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Yuri Deigin on Cellular Reprogramming in Humans

His company intends to go tissue by tissue.

Yuri Deigin InterviewYuri Deigin Interview
 

In a recent press release, YouthBio Therapeutics announced that it has left stealth mode. YouthBio is a self-proclaimed longevity biotech company with a focus on developing gene therapies that reverse the epigenetic alterations that cause us to age.

The company is hoping to reverse cellular aging in people through partial cellular reprogramming. This approach reverses the changes in gene expression that accumulate over time and cause our cells to become increasingly inefficient and behave in harmful ways.

Studies have shown that when gene expression in cells is reprogrammed from an older to a younger profile, the aged cells behave like young cells again. The race is now on to translate this approach to people in a way that is safe enough to be used. Check out our article on Yamanaka factors and partial cellular reprogramming to learn more about it.

The company is led by CEO Yuri Deigin, a biotech entrepreneur who focuses on translational research. Yuri has led a number of early-stage pharmaceutical companies and has been an active proponent of partial cellular reprogramming since 2017.

The team includes researcher Dr. João Pedro de Magalhães, who has been based at the University of Liverpool for many years where he leads the Integrative Genomics of Aging Group. His lab has been studying aging with a particular focus on its genetic and epigenetic elements. He is the Chief Science Officer at YouthBio.

Dr. Alejandro Ocampo, Lead Research Collaborator of YouthBio, is a pioneer of cellular reprogramming and was the first author of the 2016 paper out of the Salk Institute which first demonstrated that the technique could be successfully used in mice, not just in cells in a dish.

We had the opportunity to speak with Yuri about the company and his thoughts on aging research and why we age.

First off, can you tell us a little bit about yourself and how you got interested in aging research and attempting to slow down or even reverse human aging? 

First of all, I worked in drug development before I got interested in aging, and I just didn’t realize, as many people don’t, that aging is the driver of pretty much all non-infectious diseases, with the exception of inherited ones, of course. You could even say that many infectious diseases have an age-related component too.

Basically, I didn’t realize that aging was a problem, because even drug developers and medical professionals think that aging is the norm. They think that because everybody ages, it’s not a disease, so it’s normal. They just say “We’re here to cure cancer” or “We’re here to cure Alzheimer’s.”

But then someone comes to you and shows you that all of those diseases are driven by aging. Then they suggest you should try to cure aging to stop all these diseases at the root cause. That is the moment your eyes are opened and you realize, “Wow, that makes so much sense, aging is this process that drives all those pathologies.”

I got introduced to this concept – that aging is a thing we should go after – around 2012. This was when the seeds were planted in my head, and by then, there were already a lot of animal studies that showed that aging is malleable. We already can extend lifespan in animal species like rats, mice, and much simpler ones like worms and yeast.

That was the foundation that made me realize that aging was not an immutable process, that aging is something changeable, and that it makes all the sense in the world to try to change it. After all, the goal of medicine is to prevent disease and to keep you healthy for as long as possible. What our field – longevity – is doing is absolutely the same thing.

The elephant in the room is aging. That elephant is preventing all of us from being as healthy as possible for as long as possible – that’s the aging process. If you are interested in saving lives, if you are interested in developing cures for diseases, you should be trying to intervene in the aging processes.

Once you realized that aging was something that was not a one-way street, what did you do?

Once that kind of realization came to me, I got very interested in accelerating this understanding among the general public. Just as I was, first of all, unaware of aging being a problem, and second of all, it being a potentially fixable problem, most of the general public also does not know this.

I thought the best thing to do was to try to spread the word. Initially, I was much more involved as an activist in the longevity movement while still doing drug development that wasn’t related to longevity but was related to age-related diseases. Some time later, I learned about a new approach to intervene in aging, this being partial reprogramming.

