How Stem Cells Can Reprogram Our Biology To Create A Younger You - Transcript

Introduction:
Coming up on this episode of the Doctor's Farmacy.

Dr. Bob Hariri:
When you deliver a stem cell to a site like the liver, it is capable of restoring any of the corrupted software in that organ and tissue.

Dr. Mark Hyman:
Welcome to Doctor's Farmacy. I'm Dr. Mark Hyman. That's [inaudible 00:00:19] to have a place for conversations that matter. If you care about living a long and healthy life, this is going to be an important podcast for you because we're talking about stem cells and cell therapy, which is really the future of medicine. And it's something you might've heard about but probably don't understand too well, including me so I'm going to be on this ride with you.
I'm excited to have as our guest today Dr. Bob Harari, who's an accomplished surgeon he's a biomedical scientist. He's a pilot, he flies jets. He's a serial entrepreneur in two different sectors, biomedicine and aerospace. He's a chairperson and founder and chief executive officer of Celularity, which is one of the world's leading human cellular therapeutics companies. He's also pioneered the use of stem cells to treat a whole range of life-threatening diseases.
He's most recognized for his discovery of pluripotent stem cells derived... and what that means is basically a stem cell that can become anything, that are derived from human placenta. And as a member of the team that discovered one of the most important cytokines we've heard about called tumor necrosis factor alpha, which is a lot of the therapies, for example, around autoimmune disease, are focusing on shutting that down, which is helpful, but has problems. Now he holds over 170 different patents and pending patents for discoveries including placental derived stem cells. Nature recognized that as one of... that's one of the most prestigious medical journals, Nature, recognized that as one of the 10 most important patents developments in the field. He's offered over 150 published papers, chapters, articles, abstracts. And like I said, when he's not working in the lab or in the boardroom, he's flying his jets and done all kinds of cool stuff. He's produced documentaries. Bob, I'm really excited to have you on this podcast.

Dr. Bob Hariri:
Well, Mark, I can't thank you enough for inviting me and it's great to see you, you look fantastic.

Dr. Mark Hyman:
Well, thank you. We're going to get into all the nitty-gritty of stem cells, what they are, what they do, what the options are, how they can be used, and basically unpack why this is such an important part of the future of healthcare and medicine. But first, I want to highlight the fact that medicine for the last hundred years has been focused on trying to shut down or stop or interfere or block some process in the body using medications. And they've been helpful, but the body has this extraordinary healing power, this innate intelligence, this capacity for regeneration, renewal and repair that we have yet to unlock. And so we're going to talk about what that power is through the concept of cell therapy, which is what you pioneered. And it's something that I think most people don't understand that we actually have within us. Sort of like Dorothy and her ruby red slippers, who clicked her heels three times and she could go back to Kansas if she wanted at any time. She just didn't know it.
And I feel like that's where we are now in medicine. We have locked within us, these innate longevity pathways, these switches, these systems that we can activate. And that's what we're going to get into today through the power of understanding stem cells and cell therapy. But before I do, Bob, I want to ask you about how we can learn from what's happened in the last bunch of years around the research around longevity and healthy aging? Because we have so many different therapies, techniques, knowledge, technology, but we're sicker than ever. And the question is, what are the three things in your perspective that people are doing every day to shorten their lifespan? Let's start with the end in mind here. What are people doing to screw themselves up?

Dr. Bob Hariri:
You set this up very beautifully because we all know that despite all of the tools people have, nutritional tools, tools to improve their exercise and performance, we still are suffering from many of the same chronic conditions that erode our quality of life, erode our performance as we age. And I'll take the point of saying that the things that we do wrong are affecting the fundamental toolkit we have resident in our body that is grounded in these remarkable cells, stem cells, that as you kind of alluded to, are there to continually repair and renew and renovate your body during your lifetime. If you ask me what the three things are that I think people are doing wrong, well, first and foremost, there's no doubt that the way we fuel ourselves through what we eat, what we consume, that nutritional platform, if it contains certain things... and obviously there's a lot of attention being paid to preservatives and other chemicals that are not necessarily natural.
And there's no doubt that those chemicals are a burden. Our body is designed to accommodate for foreign chemicals. But when those chemicals have an impact on the genetic material, the programming of our cells, or if they in some way disrupt the normal metabolic processes, your cells suffer, your mature specialized cells that make up your body suffer, but your stem cell population suffers also. It's like if I have a component of brand new unadulterated uncorrupted cells laying in wait to fix me, and I'm damaging them every day with what I put in my body, that's not a good thing. We all know excessive sugar, processed sugar, processed carbohydrates are incredibly damaging for more than what people would think. In addition, eating processed foods, using nutritional supplements that are coming from really a chemical factory rather than from nature, clearly has a negative effect.
Stress. People don't recognize how important the neuro immune axis is and the immune system can be thought of as a giant stem cell factory and a giant stem cell repository. Things we do to create a signaling from the nervous system to your immune system that also has chronic effects that are cumulative over time. Stress, avoiding stress is essential. And then the target that you and I both care a lot about, one of the most actionable areas we have to preserve our health is to take care of our skeletal muscle tissue. Maintaining healthy skeletal muscle is essential. And there's lots of reasons for it. Aside from the fact that what we generally think the muscular system is for, forced generation, mobility and [inaudible 00:06:46].

Dr. Mark Hyman:
Locomotion.

Dr. Bob Hariri:
Locomotion. The fact is your muscle is the largest wet body mass of your body compared to everything else. Which means it's the largest venous capacitance organ in the body. And what does that mean? It means that the stuff that circulates around your immune cells and your stem cells take up transient resonance there. And so by having healthy muscle and by working your healthy muscle, you're helping to mobilize and traffic those cells into your body. And that's how we effectuate the repair and renewal and renovation process that keeps us young. Nutritional issues, stress and clearly declining muscle mass, I think are big problems.

Dr. Mark Hyman:
Cut out processed foods, darker sugar, deal with stress differently. Learn how to regulate our nervous systems through a whole variety of techniques and make sure you build and keep your muscle as you age. I a hundred percent agree, and those are the things we're not doing as a society. I think before we get into the nitty-gritty of what all these things do, what the heck are stem cells? Why do we have them? What's the big hullabaloo about this? Why is everybody talking about it and why is this the promise of the future of medicine?

