[00:00:00] Speaker A: Foreign.
[00:00:16] Speaker B: Welcome to a special two part episode of the Few and Far between podcast. I'm your host, Chris o' Brien. Today's guest was born into the world of ophthalmology with top scientists as his mentors and an operating room as his daycare. This auspicious upbringing has driven him to create groundbreaking treatments in intraretinal therapies for diabetic retinopathy, macular degeneration and other neurovascular eye diseases. Michael Tolentino, MD, is the co founder of Acuveda Therapeutics, a biotech that optimizes the power of glycol therapeutics to target ocular, fibrotic and other degenerative diseases. He is also an amazing storyteller and we're excited to have him on the podcast. In part one of this two part episode, my Mike and I zoom in on his journey so far from typing up his father's research papers in the 70s, to the draw of computer science and organizational behavior, to his milestone discovery on how to stop the production of the gene vegf, a signaling protein in the body that leads to pathological conditions such as eye disease and cancer. We'll also discuss the many mentors he had through his life, the importance of being a great communicator, and the primary goal of developing treatment in the biotech world. I hope you enjoy this episode and be sure to check back with us later this month for part two of our conversation. Okay, let's start the podcast.
Mike Tolentino, welcome to Few and Far Between.
[00:01:44] Speaker A: Thank you for having me.
[00:01:45] Speaker B: It is a pleasure. I've been looking forward to this. As you know, our very first conversation stretched for so long that it got dark in my house by the time.
By the time we finished. So yeah, I've got a lot of things I want to ask you. Let's start with your background and career journey. Tell me a little bit about how you got interested in medicine in the first place.
[00:02:03] Speaker A: Well, it's a long story and I'll try to cut it short. So I grew up in a family of Harvard Medical School professors. My father was a professor of ophthalmology at Harvard and my mother was a professor of anesthesiology at Harvard. She was actually my dad's anesthesiologist. So when I was a baby, a toddler, back in the day, there was no daycare, so. So I spent a lot of time as a toddler in the operating room, having the nurses be my babysitters. Right.
[00:02:30] Speaker B: Actually, in the operating room as a toddler.
[00:02:32] Speaker A: Well, not as a toddler. Because I was crying at that time. Yeah, yeah, yeah.
[00:02:35] Speaker B: It's pretty distracting.
[00:02:36] Speaker A: My mom put me with the head nurse who became sort of like my. Her name was Esther. She was my Aunt Esther. Right. And she took care of me as a baby. But then when I got older, I was able. If I was shut up and I had my little Tonka truck.
[00:02:50] Speaker B: Yeah.
[00:02:50] Speaker A: I could play next to my mom in the operating room with a mask on. And then I would be very quiet. And then I think I saw my first surgery. Eye surgery, actually, probably as a five year old. That I remember.
[00:03:02] Speaker B: Crazy. Crazy.
[00:03:03] Speaker A: Yeah, it is kind of crazy.
[00:03:04] Speaker B: Were you squeamish at all as a little kid or were you just like. No, no, no. This is just, you know, we hang out in operating theaters. There's blood and stuff.
[00:03:10] Speaker A: So my dad did a lot of research on eyeballs. Right. And this is kind of gory, so I'm not sure if you're.
[00:03:15] Speaker B: Bring it, bring it. We're rated adult on this program.
[00:03:18] Speaker A: We were sort of poor, all right. Because we were an immigrant family, etc. And so there weren't many toys. What my dad did for a toy was to put a. This is squeamish. Okay. An animal eyeball into rubber cement and made it into a super ball. You're kidding. Bouncy. Bouncy balls. That was one of my initial toys. All right, so say that I was squeamish.
[00:03:38] Speaker B: No, not so much.
[00:03:39] Speaker A: Yeah, No, I wasn't. I was playing with eyeballs. Right. Literally playing with eyeballs as a toddler and as a. I'm talking five year old, six year old, seven year old.
[00:03:48] Speaker B: You know, I think you've said that you started doing research. I can't remember if it was when you're 8 or 10 or some ridiculous age.
[00:03:54] Speaker A: Well, I started doing research actually at the age of eight. Eight.
[00:03:57] Speaker B: Okay.
[00:03:58] Speaker A: All right.
[00:03:58] Speaker B: Yeah, yeah. By 10 you were an experienced professional.
[00:04:00] Speaker A: Well, the thing is, is that 8 year olds weren't supposed to end up in the lab. Right. So my dad always worked after hours. He would do surgery in the normal hours and then he would do his research in the after hours. And so he would take me along and I would help him. So he wrote the first on vitreretinal surgery in 1976. And I was the one who collated and typed that baby. Right. Because my command of English was much better than my parents command of English at that time.
[00:04:25] Speaker B: Native speaker and all that, right?
[00:04:26] Speaker A: Yes, exactly.
[00:04:27] Speaker B: Okay, so you had this. And we'll talk more about mentors later. I know, you were exposed to some extraordinary people during this time and continuing on through high school. But you go to college and you study computer science and organizational behavior. Why not biology? It seems like the obvious path would have been to study bio.
[00:04:42] Speaker A: Actually, it's because of my mentors. I was exposed to the partner of my dad, which was Charles Skeppens, and he's the namesake for the Skeppens Eye Research Institute. He also invented something called the indirect ophthalmoscope. And Charles was a man of the world, actually. He was not only a biologist, but he was. He was a lot of things. He was really a Renaissance person. And he actually taught my dad, and I was along with my dad that you have to look at other fields besides your own to develop wonderful things.
[00:05:10] Speaker B: Amazing.
[00:05:11] Speaker A: Yeah, that's what I came up with. So Charles Keppens mastered optics. He was an ophthalmic surgeon, but he was a master of optics. As a result, you know, we have this wonderful invention which allowed us to peer into the retina. My dad, on the other hand, was not an engineer. So when he was developing a surgery called vitrectomy, he had to work with this NASA scientist. His name was Banco. And the guy was purely an engineer. And my dad was purely, like an eye researcher and surgeon. Right. They came up with a device of a vitrectomy device called the Banco Tolentino Vitrector. It was badly designed. I'm telling you, it was terrible. Right now it's only being used in Israel and I think in maybe Pakistan or something. Right, right, right. Because the design was actually terrible. Instead of having something that cuts the vitreous, the jelly inside the eye, it was like a Roto Rooter.