This was when the Ocampo paper came out in late 2016, where researchers showed that Yamanka factors could make cells younger in mice by partially reprogramming their epigenetic state, and could then make those mice live longer. Once I learned about this paper in early 2017, that was the point where my two paths crossed. At the time, I was writing a lot about the epigenetic nature of aging and how it would be great if there was a way to rewind our biological clock and epigenetically modulate aging.

For me this was a Eureka moment. I was like, “Wow, this is one way to do it.” Yamanaka factors epigenetically rewind everything back to an essentially embryonic state, and in the process, this also rejuvenates cells. This was when things kind of fell into place and I thought this approach had the most potential to intervene in aging systemically.

Once I had learned about partial reprogramming, I thought there would be people immediately trying to translate it and pushing to create therapies using the approach, and yet I didn’t really see that happening. I thought, “Well, if nobody else is doing it and I believe in it, then I will do it.”

It was also a good time for me because I was transitioning from my previous drug development project, and this was the perfect opportunity. If I wanted to do this, then the time was now. I just did it and started a company to translate and try it.

In 2020, I met Viet Ly, my partner and co-founder, of YouthBio. He suggested we focus on translating partial cellular reprogramming to humans, and by January 2021 we got the company registered in Washington State. This was essentially when the company was born. Since then, I have been working with him, João Pedro de Magalhães, and Alejandro Ocampo on putting together the things we need to do in terms of experiments that would answer some of our hypotheses on the translational pathway.

To set the scene, what do you think aging is? Is it programmed, is it random stochastic damage, or is it both? 

To me, the beauty of partial cellular reprogramming is actually that it doesn’t really matter what aging is. We’re taking a very pragmatic approach. We absolutely know that a lot of epigenetic changes are driving aging. Do those changes happen in response to stochastic damage? Or because of a program? For practical purposes it doesn’t really matter. We have observations that show that partial cellular reprogramming can delay aging and can reverse some hallmarks of aging on the cellular level.

We also see some reversal of those hallmarks on an organ level and potentially on a systemic level. There is definitely a delay of aging in the progeric mouse model (mice designed to age rapidly) where they lived up to 50% longer and exhibited better histology of various tissues.

We are taking a pragmatic approach to translating this research to people. We’re actually trying to make something useful rather than just taking a dive deep into the fundamental science, which of course is also important and interesting, but we ultimately want to create a therapy for people as quickly as possible.

To answer the initial question, I do think aging is programmed, and at some level, damage accumulation absolutely is responsible for aging too. The real question is, does that damage accumulate randomly? Why does it not accumulate for very long periods in a human when we’re young versus a mouse, where it accumulates 20-40 times quicker. To me, the answer to that is that there is a programmed component, which dials down the genes that deal with the damage as we age.

It’s these mechanisms that are responsible for fixing the damage that get dialed down as we age. I think we have an excess capacity for fixing the damage when we’re young. The incoming damage arrival rate is pretty stable and level. It’s always at that baseline level of incoming damage. It doesn’t matter whether you’re 20 or 100 years old, whatever occurs externally or randomly, it’s occurring at about the same rates.

But the accumulation of all of it is different. Obviously, when you’re 20, you can say there’s almost no accumulation of it because we have excess capacity for fixing any incoming damage. As we get older, that ability to prevent damage accumulation and to fix any kind of damage on the fly starts going down.

Also, there’s an interesting process that’s happening where some of the bad stuff in our genome, like retrotransposons and retro-elements, for some reason, also become more active. It’s as if something goes wrong, and for some reason, whatever is epigenetically silenced during youth starts to be released from that epigenetic jail. It starts wreaking havoc on the genome. Retro-elements start inserting themselves into various points in the DNA that could cause mutations and all sorts of bad things.

We see two epigenetic processes occurring, where the levels of good gene expression are gradually decreased, as if the volume is turned down, whereas bad stuff like harmful gene expression is getting activated with age. To me, that’s a big indication that there is a programmed or non-random component.

