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#257 - 🔬At The Bench - When serendipity drives innovation






Hello Friends 👋

In this engaging conversation, Dr. Emin Maltepe shares his journey as a neonatologist and physician scientist, discussing the serendipitous events that shaped his research interests, particularly in hypoxia and drug development for neonatology. He reflects on the importance of mentorship, the challenges of drug development in pediatrics, and the MD-PhD pathway, providing insights into the complexities of balancing clinical practice with research. In this conversation, Emin Maltepe discusses his journey through the MD-PhD program and how it shaped his career in pediatric drug development. He highlights the significant challenges faced in developing therapeutics for pediatric populations, particularly preterm infants, and the lack of attention and funding in this area. Emin shares insights into his innovative approaches to drug and device development, including collaborations with global organizations and the importance of using appropriate animal models. He emphasizes the need for policy advocacy and business knowledge in the field of pediatric therapeutics, while also reflecting on the personal challenges and rewards of balancing family life with a demanding career.


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Resources mentioned in episode:







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The transcript of today's episode can be found below 👇


Betsy Crouch (00:02.488)

Hi, everyone. Welcome back to the At the Bench segment of the Incubator podcast. My name is Betsy Crouch. I'm a neonatologist physician scientist at University of California, San Francisco. I'm thrilled today to be co-hosting with David McCully and interviewing Dr. Emin Maltepe, who's been one of my mentors and a physician scientist who's doing a lot of super cool work. And even as we were prepping for this interview, I got really excited.


Without further ado, David, would you introduce yourself and then move on to Emin?


David (00:36.336)

Sure, thanks Betsy. I'm David McCully. I'm a neonatologist and physician scientist at University of California in San Diego and Rady Children's Hospital. I am very thankful to be involved in this program and I agree I'm really excited to talk with Emin today as well. He was just a little bit ahead of me in neonatology fellowship at UCSF and I get to see him at meetings periodically and touch base and I'm really excited to hear just like how his research interests have changed over time and


what's motivating him these days. So, Emin, would you mind just introducing yourself and then we'll start asking some questions just about your background and research interests and things like that.


Emin Maltepe (01:18.687)

Of course, first off, thanks for having me, you guys. I really love what you guys are doing here. And so it's really exciting to be a part of it. And since we all go way back, this is also doubly fun because we get to just catch up on stuff. But I'm Emin Maltepe, as you mentioned. I'm also, oddly enough, a neonatologist, physician, scientist, which I think may have been by design.


Betsy Crouch (01:36.942)

you


Emin Maltepe (01:41.943)

I came to UCSF for all my clinical training, stayed on board as faculty and I've been here a little over 20 years, kind of 22 years total. So definitely stuck with the West Coast San Francisco option. And like you guys mentioned, in addition to just the clinical work in neonatology, I've been wearing a lot of different hats, pursuing a lot of different directions, going all the way back to basic genetics and stem cell biology and mouse models.


to all the way to now, we're really trying to push sort of the limits of drug and device development for pediatric indications generally, but really focus more on neonatal and maternal fetal medical indications. So that's kind of where life has brought me to today. So happy to dive into any or all of that with you guys.


Betsy Crouch (02:33.666)

Yeah, thank you for giving us the overview. I think we'll start from the very beginning, and not the very beginning. I'll say that Emin's given me a lot of of career advice on rounds. I was a fellow with Emin. But I think we'd love to hear a little bit more specifically about how you chose to be a neonatologist and about what initially led you to your research interests.


Emin Maltepe (02:40.801)

Cool.


Emin Maltepe (03:00.287)

Yeah. So, you know, like, like you guys, did an MD PhD. I was in the Midwest. I was at the university of Chicago. And one of the things that got me really excited when I was kind of trying to pick a lab was ultimately really gene knockout technologies were just coming on board back then. there are very few centers that could do it. And there was an investigator at UCSF, I mean, sorry, at university of Chicago, and the Howard Hughes Institute, Celeste Simon


who was really like at the cutting edge at that point of doing a lot of these gene targeting and knockout technologies. And I just kind of immediately knew that I wanted to get involved with that. And I didn't really have a great idea of what question I wanted to ask. It just seemed like, you know, a new era was opening in biology, enabling us to really get at the genetic underpinnings of anything, basic development or pathophysiology. So I just, I just felt like I wanted to be, I wanted in.


I like, didn't really know what I wanted to do with it. I didn't know what field I wanted to go into. So I did the, you know, it's typical MSTP of tracks. And so we did two years of medical school, and then you kind of dive into your graduate work, coursework as well as lab work after that. And then you go back to the clinical. So I really didn't know what kind of clinical area I wanted to get into. but so I got in.


