At our 2019 Ending Age-related Diseases conference in New York City, we had the pleasure of speaking with Dr. Michael West, the CEO of AgeX Therapeutics.

Dr. West can rightfully be called a pioneer in his field with a substantial background in biomedical and biotechnology corporations. After completing his PhD at Baylor College of Medicine, he founded Geron Corporation in 1990, where he launched and directed programs in telomere biology as it relates to cancer, aging, and human embryonic stem cell technology. He subsequently established the research group that went on to isolate human embryonic stem cells for the first time.

After his time at Geron, Dr. West was chairman and CEO of Advanced Cell Technology, which was acquired by the Japanese company Astellas Pharma in 2016 for $379 Million. Following his success with Advanced Cell Technology and Geron, Dr. West served as the CEO/co-CEO of BioTime Inc. for ten years.

He founded his current company, AgeX Therapeutics, in 2017 as a daughter company of BioTime Inc. Besides his work in the development of rejuvenation therapeutics, Dr. West has also been a vocal advocate of regenerative medicine. He has testified before the U.S. Congress on its potential benefits. Furthermore, Michael West has written and edited seven books on topics ranging from animal cloning to aging, stem cell biology, and regenerative medicine.

We had the opportunity to interview Dr. West during the event and ask him a little more about his research.







During your talk, you mentioned that AgeX Therapeutics has done work on BAT cells and is also working on creating young vascular progenitors. What are the reasons that you are working on these cells, which are important for metabolic processes?

There’s two reasons we’re working on making young cells for old people. In a lot of ways, we think that the human body can be kept going the way an antique car can be kept going if you replace failing components. It’s a little more complicated than that in the sense that cars are generally designed to be repaired. They’re bolted together in ways that they can be disassembled and reassembled. Some of the modern automobiles are actually more difficult. The human body was really not designed to be disassembled and reassembled in that manner, but there are ways in which, if we had a way of manufacturing all of the cellular components of the human body, we could replace worn-out things.

Let me give you a couple of examples. One would be if we had a way of manufacturing young cartilage for your weight-bearing joints, your knee and your hip, that would be absolutely fantastic. The number one complaint in an aging population is the pain of osteoarthritis, and it’s really as simple as a tire wearing out on an automobile. The cartilage wears out, you get bone on bone, and that’s very painful. So if we could just put that cartilage back, like putting a new tire on, we would already solve the number one complaint of an aging population. Well, pluripotent stem cells allow us to make young cells of every kind on an industrial scale. And we now know how to make them so that your immune system would not reject them. So that’d be off-the-shelf products for all people. We can envision fixing that problem.

Probably the most advanced example is for age-related macular degeneration, the leading cause of blindness in the aging world. While osteoarthritis may be the number one complaint, macular degeneration is one of the leading causes of disability. Imagine putting your hand right in front of your eyes and all you have is the vision in the periphery. You can’t really recognize a face, even though you know there’s someone there. You can’t read a newspaper or see your cell phone. It’s not complete blindness, you’re not in the dark, but it is incredibly debilitating. Well, the good news is that we think we know how to fix that with these new technologies. We’d make a particular type of young cell for the retina called RPE (Retinal Pigment Epithelial) cells, transplant them into the eye, and sort of patch the damage. The widespread belief in the scientific community is that this could actually stop the disease process in its tracks. Those are some of the examples of what can be done, essentially, today.







Reprogramming of cells to a pluripotent state in vivo has been shown to erase aging features, but it also has serious downsides, such as the formation of teratomas (a type of tumor), as shown by different researchers in 2013 and 2014. Can you briefly explain how AgeX will circumvent these downsides in their approach?

It’s a good question. If you take these exciting pluripotent stem cells, they’re like a seed that can branch out and make a tree, so they are the ultimate stem cells. We used to call them the mother of all stem cells because they can do that. If you inject the cells themselves into a person, they will branch out and make a mass of random tissues, which is called a teratoma. It’s actually not malignant. It’s uncontrolled differentiation, as we call it. What we do instead is make young cell types that are actually differentiated and make them very pure. Remember the example I gave earlier, in the case of the retina: we make young RPE cells that are pure and inject those in the eye, and those will not make a teratoma. They just restore the function that was lost.