Dr. Bob Hariri:
I'll take you back to when I first heard the term stem cell. This is way back in the eighties when I was training as a surgeon at Cornell in New York and my area of interest was trauma and how to take care of severe head and spinal cord injury. Stem cells hit the airwaves as this remarkable discovery that... and we all knew about this. You remember from our embryology courses in medical school, we all knew that every human being originates as a single cell. And that single cell is created by the fertilization of the egg by the sperm. Which means it is a composite of the DNA of your parents, your mother and your father. That single cell has to give rise to ultimately trillions upon trillions of cells that take on very specialized form and function. Now, if you think about this, every cell in the body of every human being, regardless of their age, had its origins way back in the placenta.
And when I first heard about stem cells, I said, wow, the fact that these cells retain their versatility, their ability to mature and specialize into any very, very specific form of a cell, like a brain cell or a heart cell or a bone cell, the ability to be a utility infielder and decide you're going to become a brain cell or a heart cell, is driven by signaling that occurs at the site of the tissue or organ that calls upon this repair and renewal process.
Every human being is about 25 to 30 trillion cells. Think about this for a second. From a single cell, you're producing tens of trillions of cells and those cells are continually being renewed in your body during your lifetime. During a lifetime, you may actually make 100, 500, 1000 trillion cells, and that's all originating in a single cell. Think about the replicative integrity and fidelity of a single cell that can give rise to cells that keep giving rise to other cells, each one of them capable of performing the function and having the features of that specialized tissue. Stem cells, first and foremost, are incredibly important because none of us would exist without them, they are what builds us. And we often make the joke that the placenta is nature's 3D printer that prints the babies.
And that's a good way to think about it. But many years ago when I tried to dissect all of this and figure out what does it mean, you know Arni Caplan, the father of mesenchymal stem cells, Arni and I were talking and I combined some of the things I learned from him and some of the stuff I learned from Craig Venter, the genomics guru, who was the first scientist to sequence the human genome. And I've put two and two together and said, what a stem cell really seems to me to be a lot alike is a master boot disc that you're using to constantly for free renew and restore the functions of the information system in your body. If I take a second-

Dr. Mark Hyman:
All the young people listening probably don't even know what you're talking about. Because in the old days of computers, you got a disc you'd have to keep in your drawer, but if your computer went on the fridge, you'd have to put it in and reboot it from the original software.

Dr. Bob Hariri:
That's a good point, they might probably have no idea what I'm talking about. But it is funny though. We know that even the best software running in the best computer over time being used it gets glitches, it gets corrupted. Craig Venter said, listen, our DNA is our biological software. It's a programming language. And Arni Caplan said, your stem cells are basically the delivery system for information. If you put those two things together, a stem cell has the full complement of biological information stored in that DNA in a uncorrupted form. So when you deliver a stem cell to a site like the liver, it is capable of restoring any of the corrupted software in that organ and tissue. And so that's how I think about it. I think about it as a master boot disc that can be used to recover the quality of that information, which is necessary for everything in biology.

Dr. Mark Hyman:
The stem cells are coming from your bone marrow, they're coming from your fat tissue. You can get them from placental stem cells, you can get them from umbilical cord stem cells, and then they can be injected into your venous system just directly throughout your whole body systemically. Or they can be directed into a particular organ like your heart or your liver or joint. And when you inject them, are they actually then becoming that new tissue or are they just secreting compounds by exosomes, which are these little packets or vesicles of information within the stem cells that then help the body to repair and renew? Is it a direct becoming of something or is it actually just providing all the medicines that the body needs to renew itself?

Dr. Bob Hariri:
You're asking a really important question. The way I look at it is when we are built, when we are going through the process of embryogenesis and ketogenesis to create the newborn baby, that newborn baby has every specialized cell type we need in our mature functioning system. The cells that go on to build the liver of a newborn will be the source of cells to continually renew that liver during our lifetime. That's done not by the cells that you're born with in that specialized tissue, but by the cells that are resonant there in this versatile stem cell form, which get called upon to repair and renovate the tissue. And so when you consider that when we're a hundred, we want to have a liver and a brain and a heart that have the elements that build that particular organ or tissue that are of the highest quality.
As long as you have a healthy uncorrupted population of stem cells in your organs and tissues. And you pointed out, you can get them pretty much anywhere. You can find them in fat, you can find them in bone marrow, clearly you can find them in other sources. As long as you have a good compliment of those cells in an uncorrupted form, they will repair you and renew you to perfection each time.
The problem is our stem cells in our organs and tissues are subjected to the same things you and I were just talking about. Bad nutritional factors, too much glucose, chemicals we're getting in our foods, et cetera. That stuff creates a cumulative damage to the under workings of those stem cells. And when they do the repair job that they're supposed to do, it's not as good. I sometimes say, whether you're renovating a house, if you have kept all the starting materials, all the tile and all the woodwork and all the materials that you built that house with originally, and they're in perfect form, when you renovate your house, it's going to look perfect. But if that material is not perfect and you're renovating with imperfect materials, it shows. The same thing happens in the body.

Dr. Mark Hyman:
In a sense, if you then are damaging your stem cells, as we age we don't have that same reparative capacity. And one of the hallmarks of aging, there was nine and I put 10 in my book because I had the microbiome and then there's another few that got added. The stem cell exhaustion is one part of the hallmarks of aging. And so what you're talking about is all the trials and tribulations we go through throughout our life. The crappy food we eat, the lack of exercise, the stressors, the lack of sleep, the environmental toxins, nutritional deficiencies, all of this does a job on our stem cells and so we get pooped out stem cells. And this is really where then your work is going, which is... and I've had this done. You suck out your fat tissue with liposuction, you get a bone marrow biopsy, suck out the bone marrow, it's a painful, expensive procedure and then you have to try to culture the stem cells.
You can't do that in America so you have to send them to Panama or you have to send them to Costa Rica. They have to come back there to do it and it costs a ton of money. But what you're saying essentially, if I do that I'm getting my old stem cells, I'm getting my Dr. Mark Hyman's 63-year old stem cells. But you created a model where you can get foreign stem cells, but without the problem of rejection, which is what happens when you get some foreign tissue from the placenta or potentially umbilical cord and you pioneered this model of placental stem cells. The question I have for you is when you inject those, let's say I inject them into my body. Let's say tomorrow I get a big load of 200 million stem cells and I just shoot them in my vein. What's happening when I do that? Versus, for example, what's happening when I inject it into my liver or my knee, if it's problematic, if I have arthritis, for example?