I started working with Celeste and that lab and that group was primarily in cardiology, even though she did a lot of work in Heme/Onc And I ended up entirely serendipitously. And I think this is going to be what really defines key aspects of my career choices is serendipity. There's a lot that chance plays in terms of what you do with your life and how it ends up.


and it's whether or not you're kind of, you know, prepared or interested in taking advantage of those opportunities when they present themselves. But we did a lot of work. Our group was in cardiology. It was led by people like Jeff Leiden, who then went off to major leadership positions in industry. But I ultimately ended up in sort of a cardiovascular space with my project and the project that I was kind of handed to, was to create the, knockout model, the first knockout for the.


Emin Maltepe (05:22.049)

hypoxia-inducible factor family of transcription factors. And I say that now, yeah, it literally was where it all began. And again, this is complete getting back to chance and serendipity, Celeste was actually collaborating with a group at Northwestern at the time that was interested in knocking out the gene responsible for...


Betsy Crouch (05:27.31)

where it all began.


I'm sorry.


Emin Maltepe (05:47.671)

sort of a systemic response to environmental toxins that used to be called the dioxin receptor or aryl hydrocarbon receptor. Now it turned out that complex has two parts to it, an alpha and a beta. And she was working with this collaborator, Chris Bradfield at Northwestern on the beta subunit. And it turned out that beta subunit, even though it mediated a lot of the effects to environmental toxins like dioxin, turned out later to be the common subunit for HIF-1 alpha.


So when we started making that knockout, actually didn't think that we were working on HIF or hypoxia or vascular development. Ultimately, this was going to be a project about xenobiotic exposures and its effects on the liver. And so we started doing this project. And I remember, you know, we got actually germline transmission. We didn't have any, you know, embryos yet or mice yet. And right around that time,


A paper came out from Greg Semenza's lab at Johns Hopkins in defining cloning actually HIF-1 alpha. So the protein responsible for hypoxic gene regulation and the University of Chicago where I was like EPO was actually a big area of investigation because Gene Goldwasser was there at the time and he had actually described like he had cloned EPO described it. He was kind of the father of EPO.


Betsy Crouch (06:57.57)

Mm-hmm.


Emin Maltepe (07:13.071)

And everybody at the time was trying to understand how EPO gets turned on by hypoxia. So there was kind of a race on to figure out what the transcription factor was that actually activated HIF. And Greg Semenza, who a couple of years ago just won the Nobel Prize for this work, actually cloned and biochemically purified and showed that HIF-1-alpha was in fact the hypoxia-responsive transcription factor in the liver, the fetal liver.


where hematopoiesis occurs early during development. And at that time, remember Celeste coming to me with the paper, it was a PNAS paper. I remember it like it was yesterday. She just puts it on my desk and walks away. And I started looking at it, I'm like, my God, this is what we're knocking out. And I literally said to myself, and again, I really didn't understand much medicine or biochemistry or physiology at the time. I was like, hypoxia? What am I gonna do with hypoxia?


Betsy Crouch (08:09.198)

30 years later.


David (08:09.706)

Ha ha ha.


Emin Maltepe (08:10.007)

And that's literally, yeah, I mean, that's literally kind of how I backed into the hypoxia field. and it's been nothing else ever since. It's just like, obviously hypoxia touches everything. So we, I was like, all right, so we're going to pivot now and really talk about hypoxia. And part of the thing that happened is as we started figuring out the phenotype of the knockout, it was readily apparent that it was.


embryonic lethal, which is not something we were prepared that we thought was going to be the case. And then once we started looking at why it was embryonic lethal, it was clear that it was a vascular phenotype. And it was this idea, and it was known at the time that hypoxia turns on things like VEGF, you know, to help promote tumor angiogenesis. And so it became very clear that hypoxia wasn't just purely a pathological insult. It's something that happened in utero that regulated where blood vessels go, how they pattern during the embryonic growth.


David (09:04.41)

Yes.


Emin Maltepe (09:09.543)

And so that concept, know, those set of experiments and putting all those concepts together really led us to propose the idea that oxygen was more than just a substrate for metabolism, but it was actually a morphogen. Right? So that ended up being like my defining aha moment in the lab. And then trying to, and then as I sort of thought about the implications of that,


The idea being that the hypoxic environment and utero helps pattern normal development. Well, if you come out of that normal environment early as a premature infant, and now you're breathing air, which has a lot more oxygen in your lungs do a way better job of oxygenating your blood than your placenta, you're like hyper oxygenating all your tissues and you're affecting vascular developments and it turns out other things as well all throughout the fetus.