At AgeX, we’re developing a couple of cell types that we think would be very important in aging. Brown adipocytes, which are sort of anti-fat cells, you lose them with age. We believe that throws your metabolism off balance, so you start getting weight gain, central obesity, and type two diabetes, and another cell type, the brown adipocytes, could reset that balance and prevent unwanted weight gain and type two diabetes. Another cell type of interest is the vascular-forming cells. In aging, your vascular system is relatively inefficient. A heart attack is basically poor blood circulation to the heart, and young vascular progenitors can help the body replumb the vascular system with young vascular cells.

What do you envision might be an effective strategy for the clinical implementation of cellular reprogramming methods in humans?

In terms of delivery, that’s a very good question. For delivery, one needs to have the cells in a form that they can be injected where they’re needed in the body and have them reliably stay there and become the tissue type that you want. Fortunately, there are technologies available today that allow cells to be delivered in that manner. An example is a matrix that we call HyStem. It’s like an epoxy glue or mortar that glues the bricks, in this case the cells, in place in order to construct things in the body. When cells are mixed with HyStem, they can be safely delivered into the body. We know that because of clinical trials. With HyStem, cells can become three-dimensional tissue safely in the body. What we imagine, in many cases at least, is that these regenerative cell-based therapies will be delivered in that manner.







Insights into cellular reprogramming have seemed to unify what were previously regarded as differing views on aging. Do you think it would be necessary to use induced tissue regeneration in conjunction with other therapies in order to realize full biological rejuvenation? If so, which therapies would you deem most suitable?

I see induced tissue regeneration as a paradigm shift. Back when embryonic stem cell technology was just some idea that a few of us had, no one had thought of regenerative medicine as we think of it today. That was a paradigm shift. In the same way, I think induced tissue regeneration is something that the majority of medical researchers have not really contemplated or envisioned.

Simply put, the idea of it is based on this: look at the Mexican salamander, of which you can amputate a limb and it just grows back completely, nearly perfectly. If you amputate a limb at the wrist, it just grows back from the wrist. You have to ask yourself, how does it do that? That sounds miraculous! We believe the way it does it is that it’s just repeating the embryology that created the limb in the first place. It never turned off that ability. In humans, we have a similar ability when the body’s first forming. It’s just that we turned it off while the salamander kept it on. The question is: could we actually find a way to reawaken that ability? If so, as I said, that would be a paradigm shift. Can you imagine the consequences?

When I was in Houston some years ago, I was in a hotel where they had a plaque on the wall with Dr. de Bakey. He was a leading heart surgeon from Baylor Medical Center. Underneath his picture, it said “can you imagine a world without heart transplantation?”. I read that the complete inverse of the way it was intended. I looked at that and said: “Yes, I can!” It’d be wonderful if we could find a way to make the heart regenerate. It can actually do that in humans, for about the first week after you’re born. If you purposely cause a heart attack in animals, we see a different effect. For a mouse, in its first few days of being born, it just regrows the heart scarlessly and repairs all the damage. After about a week, it just makes a scar and that’s what humans have for the rest of our lives. If you’re 55 years old and have a heart attack, it does not regenerate. You’ll have scar tissue, which can cause arrhythmias and of course, death.

