Dehua Pei podcast === [00:00:00] Dehua Pei: Science today has become very interdisciplinary as well as multidisciplinary. So, for drug discovery, it's truly a combination of many different fields, right? So, there's chemistry, that's physics, there's biology, that's medicine, and that's even economics involved in that. So, yeah, so it's really multidisciplinary. Jen Farmer: From the heart of the Ohio State University on the Oval, this is Voices of Excellence from the College of Arts and Sciences, with your host David Staley. Voices focuses on the innovative work of Arts and Sciences faculty and staff. With departments as wide ranging as art, astronomy, chemistry and biochemistry, physics, emergent materials and mathematics, and languages, among many others, the college always has something exciting happening. Join us to find out what's new, now. David Staley: Joining me today in the ASC Marketing and Communication Studio is Dehua Pei, Professor in the department of Chemistry and Biochemistry at the Ohio [00:01:00] State University College of the Arts and Sciences. His research spans from the mechanistic study of biological phenomena to the development of methodologies to discover novel therapeutic agents and chemical probes. In 2025, he earned the Ohio State University Distinguished Scholar Award. Congratulations, Dr. Pei. Dehua Pei: Thank you. David Staley: And welcome to Voices. Dehua Pei: Thank you David. David Staley: Well, I'm very interested in the research that your group undertakes, and I was really struck by this first one, because you frame it in the form of a question: how do biomolecules cross the cell membrane? So, what's the answer? Dehua Pei: That, well, so first of all, let me emphasize this is one of the very important questions that have been in the field for quite some time. People actually have been studying this problem for decades, in many different fields. So, we can kind of take an analogy of, so the human bodies are made of many cells, and we can kind of look at, you know, compare cell to, like, an orange.[00:02:00] David Staley: An orange? Dehua Pei: Yeah. Like, you know, so orange has a skin, the skin is basically the cell membrane, the equivalent of the cell membrane. So, what people have been wondering about for many years is how do molecules cross the membrane or the skin and get inside the cell, which is the internal components of an orange. So, for small molecules, seems very small, like air molecules, they can permeate through the cell membrane or the skin of the orange rather easily and get in. But, for larger molecules, like a huge protein, you know, the proteins are like a thousand times bigger than a, you know, small molecule, which we normally consider like a size of a water molecule or carbon dioxide, right? So, for those very large molecules, how do they cross the cell membrane, get in or in some cases get out, has been a mystery for quite some time. Now, why is that important? Well, it's important because we know [00:03:00] certain types of proteins can get into human cells, for example, bacteria produce a lot of toxic proteins, we call them bacterial toxins; they're very large protein molecules, and they can get into our cells and cause diseases, all kinds of bacterial diseases. And there are also viruses, you know, we, not long ago we had the pandemic. David Staley: Mm-hmm. Dehua Pei: So we know viruses can get into our cells as as well. But actually, amazingly people do not know how these large molecules or molecular assemblies, meaning a lot of molecules, you know, bonded together, how do they get into the cell and cause diseases? Or, in human cells, some of our proteins will actually get out of the cell and perform functions at the extracellular environment. How does it do that? That's actually unknown. And so, we've become very, very interested in that. And, you know, that's also driven by a practical need. The practical need is that in drug discovery. So, for the, all human history or you know, the history of drug industry, [00:04:00] people have been developing what is called a small molecule. It's basically, you know, relatively small organic molecules as drugs. And so, we call them sizes of, you know, 500, you use numbers as a, you know, kind of as a benchmark. Size of 500 or smaller is what they have been working with. And then, you know, about 40 to 50 years ago, we had a biotechnology industry come along, and then people start to use very large molecules with molecular, thousands of, tens of thousands or hundreds of thousands, as you know, as drugs. But what they can, what they have been able to do is, you know, when they use a small molecule, because they're small, they can go into our cells and, you know, and function and then modulate the activity of cells and act the drug. But when it comes to large molecules like proteins, they can't get it in. So all of the drugs we got outta the biotech industry for the last 40 years, we work outside ourselves. David Staley: Hmm. Dehua Pei: And so, it would be great if we can take this larger [00:05:00] monitor into our cells and then we can open up an entire new space. And so, currently, there's a quote in