James (01:03): Andy Koff is a veteran biotech researcher starting his career off about 25 years ago at the Fred Hutchinson cancer center with Jim Roberts. He currently has a faculty position at Memorial Sloan Kettering cancer center where he uses a multitude of approaches, biochemical, genetic and cellular to identify the proteins and the mechanisms that control how cells replicate. His work has applications in both oncology and in aging and age related diseases. Andy is now the president and founder of [inaudible] therapeutics, a new company that’s tackling senescent cells in a very unique way. This was a particularly interesting interview because of the fact that Atropos therapeutics is such a young company. As an entrepreneur myself, it was fascinating to talk about the problems he’s facing, the struggles and some of the rewards that come from all the hard work. It was an extremely interesting interview from a business and scientific perspective. So without further ado, Andy Koff.
James (02:11): Hey Andy, thank you so much for joining me today. Oh, it’s my pleasure. Thank you for asking me here. Well, for the audience, people that are listening, if they’ve listened to episode one, you are actually recommended to me by Tim from a Tim cash from Santa Lytics and he said you guys were working on some really awesome stuff. So I was happy to get you on the podcast. Well I appreciate it. I think Tim is very nice to me. Tim is a great guy and so the interesting thing is I don’t want to bore the audience too much because they may have already listened about senescent cells, which is kind of what you’re working on. It’s a little bit different what you’re working on, but let’s just refresh people so that they kind of have an idea of what senescent cells are and why they’re such a big issue. So it’s essence cells
Andy (03:00): It is actually a cell that accumulates in your body with age. These are cells that have left the dormancy state, the quiescence state, and they basically accumulate in your body where they are normally removed by the immune system. And what was actually discovered by Judy cam PZ and beyond vendors and maybe five to seven years ago was it’s that the actual accumulation of these cells inside a mouse would actually induce aging phenotypes. It would actually cause inflammation. It will cause tissue damage and it would make the mice prematurely age. And it also happened during like a normal agent. So, uh, the sort of idea has been that we need ways to actually control this, uh, senescence inflammation process and um, understanding the basic biology of it has the potential to actually affect aging and aging related diseases. That’s how I view it.
James (04:18): So basically the senescent cells are, they’re bad, they’re cells that accumulate over time and they’re dead cells. They release this senescent secretary phenotype, something like that. The SAS P, which it’s really, as I said in the first episode, it’s the boogeyman of the cellular world and it, it brings the cells down around them, kind of like in a zombie type situation. And generally it’s a very large part of aging. So you said earlier, you mentioned the, when a cell is in the acquiescent period and that’s actually what you guys are working on, what Atropos is working and that’s more relevant to what you guys are working on. So what exactly does that mean? The acquiescent part of the cell process.
Andy (05:03): So it’s actually called quiescent. Okay. So it’s Q U I E S E N T, quiescent. And what that means is that the cell has chosen to stop being proliferative. It has left, we called cell cycle and it sits in this non cycling state, but it retains the capacity to actually come back into the cell cycle to actually proliferate and propagate itself. So this day is really poorly understood in biology today. How is it that a cell can languish inside your body for 40 or 50 years without ever proliferating? And what happens to it when it finally decides it doesn’t want to stay that way anymore if it actually doesn’t die? Does it become senescent? Does it become now irreversibly arrested? Does it create this SAS a right and recruit the immune system to actually take it out to sort of remove it from the body because it’s no longer of any value. I do also want to add one thing. So [inaudible] is not always bad. We have to be careful with this because during wound repair, senescence is actually a very important component of wound repair. So we have to be sure that we separate bad senescence and good senescence.
James (06:43): Right? And that is something that I think I kind of glossed over with Tim in the first interview is that senescence isn’t necessarily always bad. Senescence is basically when you cut your arm and you get scars, right? That would be, it’s something that we actually, 100% need to be healthy as humans, but it, the problem is when, well the problem comes when you have too many senescent cells and they start to release that SSP. And that’s really when the inflammation starts and all, all of that bad boogeyman stuff comes up. One thing I wanted to ask was this stage, this queer essence stage is that after the Hayflick limit and for those that are unfamiliar with it, the Hayflick limit is after a cell multiplies 50 times or so, give or take a few. That’s usually when a cell enters a senescent period.