So, the question is “could you imagine a world without heart transplantation?” or one without kidney transplantation. Can you imagine a world in which a child pulls a burning pot of boiling water on themselves, and someday they’ll have that pristine skin that they originally were born with; they don’t have scars the rest of their life? Yes, I can imagine that, because humans had that ability early in our development. We believe we found the genes that regulate turning that ability on and off, and we believe it’s possible to turn that ability back on: it’s called induced tissue regeneration. What makes it three times more exciting than what I’ve already described? I believe in aging, it’s equally important. You have a lot of tissue damage in aging, so it’d be nice to be able to regrow heart muscle for example. We have reasons to believe that the molecular mechanisms that regulate this regeneration are the same mechanisms that gerontologists are studying today in regard to aging. If you extend the lifespan of laboratory animals, you’re tinkering with those same mechanisms. Thirdly, cancer. We see that about 90% of the time, which is a very high percentage, cancers reactivate the same mechanisms. In conclusion, learning how this biology works could have important applications in regenerative medicine, aging, and cancer. We think this is going to be very important in the future. Time will tell if we’re right.







My mind immediately goes to: are there likely to be any trade-offs? Because there’s probably a reason why this mechanism in humans is shut off. So I was just wondering if you have any ideas or any hypotheses about that?

Yeah, it’s very logical to conclude that. We don’t know if this is true, but it’s very logical to conclude that the repression of regeneration once the body is formed, in the case of humans, is put in place by nature as a tumor suppression mechanism. It reduces the risk that you’re going to get cancer later on in life. It’s not sufficient to cause cancer, because we all had this mechanism once, at least for a few weeks, and it didn’t cause cancer then. The way we think about this is that this new technology, ITR (induced tissue regeneration) would probably be implemented transiently. So if you had a non-healing skin wound, damage to the cartilage in your knee, a heart attack or stroke, you would have this therapy for a short period of time to allow the body to regenerate, and then the treatment is removed. You’d be restored back to this non-regenerative state, because we think it may indeed increase the risk of cancer.

I’ve actually seen an article written by researchers from the Salk Institute that transiently expressed some Salk factors and they did show that this didn’t cause any tumor formation in their models.

Right, that supports our contention that it’s not sufficient for cancer. It’s like that old saying of something being necessary but not sufficient.

Researchers have suggested that reversing telomere attrition can simultaneously reverse epigenetic changes associated with aging, because these markers influence each other through telomere position effect over long distances and other such actions [1]. What are your views on this?







It’s a very good question. A proponent of this, to give credit where credit is due, is Woodring Wright at the University of Texas Southwestern Medical Center in Dallas. Over 20 years ago, back when I was a medical student, Woody (Woodring) proposed this idea to me and others there, and it was based on yeast biology. The length of the telomere in yeast appears to be modulating epigenetics. It appeared to be having broad-ranging effects on the structure of the DNA, which we call telomere position effects. I was not a big fan of the idea. I thought it was an overly complicated model. Woody doggedly stuck to it, would never give up the concept, and he is a brilliant experimentalist. He just continued to work on the idea and ended up demonstrating that there are indeed telomere position effects in humans. I think the role of that in human aging is yet to be clarified, especially how important that is, but there may be some very important biology there. Woody certainly deserves a lot of credit for sticking with the hypothesis long term.

How far away do you think we are from implementing induced tissue regeneration in humans, and what is your estimation based on?

We’re a public company, so whenever we announce timelines, we do it through certain channels. We do SEC filings and all that. We say that we anticipate we’re going to do this and that, around this and that date. I’m not going to announce things new here, but we have filed patents on formulations that we believe would have a really good chance of working in humans as they’re formulated today. Typically, what that would mean, and I’m not saying necessarily that it applies to us, but what that would normally mean in a biotech setting is that you need to do animal preclinical work that will lead to an IND filing. There may be manufacturing issues, although many of those quality control development issues can be worked out with the FDA while you’re doing the clinical trial. So I’d say, typically, we’re a few years away, certainly not decades, not lots of years. If we were still doing very basic discovery research, it’s open-ended, but that’s not where we’re at: we actually have formulations designed that we believe could be implemented immediately. But, of course, we plan to do things in consultation with and with the approval of the Food and Drug Administration.

Besides the work that you’re already doing, do you have a personal top three aging topics that you would still want to research?