Dr. Bob Hariri:
If you understand the concept that our ability to repair ourselves and rebuild ourselves is dependent upon these stem cells and these stem cells are fragile and are potentially perishable, then the concept that we had many, many years ago was, where could we possibly find high quality stem cells that could be delivered one size fits all without the need to match the donor to the recipient? And could those stem cells do the job of the patient's own stem cell population that might be corrupted? And so it turns out that if you go back, and if we go back 30 some odd years ago, 35 years ago, when I first got interested in the field, if you remember, most of the work being done on stem cells was being done on cells derived from the leftover embryos from a in vitro fertilization event or from the byproducts of an abortion, fetal material that was being discarded.
Now, as a guy who's focused on trying to create tools for medicine, the concept of using those sources had problems. And aside from the ethical and moral dilemma around using embryos or fetal material, which I didn't really... that wasn't my primary concern, my concern was, could you guarantee the quality of stem cells from those sources was good enough to be turned into a living medicine? And so my thought at the time was, well, sure, why not, probably. But what we learned was that particularly with abandoned embryos, that at the stage of development that you isolate stem cells from an embryo, which is at the blastocyst stage, it's very early in development, that particular stem cell may or may not be of the quality necessary to be healthy years and years later. What I mean by that is this, only one out of every four or five conception events where you create an embryo actually is qualitatively good enough to go all the way to a full term pregnancy. That's why we have early miscarriages, the late period, et cetera.
That's because the genetic material that makes up that first fertilized egg that becomes an embryo doesn't necessarily have everything perfect and so nature clears that out. The term, I often use it, if you get stem cells that have made it all the way through pregnancy and produced a healthy newborn, it's gone through nature's quality control process. And so what you have is you have a cell that's capable of creating a healthy newborn human, and it hasn't been affected by any of the outside effects, radiation, chemicals, et cetera, so it's about in the best possible biological state it'll ever be. And so that was the driving force for me saying, well, we need to find a resource that's renewable, reliable, scalable, in order to turn living cells into medicines. And I give my oldest daughter credit for this, my oldest daughter who is... I'm incredibly lucky, she works for me in my business development team, and she's absolutely brilliant.
When she was in utero, she taught me lessons even back then. I was a young surgeon, I went down to the L&D suite to look at the ultrasound of my developing newborn. And for the first time, Mark, you know what, it dawned on me when I looked at the ultrasound, that although she was a peanut size embryo, the placenta was already a big organ. And as an engineer by training, I said, well, wait a second, in medical school, remember we were taught the placenta is a vascular interface between the mom and the developing baby. If that was true, they would grow at the same rate. The placenta would be this little tiny organ next to the little peanut sized embryo. The fact that it's already developed into a significant organ means, and meant to me at least, that it's the governor or it's controlling the development of the embryo and the fetus. And if that's the case, why?
And so at the same time, I'm hearing about stem cells and I know that they come in embryos, and you can find them in fetal material. I said, well, maybe the placenta is this big organ because it is a stem cell factory. And so back in the eighties, I started collecting placentas and taking them apart. And lo and behold found out, Mark, that the placenta is designed as a giant bioreactor. It's designed to propagate, differentiate, which means to specialize, and then traffic cells probably in the participation of the development of the newborn. But clearly at the end of that pregnancy, all those cells are left over in the organ. And so what happens after the baby's born? The placenta is expelled, usually when no one's looking. The doctor's off with the baby and all of a sudden after a few minutes after birth, the placenta detaches and is expelled and it's discarded as a waste material.
Back in the eighties, I started questioning, well, what if I could collect these placentas after birth and isolate the cells? And so that's how this all originated. And the cells from the placenta, number one, are incredibly abundant. From one placenta, we can recover billions of cells. And think about it, it's the most incredibly controllable environment for collecting a raw material. You know when the pregnancy's occurring, you can screen the donors through the mom and dad, and you can create the system for procuring the organ at the moment of birth, under full informed consent, with all the medical history of the parents and being able to discriminate whether or not the underlying donor quality will be good enough. And so that's what led to us creating a system to collect placentas, isolate the cells from the placentas, and isolate all the other biologically meaningful materials to turn them into therapeutic products.

Dr. Mark Hyman:
When you've gotten these stem cells and you inject them, like I said, do they go and become a part of your new cartilage in your knee, or do they help repair your liver if your liver's damaged? Or is it because of what it's secreting in the body? Is the actual stem cells then redeveloping into a new part that you have or that you need?

Dr. Bob Hariri:
That's really the perfect question to explain the complexity of what these cells can do. First and foremost, we know from bone marrow transplantation that stem cells can actually go in and totally replace and remodel an organ like the bone marrow. What that means is that they go in and they either fill a gap because the cells there are missing or they're dying or they're diseased, or you can assist that process in bone marrow transplantation by wiping out the bone marrow using chemotherapy or radiation. And now you have fresh, fertile, environment for these cells to take up residence. And what they do is they traffic... once you inject them into the peripheral vein, they're in your body circulatory system, they traffic to a whole range of different places and they know where they are, it's funny. Stem cells have the ability when they take up residence in a discrete location like the liver or the lung, they know from the underlying, what we call the basement membrane of the particular tissue, they know where they are.
And what that means is that I can inject a stem cell into my vein in my arm, the stem cells that get to my liver will become... they will differentiate and mature in an appropriate way, and they'll become liver cells. They're not going to become bone cells. And that is what is the precision of cellular medicine. We don't have to necessarily put them in a discrete location, they'll find their way, and when they get there, they do what they're supposed to do as nature designed. And that means that if I have a patient who's got, for example, liver damage as a consequence of their treatment for cancer, their chemotherapy or whatnot, if I give an intravenous infusion of stem cells meant to replace the bone marrow, the cells that wind up in the liver actually help rebuild the liver too. This versatility and this very, very mission focused ability of stem cells to replace and renew our tissues in an appropriate way is fundamental to stem cells.