the industry, it says, 75% of all disease relevant drug targets are undruggable, meaning the... David Staley: Undruggable? Dehua Pei: Undruggable, meaning the entire industry, the pharma industry and the biotech industry, have no solution for 75% of the disease relevant targets. And so, it would be wonderful if we can access to these drug targets which leave inside of our cells. If we can do that, then there will be no undruggable target left. David Staley: So what is your lab doing to answer this question that others have not done? Dehua Pei: Good question. So, we kind of stepped back and we said, okay, well, how does the leech do it? David Staley: Hmm. Dehua Pei: And right, if you know, we know that leech has produced viruses that can get in, we know that leech has produced bacterial toxins, many of them, they can get in. So we said, okay, well let's, let's figure out [00:06:00] how leech does it, and then we may able to design something that does even better. And you know, it goes into cell and do good, but does not do harm. So that's the rationale behind our research. So, then how do you solve a problem that people have been studying for decades and, you know, were not able to solve it? So we went back to the, you know, basically the fundamentals said, okay, let's forget about all biology in housing people have discovered in the past. Let's come back to the fundamental physical chemical principles. What does it take for something to go from one side of membrane to the other side? Or, if we take another analogy, you know, we're sitting in a, in a room, in close room right now. I want to get outside the room, but there's no door. David Staley: Mm-hmm. Dehua Pei: There's no, you know, so how do I get through the wall, get to the other side, and importantly, how do I get to the other side without even damaging the wall? So, that is the question, you know, we ask ourselves. [00:07:00] What are some of the ways that you might be able to do it? And it's just, don't even worry about whether that's happening in biology, just physically, you know, look at the physical chemical principles. Is it a way that things can happen that allow a molecule to go from one side to the other side? So then I remember, well, you know, a little activity that the kids do, right, kids blow soap bubbles. David Staley: Mm-hmm. Dehua Pei: You know, we all know that. So what, what we observe, of course, is if you blow a big soap bubble, which is kind of like the cell membrane. David Staley: Right. Dehua Pei: And the big bubble sometimes can split into two bubbles, and it's smaller bubble come out of the big bubble. And then we'll also observe that the small bubble actually will pop. So, now you think about it, if you have a cell, you have a membrane, if somehow your molecule can bind to the membrane and then promote the formation of a small bubble, coming outta the larger bubble, and then the molecule are being [00:08:00] enclosed in this small bubble, and they will separate, and the small bubble pops, then you have your molecule released on the other side of the membrane or get out of the cell in this case. And if you foresee to get it in, it's exact same process, just reverse process. So this is, you know, physics, or chemistry, right? So we don't know what happens in the cell. I said, well, that makes sense. So, let's just look at in the leaving system in a human cell, does this happen? And so, once you have a hypothesis, you have some ideas of what you're looking for, you just design experiments and look for it. And sure enough, we found that's exactly how things happen over there. And we first demonstrate this with artificial type of molecules called cell penetrating peptides, which people have been studying for, you know, for about 40 years as well, and people do not know how to get into the cell, and we show that's exactly how they cross the cell membrane. And I said, well, you know, if these artificial molecules can do it in, in the context of human [00:09:00] cell, what about natural occurring proteins like bacterial toxins? We look at that: sure enough, that's how they do it. Then we, you know, then we thought, okay, well what about viruses? What about all other systems? And then we, you know, then we went to literature and look for evidence, right? And then evidence turns out to be everywhere. And so now we believe this is a fundamental mechanism in nature that allows molecules to go from one side of the membrane to the other side, and that's probably a universal, we call a unifying mechanism for many, many different systems. David Staley: Hmm. Why did you decide to tackle this problem? I mean, of all the problems that one could tackle: why this one? Dehua Pei: Yeah. So, that comes back to the need for drug discovery, right? So today, yeah, sure, the pharma industry, the biotech industry are doing a great job. They're developing a lot of new drugs, each year. But still today, there are many diseases that, you know, that do not have proper treatments. We have not conquered cancer. David Staley: Mm-hmm. Dehua Pei: [00:10:00] Alzheimer's is still a big problem. And there are probably somewhere around six, seven thousand