[00:06:00] Speaker B: So it was like, stirred it up.
[00:06:01] Speaker A: Stirring up just spaghetti instead of cutting it. All right. And you need to cut it, otherwise you're going to cause retinal detachments. So while it did work, the design was very poor because it required somebody who had to hire somebody who was an engineer to develop an instrument, and then they couldn't communicate. And as a result, what you got is something that's not going to take over the world.
[00:06:22] Speaker B: Yeah, communications, the ability to maybe translate outside of your direct area of focus.
[00:06:28] Speaker A: Absolutely.
[00:06:28] Speaker B: This is a theme we see in lots of places. Right. Was that on your mind when you were choosing majors in college?
[00:06:33] Speaker A: Yes, absolutely. At that time, Charles Schepens was developing the Skeppins Ireachers Institute. Plus he also founded, like, one of the first retinal practices in the world called the Retina Associates. All Right. What I realized there, observing, I would spend time in my dad's office as well as the laboratory. Right. And I would observe the way an organization runs. What I realized was that Dr. Skeppens ran the foundation and the associates in a very vertically integrated manner, which I didn't think was right. He felt that innovation only came from him and that everybody who worked under him was going to develop innovation under him.
[00:07:09] Speaker B: You understand a command and control structure kind of.
[00:07:12] Speaker A: It's one of those very hierarchical structures. Dr. Skeppins was in the military in World War II and so that's where he got his concept. But innovation doesn't work that way. It actually stifles innovation. And that's why I wanted to study something called organizational behavior along with my computer science.
[00:07:27] Speaker B: Oh, that's interesting. So you identified this as a challenge. You had Dr. Skeps as a mentor of yours, somebody you respected, but you saw that it wasn't the system he was building wasn't optimized. Is that correct?
[00:07:37] Speaker A: Correct. Suboptimal. Because when you have that top down approach and anything, even if you do the top down approach in terms of developing a database system. Right. You can't have that. The best way to do this is through something called a neural network or a parallel processing. That's how you get the most effective output in terms of innovation and advancing of technology. And I knew that even back then.
[00:07:58] Speaker B: That's fascinating. So that's sort of the model we see in most biotechs, right? At least well run biotechs.
[00:08:02] Speaker A: Well run biotechs.
[00:08:03] Speaker B: Yeah. Well run is maybe an important descriptor, but well run biotechs have a bunch of smart people and it's not necessarily true that the chief medical officer, chief scientific officer, CEO, that they necessarily are going to have the answer to how to solve a particular problem.
[00:08:16] Speaker A: No, they'll never have the answer because answer only comes with collaboration, exchange of ideas and challenging of ideas. So you have to have the ability for somebody who maybe you're, you're a junior scientist to go to, you know, that idea sucks. It doesn't make any sense.
[00:08:30] Speaker B: Yeah.
[00:08:30] Speaker A: So why are we doing that?
[00:08:31] Speaker B: I think having an environment where people feel comfortable, safe, actually saying that to somebody who's seniors, knowing that their response to that should be to be intrigued rather than angry or defensive.
[00:08:41] Speaker A: Yes.
[00:08:41] Speaker B: Right. Because if people think that if they know that you fire them and if you get angry when they question your ideas or your thinking, you're not going to get a lot of great ideas and thinking out of your folks.
[00:08:50] Speaker A: Right, exactly. And also at that time, this was 1980 and that's when Microsoft came out with DOS and Steve Jobs came out with the Macintosh computer and so on and so forth. So at that time, computer science was where innovation was occurring and I gravitated to that. I also then studied their organizational structure. Actually, I worked for IBM as an intern and I programmed part of HTML working for IBM. All right. And the issue is that I looked at their organizational structure, compared it to like Apple's organizational structure or Microsoft's organizational structure, and I said, they're going to fall.
[00:09:21] Speaker B: Yeah, you guys can't win with this sort of rigid model.
[00:09:23] Speaker A: No, they're dinosaurs. They're dinosaurs. So, you know, again, all this fed into my ability to conceptualize and execute on biotech companies, innovative companies.
[00:09:33] Speaker B: So I want to get there and talk about structure and leadership in a little bit. But let's talk first a little bit about your research career. So your first, at least, I think the first thing that put you on the map was helping to discover how VEGF causes vision loss and conditions like macular degeneration first. Is that right? Is that kind of the first milestone? And then tell us a little bit about it.
[00:09:52] Speaker A: Well, I actually did not want to become an ophthalmologist.
[00:09:55] Speaker B: You got to rebel in some way.
[00:09:57] Speaker A: No, no, no, it's more than that. So I wanted to become a neurosurgeon. When I was 8 years old. I had very few friends in my elementary school. Only one of two Asians in my whole class. All right. And I grew up in a town called Belmont, which is now a very ritzy place, but it was a very rough and tumble place where I would, you know, get picked on and beaten up all the time. Right. I made a friend also.
[00:10:19] Speaker B: Probably a much more diverse place now than it was.
[00:10:21] Speaker A: Oh, much, much, much more, much better. But at that time it was very one sided and so it was hard to make friends. I did make a friend. His name was Peter. And I'm not going to sell you his last name because I don't want to quote him. But he befriended me mainly because he had a brain tumor.
[00:10:36] Speaker B: Oh my God.
[00:10:37] Speaker A: Yeah, I don't know what kind it was. At that time I wasn't doctor. I was only like maybe 7 years old or something like that. Right. So he came in with a shaved head and he was also picked on because, you know, he was getting chemotherapy and had all that surgery. So I befriended him. Unfortunately, befriending someone who has like a death sentence was, I'M not going to say ill advised, but it really affected me. And he eventually passed away from the brain tumor, which I don't even know what it was. I bet it was glioblastoma, because that's the most common one that would kill him so fast.