Dr. Mark Hyman:
But if I, for example, I have a bad knee and I just inject into my vein, I can't imagine it's going to work as well as if I inject it right into my knee or my shoulder if I have a shoulder injury?

Dr. Bob Hariri:
That's the issue more about dose and what's an effective dose that you need for a specific therapeutic effect. For example, if you want to... there's no doubt that intravenously administered stem cells, some of them will find their way to your damaged knee. They'll follow the signaling that comes from the damaged knee and they'll say, hey, wait a second, we got to go there because there's inflammation or there's injury and there's a needed repair. But in order to get enough cells concentrated where you want, we find that you can deliver them not just systemically, but also you can deliver them locally. And you're absolutely right, if you know that the problem you want to deal with is your bad knee, not only is local delivery into the joint space going to be useful, but if you couple that with systemic administration, you can augment the overall benefit. And that's what we're learning in cell therapy now. Cell therapy-

Dr. Mark Hyman:
It's like both, and. Its both and.

Dr. Bob Hariri:
And you know it's funny, in cellular medicine, a lot of people think that it's a one shot deal. I have never embraced that concept. I believe that cellular medicine has to be delivered with a relative dose and frequency necessary to sustain the benefit, the medical benefit. For example, if you were having your knee fixed, we'd want to get enough cells into your joint to help, number one, control the inflammatory process and turn back on the repair process, participate in the repair, and then lastly, you want them to stick around long enough to create a stable homeostatically normal tissue in your joint. And that may mean... because the reason your knee's bothering you is you're probably working out too hard and you're damaging it. And by monitoring the effect and then when the negative effect comes back will allow you to create a rationale for retreating patients. And that's where I think cell therapy is ultimately going to find its place in the field of performance and longevity medicine.

Dr. Mark Hyman:
And so in terms of longevity and aging, right now... and you know have a company called Celularity that produces placenta stem cells. But are they allowed to be provided in the United States? Can people get them? Is it something you only can do out of the country? Can you grow them? How does the legal situation work now with people who are interested?

Dr. Bob Hariri:
Celularity is the company that pioneered the use of the placenta as a source of cells for this emerging field. If you remember, if you go back 20, 25 years, cell therapy was considered to be the cornerstone of regenerative medicine. And most of the thought of applications were to use these cells to treat degenerative diseases. What we learned over the last 10, 15 years is that if you can produce mature cells of a specific type, like of the immune system, you can focus the activity and the use of those cells in a discrete condition. The biggest breakthroughs that have occurred in stem cells that have gotten into patients is in immunotherapy. What Celularity basically has focused on is taking this source material that can produce any cell type and coming up with a range of clinical candidates that can be taken in to treat everything from serious cancers and immunologic diseases to also treating some of the degenerative diseases.
Now, in the United States, all of this work for the most part is in development, it's in the clinical trial process. The United States has, as you know, a very complicated and sophisticated regulatory system. And what we are very much focused on is doing things that meet the standards of the regulatory community. However, there's tremendous demand for cell therapies for things like you just mentioned, treating a damaged knee, shoulder, et cetera. What's happened is other jurisdictions, other countries, other regulatory systems, in some cases have taken the progressive position of saying, you know what we're satisfied we know enough about the fundamental safety of these products, we'll allow them to be used in either a provisional way, like in places like Japan where they have provisional approvals, or in Panama where actual approval to use cells from newborn, from umbilical cord, are allowed for the treatment of patients. And so listen, not every country follows the same fundamental architecture of a regular system. So let's face it, there's people who recognize they can go elsewhere to get treated and that's what they do.

Dr. Mark Hyman:
Let's talk about now how those can be used for longevity. What is the effect and what does the science tell us about how we can literally reprogram our biology to a younger you? We've talked about in the podcast how we can reverse our biological age, how it's not static, that we've now used different interventions to reprogram our biology through epigenetic reprogramming and through cell therapy, through stem cells and exosomes. Can you talk about what role these stem cells can play as we think about improving our overall health, improving our function, preventing chronic diseases like heart disease and diabetes and Alzheimer's and cancer? Can you talk about how they play a role in all that and where this is all going?

Dr. Bob Hariri:
I think a fundamental objective in the longevity world is to replace anything that's damaged or defective that has occurred as a consequence of the aging process with as healthy and as young and as vital a replacement cell as possible. Now, when your stem cell population is in good quality, it does its job pretty effectively. But let's face it, there's nothing better than a cell that's recovered from a newborn and is delivered in that kind of newborn form. Now, there's some characteristics of stem cells that are important. We've learned that this characteristic of stemness, which means the cell is incredibly capable of versatile specialization. Which means simply enough that that particular cell can transcribe, can read and follow the recipe that exists in your DNA perfectly. If you think about it, we got 25,000 genes roughly, something like that. What happens in the process of stem cell differentiation to a mature cell is a series of gene silencing events.
What that means is that to go from a stem cell to a mature cholinergic neuron, a specialized neuron that makes a specialized chemical, to go there, it's a series of cell divisions where part of the genetic material is isolated from being transcribed or read. What that yields is it yields a cell that is highly efficient in reading just the genes necessary for that mature specialized form. Now that's great, but what it means is it shut the stem cells versatility down. You can shut down the versatility of the cell by the differentiation process but as you mentioned before, as we age, we're corrupting the stem cell population in our body. What that called for is, hey, if my stem cells at 70 or 80 aren't as good as newborn stem cells, but I could get replacement stem cells that are newborn, that are compatible with me, that can actually replace what's missing, now, that's spectacular. That means I have a brand new replacement part. The analogy I mentioned before.
If I need to replace a hydraulic pump on my airplane, it's a lot better for me to replace it with a brand new hydraulic pump than to get a re-manufactured one or a refurbished one. Same thing exists in biology. If we can replace the cells in our body with pristine uncorrupted stem cells that take on the specialized role, they will perform better than my original cells, so that's number one. Number two, here's the other really cool thing. You know what chimerism is? Chimerism is when a individual, single organism carries more than one set of instructions, more than one genome. It turns out that chimerism, where you put more than one specific genome into one organism, natural selection takes over and the traits that are selectively advantageous to the individual in that stem cell will get upregulated.
And so chimerism has the potential to give you the same benefits of something called hybrid vigor. Hybrid vigor is mom and dad are genetically distinct, they come together to form the offspring, that offspring has a set of genes that are better than the individual sets of genes from the parents. That's hybrid vigor. Hybrid vigor occurs between generations. But chimeric vigor would be that if I give you a cell that had got a different set of instructions and some of those instructions protect you from something you're vulnerable to, that will get upregulated and expressed. Darwinian natural selection takes place within the body as well as between bodies, between different individuals. And so the way I look at it is stem cell therapy is incredibly powerful as a way to replace the defective deficient cells in your body, but also to augment the capabilities of the cells by giving you a range of different genetic instructions.