And that's probably why we have a lot of the pathologies that we see in the NICU. And we know that's the case for stuff like for ROP or retinopetiturity. And it's probably the case for like things like BPD and probably plays a role in NEC and probably plays a role in IVH and probably, you know, like it probably touches so many things because oxygen touches everything, right? So that was kind of the ah-ha. That's, that's kind of how I got into neonatology. And then I was like, I got to do neonatology. And I, you know, finished med school and applied for PETES.


Betsy Crouch (10:21.356)

Yeah, I mean, I think you were the...


Betsy Crouch (10:30.754)

Yeah, that was a really impactful story. And I'll say that I think you were the first person to explain the support trial to me in a way that I found exciting and intriguing and kind of troubling. And I still do. I think the way that different institutions interpret the results of that trial are different.


David (10:54.511)

Yeah.


Emin Maltepe (10:54.839)

Well, yeah, and I mean, that touches on, yeah, the whole reason why I got into neonatology, was like, well, I can bring all this insight to neonatology and change practice. Like we understand how important oxygen is. We just got to give less oxygen to preemies. And obviously as I went through fellowship right around that time is those studies were starting to come out. And some of the early data was promising, but then some of the later bigger studies suggested that it was problematic to have like a physiological hypoxia in


Betsy Crouch (11:09.006)

Mm-hmm.


Betsy Crouch (11:17.966)

Yeah.


Emin Maltepe (11:23.735)

preterm infants in that even though the primary endpoints of ROP were improved, it was clearly improved. Like there was less ROP and there were clear trends towards less like chronic lung disease and BPD. The in-hospital mortality rates were like surprisingly elevated. And it turned out that they were primarily in, you know, growth restricted infants. And if you were to do the studies again, you could potentially exclude those infants, but it ultimately turned out, what's that?


Betsy Crouch (11:51.064)

What do you think is the mechanism?


Emin Maltepe (11:54.967)

Well, I think the issue and I think ROP is a great way to kind of think about it because ROP happens in two phases. There's like phase one where you inhibit vascularization. And then you have the phase two where you get the hypervascular, more pathologic angiogenesis response that ultimately causes the problems of ROP. And, you know, I have a good friend of mine who's at Cleveland Clinic. He's an ophthalmologist, foremost ROP, you know, physician scientist, John Sears.


And he did like a retrospective study basically where they looked at kids that were left with a physiological hypoxia up until about 28 to 30 weeks. And then increase your O2SAT goals. Kind of mirroring exactly the transition from phase one to phase two ROP. Because really in phase two ROP, you get too much HIF and too much VEGF because the retina gets really hypoxic. And so you kind of want to avoid


David (12:41.562)

Mm-hmm.


David (12:49.924)

Yes.


Emin Maltepe (12:52.349)

activating HIF in that phase two, but you want to activate it in phase one. So you could, you could essentially do exactly the same set of studies that were done, but do it time limited. So you had all preemies born before whatever gestational age have a physiological hypoxic, you know, set point up until about 20 to 30 weeks. And then you increase the O2 sats. And I think that would actually work. Like I think that would decrease ROP, would probably decrease chronic lung disease BPD, probably decrease the incidence of some of the other


David (13:15.662)

And you too.


Emin Maltepe (13:22.487)

pathologies, but nobody's going to touch that study. Nobody, and there's no, I mean, that would be a big lift to ask a hospital to kind of try to do that study.


David (13:26.266)

Yes.


Betsy Crouch (13:34.562)

And sorry, why did the SGA or IUGR babies have the, okay.


Emin Maltepe (13:39.327)

Not clear. So that part's not clear. So if you actually let them see more oxygen sort of after 28 weeks or so, would they have succumbed to death? We don't know. It's not really clear. So anyway, that was really disappointing for me. I was like, my God, know, everything I went into this field to do has come crashing down. However, over this time period, there's been development of sort of pharmacological ways to activate HIF.


Betsy Crouch (13:50.402)

Mm.


Betsy Crouch (13:58.251)

ahem


Emin Maltepe (14:09.195)

Like if we're saying you need hypoxia because you need HIF, which is clearly one of the main reasons you need the hypoxia is to turn HIF on. There are drugs out there that are actually now FDA approved in adults to turn on EPO in the setting of like renal failure. So people who are normally injecting themselves with EPO, there's now an oral drug you can take that activates HIF to turn on EPO. And so one...


