At the Undoing Aging 2019 conference, we had the opportunity to interview Yuri Deigin, the CEO of Youthereum Genetics. His company is developing therapies that focus on OSKM, the Yamanaka factors known for turning cells back into a pluripotent state. By partially reprogramming cells using a single component of OSKM, Oct4, the company hopes to remove epigenetic aging from cells while still allowing them to retain their normal functions.
Do you think epigenetic alterations are a cause or a consequence of aging, and why?
Well, this question has so many different parts that need to be addressed. Of course, there are alterations that are consequences. Some of the epigenetics are consequences of aging, like epigenetic drift, with things that aren’t methylated in cells, as they divide throughout the lifetime, that methylation seems to get diluted away with subsequent divisions, but other parts of the genome, many of the epigenetic changes that happen that we can track throughout the aging of an organism are definitely not consequences of aging; they’re actually, from what I understand, causes of aging or causes in the change of metabolism and change of homeostasis, change how the organism behaves, essentially, that are driven by some high program in animal development, that basically silences some genes and activates other genes.
We see this not just in aging but in many changes throughout the ontogenesis or an organism, from embryogenesis to childhood to sexual maturation, and then on, the changes seem to keep going. That’s why we can have a methylation clock, where we actually see that in people the same age, the same epigenetic pattern emerges, and we can actually say that probably all these genes that are in the clock are somehow causally related, or at least one step removed from causally related changes in the epigenetics. I’ve probably said way too much to the kiddie question, but hopefully this answer will be at least close enough to clarify what I think about how epigenetics is related to aging, But, in short, I think aging is an epigenetically controlled process. So, if you need a short definition, there’s a short answer.
It’s something that we get asked quite often. Some people would argue that it’s a consequence, and some others would suggest it is actually a cause. The jury’s still out, really. My personal view is that I don’t think we’re too far away from actually discovering which is which.
Of course, they’re both. It’s so hard to differentiate because they’re both aspects; some epigenetic changes that we see in animals are consequences, basically, the body’s response to external stimuli or just the internal clock running and saying, we need some genes to be active during the day and other genes to be active at night. The epigenetic expression, the gene expression changes, and the epigenetics of those genes change, on a daily basis. Same thing with external insults: something happens, and you need to upregulate, say, gene response to fix DNA breaks; maybe you’re in sunlight, and you have some sunburn, and there’s UV damage to the DNA, so, the genes that are responsible for fixing and tracking down DNA damage, they upregulate, and we see those epigenetic changes. Basically, those epigenetic changes are external to the organism, but there are certainly internal epigenetic changes that occur in the organism during its normal course of life.
It’s a fair answer. You’re using Oct4, which is one of the Yamanaka factors, when many others are using OSKM, which is all four of them. Some people are even using OSKMLN, believe it or not, to partially reprogram epigenetics in cells to reset their aging markers. Why did you choose to only use a single Yamanaka factor, in particular, Oct4; what is it about Oct4 that’s special?
Our main goal is to translate OSKM therapy because we know it works. It has been demonstrated in several animal studies that it successfully rewinds back epigenetics without causing cancer. This approach, we call it the bird in the hand. The problem with Yamanaka factors is, because the therapeutic window is so narrow, that you have to be very careful not to overstimulate their expression, because if you do so, you may end up with cancer, teratomas, or maybe other unwanted consequences. Basically, we know that mice who have overexpressed OSKM factors for longer than, say, three days start dying, and this is something that we urgently need to avoid if we want to have safe epigenetic rejuvenation therapies. One of the hypotheses was “let’s just try maybe just one of the four factors because what OSKM is used for is not really what we need it for.” We don’t need full reprogramming as originally Yamanaka tried to obtain; we actually need the cell to stay in its differentiated state. We don’t need it to lose differentiation and become pluripotent. We actually want it to stay the same differentiated cell, and that’s why we try to look for safer factors, and Oct4 is the prime candidate because when we look at the studies that people have published, what actually happens during the reprogramming process, which factors are upregulated first, which factors are upregulated later, we see that Oct4 is actually the factor that is active in the beginning. It’s the first one to be upregulated.