Andy (07:33): Right? So it’s actually the Hayflick limit sets up a cell that actually becomes senescent. In order to become a senescent cell, you have to exit that mitotic cycle that, uh, gave rise to a flick limit, right? Because telomeres get disrupted, damage basically accumulates. So this state of non cycling is actually evident throughout your body. Most of your cells do not engage in the cell cycle at any given period of time. So this is simply a state that is ill defined, but it is a state where a cell has left the mitotic proliferative cycle and is sitting there waiting to be called upon. You can think of it this way as an analogy that when you were little, you’ve got a immunization against some other kind of leg virus and for 40 or 50 or 60 years you have retained immunity to that virus because there are basically immune memory cells. These cells are sitting in your body in a non cycling state just waiting for that pathogen, that virus to actually infect you again. And at that point they come rushing back into the cell cycle. They expand in number and they kill the virus and the virus infected cells. So quiescence is that longterm resting state holding the capacity to actually return into cell cycle.
James (09:28): Right. Okay. So the quiescence is basically, if I’m understanding this correctly, it’s the point between when a cell replicates,
Andy (09:38): when a cell replicates is exactly right. It is the point at which it makes the decision, should I replicate or should I?
James (09:49): And so that is what Atropos is doing, which is different than what Tim cash and what a lot of these other companies is working on. You guys have kind of figured out this biomarker which is ATRX foci or FOCI, ATRX, pho PSI, which is a biomarker that kind of lets you guys know right before this cell decides it’s about to replicate and then it decides, no, we’re going to be senescent now and this biomarker starts to show off when that happens.
Andy (10:19): This is correct. The big big discovery by like Marta Kovacevich when is she was in my lab was actually the recognition that a quiescent cell can actually become a senescence South. And the earliest event that we could find at the time was the change in this ATRX protein. This a pho PSI formation. So what that marks is a cell that is embarking into the senescence pathway from a non cycling quiescence state. Right? So that is the underpinning science of [inaudible] is that concept that we can follow a cell that is entering into a senescence pathway and therefore we could probably target a cell that is entering into this pathway.
James (11:28): Okay. And so what does Atropos? What will your treatment do once it, it basically shows that this cell is about to become senescent.
Andy (11:37): This is, I’m going to use, I am actually going to use the analogy that is present day Covid 19 right? We are in the process of actually flattening the curve, slowing the rate at which we get infected people into a hospital environment so that the health care capacity can actually deal with them. So now when you are getting older and these senescent cells are actually accumulating, you have to suspect that this is because the normal immune response to these cells is in fact declining with age. They too are undergoing senescence. They too are becoming nonfunctional. So we think the way to sort of target senescence is to simply slow the rate at which quiescent cells become senescent. We got in a flat in the curve and that will allow the sort of declining immune system that we all have as a weak age to actually keep up with it. Right. To actually clean up senescent cells in a very natural normal process. So where other people, like Tim has actually talked to you about modulating the SAS pee, he has talked to you about killing senescent cells. He has actually talked to you about targeting cell surface immunological proteins. We are actually thinking we would like to do is simply slow the rate at which they occur so that the body can handle that capacity as it undergoes chronological agent.
James (13:37): Okay. So I think I understand it a lot better now. So basically, yeah, using the Covid 19 as an example, flattening the curve that things are going crazy right now with Covid 19 and we’re getting more and more cases and that’s basically what is happening to our senescent cells. As we age, we’re getting more and more senescent cells, more and more Covid 19 cases. And the doctors and the nurses and our healthcare system is our immune system and they are being overrun by this. The immune system is being overrun by these senescent cells. So basically what you’re doing is by slowing down the, let’s say, determining of regular cells into senescent cells, we’re allowing the immune system to catch up, just like we’re flattening the curve with Covid 19 allowing our nurses and our health care system to catch up. And with that, the immune system can come in there and they can help clear out these senescent cells a lot easier than if they were going at the regular pace, if the curve was still going at an unregulated speed.
Andy (14:43): Right. That is absolutely correct.
James (14:46): That feels really awesome to be able to understand that properly. So that actually kind of, I think I answered a little bit of the next question I had, which was why would someone want to choose this, which is kind of slowing down senescent cells as opposed to getting rid of senescent cells using senescent cells?