And I can't disclose a whole lot more because of NDAs and whatnot, but there is one company that's interested in looking at this as a drug to give to premature infants to prevent ROP. And so that's one, that would be like one great extension of the work that I've been on is to try to get this compound into, you know, start with a phase one trial, figure out all the dosing, do the safety and toxicity, make sure it's, you're fine to do it.


and then move into later stage clinical trials. So that development path actually exists. Whether it'll actually happen or not, I don't know. mean, this is part of it. My big sort of, you know, I've switched from hypoxia as my soapbox to drug development for neonatology as my soapbox topic. And so this is really, I hope it will happen, but there are no guarantees. I mean, this.


Betsy Crouch (15:26.763)

Mm-hmm.


Emin Maltepe (15:33.387)

The drug development path in pediatrics in general is something most companies don't want to touch. But ROP might be something that they would be willing to go because it's a very interesting market for a lot of different reasons.


David (15:48.016)

Emin, can I ask you a question just try to understand your like broad motivation a little bit more. I mean you kind of leaped into like genetic knockouts as something that you're interested in studying very early on and that led to this whole pathway. I'm just wondering like why was that attractive to you? How did you think that doing an MD-PhD was going to be something that was you know going to open your career like how start back a little bit further and


Emin Maltepe (16:13.953)

Sure. No, I was, yeah.


Betsy Crouch (16:14.99)

Let me interject because, Emin, you may not know because of David's research prowess, but in fact, David does not have a PhD.


David (16:23.204)

That's right.


Emin Maltepe (16:24.808)

I sort of assumed. Now, 100%.


Betsy Crouch (16:25.166)

Yeah. So I mean, and that's one of the points, right, is that you can do it that way or you can not do it that way. If you don't want to be a student until you're in your early to mid thirties, then there are other ways to get into research as a neonatal physician scientist.


David (16:34.992)

You


Emin Maltepe (16:35.775)

Well, that's exactly right. And I go back and forth. I frequently recommend to people not to bother with the PhD, just get their MD if they're really driven about medical research and really dive deep during fellowship. Because there are lot of ways to support oneself during that period. But getting back to your earlier question, I was very sort of idealistic and really wanted to understand.


Betsy Crouch (16:44.75)

Ooh, juicy.


Betsy Crouch (16:51.148)

Hmm. Hmm.


Emin Maltepe (17:00.971)

you know, I was kind of looking for God in the cell. Like I really wanted to understand the meaning of life and, you know, genetics obviously was exploding in the nineties and really trying to understand the genetic determinants of both development and disease and just really, I mean, you know, not to be overly grandiose, but kind of like the meaning of life. Like I was like, this was fascinating. And that was an area that I wanted to be involved in.


And early on, I wasn't interested in medicine at all. Like as an undergraduate, I was working in a cancer research laboratory led by really one of my all-time great mentors, Janet Rowley, who actually could be credited with the idea that cancer is a genetic disorder. She identified key chromosomal translocations as contributory to


leukemia progression, notably the Philadelphia chromosome, the 922 translocation. That was her, and then she spent an entire career identifying chromosomal abnormalities associated with various cancers. So I was really in this group that was a very genetics-oriented research environment, but with a disease focus. They were trying to cure cancer. And so I got infected with that excitement of...


understanding the genetic origins of disease, primarily cancer, and really working with physicians and kind of tagging along with them in clinics and talking to them about their patients just really got excited about the potential direct human impact of the work outside of just kind of satisifying my intellectual curiosity. And so I got really interested then in doing this sort of MD-PhD track.


And that's what I kind of pursued. So it was really the exposure and being in a cancer lab that got me interested on the MD side. I was always very interested on the very PhD basic side.


David (19:00.248)

as an undergraduate, because I just remembered going to our fellowship review meetings and we would all present our research. And I was interested in heart development and genetics as well. And I felt like I was presenting a very simplistic story compared to yours, because it seemed like your PhD had given you so much more research experience. And it really made me wonder, how am I going to succeed in this environment? And I sort of.


Emin Maltepe (19:03.009)

Yeah.


David (19:28.624)

Went in with the idea that okay I need to learn from PhDs to make progress Because I need to learn how they learned how they are asking questions how they test hypotheses like things like that But it was so clear that your PhD training had given you just a wealth of experience that I always wondered how I was gonna be able to Gain or somehow mirror


Emin Maltepe (19:40.63)

Yes.


Emin Maltepe (19:51.881)

I hear you, it's great training. It's great whether you actually need it to kind of succeed and however you want to define success, right? Like to actually do what you want to do as a physician scientist. I'm not a hundred percent sure. I mean, it's a significant time commitment in addition to clinical training. And there are ways to kind of do your clinical training and research, but you end up forgoing like the coursework of grad school.


Betsy Crouch (20:15.906)

Mm-hmm.