Taking it to the next level then, is it a program that was designed this way, or is it a program that just kind of goes haywire but wasn’t designed by evolution? Perhaps, evolution beyond some point does not care about or cannot do anything about this program.

This is kind of the merging of antagonistic pleiotropy and the developmental program aging theories. Some researchers, such as Mikhail Blagosklonny, think that aging is a developmental hyperfunction or a shadow of the developmental program, the program that helps us mature. After a certain point, the developmental program enters a mode that evolution doesn’t care about, and it is this programmed element that could be driving aging.

I mean, nobody would argue that there is a developmental program where everything is very tightly regulated in an organism between embryogenesis, sexual maturity, and other stages. These are controlled, coordinated, and have specific time points when things happen.

There is the period of childhood, adolescence, and the journey towards sexual maturity, which are tightly controlled and happen in stages. These are programs, and aging also looks very similar because it happens like these stages that occur in earlier life. There is a similar time schedule for different individuals of the same age. To me, it seems like there’s a large non-random component to aging.

Let’s talk about YouthBio Therapeutics. You’ve just come out of stealth mode; what can you tell us about the company and what is it you are doing?

Basically, we are trying to translate partial cellular programming, but we have a tight focus right now on humans. Our approach is to use gene therapy to deliver reprogramming genes once into tissues of interest and then activate them with a small molecule in a similar manner to Ocampo in 2016, where they used a doxycycline inductor to activate the reprogramming genes.

Ultimately, we feel that partial cellular reprogramming will need a tissue-specific approach. Different organs will probably need different reprogramming factors and definitely different dosing regimens.

Our goal is to move away from doxycycline and create tissue-specific gene induction systems that, for a given tissue, can activate a specific set of genes. That platform doesn’t even have to be used for partial cellular programming. It could potentially be used for any other gene therapy that needs several different gene cargoes that need to be activated in a different manner.

Eventually, we also want to move away from Yamanaka factors, because they weren’t designed for partial programming. They were designed for full reprogramming, and for our purposes are too dangerous, because full reprogramming causes cells to lose their identity.

This is something we obviously do not want, so we’re looking for other factors that are better suited to partial reprogramming. Basically, the holy grail for us is to split the rejuvenation from the dedifferentiation. We want to just rejuvenate cells if it’s possible.

We’re obviously betting that it is possible, or at least we can shift these two states farther apart than we can with Yamanaka factors, so there is a greater margin of error, making it easier to just activate the rejuvenation process.

Thankfully, what we observe from full reprogramming is that rejuvenation happens at the very beginning of the process and dedifferentiation happens later. There’s a point of no return, so this gives us this kind of Goldilocks zone where we can partially reprogram cells without fully resetting their identity. The cell can still remain whatever it is, such as a skin cell, but it’s rejuvenated by the burst of reprogramming that happens in the very beginning.

We’re looking for factors that can maybe delay the point of no return phase but give us a wider therapeutic window where we can hopefully extract more rejuvenation and allow us to push the important genes that are more responsible for the rejuvenating effect of partial reprogramming rather than those involved in dedifferentiation.

There does appear to be a therapeutic window, and research does suggest that different cell types require different levels of exposure to Yamanaka factors to rejuvenate them. Given this and the balance between rejuvenation and the point of no return, how can we get around this without it becoming an exercise in massive complexity?

This goes back to what I said, that we think partial reprogramming will need tissue specificity. You’re saying exactly the same thing as we are, that different cell types might need different approaches. With the Yamanaka factors, this manifests itself in different durations of exposure, but the next stop is to try to find tailored factors for a given tissue. 

For example, the brain might not need the Yamanka factor Sox2, which is already expressed in a lot of brain cell types. That’s why we’re developing a tissue-specific induction platform where you can have, for example, to activate rejuvenation factors in the brain, you would take molecule one, and no other tissues would be activated by it. 