Dr. Mark Hyman:
And so it'll basically help turn back your biological clock if you get an injection of a certain number of placental stem cells? Is it once a year or twice a year? What should people be thinking if let's say one day down the road it becomes affordable for most people? What would be a regimen that you would recommend that would help people to help rejuvenate their biology, to reverse chronic disease, to increase their health span and their lifespan? How are you thinking about this as you're looking down the road towards the future?

Dr. Bob Hariri:
Some of the things that are necessary for us to do now is to understand the dose and the frequency that you will need to get these newborn stem cells in order to effectuate the benefits we've been talking about. If you think about it... and this is something to consider, when we first thought stem cells may be at the corner, the heart of why we age, damage to our stem cells or defective stem cells might be at the heart of that. We did an experiment. We did a little skunk works experiment. We collected stem cells from rats at birth from their placentas. We processed them and froze them away, cryopreserved them. And then we gave the animals back doses of their own stem cells every month after they reached sexual maturity. And what we saw was really pretty cool. The animals who got back their own stem cells because they were collected and stored at birth, actually lived 40% longer than their litter mates.
And it was just simple replacement or augmenting their system with these newborn stem cells. Now, what's the dose and what's the frequency for humans? That's the stuff we got to work out. And so that's going to be understood better through the clinical programs, clinical trials that we do. But I would suspect that if you think about the lifespan of a stem cell in your body, we'll figure out the interval based upon how long that stem cell remains in its perfect form. And then when that starts to degrade, you just give you another dose of those newborn cells. Now this is also-

Dr. Mark Hyman:
This would be if you took your own cells at birth? So if anybody born today should have their umbilical cord cells frozen?

Dr. Bob Hariri:
Their placental cells, that is the heart of which has created them, that's the easiest, most actionable way to store away that starting material for later use in life.

Dr. Mark Hyman:
Short of that... I was born in 1959, I don't think anybody ever heard of stem cells back then. Do I have to rely on placental stem cells and is that safe? And could that be as effective, you think?

Dr. Bob Hariri:
Here's the cool thing about the placenta. Aside from all the great features we've been talking about, the placenta is nature's professional universal donor tissue. And let me explain that. A placenta, as we talked about, is made up of cells that are created from the original fertilized egg, which is the combination of mom and dad's DNA. All that tissue makes up the placenta and the developing fetus so it's only a 50% match to mom, mom carries it for nine months without an immunologic conflict. You know that you want to transplant an organ, you want to match the organ from between the donor and the recipient.
But think about this, in surrogate pregnancy, a mother's not even related to the fetus and placenta she carries, she doesn't reject it. The placenta has this incredible ability to induce a state of immune tolerance. Which means that any cell from any placenta can be given to any recipient unmatched without the fear of a aggressive immune rejection phenomenon. Those cells have suppressed expression of certain things which identify them as foreign. And they also release factors that tell the host immune system, hey, I'm okay, you can allow me in. The beauty of that means that what we do at Celularity, which is to produce high quality stem cells from placentas, is that we have a one size fits all medicine, biological living medicine. And that's where the future holds promise for you and me. And by the way, we're the same vintage, we're in the last of the fifties guys. The fact is that we can receive stem cells from an unrelated placental donor and they will provide benefits to us even though they're not our own cells. This unique-

Dr. Mark Hyman:
It works as well, you think, as my own cells? If I took those placenta cells and I injected a hundred million or 200 million on a regular basis, that I could have the same effect as they did in the mice, is that what you're thinking?

Dr. Bob Hariri:
I think that not only is the promise that they'll be as effective, they may in fact be more effective than your own cells. And the reason being, if the donor happens to have a set of genes that you don't have, and those genes confer a benefit like resistance to Alzheimer's disease or resistance to heart disease or resistance to metabolic syndrome... oh, I'll give you a perfect example. We now know that in our population, roughly 4% of the population is resistant to developing HIV. They can't develop HIV because they don't have a gene to express a molecule called CCR5. CCR5 is a molecule on the surface of white blood cells that the HIV virus has to dock onto in order to infect the cell. If you don't express CCR5, if you're a CCR5 knockout, which occurs naturally in the population, you will not get disease from HIV.
Now, if you take a donor who's CCR5 negative and you take their stem cells and put them into an HIV positive patient, it's now been shown, you can convert that HIV positive patient to HIV negative. That's chimeric therapy. What you've done is you've basically taken a small percentage of that individual's cells and given them a genetic superiority advantage. And that gets expressed and provides a disease resistance that you weren't born with. I actually think that getting stem cells from a placenta that ain't your own is probably packed full of advantages that you don't get from your own cells.

Dr. Mark Hyman:
And what would people notice? Let's say I decide, I want to spend the money and get my placental stem cells, what would I expect to notice? Would I feel better? Would I have less pain? Would I have more energy? Would I feel younger? Would I have better sex drive? Would my hair turn black? Would my wrinkles go away? What kind of stuff can we expect? Because I'm asking that because I want to talk a little bit about the Yamanaka factors and epigenetic reprogramming so we'll get to that, but I want to push you on this. What would I see?