[00:11:05] Speaker B: It's plausible.
[00:11:07] Speaker A: And, you know, I went to my dad, who was developing treatments for blindness, and I said, dad, why couldn't we cure him? I mean, we're doing all this research in your lab, and you're solving blindness, et cetera. Why couldn't you? Why couldn't you cure Peter? Right. So that sort of was the forefront of why I wanted to become a neurosurgeon overall. And then I realized, from doing neurosurgical research, this is how I came up with the concept of anti vegf or vegf. Really?
[00:11:31] Speaker B: Okay.
[00:11:32] Speaker A: Yeah, yeah, yeah. So I was doing work on developing a antibody drug conjugate to glioblastoma, and I was involved in the neurosurgical world, so I went to a lot of meetings, I read a lot of journals, et cetera. And there was one article that was presented at a neurosurgical meeting by Eli Kashet. He's from the Wiseman Institute over in Israel. He demonstrated that there was this molecule called vegf, which was upregulated by hypoxia, that was found in the ischemic regions of brain tumors. Well, it just so happens that I had met this professor from England back when I was much younger, at the Schepens Iris Institute. His name was Norman Ashton, who came up with the concept that there was a molecule that caused diabetic retinopathy and macular degeneration. Now, this is dinner conversation at my house.
[00:12:12] Speaker B: Sure.
[00:12:12] Speaker A: I mean, this is what we talk about all the time. So here I am working on brain tumors. You know, my dad's like, why don't you become an ophthalmologist? You know, all my mentors say, why don't you become an ophthalmologist? And I go, I gotta cure brain tumors. Because, you know, my friend died from it.
[00:12:26] Speaker B: Yes. Yeah, I have a. I have a passion for this.
[00:12:28] Speaker A: Yeah, yeah, I have a passion for this. But then once I brought this up to my dad and everybody at Harvard, you know, I was only in medical school at that time. Right. And I was applying to be a neurosurgeon, not an ophthalmologist. But I did have a passion for research, and I did have a passion for this. So another one of my mentors back in the Day, a guy named Judah Folkman. He was one of my mentors as a teenager, but it's because he was a friend of my real mentor, Elliot Burson, who was the founder of Retinal Generations. They went to the same synagogue together back in the 70s. Right. You know, it was like I was Dr. Burson's sort of son that he never had, and he always treated me like a son and also as a student. So, you know, I started working with him around when I was 10 years old, and he started the Berman gun lab when I was 8 years old. And then my dad said, you got to work with this guy because, you know, he's like one of my dad's best friends. Right. You know. Right. And I said, okay, yeah, I'll work with him. And so this relationship with me and Dr. Burson really has inspired me to cure retinal degenerations and also brain tumors. So, again, I'm an odd duck. I'm sorry. You know, nobody should live this type of life.
[00:13:33] Speaker B: Well, it's one of the things that's fascinating is that just the idea that as a child, as you said, you were lonely, you didn't have a lot of friends. You got nothing on that side, but on the older mentor figure side.
[00:13:42] Speaker A: Oh, yeah.
[00:13:43] Speaker B: Wildly blessed. Not only did you have mentors, but they were extraordinary people. They were extraordinary, extraordinary leaders in their fields.
[00:13:49] Speaker A: Yeah. And because I didn't have many friends.
[00:13:51] Speaker B: Yeah.
[00:13:51] Speaker A: I gravitated to that.
[00:13:52] Speaker B: Right. That. That makes a lot of sense.
[00:13:53] Speaker A: It's just what you do.
[00:13:54] Speaker B: You'd have been more open to that.
[00:13:56] Speaker A: Yeah, yeah, yeah. I have a large capacity, intellectual, I call it, where I can absorb. I'm like a sponge. I can learn things very, very quickly and very advanced in a lot of my understanding of things.
[00:14:05] Speaker B: Yeah. So that's really fun for a self confident, talented senior person. Right. To engage with a younger person who's interested and has the capacity to then also digest and add and bat the ball back and forth.
[00:14:16] Speaker A: You got it. And plus, I have an extraordinary capacity to work, meaning I work all the time. Because it's not really work. It's like play for me, you know, that's how it works.
[00:14:33] Speaker B: Hi, this is Chris o' Brien, host of Few and Far Between Conversations from the Front line of drug development. We'll be right back with this episode in a moment. I personally want to thank you all for listening to our podcast now in our fifth season. It continues to be an amazing opportunity to speak with some of the top thought leaders in the drug development Industry. If you're enjoying this episode, please leave us a review on Apple Podcasts. It really helps people discover the pod. And don't forget to subscribe to Few and Far between so that you never miss an episode. One last request, Know someone with a great story you'd like to hear me interview. Reach out to
[email protected] thank you. And now back to the podcast.
Let's go back to vegf. So now you have an inkling that this might be the direction. What do you do?
[00:15:19] Speaker A: Well, what I did was I gave this idea to Fred Jacobiak, who was the new chair at Harvard. And my dad was on the board of surgeons at Mass Eye near, which is the Harvard ophthalmology department. And Fred tried to convince me to take some time doing research, maybe get a PhD. All right. So I decided that I would go into research, do some research, and then I would decide which direction I would go. Would it be in ophthalmology or in cancer? So I ended up working in Judith Folkman's lab. Got it. All right. And this is sort of the crux of everything. In Judith Folkman's lab, I was able to study angiogenesis. And by doing that, I had all. I mean, he was the best funded and most famous cancer lab in the universe at that time.
He was the father of the field called angiogenesis. And I was looking at something called vegf.
[00:16:04] Speaker B: All the pieces kind of came together.
