the stem cells I was reading about these things called natural killer cells.
Robert Hariri: Natural killer cells, which, by the way, we undertook many years ago to understand why the placenta is such a good self-defense system, even protecting against infectious disease. And we found that this natural killer cell is really, really good at identifying, and targeting these virally infected cells that express stress antigens. Those are molecules that get put on the surface of the cell that say, hey, I’m damaged, I’m dying.
So natural killer cells are designed by nature to go and identify those stress antigens and destroy the cells. That’s a process of kind of weeding out these senescent old, virally infected cells that can cause more damage than good. . Here’s the beauty of natural killer cells from the placenta. They will kill virtually any virally infected cell, which means if Covid was a dress rehearsal for the next more deadly pandemic, then we need to have stored away a therapy that can be administered to people who get infected, start to develop the diseases, and then need to be protected from dying or having serious illness.
What better way to do that in my mind? What better way than to use nature’s tool? Nature’s tool to treat and protect from viral infection is the natural killer cell. Those cells can be cryopreserved, frozen down to minus one hundred and eighty degrees centigrade and they’re good for decades. They have a shelf life that’s measured in decades. So here’s the proposition. You want to be protected against the next pandemic, the next virus that hits us. Stockpile doses of natural killer cells that are effective at identifying and killing those virally infected cells and use it as part of the treatment regimen. That’s the kind of stuff that we’re exploring and I think has tremendous promise.
And by the way, you mentioned vaccines Phil, you know, a vaccine is only as good as the immune system it’s injected into. Right. That’s why a lot of people who’ve been vaccinated are not making the quality and quantity of antibodies they should. So even there, I think cellular immunotherapy will play a role to help boost and augment even the response to the illness, the ability to make antibodies and the response to the vaccination.
Phil Stieg: Talk a little bit about just the number of cells that you can get from a placenta, the anti-inflammatory cells, the natural killer cells The beauty of it, as I see it, is that this makes it so. This is just so much more like a pharmaceutical agent.
Robert Hariri: Yeah, I agree with you. In fact, you know, the whole reason that I you know, I’ve devoted the last twenty-five years of my life to turning living cells into medicines is: number one, I believe that they have the ability to transform how we manage these diseases. And number two, we found a source that can meet pharmaceutical scale and grade and economics. And that’s why for me, it’s so fundamentally important that we demonstrate that our technology, all derived from the postpartum after-birth placenta, puts no one at risk. Right. There’s no risk to the donor whatsoever. Remember, the cells in the placenta Phil, right. Think about this. Right. That original totipotent single cell that started the process of building the placenta goes on to produce hundreds of billions to trillions of progeny, if you think about it right, every cell in our body, every cell in your body, in my body at our age originated from the cells that trafficked in from the placenta. They just take up residence and keep on dividing and expanding. And that’s what gives us this, you know, lifelong biological supply system. It all originates in cells from the placenta. That means that if I’m going to start producing a product from that same source, it’s going to be highly proliferative as well.
So from one placenta, I can make hundreds of thousands of doses of the pluripotent cells that can control inflammation and stimulate repair. We can produce thousands of doses of immune cells from a single placenta. So if you think about it, with one hundred and fifty million placentas thrown away, thrown out a year in the world, I mean, one hundred and fifty million placentas. Let’s do the math. If you can make a thousand doses for from one hundred and fifty million, that’s one hundred fifty billion doses, right? Yeah. That’s the kind of supply you need to service the global community.
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Narrator: You may be familiar with the concept of a supreme being who is “omnipotent”, but have you ever heard of a cell that is “totipotent”?
Scientists use the word “potency” to describe a stem cell’s ability to develop into other, more specialized cells. The wider the range of tissues a stem cell can grow into – the greater its potency.
At the modest end of the scale are the “multipotent” cells.
As the name implies, these “talented” stem cells can divide and grow into a number of different tissues, but generally in the same category –
Music (solo violin leads to string ensemble)
like a violin that could grow into an entire string orchestra – but no drums or trumpets. For example, some stem cells in your bone marrow can develop into a number of different blood cells, – but not into a heart or kidney.
“Pluripotent” cells work with a much larger palette – and have the talent to develop into just about every type of cell found in the body. A pluripotent cell can develop into anything – including internal organs like heart and lungs, muscles and bones, or skin, teeth and hair.
At the top of the potency scale is the “Totipotent” cell. From the Latin meaning “the ability for all things”.
Each of us started out as a single Totipotent cell – A fertilized egg. Cells are only totipotent for the first few cell divisions of that egg. Totipotent cells are the only cells that can develop into a placenta in addition to all the other pluripotent cells that eventually form into a human baby.
This is what makes the placenta such a rich source of those “highly talented” pluripotent stem cells.
So, no matter how narrow it may seem your life has become, or how impotent you may feel some days, you can seek comfort in the fact that at one time you had the totipotent ability for all things.
Phil Stieg: Bob, really explain to us the fact that you don’t have to match these cells. They really can come out of the jar and be used in any person in public.
Robert Hariri: Yeah. So, the placenta is designed by nature to exist in an unmatched recipient without immunologic conflict. No battle between the immune system if you think about it. Right, mammalian evolution could not have occurred unless the placenta developed this system to make itself tolerated by a different immune system. That’s incredibly important. I mean, that’s biology at its best. That’s evolution at its best. So it turns out that the placental cells, since they are they are in essence invisible to the immune system of the recipient. We’ve treated patients with placental cells and in clinical trials, in Crohn’s disease and multiple sclerosis, in peripheral vascular disease. And these cells are mass-produced. They’re from a donor that has their own specific tissue type. But I can give them to any recipient without matching them. And the recipient will accept them. And they don’t reject them. They don’t have an immunological response. And more importantly, they don’t develop sensitive sensitivity to the cells. So we can actually treat people with the same donor cells repeatedly. And you didn’t sensitize them to have an immune reaction. That’s really remarkable. And that means that the placenta is nature’s “one size fits all” stop-and-shop for cells.