Dr. Bob Hariri:
What we know from the various clinic environments around the world, you mentioned places like Panama, Costa Rica, Eastern Europe, Asia, what we have found is that patients who receive stem cells derived from newborn material, umbilical cord blood, umbilical cord tissue, the placenta, et cetera, usually express that they see some very common phenomena after being treated. Among those things, stem cells, particularly newborn stem cells, are really good at controlling inflammation. And so the anti-inflammatory properties are associated with reduction in pain, improvement in certain functions of tissues like your joints. They also find that there's generalized improvement over time in the way your body is renewing itself. One of the most common things that was seen even in the bone marrow transplant community is that patients who got stem cells from a younger donor would often say, you know what, my cancer was controlled by that stem cell transplant, but my hair is thicker, my nails are better, my skin is younger. I used to have gerd, I used to have reflux, that went away.
People will often express that they see generalized improvements in things that started to go wrong as they aged. And by the way, one of the most exciting and lucrative places to use all of this is in the aesthetics world where we already know that our skin starts to change as we age because it accumulates the consequences of bad structural protein synthesis. Wrinkles are in a large part due to the collagen content of our skin and the other structural protein content changing. The plastic surgeons showed us that if you inject stem cells even from adipose tissue, those stem cells can restore the youthful function of the skin. If you're able to deliver cells from a brand new young newborn donor, we expect, and we've seen experimentally, that you actually can restore some of the functionality of those tissues back to almost a newborn state. And there's something that's important to keep in... it's something to keep in mind when you look at different sources of stem cells.
Our age, our biological age, it's a calculus. It's the sigma, the sum total of the average age of every cell in our body. So you know that now we're measuring age of cells by looking at the epigenetic changes, the methylation that's occurring to our DNA. Methylation means that certain chemicals get attached to our genetic material and if you measure that, you can get a sense of how old the biology of the cell is.
Now, if you think about it, newborn cells, aside from the fact that they don't have any of those accumulated changes, they don't have the methylation of the genetic material, they don't have shortening of the telomeres on the cells, which is associated with stable cell division, and most importantly, they have young mitochondria. Newborn stem cells have youthful mitochondria. The age of a stem cell, maybe the age of the newborn, if you do the calculus, how many cells in the recipient? If you give a billion cells, a billion newborn cells to someone who has 10 or 15 trillion cells in their body, just do the calculus. You've changed the average age of the individual by a certain amount so that's one way to look at it.

Dr. Mark Hyman:
Interesting. Now, in terms of other cell therapies besides stem cells, people are using exosomes and natural killer cell therapies. Can you explain what those are, how they're different and where they would be used? When you decide to use, for example, stem cells or exosomes or natural killers cells? And I personally have had the benefit of using exosomes to deal with a lot of back issues and various injuries and trauma so love to hear your perspective on that?

Dr. Bob Hariri:
In the quest to get access to these remarkable stem cells, scientists, clinicians and the general public have looked for alternatives to actual whole cell therapy. And so they have said, well, how do stem cells effectuate the benefits we see clinically? And you mentioned it before, the little microscopic nanovesicals, nanoparticles, that are broken off of stem cells that carry inside the payload, they carry information in the form of genetic material like RNA, they also carry growth factors and other small molecules and other biologic materials that can be transferred to your cells. And in some cases signal processes that are beneficial. Exosomes are a poor man's way of getting the benefits of cell therapy, but in a microdosable way that will have effects, but those effects will be somewhat transient. It's a way to deliver the power of stem cells in a dosable manner.

Dr. Mark Hyman:
Are you saying that exosomes give you a short term benefit whereas the stem cells give you longer term benefit?

Dr. Bob Hariri:
That's right. If the objective in using an exosome is to treat your back pain, the exosomes that are delivered that have anti-inflammatory payloads will actually lower inflammation and give you clinical benefits that will have an effect for a period of time. And depending upon what the origin of your back pain is? Is it a chronic injury or was it an acute injury that you simply wanted to get under control? The duration of effective exosomes will vary.
Let's say you overdid it, you strained your back, you have inflammation in the paraspinal muscles and maybe in the disc spaces of your vertebral column, exosomes will deliver the materials to control inflammation and stimulate repair, but it'll stimulate repair by calling upon your own stem cells. Exosomes also are exciting because they are a relatively scalable and ultimately economical tool that can give you the benefits of cellular therapy without having to deliver the living cells. That's why there's a lot of popularity and a lot of work going on. And by the way, arguably every cell is making exosomes all day long. So if you have a cultivation system and you're producing cells, those cells will dump exosomes into the soup and it can be collected and delivered as a therapeutic.

Dr. Mark Hyman:
Not just stem cells, but all cells?

Dr. Bob Hariri:
All cells. Stem cells are particularly good at producing exosomes for obvious reasons. They're highly synthetic and so on. But you touched upon something which is near and dear to my heart, which is what's going on in the natural killer cell world? We hear it all day long, all the different approaches to longevity have evolved into what are the mechanisms of the processes of dysfunctional aging you want to correct? And one of the processes that's been well recognized is that as we age, some of our cells become senescent. They wind up becoming defective, they accumulate problems. And some people refer to them as zombie cells. And these zombie cells are walking around your body, they're doing their job, but they're doing it less and less effectively and efficiently. And eventually they start to do things abnormally and that contributes to the accumulated problems we see as the signs of aging.
Now, we know that the body under normal circumstances, has a system to clear away those zombie cells, those senescence cells. And so there's an entire field called senolytic therapy where what you're trying to do, you're trying to hasten the removal of those cells either by stimulating a normal biologic mechanism or by specifically killing those cells and getting them to be cleared away. Well, nature figured out how to do this better than we do it. And the way nature does it is to use a cell called a natural killer cell. And natural killer cells are part of what we call the innate immune system. They are pre-programmed to identify and destroy threats that occur generally in biology. When we were first studying the placenta and we were so intrigued by this incredible organ, one of the observations that was made was, it's interesting, but one in every thousand women who's pregnant has some form of cancer during pregnancy. It's a pretty high frequency.
But the incidents of a mother transmitting her cancer to a developing fetus essentially is zero. There've been some isolated case reports, but they're not linking the mom's cancer necessarily to the newborn's cancer. We were intrigued and we asked ourselves, why is it that the fetus is protected? And obviously our attention was directed to the placenta. About 12, 13 years ago, I sent my research team on the mission to find out what is it about the placental immune system that is defensive against the transmission of cancer? And we identified this unique natural killer cell from the placenta. It's a white blood cell that is specialized to be pre-programmed to identify things that are common threats. What are some of those common threats? Well, viral infections, fungal infections. It turns out that we learned that these newborn placental stem cells are pre-programmed to attack and destroy cells that express things called stress antigens.
One of the things our cells do when they're in trouble, when they're sick, is they express on the surface of the cell molecules that signal stress. Those stress antigens actually recruit and allow natural killer cells to target and destroy very specifically those old senescent cells. And the mechanism is common to the way we react to viral infection, cancer and senescent cells. Upon that observation and discovery, we decided we were going to take placental natural killer cells and use them as a tool in all of those clinical areas, treating viral infections, treating cancer, treating age related senescent cells. And here's the beauty of it, the NK cells are very, very well tolerated. They can be administered by systemic infusion, and they are really, really good at hunting down and clearing you of your senescent cell population.
And there's a lot of work ongoing. You've probably seen publications now. NK cells may in fact be the cornerstone of therapy to treat movement disorders like Parkinson's disease. Because it appears that they actually identified the defective cells in the part of the brain that's damaged during, in Parkinson's disease and clean those out so I'm very hopeful. I'm really hopeful that natural killer cells from placentas will be a tool we use to enhance the senolytic processes that cull the herd and clean up our biology as we age. And I think we know, effective senolytic activity benefits us biologically.