Then, once the reprogramming process takes hold, other factors kick in. Sox, Klf, c-Myc, they are actually further downstream in the reprogramming process, so, as we actually need to just give the cell a little epigenetic shake, so to speak, and return it back to a more youthful epigenetic state, we think Oct4 might be just the prime candidate to do so but without causing the cell to lose differentiation. This is just a hypothesis at this point that we want to verify. We’re starting just a very small-scale experiment in vitro to see if this hypothesis would hold, and if it does, then we’ll take further steps to work on it, translate it, then, hopefully, if it pans out, maybe just this one factor could be enough, and it opens up the door to so much wider application, because if it’s just one factor, and you know this quite well, maybe we could find small molecules that can upregulate it. Maybe we don’t need a gene therapy; maybe we can actually have one step removed like a small molecule that can upregulate it, either systemically in the whole organism or in just specific tissues that we want to target. But, again, let’s not get too far ahead of ourselves; first, we actually need to establish that the hypothesis is correct and that Oct4 is our guy.
Makes sense, one step at a time. If Oct4 does indeed activate early in the reprogramming process, there’s plenty of literature to support that. At least in fibroblasts, it certainly appears to reduce epigenetic age at a gradual rate as it’s exposed over a period of time. Do you plan to confirm that this happens in other cell types found in the body?
Note: We have seen groups like Belmonte et al. using transgenic mice designed to transiently induce OSKM when exposed to doxycycline (Dox) to reverse epigenetic aging in cells. However, this cannot be done in normal animals or humans that do not react to doxycycline.
Absolutely, but one step at a time. We’re starting to look at it, just in fibroblasts, to see if the short-term upregulation of Oct4 or short-term expression of Oct4 that might be essentially below the detectable expression in normal cells, if this partial Oct4 reprogramming reduces the cells’ epigenetic age, basically the Hovarth clock, then this is a first proof or first evidence that it can, alone, bring back the epigenetic profile of the cell to a younger state. It will be evidence to support this hypothesis, and then we’ll take further steps, look at other cell types, maybe find a different dosing regimen. OSKM factors, you can only dose for two days in vivo, at least in mice, but maybe Oct4, you can do for longer. This will reduce the epigenetic clock even further, but still, the cell will maintain its differentiation. It’s a miracle of nature that reprogramming is a gradual process, that we see the cell becoming epigenetically younger before it irreversibly loses its differentiation profile.
Maybe if we only use Oct4 in this therapeutic window of opportunity, the therapeutic window is actually expanded, and we have more leeway in how we can treat aged tissues and aged organisms; maybe for an older organism, we’ll need a longer therapeutic period of expression. With OSKM, this will probably be unavailable because you’re risking cancer; but Oct4, maybe, and, again, I’m very much in conjecture land here, but maybe, just maybe, it will be possible, whereas a younger organism is not that far removed from a young epigenetic state, so it wouldn’t need a prolonged expression of consecutive days of epigenetic partial reprogramming. Again, I’m giving you a long-winded answer to a very short, straightforward question, but definitely other cell types are on the radar if, provided, we get some good data to support that we’re not completely off our rocker here.
Well, yeah, that’s quite sensible. Makes sense. So you’re obviously on the caveat that it does pan out, and a lot of this is speculative and this conversation is fairly speculative at this point, but it’s still fun nonetheless to discuss it. You guys are proposing to deliver OSKM cassettes to target cells using a lentiviral carrier, so that the cells can then have Oct4, in particular, induced using doxycycline, which is an antibiotic often used in veterinary medicine. I’m sure I’ve given my guinea pigs doxycycline.
Humans too; the tetracycline family of antibiotics is used quite widely in humans for various indications. It’s just this cassette that was developed for essentially experiments that you can stick genes of interest into this cassette and have it only become active if you introduce doxycycline or tetracycline into the animal, only then will those genes be expressed. It’s a very useful cassette. In that sense, tetracycline or dox, they don’t have any biological role other than just to activate the cassette. This is something that we ideally would like to move away from and actually develop a different cassette that will be activated by a different, inert molecule, hopefully, a novel chemical entity that will be patentable. The primary concern is that it’d be safe and inert, because you don’t really want a healthy person to take an antibiotic on a regular basis, just because you’d mess up your gut microbiome and all other things.
There’s definitely strong data for antibiotics in the gut microbiome, which is a pet topic of mine, and it shows that the gut microbiome diversity in older people does reduce. Often, they’re highly medicated, of course. Antibiotics are taken by older people quite a lot, so there’s some correlation there.