[00:16:05] Speaker A: Absolutely. So my first project actually was to find inhibitors of angiogenesis. And I worked with some of his postdocs there to determine that. And then eventually the idea of VEGF causing retinopathies and macular generation was taken up by Tony Adamus, Pat Damore, and Joan Miller. These were all very young faculty members who didn't really have much background in terms of research. They had all finished their residencies in ophthalmology and they were now being recruited by Fred to man their department. And then Pat Damore was a young principal investigator, you know, studying this whole stuff. So I decided to work with all of them. So with that team of very successful young junior faculty at Harvard under the auspices of Judah Folkman, we were able to develop the whole concept or the whole construct of proving that VEGF is the molecule that causes diabetic retinopathy and macular degeneration. This is a postulate that comes from. His name is Dr. Koch and it's called the Koch's Postulate. He proved that bacterias and infectious materials caused infectious disease and he had four postulates that he put forth, and I just modified them to prove that VEGF caused all the findings of diabetic retinopathy, macular degeneration, and ischemic retinopathies. And then one of the last icing on the cake was to prove that if you inhibited it in a model of disease, that you would stop the disease. And I did that by purifying Avastin for intravitreal injection. So I pioneered literally all anti vegfs.
[00:17:31] Speaker B: Incredible. Incredible. How does that lead to the founding of your first startup, Acuity?
[00:17:37] Speaker A: Well, I had worked on proving that VEGF was the cause of all eye disease exudative diseases. So the next step was, and this was actually Dr. Folkman's advice, so we had an antibody, which now is called Avastin, that was able to shut down or neutralize VEGF when it's in the eye. But Dr. Folkman always said you need to find better technologies to inhibit the target. Right? Think of every cancer drug, right? You always know what the target is. Like, for example, most chemotherapy is cell cycle. So you develop all these different therapies to attack cell cycle. Now there's checkpoint inhibitors, for example. And now everybody's piling onto that. You have the target, but the technology to shut down that target you need to work on. So I go back to my mentor, Elliot Burson, who is, of course, Judah Folkman's good friend, and Elliot tells me, well, you know, I had a student, her name was Jean Bennett, and she's working on gene therapy. So I go, wow, okay, so what does gene therapy have to do with anti vegf? Well, once I started understanding this, I realized that I could deliver gene therapies to shut down VEGF production. All right? And this was around 1998, 1999. One of the things I always did, and I was at that time a resident in ophthalmology, and I had just decided not to get my PhD. All right? What I learned was that if you could silence a gene, for example, VEGF is a gene, then you could actually stop the production of VEGF in the Boston area. At that time, there was a person, he's a Nobel Laureate now, but his name is Craig Mello, and he was working on something called antisense oligonucleotides. And I knew a lot about that stuff, you know, I mean, because we had been working on, instead of Avastin, one of my friends was working on something called. From a company called Hybridon, which was an antisense oligonucleotide When Craig came out with this new concept, I forgot which journal it was, but I read it. It goes, he could silence a gene with a double stranded rna. You know, I said, wow, that's something. Okay. And so at that time, I was in transition. I was moving into the faculty of molecular biology and gene therapy to work with Gene Bennett, Jim Wilson, the founders of gene therapy over at UPenn. And I had just gotten assistant professorship, et cetera. I was also doing my Retina fellowship at the same time, running an NIH funded lab, all that kind of stuff. But this concept was very, it was very prominent in my head. So what I did was I wrote an algorithm. Well, it wasn't really an algorithm, it was a sort of an AI bot, I call it, that could search down and try to find out how to make these double stranded RNAs. And what was the trick? What was the key to silencing genesis?
And of course, you know, my AI programming abilities from the 80s. Really, nobody was using anything with AI or programming at all. So nobody knew how to march down the gene database. Right. You know, it's very easy. You go look at a sequence and then you know, voila. You know, you can have a computer do a simple program and you can find the uranium develop. Yeah, yeah. Also, VEGF is only 165amino acid length. Wow. Yeah. So hello, you multiply that by three and that's what you have. And you know, a simple program to march down that and look at all the different sequences that that potentially could. And then you put in. So another inventor of RNA interference was a guy named Tushel from Rockefeller. And so he had developed these heuristics about double stranded RNA plus. I was the master of vegf. So what the heck, you know, I put two and two together and I invented the first RNA interference drug called Bevisirnib. And at that time I had another mentor. His name was David Guyer. And he founded a company called iTech. And he founded that company based on my research.
[00:21:10] Speaker B: Oh, really?
[00:21:10] Speaker A: Yeah, yeah, yeah, yeah, yeah. So I did all the research on vegf and he founded this company to, to have an anti VEGF injection in the eye. And he did very, very well. Now Dave is currently the chairman of my board of my current company and he actually showed me the way, actually he was a chairman of NYU Ophthalmology. He was a very strong academic, he had done lots of clinical trials. Very, very famous. And he decides to jump into biotech. Imagine that. I mean, and he does very, very well first of all, he has a launch of Macugen, which is the first anti VEGF drug, and the sales went off the roof. He then sold the company to, again, osi, and he partnered with Pfizer. I mean, my goodness. I watched him take the data that I produce. Convert it into a therapy.
[00:21:53] Speaker B: Yes.
[00:21:54] Speaker A: And then make a lot of money.
[00:21:56] Speaker B: Convert the therapy into money.
[00:21:57] Speaker A: Right, right, right, right.
[00:21:58] Speaker B: Exactly, exactly. Winning all the way. All the way down. Yeah.
[00:22:01] Speaker A: If I hadn't seen that, I would still be a professor at uc and I would be probably tenured and I'd probably be in all these committees and I'd probably be running the NIH or whatever. I don't care. Right.
[00:22:10] Speaker B: I'd be sitting in a lot of.
[00:22:11] Speaker A: Boring meetings watching Dave Guyer. I mean, he is the vibrant individual I know, and I know him a lot because he showed me the way.
[00:22:19] Speaker B: How did you find him, Mike?
[00:22:20] Speaker A: Oh, no, he found me.
[00:22:21] Speaker B: Because he found you because of your anti VEGF stuff.
[00:22:24] Speaker A: Oh, of course.
[00:22:24] Speaker B: Okay. That makes sense.