Dr. Mark Hyman:
Now, are the actual natural killer cells from your body that then are cultured and grown and then given back to you, or are these coming from the placenta as well?

Dr. Bob Hariri:
If you isolate the cells from the individual, you can deliver them back and they'll have a benefit. But like we were talking about, if they're old cells, they may not be as effective as cells from a newborn. The beauty about the placental natural killer cells is that we can manufacture them to very high quality standards, we can subject them to very rigorous controls, and we can deliver them as a one size fits all product. We've taken these natural killer cells into clinical trials in cancer, and ultimately we want to take them into degenerative diseases as well as age related, senescent related phenomena. Like our hair loss, skin changes, potentially even things that occur in the brain. But the beauty of it is that it's nature's tool, this is what these cells do naturally. This is what they're pre-programmed to do so we're just basically using them in their normal function.

Dr. Mark Hyman:
This is exactly what I said at the beginning, is the body has its own innate healing system. It's way smarter than our medications. And a lot of the cancer immunotherapies are actually taking advantage of the body's own military, its own defense system to help go and find and kill cancers. And it's working better than any therapies we've had for a number of different things. It's not universally effective across all cancers, but it's very promising. And what you're talking about, whether it's stem cells, whether it's natural killer cells, exosomes, these various kinds of cell therapies, they play a role in basically being this globally effective therapy for all sorts of different problems because it treats these common underlying problems of degeneration and aging that happens in the body that have universal causes.
And so you're attacking these universal causes at the root, whether it's inflammation, whether it's the breakdown in tissues so you're seeing these can be a key part of medicine in the future. Right now it feels like these are inaccessible, they're still part of large research trials. You can't really go and get them easily. There's clinics here and there where you can try to get them, or you can go out of the country to get them. But how far away are we from having this being part of regular medical practice?

Dr. Bob Hariri:
Your books explain to everyone exactly what you were alluding to, which is that we should go to the root cause of the problem. And in many cases, nature has already developed a system to address the root cause. I love it, man. Nature's a lot smarter than we are.

Dr. Mark Hyman:
Yeah, totally.

Dr. Bob Hariri:
If you have a teleological approach to things, the beauty is evolution and the natural selection process leads to the use of those tools that are most effective, the ones that are effective, the ones that stick around, and the next generation and the next generation will have them. The truth is, what we're doing in Celularity and in the cellular medicine industry, is trying to produce a product that can be delivered in the conventional healthcare system reliably, logistically, conveniently, and economically, so that we can enhance all of the systems that nature built to keep us healthy.
At Celularity, we have spent decades, two decades, on figuring out what the placenta is all about, what we can get out of it, and what the clinical value of those cells could be to treat some of the things we've been discussing today. Serious diseases like cancer, all the way to improving the thickness and the quality of our hair. And I can tell you that this is now the hottest game in town in many areas. There are parts of the world, the Gulf States, the Middle East, parts of Asia, clearly some areas of Eastern Europe where a progressive receptive approach to cellular medicine has created an explosion of applications of this technology to treat diseases. Celularity recognizes that the global opportunity is vast, maybe the biggest, maybe the most lucrative opportunity in all of healthcare. But what's great about it is it's going to drive us to proactive treatment rather than reactive treatment.
If we know the reason that we develop joint problems is that as we age, chronic inflammation damages our joints, maybe what you do is you treat it before it becomes symptomatic, and you deliver a cell therapy product that helps to build your cartilage back better, control inflammation in the joint, and you never get to the point that degenerative disease actually affects your life. Cell therapy has the potential of transforming healthcare because it can be very proactive.
And companies like ours are working to deliver these products at scale, conveniently, and with the economics that fit the healthcare system. I'd much rather prevent somebody from getting joint disease than have to replace them three times in their lifetime with prosthetics. That's the promise of cellular medicine. And I think obviously Celularity is at the forefront of this because our source material is abundantly available. We have almost 200 million placentas thrown away a year in the world. By collecting this biological waste material, isolating the cellular components, and then producing them to scale, for example, one placenta can produce tens of thousands of doses of cells. And so the incredible scalability, the logistic ease of getting that raw material and the economics of it ultimately, I think, are going to help drive this to being the tool that we use proactively as well as reactively in response to disease. And so the promise is enormous.

Dr. Mark Hyman:
That's huge. And so clearly proactively it makes a lot of sense. Well, let's say your joints already beaten up and they're telling you need joint replacement or you're having memory loss and you have early dementia, or you have plaque in your arteries, are these kinds of therapies helpful in those situations? And how helpful? Could you avoid a knee replacement? Could you reverse plaque in your arteries? Could you reverse the challenges of dementia that happen in the brain with inflammation?

Dr. Bob Hariri:
What I can tell you is that the mounting data is beginning to point to, yes, cell therapy, especially cell therapy derived from newborns, has very profound effects of controlling inflammation and stimulating normal repair. You and I can use our personal examples. I have two horribly destroyed shoulders, two completely destroyed rotator cuffs. And aside from the obvious, the terrible pain and the loss of function, I was faced at a relatively young age... and this problem started when I was 60, 61 years of age. Like you I'm 64 now. I think you're a little bit younger than me.

Dr. Mark Hyman:
Biologically I'm 43, but I don't know.