Andy (15:07): Right. So it’s because a, there are good senescence, right? So sort of getting rid of senescence just to get rid of it. You would need some much more efficient targeting. If you think about oncology failures, it’s because we didn’t know how to target the cancer cells specifically until we had a sort of mutation within that cancer cell that a drug could be designed for or else that we could harness the immune system to a specific protein on that cancer cell. So I think just killing things in general has a risk unless you can target. So that is actually one reason. The second reason is they just gives you another tool to actually think about the problem. What it does not give you. It does not give you rejuvenation. It does not give you, I am biologically old, which is different than my chronologically old, right?
Andy (16:15): Because we all know 80 year olds who were incredibly fit playing squash every day, right? Compared to an 80 year old who isn’t. So there’s a difference between age, by years of age, by biology. But why a person who is biologically old would not necessarily see an immediate benefit from the Santo suppressors that we’re talking about. However, the rate of their decline, the rate of further biologic aging, we would hope would be blunted. It would be slow. So this is an idea about improving the health span from that time until the machine ends, right? Because we are all going to die. The machine will end somewhere.
James (17:14): Okay. So basically you’re just slowing down aging pretty drastically. And ideally the sooner you switch you were to start your treatment would be the better.
Andy (17:24): The sooner within a limit. For example, and again, this is all speculative because you know the company doesn’t have it yet, right? Is the idea is, is that when you were 35 years old, right? Lexus call it young biological age 35 your systems primed. It’s run in great. You don’t have to worry about this when you’re a 50 maybe this is, this is actually the time to start thinking about it, right? That you want to improve your health span, you want to improve your mobility, your strength, your sort of daily living. I would call it right and that is actually when something like a of suppressor will in fact be useful. It would just give you a sort of greater health span for a longer time that might result in like lifespan extension, but that’s not really the goal of Atropos.
James (18:27): So the goal of Atropos is really the health span extension part to really be living a happier fuller life for longer. That’s correct. I want to play squash until I am 95 years old. Okay, so that’s kind of what separates you from companies like Oyston Biotech and Sanalytics then? Correct.
Andy (18:46): That’s absolutely right. These guys are more on the repair rejuvenation issues. I am more classically on the, I would rather never need repair or rejuvenation. I would rather prevent the problem from occurring and people have actually tried this before. Lenny Garanti was actually one who has really been pushing any day. There are people in Austria who are have just in the last year put out some other supplement. These are more of a sort of over the counter supplementation. We are different from them only in the sense that we have a defined molecular target that is, as far as we know, unique for this quiescence and to senescence transition.
James (19:47): Okay. That’s a great answer. So I’ve gotten quite a few questions about this. So in your deck, you mentioned an AI partnership with Adam Wise. I’m very curious about what that means and what’s going on with that.
Andy (20:03): So what this means is that what Atropos has actually done is that Atropos has reached out, well actually we never reach out. It just sort of evolved in this typical Andy Koff organic way I would call it right where conversations started. And what this company does is it’s that when you give them a, a protein target, right? The proteins are the workhorses of the South. They based on a structural knowledge of what that protein looks like, homology, directed knowledge, all of the proteins look like can actually use an AI algorithm that, and they had a developed in order to nominate chemical compounds that can interfere with that protein. So we were talking and they got really excited about this sort of work that uh, we had, uh, done academically on this or quiescence into a senescence transition and how we had placed ATR racks, a, a chromatin remodeling enzyme into this and how we have shown that this event of that protein is really unique to this biology.
Andy (21:30): So they felt it would be great to point their AI structure based drug design knowledge at our problem. And we thought, well it’s cool, it’s not the way we were looking. We were looking at a phenotypic screens, high content drug development stuff and so we’ve directly deal with them. And uh, that deal was just finalized this past month and we will be testing what their AI engine spits out to us and we would be working iteratively between their sort of AI base pattern recognition, ideas like that. You know, it’s all about like kava facial recognition machines work and everything over to a real biologic system in the hope that we can create a molecule that would specifically affect ATR expo PSI formation and thus slow down the rate of senescent cell formation. It’s really, really cool. It’s a great opportunity to work with them. They’re very exciting guys doing really cool stuff that is nothing what we normally do. So it’s a great collaboration.
James (22:50): Yeah, absolutely. And AI and biotech are going to have a very symbiotic relationship going forward as as things progress and as they both grow, they’re both going to help each other grow even further. It’s really exciting. Some of the stuff I’ve read about that’s going on with AI and biotech, it’s you can just kind of sit back and wait for the explosion because it’s gonna speed things up so much. It’s really gonna be an amazing thing. Now what I want to talk about your guys’ results. You guys are in preclinical trials right now, right?