[00:22:25] Speaker A: Tony Adamus and Joan Miller. All right. Were his generation. And also Sam Patel, who was the co founder, was also the generation of fellows that were with Tony Adamus and Joan Miller. All right. And so they sort of, like, knew each other, and they knew that we were doing wonderful things, et cetera, et cetera. And. And lo and behold, that's what happens. And that's why he actually found us, not the opposite.
[00:22:47] Speaker B: There's a lesson there. Maybe it's not that helpful to people, but if you are quite good at something, you will attract people who are interested in whatever that thing is.
[00:22:53] Speaker A: Absolutely.
[00:22:54] Speaker B: Somebody wrote. If you're a researcher, learning to be a really good writer and a really good communicator is a critical element for your success, which I completely believe. Because if you're not able to talk about the thing you're developing expertise in, I think this applies well beyond science. Then those people who could find you are gonna. It's gonna be harder for them to discover you and discover your talent.
[00:23:12] Speaker A: Balance.
[00:23:13] Speaker B: And so you guys can.
[00:23:14] Speaker A: Absolutely.
[00:23:14] Speaker B: Okay, so then were you like, okay, I'm gonna go do that now?
[00:23:17] Speaker A: That's exactly what I did.
[00:23:18] Speaker B: Yeah. Yeah, yeah.
[00:23:19] Speaker A: Exactly what I did. All right. And what's interesting is that what I realized was that I have a business background, but not really. Really. My strength is that I'm an innovator in terms of science and research. That's my background. So what I decided was that you needed to find somebody like Dave Geier. Okay. Because he's not the scientist. He's just the one who can vocalize or express or actually pitch or sell the idea to people who have money. Correct? Right. I mean, in academics we're told to do that because, you know, we have to talk in front of patients and to raise money and donations, et cetera. Right. At Harvard, that's the big thing. If you're like a chairman of the department, that's what your skill is. Now, that skill didn't come naturally to me, mainly because, as I told you, I did have many friends as a child and I wasn't very vocal at that time. My mentors also, except for Judith Open. Elliot Burson was not a very good speaker. He couldn't explain things very well. My dad was very difficult in the explaining things. You know, Charles Keppens was fantastic. So I realized that I needed to either develop my skills in terms of expressing myself and telling the story like Charles Cappens did and Dave Guyer did, et cetera. Right. Or I had to find somebody who could do it because it's moving too fast.
[00:24:29] Speaker B: You are a communicator. So you chose that other path.
[00:24:32] Speaker A: Well. Well, exactly. Well, I eventually developed it, but at that time, asked my wife, newlywed wife, she said, you can't give a speech for beans.
I'm telling you, you know I love you.
[00:24:42] Speaker B: And I'm still telling you this. Ye.
[00:24:44] Speaker A: She's a psychiatrist, by the way, so she knows a thing too, about expressing herself. And she would always comment on how I couldn't express myself very well. She'd also read my papers and what I'd write. And she says, my God, it's so boring. And I'm going, it's science. How could it not be boring? Okay, so it's taken a long time, but I've learned, I've learned the skills. But when I started Acuity, a grad student, his name is Sam Reich, he had just won the. He had second place in the Wharton Business Plan competition.
[00:25:12] Speaker B: Competition.
[00:25:13] Speaker A: He was a grad student in our lab. He also had a very strong knowledge of RNA interference. I mean, in terms of the nitty gritty of doing RNA interference. So I made him my co founder. He sort of became somewhat of a spokesperson eventually. Then I recruited a really seasoned CEO. His name was Dale Post. And Dale actually was the CEO of Oxford Glycosciences and Orchid Biosciences. You know, he a serial entrepreneur and actually I convinced him to become the CEO of my company by cold calling him and just trying to pitch him the best I could could. And it was because of Dale, that I actually honed my skills.
[00:25:46] Speaker B: He encouraged you to or. What do you mean?
[00:25:48] Speaker A: No, no, no, no. He forced me to.
[00:25:49] Speaker B: Okay, okay, there you go.
[00:25:50] Speaker A: Yeah. So he realized that I had certain skills in terms of networking, so it would just be an easy refinement to make me a better pitcher. So what he did was, you know, he would set up these meetings with venture capitalists. One week, I did 52 VC pitches. All right?
I did it all by myself. And Dale would sit in the back of the room and take notes, and then he would just tell me, you sucked. You sucked.
You should have done that. Yeah, yeah, yeah, exactly. Now, my ego was really bruised at that time, but I learned from the master.
[00:26:21] Speaker B: And you got a lot of at bats in a short period of time, right?
[00:26:24] Speaker A: Exactly. Yeah, yeah. And practice makes perfect, right?
[00:26:26] Speaker B: Yes.
[00:26:26] Speaker A: So eventually my pitch got really good and I was able to raise money, you see, and it's all about telling the story. And that's how we started. I had all the other skills, by the way, you know, in terms of drug development and all that kind of stuff, because I had already watched since I was a kid developing all these things.
I grew up with it. So what I needed to do was enhance my other capabilities. And so I think I've done that.
[00:26:49] Speaker B: I completely agree with that, having spent time listening to you speak in front of a group in our conversations. I concur. You have absolutely done that. Were you that analytical about it, or is that a story that is only obvious in hindsight to you?
[00:26:59] Speaker A: I'm always analytical. My mind always analyzes everything.
[00:27:02] Speaker B: So what is the gap that I have? I have a gap around this.
[00:27:05] Speaker A: Yes, yes, yes.
[00:27:06] Speaker B: And I'm going to work on trying.
[00:27:08] Speaker A: To close that gap I've always lived by. You have to work on your weaknesses and enhance your strengths.
[00:27:13] Speaker B: Yes.
[00:27:13] Speaker A: All right. And as I told you, I'm relentless when I comes to work. You know, I'll work and work and work to accomplish something, including improving a skill, especially my weaknesses.
[00:27:22] Speaker B: Yeah. Okay, great.
[00:27:23] Speaker A: I'm an expert skier, but I am a terrible surfer.
Okay.
[00:27:28] Speaker B: There's only time for so many things.
[00:27:29] Speaker A: I get it. I get it. So I tried to become a surfer, but I realized that it was a skill that was not important.