Betsy Crouch (20:19.566)

Mm-hmm.


Emin Maltepe (20:19.573)

which I think is a really great exercise, a really great training path. so you just have to go, you know, it's one of the things that keeps coming up, know, it's sort of like, depending on how long your PhD takes, mine was three years and then actually stayed in an extra postdoc year. So I was out for four years, but it's sort of, it's four, it's, can almost think you're delaying your, your actual paid career by four years.


Betsy Crouch (20:22.401)

Mm-hmm.


Emin Maltepe (20:46.571)

so it is a sacrifice in terms of, you know, your entire career earnings potential, let's say, like if you want to put it as crudely as that, but it's fantastic training. and I think particularly in pediatrics, people who are really motivated to do research can get pretty significant support during fellowship, to do that. And then there's all kinds of funding opportunities, but it's, it's a trade off, you know, you definitely don't get the rigorous.


Coursework and just training of going through a true PhD program. There's no question so it's it's a I mean again, I go back and forth because there's only certain enough hours in the day and years in your life and What's the right this was definitely the track for me. I loved it. I thought it was fantastic training I got super lucky in that I kind of backed into this really impactful project


that I've been able to carry through for the remainder of my career and really apply it to everything that I've touched. And I've been able to touch a lot of different things as a result. So it's been great. So I don't have the right answer. think it's definitely, you everybody kind of needs to make that decision for themselves. But there's pluses and minuses to both.


David (21:59.396)

I mean, you could say that it seems like your undergraduate experience really motivated you to apply for an MD-PhD program, but that put you in an environment that set you up for this serendipitous connection with a great project that now has been in the course of your career very successful.


Emin Maltepe (22:06.955)

Well, for sure.


Emin Maltepe (22:17.269)

Yeah, no question it dictated both my choice of clinical direction as well as all the research thereafter. And a lot of people change the kind of research direction. They get their PhD, but then they go into an unrelated fellowship and do a topic. It still provides you with great training on how to craft questions and craft a research program. But is it critical? I've worked with some people, unbelievably productive physician scientists that


didn't do PhDs. And I've definitely seen people with PhDs not be, you know, very productive or successful or actually just leave and do clinical work, which is again, fine, right? Like, it's not at all judgment. Some people really, really prefer the clinical work after they've gone through like an MD PhD. And some people don't take up the mantle of doing any clinical work and go straight into research or finance, you know, I mean, there's people who go that route.


Betsy Crouch (22:48.011)

Mm-hmm.


Betsy Crouch (23:13.454)

More consulting or biotech?


Emin Maltepe (23:16.587)

Yeah, exactly. mean, that didn't exist. mean, Genentech was just getting off the go ahead and that was this kind of like the only player in town. And it wasn't something that I ever contemplated in med school, grad school or undergrad. Whereas now that's probably where most of the graduate students are heading. Yeah.


Betsy Crouch (23:38.222)

So I'd love to hear, know, spend some time talking more about your experience with pediatric drug development and pediatric device development. Because, yeah, I also am new to this field. But even with somebody who's a relatively new researcher, it's pretty obvious that pediatric disease doesn't receive the same attention.


or funding opportunities from anybody and that feels, what is the word? And that feels inappropriate or a lost opportunity. Thank you.


Emin Maltepe (24:16.727)

Criminal? Let me help you. Criminal might be a word to use. Yeah, well, I mean, this just goes to my, you know, initial impressions of you that you're much smarter than I am. It took me a lot longer than it took you to come to that realization. Honestly, took me probably about like almost seven or eight years as an attending, you know, after fellowship to kind of really sink in that there was just nothing being developed for us.


David (24:17.048)

Lost opportunity. Yeah.


Emin Maltepe (24:46.871)

I mean, if you just think about it, there's only one drug that's ever been developed specifically for preterm infants and that's actually FDA approved. And that was discovered at UCSF by John Clements who just passed away at the ripe old age of 101, absolute leader, and it was surfactant. And that was FDA, the first approval for surfactant I believe was 1989. And there's not been a single drug


Betsy Crouch (25:04.025)

Yeah.


Emin Maltepe (25:14.749)

specifically developed for like, let's say premature infants, that's gone through a drug development path, full clinical trials and gotten FDA approval. Like things like caffeine have been approved for kids, but it wasn't developed specifically. So if you kind of just do the math, there's about 20,000 drugs total that are FDA approved out there. There's only about 20 that are approved for premature neonates, for example, and only one was developed specifically for them.