Phil Stieg: Do we really understand how these stem cells work then? Is it that you’re just giving somebody a booster? You know, I got to go. I’m going to replace some of my old, tired stem cells or are they replacing the cells that were already there? Do they turn on your immune system so that it’s more active? Is there one mechanism? Are there various mechanisms whereby these cells activate us?
Robert Hariri: There are principal mechanisms by which stem cells respond to local signals and they will actually mature and specialize and secrete factors based upon the environment they’re in, in order to, what I often say is, they’re trying to return that tissue or that organ back to the state that existed in a fetus. I often say every stem cell, regardless where you get it from, thinks it’s in a fetus. And what’s great about the fetal environment is it has a very, very powerful regenerative ability. So by giving stem cells you’re recharging the reservoir, that or the fuel tank that’s used just to drive, repair, renovation, and renewal.
Phil Stieg: We all know that part of aging is loss of muscle mass, deterioration of your joints and cognitive skills. So what’s been your observations about how stem cells help with these components of aging?
Robert Hariri: You know, I’ve studied this for many, many years. A couple of interesting things struck me many, many years ago. I was looking at bone marrow biopsy data from clinical trials, patients with cancer and other diseases. And one of the observations, an investigator in Scotland had published that if you look at the bone marrow of individuals of different ages, the number of stem cells in the bone marrow dropped precipitously with age. In fact, you lose about a thousand times the number of stem cells when you’re in your 80s that you had when you were an infant. And we actually did work to validate and confirm that in animals. And sure enough, age does reduce the number of functional, viable stem cells.
So that kind of suggests that age-related decline in stem cell number and quality might be related to some of the loss in our resilience to disease, into the quality of our tissues and so on and so forth. So we actually explored it. And in some animal studies, we showed if I collect stem cells from a newborn animal, in this case, rodents, and I process them the way we do with our placental cells and then give them back to these animals as they age, the animals were living 30 to 40 percent longer than their littermates.
Now, that’s an animal study. It doesn’t necessarily correlate exactly to what would happen in humans, but it strongly suggests that if you could administer cells to restore and replenish the reservoir of stem cells that is lost as we age, you might restore some of that renovation and repair activity that’s necessary to keep us young.
Phil Stieg: So placental stem cells are readily available, and the reason you’re using them is because as we age we as humans have fewer stem cells for you to use…
Robert Hariri: That’s right. So the beauty about stem cells from the placenta is the abundance, the high quality, the expandability, the scalability, and the youth. Let me try and explain it this way.
What’s unique about a stem cell is that because it hasn’t gone through the process of maturing and differentiating, which is to specialize into a, for example, a neuron, OK, it hasn’t silenced any of the genome. So think about this for a second.
Your genome is your biological software. It resides in the nucleus of your cell and it gets called upon to be read. And then the recipe from that genomic code is translated into producing proteins and other molecules that make up the body. If you look at a neuron, a neuron only a mature neuron only expresses a fraction of the total genome. You know why? Because it’s specialized. In order for the cell to have an efficient synthetic apparatus, it has to take some of the code, some of the recipe, and tear those pages out of the book.
Actually, the best analogy is — you ever build a house? When you build a house, you get a set of blueprints That’s maybe one hundred pages long. And as you go through the process of constructing the house, you tear the page that you’ve just completed away, so that by the end of the construction, you only got about three or four pages left, that’s what happens to your genome.
In a stem cell, you have all the instructions available to make everything. In a mature cell, you have a fraction of it. What’s unique about stem cells is they keep that full transcribable genome active and available. And what it means is that if you get those cells back when you’re older, you now have the synthetic ability to make the whole repertoire of proteins and molecules you need for health. That’s why I think it’s going to be so valuable in treating age-related diseases.
Phil Stieg: We’ve done a little bit of a historical review, we’ve talked about how cell-based therapies are used, we’ve talked about the diseases where you’ve thought about applying them. So what’s next?
Robert Hariri: So, you know, for Celularity, we are very focused on delivering on our clinical trials, exploring derivatives of our placental stem cells and immunotherapy of cancer. We are in parallel getting back into treating autoimmune diseases and other degenerative diseases. And there’s going to be a process by which we present our data to the regulatory authorities, petition for approval and then get into the commercial business of delivering these for patients.
That’s the goal and the objective of our company. And we intend to leverage every success by investing more and more in the broad array of clinical applications that are out there.
Phil, between you and me, cellular medicine is here to stay. We already know it’s transforming the way we treat cancer. Cellular medicine is intuitively logical. And I believe that in the next 10 years we’re going to be using cells to treat brain tumors. We’re going to be using immune cells to prevent recurrences. We’re going to be using cells to restore neurologic function in brain damage. So the future of living longer and living healthier – no doubt – is going to involve stem cells and the byproducts of stem cells.
Phil Stieg: Dr. Robert Hariri, aviator, scientist, surgeon, entrepreneur and now CEO of a new startup publicly traded company. Thank you for really shedding some light on the utility of STEM Cells I’m extremely hopeful that they will become more readily available to the public in the near future. Thank you so much for being with us,
Robert Hariri: Dr. Stieg, It’s great to be with you. Thank you. And I’m looking forward to working with you to try and advance how we treat brain tumors and other diseases.