[00:27:35] Speaker B: Yeah. Not sufficiently important to you. Right? That's the.
[00:27:38] Speaker A: Exactly, exactly.
[00:27:39] Speaker B: That's the math that one should be dealing with any. Any of these things.
[00:27:42] Speaker A: I'm not going to be a world class surfer or anything like that.
[00:27:44] Speaker B: Yeah, you can probably get pretty good at most things.
You're not going to necessarily win the Olympics. Right. You can probably get pretty good at lots of things, but you can't get pretty good at everything.
[00:27:52] Speaker A: Not everything. You have to make your choices and what's important to you.
[00:27:54] Speaker B: So. Okay, I love that. All right. So the challenge in our conversation, of course, is that there's too many things that I want to talk about, so I'm going to fast forward.
[00:28:00] Speaker A: Okay.
[00:28:00] Speaker B: You told a story to me that I really want you to hit on, which is how you came up with the original insight around Aviceda. You read a journal, an article in a journal by a guy in Ireland, and you thought, this is intriguing. Tell that story, would you?
[00:28:13] Speaker A: What.
[00:28:14] Speaker B: What happened?
[00:28:14] Speaker A: Sure. So I'll tell you the beginning of this story. First, though, is that one of my childhood teen mentors was a guy named Charles Janeway who invented discovered the innate immune system. He was credited in 1997 for describing the toll like receptor. In 2002, he wrote an article in Science that postulated that the way to control immune cells and the immune system was through a computer code that was written in sugar. All right? He had postulated back then, he quoted the work of Ajit Varki from UCSD that sialic acid, a sugar that we know is ubiquitous in all vertebrates and all human life forms, is the true checkpoint ligand for immune cells. And Ajit varki in the 90s, discovered a family of receptors called Siglecs. These family receptors, siglecs are the largest family that contains something called the itim itam domain. What this does is itim domain, actually is found in PD1, PD L1, which is the target for Keytruda and most checkpoint inhibitors. So you have here one checkpoint inhibitor, which is like Keytruda for PD1. And the family is only one. It's a special form. All right? The largest family that contained this sort of checkpoint pathway is the siglecs. And siglecs only bind to sialic acid. So this was postulated back in 2002, before Charles Janeway passed away from cancer. And it's stuck in my head. The problem is, is that, first of.
[00:29:38] Speaker B: All, it's stuck in your head because maybe this is an operating system.
[00:29:41] Speaker A: This is the language that I have to decode.
[00:29:43] Speaker B: This is the language I have to decode.
[00:29:44] Speaker A: Think of it like Charles Turing. You know, how he decoded the Naz. Yeah, yeah, yeah, yeah, yeah, yeah.
[00:29:48] Speaker B: Right, right.
[00:29:48] Speaker A: Well, that's exactly what this was. Right? Here's my challenge. My challenge is to decode the immune system's military code that commands it all right, so there I go, I start reading all about siglecs and all about sialic acid, et cetera. And then there was a paper where Carolyn Bertozzi, I think it was in 2001, 2002, this is the source of her Nobel Prize. She actually linked sialic acid to a polymer using bio orthogonal chemicals. Chemistry. Look, I'm a nerd. I know all this stuff, right?
So I was starting to see pieces coming together. All right. But it's still very difficult. I mean, you know, here you have. First of all, let's say I decipher the code. How am I going to instruct the immune system? Right? So first thing I did was I tried to find proteins and I did find a couple proteins. One was something called pentraxin 3. That is the source of. There's a drug that are common in Pentaxan 3 from Probiotor that I helped work on, et cetera. Yes. And I thought that's the way to do it. You have to find these naturally occurring proteins that carry sialic acid and then I can make them recombinant form and then I can, I can use them to treat disease. Yes. Well, come 2015, I read this science translational article. I mean science translational is a good journal. It's not the top journals that I read, but there's this paper that shows that you can decorate a nanoparticle with sialic acid and you can abrogate a sepsis. So this is Chris Scott's lab at Queens Belfast, and he was the head of the Patrick Johnson Cancer Center. So I went to Carolina Lortozzi, I went to Jim Paulson. I asked Jim and Carolyn, well, what do you think about this stuff? They go, eh, it's probably not real. It's too good to be true.
[00:31:20] Speaker B: Too good to be true.
[00:31:22] Speaker A: Yeah, yeah, yeah, yeah, yeah. When I get this from a would be Nobel laureate and the head of molecular medicine at Scripps. Yes, you go, there's something there. All right. And so what I did was I set out to replicate his experiments, you know, on my own dime. And we did that and we showed that even with my poor replication, it worked. It worked, it worked. Yeah. Now this was in cell culture. I didn't go all the way to like sepsis model, but because census models are very difficult come by very expensive. So from that I decided, well, okay then this is something that has teeth and legs. Now at that time, hold on, I.
[00:31:52] Speaker B: Want to, I want to unpack that a little bit more. So what you did there, there are two big insights there. The first one is, first you went to some mentors, world class mentors, and said, what do you think about this? And then the fact that they were dismissive didn't cause you to say, no, that's maybe a little bit of contrariness that you have always, you know, well, we don't know that it doesn't work, work. But then you knew what your next step was, which is to go and figure out if you could test it. And then you built a simple test. Right. That's another important point, so that you could do it efficiently and prove to yourself that the core mechanism worked. And once you had proven that to yourself, okay, we probably have something.
[00:32:25] Speaker A: Is that right? Yes. Plus it goes back to the basis of, you know, understanding the native immune system.
[00:32:31] Speaker B: Yes.
[00:32:31] Speaker A: If this was going to be the proper way, it would have to fit into my whole scheme that developed by the broader scheme developed by Ajit Varki and also Charles Janeway. All right, once that does, the picture just came all together.
[00:32:46] Speaker B: Yes.
[00:32:47] Speaker A: It's the same thing with vegf. Look, vegf, I had been told this theory in the dinner table forever as a kid.
[00:32:53] Speaker B: Yeah.