genetic diseases, very few of them have proper treatment. So, there are lots of diseases that are currently undruggable, and it's generally believed that if we can take large molecules like proteins into the cell, that will solve the undruggable problem. So there, there certainly has been a lot of incentive for figuring out a way to take a large molecules like proteins into the cell. And there's a lot of research going on in this area, so we're not, certainly not the first one to look into this problem. You know, like I said earlier, this is a, you know, very well known problem for quite some time. David Staley: Are you confident, optimistic that you or someone will solve this problem soon, soon enough? Dehua Pei: Well, so mechanistically, we feel like we have solved the problem. There's still, obviously, there are a lot of different systems. We have looked at a few systems and in the systems that we have looked [00:11:00] at, you know, the, the molecules do cross membrane by the mechanism that we discover. We call it the vesicle budding and collapse mechanism or the VBC mechanism. And so, yeah, so that seems to be the case. So, that's still a lot of work to do for us and for others to look at other systems. So, is it a truly universal mechanism or the unifying mechanism for many different systems? So that remains to be determined. I am cautiously confident that will turn out to be right, but science of course is, ultimately, you know, proven by evidence, right? So that's research left to do over there. At the same time, we have taken advantage of the knowledge that we've gained in the system to design artificial systems that can cross a cell membrane with incredible efficiency, more efficiency, even than the lateral systems. So, for example, we develop what is called a cyclic cell-penetrating peptides, which you mentioned early on, yeah, the thing on our website, and those are the molecules that designed to be [00:12:00] very stable metabolically. That's good for being a drug, you don't want your drug to be destroyed by the body, you know, in, in a very short time. And so, those are the molecules we develop. They're very efficient, again, into the cell, and they can take drug molecules into the cell. And this is already commercialized, and there's a company that I co-founded about 10 years ago called Entrada Therapeutics, and that, currently, is taking three to four drugs into clinical trials, and so that's going very well. You know, so we'll move from fundamental research in the lab all the way to commercial space, and hopefully, you know, in a few years, patients will actually benefit, directly from our research fruits. David Staley: Protein-protein interaction inhibitors. Tell us what this means. Dehua Pei: Sure, yeah. So, when earlier I was talking about undruggable targets, so protein-protein interaction, what we call the PPIs, those are the classical examples of undruggable targets. So, here you have two proteins function by interacting with each [00:13:00] other, and that's how they perform their biological functions. And when you have two proteins bind to each other, they're very difficult to interfere with using a small molecule. And so, small molecules usually work as a drug. They work against targets, usually proteins that already have a little cavity on them. Because small molecules are small, they don't bind to most proteins with a affinity. So, if they're gonna bind to protein with high affinity, the protein has to have a needle bit of, you know, cavity or pocket on them. And so, only 10% of our proteins have that. And so, for most proteins, you know, especially proteins involved in PPIs, they don't have such a pocket, so small molecules can't do the job. And so, we need a large molecule, like a protein, you know, specifically, you know, proteins like antibodies, and that can bind to essentially anything. And so, if we can get large proteins into the cell, they would be [00:14:00] binding to one of the two proteins involved in PPI, and then they can interfere with a normal PPI and therefore modulate the cellular activity and potentially act as a therapeutic agent. But this, we have these large molecules, of course, come back to the question of how do you deliver them into the cell, right? David Staley: Mm-hmm. Dehua Pei: So that comes back to penetration and the mechanism by which housings get into the cell. So this is why all of the things happen in my lab, they're, they're related. David Staley: Hmm. Another area that you're working in is the development of intercellular biologics and chemical probes. What's a chemical probe? Dehua Pei: So, intracellular biologics intended to be a new class of therapeutic agents, which is basically large proteins and other large biomolecules, delivering into the cell, then they can access therapeutic agent. Chemical probes, meaning we can also use the same types of molecules as a research tool, and that research tool can allow us to ask [00:15:00] specific questions. Okay, so what is the function of this protein inside the cell? And if I use a chemical probe to eliminate the function of that protein, and then the cell should have a phenotype, right, we