This would mean you could do bouts of brain-specific partial reprogramming. Then, you switch to the next tissue, the next tissue, the next tissue, and each would have specific activation molecules.

You could probably do it in parallel, using the specific molecules to rejuvenate each target tissue without affecting others, or you may want to separate them out. That’s definitely a question to be answered much later on when we’re developing an actual combination therapy, but initially we’re trying to study which organs need which regimens or which cell types will respond better to which factors and which durations of treatments.

The short answer is that to provide that differential treatment for different organs, you need different gene induction mechanisms that won’t overlap. This is a platform that we’re developing.

Can you speak to the shortfalls of gene therapy in the context of delivery? Specifically, it is known that delivering the payload to target cells is not perhaps as effective as we would like. How can we solve this?

Well, the delivery problem is a whole kind of different level and essentially a research project in itself. As we are tissue specific, we can piggyback on best practices in transducing a given tissue. There are many hundreds of gene therapies that are targeting various tissues that we can just pick up and use as the best delivery vehicle for the tissue we want to target.

We’re not tied to any delivery mechanisms, and we will just use whatever the best system is at that time. Hopefully, in the next two years, while we’re working on our partial reprogramming and our research, the delivery area will benefit from the advances made by other companies and research labs. 

There’s also other novel delivery approaches that are being developed, and we are keeping a close eye on that.

Given how things work at the FDA, NIH, and other regulatory agencies, what do you think is a realistic timeframe for partial cellular reprogramming to reach humans?

Well, there are certain disease areas where you can see clinical trials happen much sooner than others. This kind of goes back to our initial strategy of focusing on two therapeutic areas, where there’s a huge unmet clinical need. Potentially, as soon as researchers can demonstrate in animals that partial reprogramming can produce a meaningful therapeutic effect and if we come to the FDA with those data, they’ll be happy to let us conduct a clinical trial.

I think it will not happen in a month or two, but it definitely could within the next few years that clinical trials can happen. Obviously, that depends greatly on the animal data.

If we see in animal models of a particular age-related disease that partial reprogramming produces a clinical effect, we can then take that therapy and try to apply it in humans. This is why we’re going after gene therapy. We think it’s a very effective modality for both partial programing and the disease areas that we’re targeting.

There’s no one timeline for all diseases, and the FDA is not saying “Thou shalt not try clinical translation or clinical testing of partial reprogramming until year X”. As soon as you have compelling data and if you know that a disease area doesn’t really have any treatment options, the FDA will, I’m sure, be more than happy to let you try it for those patients, because those patients don’t have anything else.

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About the author

Steve Hill

Steve serves on the LEAF Board of Directors and is the Editor in Chief, coordinating the daily news articles and social media content of the organization. He is an active journalist in the aging research and biotechnology field and has to date written over 600 articles on the topic, interviewed over 100 of the leading researchers in the field, hosted livestream events focused on aging, as well as attending various medical industry conferences. His work has been featured in H+ magazine, Psychology Today, Singularity Weblog, Standpoint Magazine, Swiss Monthly, Keep me Prime, and New Economy Magazine. Steve is one of three recipients of the 2020 H+ Innovator Award and shares this honour with Mirko Ranieri – Google AR and Dinorah Delfin – Immortalists Magazine. The H+ Innovator Award looks into our community and acknowledges ideas and projects that encourage social change, achieve scientific accomplishments, technological advances, philosophical and intellectual visions, author unique narratives, build fascinating artistic ventures, and develop products that bridge gaps and help us to achieve transhumanist goals. Steve has a background in project management and administration which has helped him to build a united team for effective fundraising and content creation, while his additional knowledge of biology and statistical data analysis allows him to carefully assess and coordinate the scientific groups involved in the project.
  1. jlagunez
    May 5, 2022

    THIS IS THE WAY TO GO….CONGRATULATIONS!
    WARM GREETINGS TO JOAO FROM ME, GIVE A CALL PLEASE.

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