[00:32:53] Speaker A: And then in a cancer lab, I look at it and go, oh, my God, that's vegf.
[00:32:58] Speaker B: Yep.
[00:32:58] Speaker A: That's factor X. Okay. Same thing here. You see, I've been looking for this. Finally somebody shows me that it's possible.
So I go back and I look at all the research I had done on decoding or deciphering the language, you see, and I took that concept and I created using my programming language that I had deciphered and placed it onto the nanoparticle that is now being used in geographic atrophy patients with Mac degeneration. So that's the whole concept.
[00:33:28] Speaker B: Yeah. Fantastic. So when do you call Dr. Scott and tell him, hey, did you talk with him before you run the experiment or when?
[00:33:35] Speaker A: Oh, of course, yeah, yeah, yeah, yeah. I did it all with him because that's why we decided to license his technology, because nobody else liked it, you know, nobody else was looking for it, you know. Right. And he even got the whole patent because nobody knew what nobody else was trying. Nobody else was trying. Nobody else knew what this was about.
[00:33:51] Speaker B: That's fantastic.
[00:33:52] Speaker A: So guess what? It's novel, but yet it's not novel. You see, if Charles Janeway was still alive, he would say that obviously what it's supposed to be, you understand?
[00:34:00] Speaker B: So do you think that was it just sort of lucky in a way that he was in Belfast, he wasn't at MIT or something like that? Or was there some reason that it was off that no one was picking up on? I mean, you said it was in a fine journal, but it wasn't in nature or something like that.
[00:34:14] Speaker A: Yeah. So there is an issue with developing technology that actually is deemed towards therapy. It's actually looked.
It's not cool.
[00:34:23] Speaker B: Yeah. It's not as sexy as fundamental.
[00:34:25] Speaker A: I'll tell you my own example. I wrote sixth grade grants when I was developing a bevisarnib, et cetera. The biggest one. I was about to get something called an R01. All right. For bevisernib. I got a very high score. But the study section told me that I shouldn't be looking into developing a therapy. I should be looking into using my technology to understand R2D2 protein and the risk complex. So if I wanted to get this grant, I'd have to rewrite it with different mission statements. Same experiments, but different mission statements. And that's when I decided I'm going to just leave. And that's what I did. Did. I left. I went to, you know, sort of the biotech world, other side, the dark side, et cetera, et cetera. That was actually a big decision for me in particular was that if I was to stay in academics, I would never be able to develop a therapy. Now, remember the Vastin story? You know, the funding for those experiments was not from the government.
[00:35:15] Speaker B: It was private sector funding.
[00:35:16] Speaker A: No, no. It was a foundation called the Lions Eye Institute. I see.
[00:35:19] Speaker B: Of course.
[00:35:19] Speaker A: Yeah, right. The Lions foundation was the sole benefactor for those experiments. Nobody, except for maybe Pat, had an NIH grant. So Tony and Joan did not have NIH grants until after we had discovered this whole thing. We were all doing all the experiments based on material transfer agreement from Genentech and from alliance foundation grant. Also we had another small grant, I think departmental grant, et cetera. But this was not the nih.
[00:35:41] Speaker B: That's fascinating. You know, you said something a second ago that. That scientists will often say referring to commercial world of biotech and pharma as the dark side.
[00:35:49] Speaker A: Yeah. Will you talk a little bit about that?
[00:35:50] Speaker B: You made that choice to come over. Why is it the dark side to try and develop treatments that are actually going to heal people.
[00:35:56] Speaker A: It's something called purism. I went into research to develop therapies. That's why I'm literally only an MD. All right. I'm not a PhD. But when you. You go to the hallowed halls of phdum, I guess I call it.
[00:36:08] Speaker B: Yes.
[00:36:08] Speaker A: They're trying to produce people who look like them, you understand? And the purist, it's like being orthodox, anything, you know. Right.
[00:36:16] Speaker B: Yes.
[00:36:16] Speaker A: It's the religion of science. And the orthodoxy of that is determined by the high priest priests. So who are the high priests in science? Well, they're the Nobel laureates, they're the chairs of molecular biology departments, they're the heads of the nih, the heads of the nei, you know, all that kind of stuff. Right. They're the ones who are deemed high enough in stature to actually dictate where science goes. And this is the problem. I've been in that world and this hierarchical world where the top person tells you what science you can do.
[00:36:47] Speaker B: Yeah, right.
[00:36:48] Speaker A: And I told you I studied organizational behavior to avoid that. Right.
[00:36:52] Speaker B: That's not a good way to do it.
[00:36:53] Speaker A: Yes, it's the worst way to do it. You're not going to create anything.
[00:36:56] Speaker B: Right. There's this sense that because those are non commercial people and ventures, universities, that they're part of government granting agencies, etc, that they are disinterested and pure in some way. And ironically, every, everybody, actually, everybody wants better treatments for patients, including themselves and their family. Sure, of course. It's just funny to me. I've worked in a few different industries and I've never seen such a largely virtuous industry that is referred to as the dark side by some of the people who are tangential practitioners.
[00:37:25] Speaker A: Well, the other thing is this, all right, Is that when you study biology, what you want to do is you want to unravel technology.
You want to understand the inner workings of life in general. Correct. That's what scientists do. The issue is that in your search for a more complex way of doing things, things, for example, gene editing. All right, we'll talk about gene editing. Gene editing is not a physiologic situation. We got this from bacteriophages, you know. Right. And even RNA interference is sort of a tool that is, you know, I used it as a therapeutic, but it's not the optimal therapeutic. Why? Because it's an intracellular situation. And one of the biggest problems with delivering any of these gene therapies or regenerative medicine therapies is that you can't get it into your target cell.
[00:38:15] Speaker B: You gotta get to the right spot.
[00:38:16] Speaker A: And that technology is, you know, who controls that technology? Right. Viruses and pathogens. So what you're actually doing is you're weaponizing biotechnology. That's why you develop these things. You know, it's like it's a weapon against Disease, but we don't want a weapon against disease because weapons are destructive overall. Right. What you need is something physiologic, and that's why translating a code and shutting down immune cells by their own language is better than shooting bombs at them. Them. I mean, again, philosophically, in the world, you'd rather stop a war by diplomacy rather than blowing up the whole country.