Dr. Bob Hariri:
Well, that's the important thing, man. That means your stem cells in your body are 43 or younger. But what I realized was I was faced with a choice, either get a prosthetic shoulder replacement, which has significant functional limitations, or try to control the inflammation and stabilize the joint with the use of regenerative therapy. And so I went offshore and I got placental stem cells as well as placental derived exosomes injected into my shoulders. And let me tell you what my result is. I'm now four years after these injuries, and I have restored a pretty profound amount of function. But most importantly, I've done two things that are meaningful to me. One, is I've controlled the pain. And you know shoulders are terrible. You can't sleep, it's miserable.

Dr. Mark Hyman:
Yeah, it's bad.

Dr. Bob Hariri:
Number one, I controlled the pain. But number two, I actually showed that I can actually address the arthritis that was developing in my shoulders. In the shoulder that got placental cells, I actually reduced the arthritic bone spurs that I'd had that were developed while my shoulder was damaged. On the exosome treated side I had great pain relief and I had some degree of control from arthritis, but not as good as the cells, which gets back to the thing about dose and interval and frequency. My intent is to go back and do this until I figure out that there's a surgical solution that's going to work for me.

Dr. Mark Hyman:
That's great. Yeah, no, I've also had back pain for 30 years and using exosomes, it's really revolutionized my life because I don't have this chronic low grade back pain all the time anymore, and it's just gone and I'm just marveling, I've had this for so long. And on the x-ray my back looks pretty bad, but it's actually... feel pretty good so it's amazing. This is just such an exciting field and it sounds like in other countries are far ahead of us in the application of these therapies, but we're getting there. I actually was in the UAE a couple weeks ago, and I went to their stem cell research center in Abu Dhabi, and it was just stunning. The amount of work they were doing, the technology they had, the scientists they had from all over the world doing this work. And we're ahead in many areas in medicine, but this area for some reason, just such fear and concern about it, and I'm not sure why. I think hopefully the regulatory situation will improve.

Dr. Bob Hariri:
It's interesting, you mentioned what happens in places where you've got progressive, youthful, risk tolerant leadership. Saudi Arabia, the Emirates, you've got countries with really brilliant leaders who are open to advancing the state of knowledge understanding that we're not necessarily at the point where we've perfected all this, but it's worth the investment to explore and develop these things into tools for healthcare. Clearly the Middle East and the Gulf States are going to be important leaders here. But similar leadership exists in Asia. I just got back from Korea. I was fortunate enough to be at a conference, the IPMC conference in Seoul with Scott Gottlieb, the former head of the FDA and our good friend Josh Hare from Miami. And we talked about the breakthroughs in longevity and specifically how countries like Korea, Indonesia, Malaysia, Japan, even China, as long as they're receptive to the use of these tools and they encourage the scientific exploration of the activity of these products, we're going to be able to put these in the hands of clinicians much faster than in places that are much more risk averse and basically create roadblocks to advancing the state of knowledge.
Look, here's the bottom line, Mark, cell therapy has been around for a long time. I would argue that compared to most therapeutic tools, cell therapy is intrinsically safe. Remember, the first bone marrow transplants using hematopoietic stem cells from an unrelated donor into a recipient was done 40, 50 years ago, rudimentary technology. We didn't have all of the ways to assess the quality of the cells. And to be honest with you, even the preparation of the cells for those treatments was done in tiny laboratories without a lot of sophisticated equipment. Today, cell therapy products are made like pharmaceuticals. And so I would argue that on the basis of decades of safety, there's a rationale to be somewhat more permissive to try these in different indications. I don't have a problem at all in the United States doing these under controlled clinical trials and so on, but if you have an opportunity in certain jurisdictions to be a little bit more liberal with their use, why not collect the data?

Dr. Mark Hyman:
I think it's great. Well, this is amazing work, Bob. I think we're just at the beginning of the application of these technologies. And I think as I began to really dig into the field of longevity, these are the things that activate the body's own repair systems, that activate the body's own innate intelligence. It uses its own technology that's far greater than anything doctors have ever invented and work far better. And I think we're going to just see this field continue to explode and hopefully the regulatory environment will change.
But right now, people can go to other countries like Panama or places in Asia or Costa Rica or the Cayman Islands to actually get these therapies. And if they're struggling, they can find significant benefit. Athletes use them, I've used them, you've used them. It's often a barrier of cost and access, and that's unfortunate. But I think all that's going to get sorted, and I think it'll come down in cost, it'll be more scalable. It'll maybe even be covered by insurance. And I think it's an exciting moment of medicine. Thanks so much for what you do. I look forward to staying in touch and working with you on bringing this to more and more people so this is quite amazing. Any last thoughts, Bob, on what people should think about and know about this whole field?

Dr. Bob Hariri:
Well, Mark, I'm a huge one of your fans and what you've done in bringing to the presence of mind that aging isn't an inevitability per se, dysfunctional aging isn't an inevitability. We can address it, like you said, guys, like you and me said, why not look to what nature does and use those tools and why not create a very proactive approach to maintaining the quality of our lives, our performance. And I always say healthy aging is basically four things. It's maintaining high performance mobility, high performance cognition, high performance immunity, and youthful aesthetics. Those four things are all addressable with the tools you and I know are available. So why not pursue it aggressively? And I'm looking forward to being in the UAE with you and other places where we can help drive the field.

Dr. Mark Hyman:
Amazing, Bob. Well, thank you so much. Everybody listening, if you love this podcast, share it with friends and family. I'm sure they'd love to learn about this whole new field of stem cells and cell therapy. Leave a comment. Maybe how have you used these therapies for your own benefit and health? We'd love to learn. And subscribe [inaudible 01:11:16] podcast, and we'll see you next week on The Doctor's Farmacy.

Closing:
Hi everyone. I hope you enjoyed this week's episode. Just a reminder that this podcast is for educational purposes only. This podcast is not a substitute for professional care by a doctor or other qualified medical professional. This podcast is provided on the understanding that it does not constitute medical or other professional advice or services. If you're looking for help in your journey, seek out a qualified medical practitioner. If you're looking for a functional medicine practitioner, you can visit ifm.org and search their Find a Practitioner database. It's important that you have someone in your corner who's trained, who's a licensed healthcare practitioner, and can help you make changes, especially when it comes to your health.