There’s definitely a correlation here. At some point, I didn’t even think of the correlation that maybe older people take a lot of medicines.
Older people are dealing sometimes with various co-morbidities, and they could be on a number of antibiotics and different pills. As aging goes on and more conditions develop, we’re now starting to realize that it can have a devastating effect on the microbiome itself, which is thought to drive aging and inflammation in particular, so we’ve got to be careful. How practical would an approach of adding a cassette or effectively a switch be to every target cell in the body, as we’re talking about a huge amount of cells?
I think this is the Achilles heel of the whole concept, but it’s not just our Achilles heel; it’s for any gene therapy that needs to target multiple tissues. Delivery at this point is the biggest problem, but I don’t think it’s an insurmountable problem in principle, and I think a lot of companies and a lot of labs are working on the delivery problem, because many therapies will need to deliver their genes of interest to many tissues. There are companies like Oisin who do successfully deliver genetic payloads, not cassettes, not integrative cassettes, but some genetic payloads to multiple tissues because Oisin needs to clear senescent cells, and there are many different issue types that it has to be delivered to. I fully recognize that this is a tough challenge to deliver the necessary genes to all the tissues, compounded by the possibility that maybe some tissues will actually need a different dosing regimen than others; the cells, tissues with low cell turnover, maybe they don’t need to be targeted as frequently as other types of cells that divide much more often. Maybe there could be other approaches, maybe if it’s for the brain, we can use AAV, we can use non-integrative vehicles, gene delivery vehicles. Absolutely, there are still a lot of things to be worked out. The principle that we need new genes in our body that we can integrate and activate at will is a common principle of many gene therapies, and I think this issue will eventually be solved.
It’s challenging but not insurmountable.
Absolutely, but there’s a lot of challenges that seemed crazy to begin with, but then we as humanity conquered them. Getting to the moon or developing an iPhone; the computing power in your smartphone is millions of times greater than the computers that were initially housed in the size of this room. So there’s progress, and it’s quite fast within a lifetime, the technological progress can be mind-boggling. I think that within the next decade, these gene delivery issues will be worked out.
But in the meantime, and you did mention it earlier, a small molecule approach may, initially for the first pass, might be a more equitable solution, especially from the FDA’s and EMA’s point of view and the small molecule is something familiar to Big Pharma and is something that’s already deeply ingrained in the regulatory process. It might perhaps be the case that small molecules to activate Oct4 or whatever, come first, then refined with a gene therapy approach. Do you think that that may happen?
It’d be great if it was possible. Initially, I was more optimistic than I am right now, because there were some papers published many years ago; that said, there is a small molecule chemical cocktail that can essentially do the work of Yamanaka factors or essentially activate Yamanaka factors, essentially a small-molecule cocktail that can reprogram cells down to the fully pluripotent state. When I looked at those papers, my optimism started to wane a lot, because first of all, some scientists claim they couldn’t reproduce the results that were published in those papers. Also, it seemed that there’s a very low efficiency of reprogramming of those cells, so maybe it’s just that this cocktail is maybe just toxic to the cells and it’s making them dedifferentiate down to pluripotent cells in response to some kind of huge insult, toxic insult or another kind of insult, so it wouldn’t be, at least that kind of cocktail, really something that you can put, in vitro or in vivo, in a live animal and expect it to work efficiently without actually killing the animal. At least those cocktails, I’m quite certain that we couldn’t do anything with them to use them as small molecule activators of OSKM or just Oct4 by itself.
That said, if Oct4 by itself works, this narrows down our target space immensely, just because we don’t have the permutations that we actually need four genes to be activated by, I don’t know, one or several small molecules. That would make me more optimistic if Oct4 itself is enough, that maybe it’s possible to find or design a molecule that somehow will activate this pathway, but, there are so many layers of ifs here that we just have to try it out and see if it turns out. I certainly wouldn’t say that it’s impossible, because many small molecules activate many pathways. It’s completely not out of the question that there could be one for Oct4, but let’s just try it out. Science will give the answer to this question if it’s possible or not.