Andy (23:24): We are in pre pre-clinical trials. My friend, we are at, I would affectively call a pre-seed stage trying to actually get into a seed stage now. So we are, we have actually done screens. We some hits, we have a natural product pipeline opening up. We have the Adam Wise pipeline opening up, but we are in the process of second year of a company. Really trying to find out which hair is going to grow into a lead. So we’re a real baby on the biotech scale I would say.
James (24:13): Is there, are there any exciting results from anything so far that you can share?
Andy (24:17): We got hits and the hits are actually being tested in a much more diverse complex systems. Now. There’s sort of like a mouse model systems, other types of cells. So I would say we are exactly where we predicted we would be when we started a year ago with lab work. We got a funded by the national Institute of aging, a small business research program for phase one. And the goal was was to prove that ATR expo PSI can and be a targeted inside a a high content format and this is the year to actually go show that some of those molecules work in multiple systems and then step from there into why would be the seed stage couple of million, you know, $5 million fundraising so that the company can go for two or three years with the pre-clinical work.
James (25:31): Well that’s a very exciting time to be running this company. And the entrepreneur inside of me is curious what is it like to be at this point? I’m sure there’s tons of stories happening, tons of exciting stuff happening, tons of probably let downs that happen. I mean, I’ve been at that point and I love the hustle. I love hearing stories about it. So I’m just curious. Starting a brand new biotech company, what are some of the struggles you’re having? What are some of the rewarding things that are happening? Any stories you can share? Sure,
Andy (26:05): So I would actually say that you need to first know that it had never been my intention to actually be an entrepreneur and a start a biotech company. So never was one of the things that motivated me. This was something that just sort of fell into my lap. But I would say the greatest things about it are in fact the learning, right? The sort of interactions with the investors, the organizations. It’s all of the things that, as an academic guy, I always didn’t pay attention to all the indirect costs, issues on my like grants and why there’s such a big administration to it. But it’s also exciting in that you can really see an idea that is academic in nature, take on a new commercial problem. I mean health span is a real economic issue. I mean with people not being healthy, not only the cost to the medical system, the cost and workforce, the cost and mental health for providers and family.
Andy (27:24): It is a tremendous issue and although I have always studied biologies that had impact in cancer and cell cycle growth control, they never reach that level of worldly magnitude and the people that I have been able to meet because of this and to share the excitement, the science behind it has been really, really amazing. That said, it’s had its problems. There used to be two cofounders and now there’s only me as a co-founder. Right. And I brought in a different co-founder. It definitely goes through its growth phases. It’s hard. I don’t do it full time. I actually have my faculty position as a full time position but this opens up newer concepts, newer ideas and a lot of the ideas I have learned as an entrepreneur are directly related back into how I do science inside my own a laboratory, so it’s been people in the community where my laboratory is out in a San Francisco, like a Douglas Crawford at like a NBC Biolabs has been super, super helpful to me and my advisors have been because the best thing I think that an entrepreneur ought to learn is admit you don’t know anything and then people are really willing to sort of give you opinions and then you just pick and choose which ones are going to work for you and you just have to be open about it.
Andy (29:09): And I think that’s been one of the greatest things about it. I mean I will never do this again. I don’t know how people do serial entrepreneurship, but I assume you are all younger than I am so you could keep doing it.
James (29:24): Yeah, it can be quite a roller coaster, but it’s a lot of fun and the ups and downs are definitely worth it. When that one thing hits, all the downs are worth it when that one thing hits. And it sounds like you guys are on to something very promising. So I’m really excited to follow along Atropos as things goes on and we’ll definitely stay in touch with that at the end of every interview. I like to ask just a few fun questions. I think you’ve probably heard them a Tim, just to see what you think the world is going to be like in a few years. What you expect is going to happen from the biotech industry. I like to get people excited about the industry itself and the promise that it’s really, really gonna change everything in the next 10 to 20 years. So I guess the first thing I’ll start off with is what is what, what is the most, with the wildest thing you could see happening in the next five, 10 and 15 years?