can look at the phenotype, well look at, you know, what cells ha, you know, what happens to the cell if you lock out the function of a particular protein? And that can tell us a lot about what is the biological function of the protein of interest. So yeah, so the same kinds of molecules, the larger molecules deliver into the cell can also act as incredibly powerful tools for us to study additional biological mechanisms and understand fundamental biology behind, you know, the living system. David Staley: Hmm. So, as you've been talking here, the question I keep asking myself is, are you a physicist or a chemist or a biologist, or maybe all of the above, or maybe none of the above? Dehua Pei: I, well, so that's a, [00:16:00] that's a great, you know, observation you have made, David. Science today has become very interdisciplinary as well as multidisciplinary. So, for drug discovery, it it's truly a combination of many different fields, right? So, there's chemistry, that's physics, there's biology, that's medicine, and that's even economics involved in that because you ultimately, you will make a drug, you have to be able to, you know, make a profit, right? So, yeah, so it's really multidisciplinary. So, my training was in organic chemistry, it's one branch of chemistry, and then, you know, from there I branch out into biochemistry, cell biology. And of course, you know, today I also branch into medicinal chemistry, drug discovery. Yeah, so I call myself as a chemist. David Staley: Why did you settle on chemistry? Because you were trained in organic chemistry, that's just what you sort of settle on, or...? Dehua Pei: Well, that's, that's... David Staley: And you're on, you're in a chemistry department, I suppose. Dehua Pei: That's what I'm in chemistry department. That's, that is [00:17:00] true. You know, if I look at everything we do, chemistry is the foundation of everything, you know, we do in the lab. So, yeah. So I think I call myself as chemist is probably the most appropriate. David Staley: Before we started recording, you and I were talking about research methods, the reasons for research, and you said something to the effect of there are two, two reasons or two drives, I suppose, for research: societal needs and curiosity. Say a little more about that distinction, and maybe what drives your own research agenda. Dehua Pei: Yeah, you know, so I would say a lot of my colleagues, they do research, you know, mostly driven by curiosity, right? So there are a lot of, let's say, biological phenomena or chemistry, physical phenomena that are not completely understood. And so, you know, so people do research, try to discover truth, right, scientific truth? And that's in fact, that's, you know, science, it's what scientists supposed to do, right? But then, at the same time, there are true [00:18:00] societal needs. And so, what's driven me, the two things, right: one is the need for treatments for, you know, many diseases. You know, I mentioned earlier there are lots of disease that do not have proper treatments today. I'm particularly interested in genetic diseases where there's really no good solutions, other than intracellular biologics that, you know, we mentioned early on. And then, I'm also getting interested in recent years for sustainable agriculture. And I may say, well, medicine and agriculture, how do they have in common? Well, actually, they have the same thing in common, is that, you know, in the, in the past, even at, you know, to a large extent, at the present, you know, the agriculture heavily depends on chemicals. David Staley: Mm-hmm. Dehua Pei: You know, pesticides and insecticides and things like that. And they are being effective, but, you know, when we dump, you know, millions of tens of chemicals in the environment each year, and these things can stay there for quite some time, [00:19:00] and eventually, you know, that's gonna do a lot of harm to the environment. And so, there's a lot of push recently from governments, particularly Europe, for something that's more sustainable, that's impactful on the environment. And so, one of the directions moving from small molecules to biologics, you know, larger proteins, because the proteins can be degraded shortly after they applied, and then, you know, degree into amino acids, which are lateral components, so they have, essentially, no impact on the environment if we do them properly. David Staley: Mm-hmm. Dehua Pei: And yeah, so, you know, we also become very interested in that. In fact, you know, one, one of my OSU colleagues and I co-funded another company called Scioto Agritech, and we are taking advantage of the technology we develop here, delivery of large molecules into the cell, and try to generate products that hopefully will benefit not just the sick people, but everybody in the society, and by providing, you know, high quality foods, that's free of [00:20:00] contaminants. And, so the idea is very simple, is that we are gonna take a protein and we're going to deliver into plant cells, maybe are, deliver into fungal cells, you know, fungi cause a lot of, plant diseases, right? David Staley: Mm-hmm. Dehua Pei: And then we can