So it's, I mean, it's criminal if you think about it. On the one hand, it's criminal. On the other hand, it's really a testament to the field of neonatology, how far we've come without actually developing any drugs for our patients, which is crazy. If you think about it, right? Like having the survival rates. And if you thought, if you thought like, if you had a surfactant like drug every five years, where we would be compared, I'm looking at surfactant, surfactant enabled neonatology before then.


Betsy Crouch (26:06.286)

Yeah.


Emin Maltepe (26:12.841)

all these babies were dying from severe lung disease, right?


Betsy Crouch (26:16.686)

Yeah, I love that story too, right? was Patrick Kennedy, right? President Kennedy's son who died of surfactant deficiency as a 35-weeker in 1963. I looked this up recently.


Emin Maltepe (26:24.139)

Right. Right.


Emin Maltepe (26:33.429)

Yeah, it's pretty remarkable. So that was really the impetus or incentive impetus for me to kind of really think about this. And part of the other thing was I was surrounded, you when I got my lab at UCSF, I was really put next door to people who weren't mouse developmental geneticists at all. They were all large animal physiologists who had actually discovered surfactants, discovered, you know, figured out all of the cardiovascular physiology of the human in utero, the fetal.


neonatal transition, all that stuff using sheep models. And I very slowly appreciated, you know, the importance of all of that work and really the power of those models as a translational model for drug and device development. And again, like it was really, I was a latecomer to that. I was very slow to pick up on it. But once I did, it just was, it's a tremendous resource that I saw that was falling out of favor because so many people are really driven by the, know,


the power of like mouse genetic models to go after disease and try to translate from there, but nothing really translates very well from rodents to kids. I mean, it's just, except maybe in the cancer realm, which we can talk about separately. But in terms of cardiovascular physiology, brain injury, like hypothermia was developed in sheep as well as piglets. Like that's where Alastair Gunn showed the ability of hypothermia to be neuroprotective. And that's standard of care for HIE.


Antinatal steroids were first kind of worked out in large antishEEP models, you know, so pretty much everything we do that works came from sheep, which is why, you know, I've really, I pretty much like 80, 90 % of what I do is in sheep models. And so what I ended up doing was kind of really joining forces with all these people that have like 50 years of experience doing preclinical.


Betsy Crouch (28:12.214)

you


Emin Maltepe (28:27.735)

development and discovery using these large animal models that are physiologically appropriate and forged a partnership between myself, them, really led by Jeff Fineman, who's the head of critical care at UCSF, and then folks out of the School of Pharmacy at UCSF, particularly Janelle Boyle, who exclusively focuses on pediatric pharmacology. And we created a nugget at UCSF that can really help with


pediatric drug development efforts, do all the preclinical disease modeling, do the pharmacology, safety toxicity. And the one thing we didn't have at the time was really regulatory expertise, because that's a whole other side of the equation. Like, how do you actually get FDA approval? How do you do like clinical trial design? And what are the FDA benchmarks you have to hit? So we partnered with a group out of Maryland that came out of the FDA that had that expertise. And we created this organization that we call the Initiative for Pediatric Drug and Device Development.


And that sort of has really led me to do a lot of really what I think is exciting drug and device development work, which I never would have been able to do had I not really kind of broadened my focus into this huge critical unmet need of therapeutics development for our patient population.


So that's kind of how that evolved. so we're doing things, again, everything is hypoxia pretty much at the end of the day that I'm working on. So the drugs that we're developing are either for hypoxic ischemic encephalopathy, particularly in low and middle income country settings. And we're doing that, for example, in partnership with the Gates Foundation. And we did this really kind of cool international collaboration where we said, all right, if you want to.


David (30:06.352)

Mm.


Emin Maltepe (30:19.735)

because hypothermia doesn't work in a lot of low and middle income country settings. And it turns out it's probably contraindicated. And so they have, there's no drugs. So how would you develop a drug? Like the question that came to IPD3 to us with is if you were to try to develop a drug to take to a large global clinical trial, how would you do it? And we put together this concept of having like initially going through all drugs that have ever been shown to be neuro therapeutic, of whittle it down.


to a few dozen that you could test in rodent models. And we picked the Rice-Vinucci rodent model. So it's like a medium throughput down selection algorithm that was done by a collaborator of ours in Germany at the University of Bonn led by Hemmen Sabir, unbelievable lab and setup where he was able to screen a couple of dozen compounds in the Rice-Vinucci model head to head and score them from most effective to least.


and including versus therapeutic hypothermia. And for example, caffeine there turned out to be the most neuroprotective of all the compounds we investigated. And we then took that into a sheep model of birth asphyxia. And we just published that. And caffeine clearly showed it was safe, it was efficacious. And now there are global clinical trials being planned to test the efficacy of caffeine in low and middle income country settings.