I’m a little nervous about this, because I’ve been working in the cell-based therapy area since 95. I first started trying to culture human pluripotent cells that early, and then, of course, we had the (pluripotent) cells in 1998. There’s a mad scramble ever since then to try to turn those into therapies. Induced tissue regeneration, quite candidly, has the potential to make obsolete a lot of cell-based therapies. It would appear that nature has built in developmental programs that can be reactivated that can do the work for us in a much more sophisticated manner, because a lot of tissues are very complex in their organization. If you go back to the example we gave earlier of the Mexican salamander, you can chop off a limb, and it doesn’t necessarily have to be a clean amputation, but, nevertheless, the cells can recognize where they are. If the damage was at the wrist, they say “look, we’re wrist cells”, and they reorganize the tissue and build a new hand with nerves and blood vessels and muscles. It’s just amazing what the developmental program can do.







Someone said once that the miracle of development is made all the more miraculous when you consider it’s more complicated than a modern jet airliner. Imagine that the challenge was to build, let’s say, just a jet airliner, which is far more simple than the human body, but, as we’re making it, the jet has to fly every step of the way. From the first bolt put in place, it has to be a functioning airliner. During human development, we’re alive every step of the way. It’s not like we’re built and then a switch is turned on. It doesn’t work that way. That makes it even far more amazing. So the ability that nature has built into our genome to construct the human body is still resident in the genome (at a later age), and reawakening it has absolutely mind-boggling potential. Much of medicine is about fixing that which is broken in the body, at least modern medicine. In the old days, people died of infectious disease and things like that. Now, we can kill all those bugs. Increasingly, medicine’s facing how to fix hearts after heart failure and trying to deal with the loss of neurons and Parkinson’s disease, etc. Being able to utilize the body’s own brilliant mechanisms to not only generate but regenerate the body in the context of disease is going to have really significant implications for medicine. I think that reversing the damage done in aging is a far simpler maintenance problem than regenerating an amputated limb, for instance.

Is there a question that no journalist ever asks you that you would like us to ask you?

This one comes to my mind: “Why do we do what we do? What’s the motivation?”

I guess maybe someone might have asked me that question once. A lot of people may think that the people working to really intervene in aging, and maybe extend human lifespan and so on, are doing it because they don’t want to die, that they want to live forever. There are people like that in the field of aging research, but if speaking for myself and others in the field, some of us are humanitarian. We all have family members that we’ve lost. Let’s put it plainly. They’re dead. I had this wonderful, wonderful father, and I buried him in the ground.

He (my father) had a truck business. I used to work with him in the parts department. It just pains me thinking about how he would go into work in the middle of the night if the city plow that was plowing snow would break its crankshaft. They called up Fred West, and he’d work all night. He had the parts, he’d pull them out, and he’d fix the darn thing. And it was back on the road on time for the children to get to school in the morning. We could fix the city snowplow, but when my dad had a heart attack, no one in the world knew how to fix it. The reason some of us work on this sort of thing is we want to put an end to that kind of loss. The world is a poorer place without my father in it, and when you multiply that by the millions and millions of people that suffer losses like that every day, this is a wonderful thing for scientists to work on, and it’s certainly my motivation personally.







We would like to thank Dr. West for taking the time to do this interview with us. Dr. West gave a talk at Ending Age-Related Diseases 2019 entitled The Reversal of the Aging of Human Cells: Strategies for Clinical Implementation.

References







[1] West, M.D., Binette, F., Larocca, D., Chapman, K.B., Irving, C., Sternberg, H. (2016). The germline/soma dichotomy: implications for aging and degenerative disease. Regenerative Medicine, 11(3), 331-334.

[2] Vaziri, H., Chapman, K.B., Guigova, A., Teichroeb, J., Lacher, M.D., Sternberg, H., Singec, I., Briggs, L., Wheeler, J., Sampathkumar, J., Gonzalez, R., Larocca, D., Murai, J., Snyder, E., Andrews, W.H., Funk, W.D., West, M.D. (2010). Spontaneous reversal of the developmental aging of normal human cells following transcriptional reprogramming. Regenerative Medicine, 5(3), 345-63