The great thing is even if there isn’t a small molecule in nature, that’s found as a metabolite in plants and herbs like many medicines have come from, it doesn’t necessarily preclude us designing one, because we’re at the point where we can synthetically create molecules to do specific things. Thanks to things like in silico medicine, we can decide that we want to create a small molecule that does this. I think there’s a lot of scope there, and as you say, it all hinges on that Oct4 hypothesis. Does it give a complete-enough partial reprogramming? Does it do the job properly? If it does, it does definitely make the proposition a lot more reasonable. We need to find a single molecule for a single target rather than four, five, six factors that you might need, so there is hope yet. I’m sure that people at home are really wanting to know this; this is a top question, I’m sure. You’re hoping to develop this therapy initially for pets, such as cats and dogs. What’s the rationale behind that? Why do our furry friends get to go first?
Well, the rationale is quite simple: it’s to get something quickly to the market, and from a business strategy standpoint, this was one of the important things because the horizon of this therapy’s so long for any investor to invest in this thing; he or she wants to have the biggest probability of returning their money quickly if there’s something that can generate revenue as soon as possible from this kind of therapy. Because we’re lucky that this approach is not exclusive to humans; if it works in one type of mammal, it will work in pretty much all others, maybe with the gene homologs for the appropriate species. If it works, we want to generate revenue as quickly as possible, and, from a regulatory standpoint, there’s a much lower barrier to market entry than humans. That was our thinking: get to the market as soon as possible, start generating revenue and financing further studies with this revenue rather than investments. Now, a lot of other companies also embrace this paradigm that we can start with pets, animals, competitive animals, maybe racehorses, because that’s also a very big market, and then move on to humans, because you kind of get the double-dip benefit of not only generating revenue but also generating data, useful data from those animals that you can then later apply to humans or maybe tailor the mechanism or the delivery, the dosing regimen to humans that we will learn from animal studies.
As a cherry on the proverbial cake here, because it would be pets, and a lot of people have got pets, that it’s going to be applicable to a lot of the general public. If they see that Woofie or Tibbles the cat, that their pet’s healthier and happier and seems to have de-aged, I think that will cause quite a phenomenon and a wave of support from the public point of view as well.
I totally agree that we seem to value the lives of others much greater than ourselves, and it seems that we seem to value the life of our pets even greater than some of our humans. People definitely already spend a lot of money to prolong the life of their pets, or just to give them better health or even just pamper them, and I’m sure if there is an available therapy for pets that successfully extend their lifespan, those people would then start thinking, well, why don’t I apply this to myself or my loved ones? If I’ve managed to extend the life of Tibbles by 25% or maybe greater, than why not for grandma or myself?
First for Poochie and then for grandma, but I think most people can agree that extra healthy, happy years for themselves as a desirable thing, but for their pets too. Where’s the joy if you can’t sort of enjoy a longer life with your best friend, which is obviously your dog or your cat? It sounds that you’re taking the right approach to win hearts and minds as well as being practical. Do you have anything else you’d like to tell people about your company or your work? Or just generally anything as a take-home?
Just be on the lookout for this approach, this epigenetic, partial reprogramming for rejuvenation is definitely taking off, and it’s not just us. There are other companies that are emerging, two very good companies emerging out of Stanford and Harvard, and it’s great to see this approach finally get the attention it deserves and get the big hitters behind it to propel it forward to success, provided the science holds up and we can actually tailor the partial reprogramming to our needs. I think the people who are now getting behind it will definitely make it work, provided the science is there. So I’m very excited for the industry in general, because we’re not really competitors; we might be in the business sense, but we all have the same goal, and many people in this industry would love to see their competitors succeed because it means that those therapies that will be successfully developed by the competitors will also be available to everybody. Our primary goal here is not to make money but to provide humanity with tools to extend lives and extend health as much as possible.
Definitely helps their happiness and healthiness; and the independence is, at the end of the day, what we’re all in this for, rather than just extended decrepitude, which absolutely nobody in the field is seriously for.
I know, it’s probably one of the biggest misconceptions.
It is. Just to assure folks at home, you know, we are definitely in this for happier, healthier years. That is what it’s all about really, and if we can do that for us and our pets, then all the better. Thank you very much, and hopefully our audience enjoyed it. We’ll be keeping an eye on you, young man; we’ll be checking in and seeing how old you look next time we see you, and if you look younger, because you look younger already, I’m going to be a bit suspicious that you’ve been using some of those lentiviruses.
All right, sounds good.