Betsy Crouch (31:27.822)

Mm-hmm.


Emin Maltepe (31:40.691)

as a potential therapy that prevents neurodevelopmental negative neurodevelopmental outcomes to babies born with HIE So that trajectory to me has been like unbelievably rewarding. And again, if caffeine works in any fashion in that setting, it's just going to have been amazing. So that's been one direction. And then we also work with private companies that have interesting technologies that we're trying to help them develop for, again, pediatric indications.


David (31:59.396)

That's so exciting.


Emin Maltepe (32:12.331)

Yeah, but there's a lot of different directions we've kind of gone, including devices.


Betsy Crouch (32:18.316)

Yeah, read that. I mean, I've seen you present that data, but I read that paper this morning in anticipation of talking with you. And I didn't realize that caffeine had effects on the blood-brain barrier. So I'll have to go back and dig through that data. So thank you for that good work and for the babies in low and middle income countries and for the work going on in my lab specifically.


Emin Maltepe (32:39.765)

Yeah, no, it's been incredibly rewarding. A lot of stuff going on. So we're trying to expand that now to, for example, think about genetic models of cerebral palsy as opposed to sort of injury induced, acute birth injury induced. So we're now trying to branch out into doing some transgenic large animal models that we could pair with, you know, mouse knockout models where we do again, like a screen of compounds.


In mouse knockout models that would then we have the large animal equivalent that we can actually do the preclinical testing of the drugs. And again, like a physiologically relevant system to then get to a clinical trial. So we've really kind of turned into kind of a drug company, nonprofit drug company. But the good thing is we're very drug agnostic. Like we don't develop the drugs. We're just trying to find ones that'll work for the indications. So we're letting the indication lead the need leads and we follow.


and try to come up with an approach that's gonna tackle a significant problem that we're dealing with clinically.


David (33:46.769)

It's really exciting to hear about that. I often think about this myself. mean, we're trying to use genetic models to understand the basis of lung development and trying to think about how we can use abnormal gene expression as a way to find new ways of treating pulmonary vascular disease or something like that. We've gotten pretty far with some molecular approaches and then I kind of


always get into this point where I'm wondering like, why am I thinking about how to better deliver this agent in the blood vessels in the lungs? Like I feel this is the role of someone that's not working in developmental biology and genetics, but I could, you could see that you could totally follow that path into a completely different avenue of like new drug development. How do you package this thing to have it be delivered in the lung more effectively, which has nothing to do with genetics anymore.


Can you just talk about that switch in your motivation a little bit and just how like your ability in running a lab and you know answering a complex question with hypotheses and things like that kind of help give you training that's allowing you to be successful to do what you're doing now.


Emin Maltepe (35:03.115)

Yeah, I'll tell you, I'm not entirely sure my like PhD training is what is leading me to be able to do this. I think one of the things I have a short attention span, so I like, or, you know, I can focus on multiple things and keep them in parallel tracks. You know, so I like doing a lot of different things and I like growing all the time. And so that's really been, I think that there is a,


I think it's a little bit of a personality that can kind of do this type of work and kind of move from one thing to another and not feel completely unsettled. I mean, it's very unsettling. I'm always in conversations with people that know way more about whatever it is that we're trying to work on than I do. And that to me is both unsettling and invigorating. And ultimately, like, I know this is the right direction.


for the field to go. And so I'm just trying to figure out how to get myself there and hopefully to be able to get the field there. So I don't really know quite honestly what the right training track would be. Some trainings that I wish I had gotten much more of, business, know, general accounting, like how do you balance a budget? Like what are accounting tools, right? You guys run labs, you know what that looks like.


David (36:20.176)

Mm.


Betsy Crouch (36:23.374)

You


David (36:25.072)

trying to write that.


Mm-hmm


Emin Maltepe (36:28.351)

really understanding policy, how policy governs our lives. So public policy, there's so much with respect to why things happen in pediatrics the way they do that comes from the policy world. But really much of it, you we're in a capitalist society. So much of it is all for-profit driven drug development. is profit coming from? Companies are not benevolently gonna go into pediatrics. We have to really significantly de-risk these ventures for them.


for them to get interested in it. There's very few companies out there that really care about this space. There are some, but very few, some of them are doing really critical things, but it's a completely forgotten, it's a backwater. I'm trying to learn now about both policy, economics, business decisions.


David (36:58.096)

Mm-hmm.


Betsy Crouch (37:19.79)

Mm-hmm.