[00:38:52] Speaker B: Well said. Well said. I think we're going to stop part one here.
[00:38:56] Speaker A: Okay.
[00:38:56] Speaker B: Because we have. I have tons of other things I want to talk to you about. And we're going to continue with a second part of the interview with Mike Tolentino. So if you're listening, stay tuned for company building and leadership and the future of biotech, part two of our conversation.
Welcome, producer Ash Adam.
[00:39:15] Speaker A: Thanks, Chris. Really enjoyed listening to Mike. I guess I want to start off with his quote, you have to look at other fields besides your own to develop wonderful things. How important is a different perspective in realizing clinical research?
[00:39:27] Speaker B: Yeah, I think that's a fantastic quote. First of all, thanks for emphasizing it. I think very important. I think a lot of the most exciting things that happen occur when people bring a new perspective, expertise from a related discipline, et cetera, to bear.
[00:39:40] Speaker A: And.
[00:39:40] Speaker B: And it's hard to do in our contemporary world of extreme specialization. So I think part of what Mike is saying there is, you know, open yourself up a little bit, listen, read, explore, talk with people who are outside of your direct discipline, be curious. And that's pretty good guidance, I think.
[00:39:57] Speaker A: I think so, too. And I notice we have a lot of people on the podcast who talk about their marathon running and some philanthropic works, and I think that that relates to.
[00:40:06] Speaker B: Yeah, that's right. I think having your brain stimulated in different ways, probably a plus for most of us.
[00:40:10] Speaker A: Us very cool. In talking about some of the new innovations, I noticed that a lot of them are based on older research or underdeveloped trials. When did this become such a fertile ground for biotech?
[00:40:21] Speaker B: Yeah, I think it's been fertile for a while. Obviously, if something has gone to the clinic and its safety profile is understood, but it didn't prove out to be efficacious for whatever the original condition was. That's a very interesting place to start. If you've got a thesis for how to apply that, you know that IP in some other way. I think the challenge is finding those opportunities. And that's again, comes back to this point that Mike made about reading lots of journals and just kind of chasing down leads. He told us an exciting story about one Discovery. But we can assume. I probably should have asked him. I think we can assume that there were a whole bunch of things that went nowhere, probably lots and lots of them before you find gold this way.
[00:40:59] Speaker A: I believe that. I really do. So I want to say that a lot of our previous guests explored computer science before it was cool. Have technology and fun funding always been the key factors in a biotech success?
[00:41:11] Speaker B: You're absolutely right. I do think this is a theme that some people who got interested in computer science and all the sort of direct math related disciplines early seem to have an advantage right now. We can figure out what's going to be really, really useful in 10 years. Might not be the most actionable advice that we can provide, but I do like this idea that many of our innovators that we have on the program have not had a strong straightforward path where they just went from climbing the rungs of a straightforward ladder in biology, but instead did work in computer science or tried to become a professional basketball player or whatever other thing that they might have done in their journey. I think it makes them probably more interesting people on average. And that exposure to other disciplines, other ways of thinking, I think sometimes helps you to see connections that maybe folks who have not done that can't see.
[00:41:58] Speaker A: On that topic, one of the things that Mike talked about was about how many academics see the biotech world, world as the dark side. How do we get those two teams to work together?
[00:42:08] Speaker B: Yeah, I still find that shocking. And we hear it pretty often. We hear people say versions of working for a commercial entity is coming to the dark side. When of course, you know, the people who work in biotech, we know lots and lots and lots of them and they are generally mission driven people and they are using the tools of capitalism to develop treatments for disease. What higher purpose could capitalism serve than that? I can't think of one. I think some of that is about biotech entrepreneurs telling their stories and coming back to campus to meet with academics and students and talking about when it makes sense for an innovation to come out of academia and into company formation and capital raising. You just really can't do the things that most of these entrepreneurs want to do within the confines of academic institution that you just can't raise the money. So absolutely not the dark side. There are of course dark individuals, but I don't like that term of a dark side.
[00:42:58] Speaker A: Yeah, I could understand that. I just have one final question. I wanted to talk about Mike's eureka moment, just about his sugar study that he replicated from an experiment From Chris Scott at Queen's University in Belfast. It's just an amazing story.
[00:43:13] Speaker B: Yeah, I completely agree. And there are a few things I took away from that. First, this was an article in a good journal, but not the top journal in his field. Chris is at a very good university, but he was not in the United States. He was not at Harvard or someplace like that. And the results initially looked too good to be true to Mike's mentors. Mike's response to that was not to say, well, then it must be nonsense. I'm just going to ignore it. But to say, wow, then if it is true, it's a really big deal. So what did he do? He then went out and replicated the core finding, you know, in his own lab and validated that there was really something there and then had the confidence, confidence in his own work to then go and pursue it. And I think he was motivated by the fact that he had talked to, you know, true world class leaders, including a future Nobel Prize winner, and they had been a bit dismissive of this as probably not, probably not real, too good to be true. Right. So there's a great lesson there that if you see something interesting, don't blindly accept it. Go and figure out how you can validate it. And if you find that it's real, you know, double down and double down hard. And that's for sure what he did.
[00:44:12] Speaker A: Very cool. I guess we're ready for part two later this month for sure. Yeah.
[00:44:16] Speaker B: Another exciting jump into Mike's creation career. Thanks, Adam.
Thank you for listening to the latest episode of Few and Far Between Conversations from the Front Lines of Drug Development. Our podcast is now available on Apple Podcasts and other streaming services. Please take a moment and leave us a user review and rating today. It really helps people discover the podcast and we read all the comments. Those comments help us make Few and Far Between Better and better. Also, be sure to subscribe to Few and Far between so you don't miss a single, single episode. Got an idea for a future episode? Email us at fewandfarbetweenrossi.com or contact us on our
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