Andy (30:21): So I think we’re seeing is a revolution in biology where it’s becoming a sort of engineering discipline that we could take the tools of fundamental biologic discovery and we can change things. We have people working with three D printers spinning out organ parts now. We had the whole area of rejuvenation medicine. We have an incredible AI contribution to actually understand very, very big and complex data sets that are generated by scientists. I think as this feeds in, it’s, this is the time when biology would be what chemistry was in the early 1930-1940 area. We’re just going to be making brand new discoveries every single day and every one of those discoveries is in fact going to be about improving human condition. We now have bacteria that can eat. Plastics were just reported understanding. This is going to catalyze an incredible amount of bio-engineering work to actually think about how can you modify it in the sort of healthspan space.
Speaker 3 (31:48): I said 3-D printing, Oregon ports pieces, ears, stuff like that. In the sort of healthspan area, how do you improve a patient’s ability or not even a patient individual’s ability to move and interact within their environment? It’s just going to be amazing. And this is the time when I would say college age, kids should really be thinking about what can you do? This whole thing with Covid 19 how did this happen? Right? Where were the big sovereign nation funds throwing money into directing Sentinel programs and then having virologist around to do things, diagnostics for an, for an after infection, vaccine development. Should we use nucleic acid? Should we use proteins? It’s just, it’s a phenomenally exciting time in a science and the challenge will be how do you get government industry and academics to work together to actually see this realization? And I have no answers for that one, so, but at least we could define it.
James (33:09): Yeah, that’s going to be a real tough one. And I want to be hopeful that at least on that, that where you just finished off will be possible in the future. But I think we, I’m not, I’m not super hopeful on that end, but regardless, humans find a way and with enough time we’ll figure things out. What are you doing, if anything, to stave off aging? Is there any protocols you’re taking? Supplements, habits you do?
Andy (33:38): So some of my colleagues have by enough me, I actually at the age of 40 decided that I actually wanted to understand the athlete mindset, which I had ignored as I was a kid growing up becoming a little scientist to B. And uh, I actually started playing squash and uh, the things which I have actually found is that physical exercise, a good diet. That’s really it. That’s actually the best way to actually do this is to just have that physical exercise, diet idea. I’m not a big fan of dropping foods that I like to eat. So that’s all that I would say is I really think it’s just about living well, you want to drink, drink, you want to smoke a little smoke a little right, but just don’t do it in excess.
James (34:38): And do you have faith that in the future, the repair side of things within 10 15 years is going to kind of be able to fix a lot of those issues anyways?
Andy (34:48): Yeah, I do. I think, I definitely think that uh, it would be possible. I don’t know what the costs will actually be and therefore I don’t know if it would be limited to only the wealthy for example, where you are, there is a big problem in terms of getting a car T cell therapy into a patient in that part of the world. Because in America these things are costing a half a million dollars a patient and in that area of the world, a half a million dollars is really limited to a very specific slice of the population. So I don’t know whether rejuvenation and three D printed organs are ultimately going to be cost prohibitive. We’re going to have to figure out a way to sort of scale down cause it’s for the public good. It’s for the good of everyone that we have. The sort of tools available sounds a little bit star Trek, right? Beverly crusher can Strava problem in 47 minutes, but I think that is the right direction in which to shoot.
James (36:06): Yeah, and I think a really interesting conversation that more and more people are having now that they’re realizing that this aging thing and this repair thing is likely going to happen. Certain people are 100% positive that it’s going to happen, but the interesting thing is how it’s gonna affect culture, how it’s gonna affect income disparity. If this is an expensive thing and the rich are just going to live forever, it’s going to be really interesting and that’s going to open up a whole other can of worms. But as far away for now, let’s just try and make the science work.
Andy (36:39): It’s exactly, it led to science work and then let all of this be part of the discussion around it, but not be the leader in it.
James (36:49): Exactly. Exactly. Well Andy, I really enjoyed this conversation. I learned a ton and it was a pleasure speaking with you,
Andy (36:57): As did I. I really enjoyed it and thank you so much for reaching out to me.
James (37:03): If you got this far, I just want to say thank you so much for listening. If this was all interesting to you, I’d love to connect on Instagram and hear your feedback. I’ll also be posting clips from the latest episodes as well as anything else I find interesting about the biotech industry. You can find me on Instagram/simplebiotech, and if you’re interested in the companies that I’m looking at and the companies that I’m excited about, connect with me on angel list at angel.co/jamesruhle. That’s James R. U. H. L. E. thank you so much and be safe out there.