Emin Maltepe (37:24.843)

So I wish I had gotten that training. If I gotten that training, like I think every physician scientist should get probably at least six months of training in basic business and economics and accounting. Just to understand where grants come from, know, taxes, how do taxes support, who, where does the NIH money come from? Where does that budget come from? You know, I mean, there's so much we don't know. And we're just really focused on this narrow, you know, scientific study.


And really putting that into the larger societal context, I think is what's absolutely critical. And we're not trained to do that. So that I think is what's really lacking in all of our trainings.


Betsy Crouch (38:06.062)

Where are you motivated to try to make an impact on science policy these days? Because I find that incredibly intimidating. mean, I'm voting. I'm being careful about my voting. But everybody vote. But beyond that.


Emin Maltepe (38:14.135)

Yeah.


Yeah, really advocating for, you know, pediatric therapeutics development in any way you can. Right. And there's lots of different ways you can do that. Well, one, working on it. Secondary, there's, can actually try to, I mean, I get, there's so many different ways. I mean, the way I've done it is to create this organization that just does it. Right. But then there are other ways where you can get involved, you know, just, just starting to read like.


What is PREA? What is BPCA? What are the regulation? What are the laws that were passed to support pediatric drug development, like the carrot and stick approach the government has taken? And why is that not working? And there's a lot of reasons why that's not working. just learning, just start reading. What is PREA, P-R-E-A, or BPCA? When did that become law? Who supported it? And what's been the result?


of that, like who has benefited from it, who hasn't benefited from it, and what are the easy workarounds for companies to not actually fulfill those obligations and still develop drugs specifically for adult indications. Learning about it gives you the tool, gives you the initial understanding that allows you to then go out and do something about


Betsy Crouch (39:36.238)

Thank you. think those are good first steps. You know, we really appreciated your time. It's flown by. We like to end on something. Yeah, it does. And yeah, you're literally flying by. We're going to call this one moving forward, literally, in your career trajectory. But we like to end on something fun. So you can interpret this any way you like.


David (39:36.336)

That's great.


Emin Maltepe (39:43.895)

It has fumbas.


Emin Maltepe (39:54.389)

Yeah, the flyby. Yeah.


Emin Maltepe (40:01.451)

Okay.


Betsy Crouch (40:04.802)

People often talk about the things that they enjoy doing outside of their professional activities. Is there a hobby that you enjoy that you'd like to share with us and our listeners?


Emin Maltepe (40:15.125)

Honestly, it's gonna sound a little corny. mean, my daughter is just having raising a kid has been the hardest thing I've ever done. It's been the most rewarding thing. I have an unbelievably supportive wife who is is solely responsible for the fact that I have any success whatsoever by really supporting our household and really coming up with kind of the vision for how to structure our lives. honestly, like


They're They're it like, you know, outside of the work. The problem is my work is like takes up so much of my brain space. And you guys know how this is. You live and breathe and you wake and sleep thinking about this stuff. And it gets in the way. It's it's a very selfish endeavor. And I've had unbelievably wonderful, wonderful spouse and a wonderful child along the way. And, know, all my hobbies, who cares? They're not that interesting.


Betsy Crouch (41:13.324)

Yeah, that's beautiful though. Family, right?


David (41:15.652)

Yeah, I agree.


Emin Maltepe (41:15.841)

Family. The children. Let's do it for the children. No, it's really true. It's really true.


David (41:19.992)

Exactly.


Betsy Crouch (41:22.446)

for the children. Well, there we go. Thank you for transitioning us nicely to our conclusion. Thanks everybody for joining us. Emin, Dr. Meltepe, physician scientist, policy, new policy guru, be Capitol Hill wonk someday and we'll all be, us and the babies will all be very grateful after you're tired of dealing with sheep, but that might take a while.


Emin Maltepe (41:27.947)

Yeah, yeah.


Emin Maltepe (41:33.718)

This was great.


Emin Maltepe (41:39.639)

I know about that. Maybe one day.


Betsy Crouch (41:51.18)

All right, thanks everyone for joining us. Look forward to.


Emin Maltepe (41:53.345)

Thank you guys for doing this. This is a great idea. So keep it up.


David (41:56.432)

It's fantastic to talk with you, Emin.


Betsy Crouch (41:58.528)

Yeah. Hey David, do you want to, I feel like I've talked a lot. So do you want to wrap this up?


Emin Maltepe (41:58.711)

Thanks, man.


David (42:03.342)

No, that was great. Thank you, Betsy. You did a great job hosting this episode. so thanks to our audience. We're excited to talk to you again soon from At the Bench.


Emin Maltepe (42:16.631)

Thanks guys.


David (42:17.968)

That was awesome, Emin, nice job.

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