hopefully prevent fungi you know, from replicating in plant cells. And that will be a, you know, wonderful type of agricultural product. David Staley: Hmm. These two drives for research, societal needs versus curiosity. Were you always driven by societal needs, or did you begin as someone who had a natural curiosity and you've moved toward an interest in societal needs? Dehua Pei: That's a great, question. So, I try to combine the two. You know, I was trained, you know, I'm trained as a scientist, so naturally I have a lot of curiosity. I'm interested in how things work, and scientists, you know, in, in, the academic world, I think making fundamental discoveries is still highly regarded. [00:21:00] And because these are the, you know, things that can have a long-term impact on human, you know, society, right? So, yeah. So, making fundamental discovery is certainly very important, and I'm, you know, very interested in doing that. So, what I try to do is do both, and look at the societies and ask question, why is that people have not been able to solve this problem? And usually it's because it's a fundamental piece that's missing, you know, something that people do not realize, and certainly that's true in, our case, right? You know, these big molecules across the membrane by this VBC mechanism, which is something that people never, never thought about. And so, the discovery, the mechanism, the VBC mechanism is a fundamental discovery, and that hopefully, I hope one day will get into textbooks. Right? So that's a, that's purely curiosity driven type of research. But at the same time, once we understand this mechanism, it's incredibly powerful in terms of driving technologies, and so [00:22:00] we're able to develop several powerful technologies based on this, unique mechanism. And so that, and then allow us to solve societal problems. David Staley: Hmm. What got you interested in chemistry? Or I guess, maybe another way I was asking this is, why are you a chemist as opposed to, I don't know, a biologist or an historian or I dunno, a basketball player or something. What got you into chemistry? Dehua Pei: You know, even when I was very young, I was always, you know, curious about how things work. So getting, you know, into science was pretty natural for me, and I was pretty good at it. You know, I, I'm interested in stuff. I, I like to think about things and I like to fix, you know, how, things work. And so, getting into science was natural; into chemistry perhaps is more, perhaps by accident. You know, I guess, I did it very well in chemistry in high school, and, when I was going to college, you know, I really didn't know. You know, I got to college in the early eighties, so that's the time before internet, didn't know what's out of there right, [00:23:00] so you kind of do things that are more familiar with. I was very good at chemistry, I was interested in it, so I said, oh, I, you know, let's do chemistry. and of course, you know, in college and I fell in love with it. David Staley: You've mentioned that you founded at least two companies, maybe there's more you've founded, but, I wonder, when you were starting off in college, when you were starting off as a chemist, did you imagine yourself as a founder of a company? Dehua Pei: Oh, that's, yeah, I never thought that I would be a founder or co-founder of a company. That's not until I went to graduate school, I would say. Yeah. So, in graduate school, then I realized that, yeah, research can actually be directly used in the commercial space, because my former advisor, that's Professor Peter Schultz, who is currently president of Scripps Research Institute, who was phenomenal scientist. He's a phenomenal scientist, but also a very sured entrepreneur, and he started many companies and become very successful in that space. [00:24:00] And so, we saw how one can take a fundamental discovery from the lab into the commercial space. David Staley: Is this an expectation now for scientists, that in addition to being researchers , that they're to be entrepreneurs? Dehua Pei: I wouldn't say that should be expectation. I think if someone can make truly fundamental discoveries that can benefit the human society, that's fantastic. I mean, that's, if you can do that, that you are doing better than most people already, right? But I would say, you know, to people who are interested in, you know, taking their research into the commercial space, yeah, you know, give it a shot. You know, not guaranteed to succeed, but it might succeed, and it is very satisfying when you can take a research to this commercial space and make products out of them and see your research directly benefit people in some ways. David Staley: Mm-hmm. Is this how you teach your students, your graduate students, the postdocs in your lab? Dehua Pei: That is [00:25:00] only true and, and actually as a result of that, many of my students direct go from my lab, you know, to pharma companies, to biotech companies and, you know, continue the kind of research they do here. Hmm. David Staley: Tell us what's next for your research. Dehua Pei: As I mentioned earlier, the VBC mechanism, it's been demonstrated in a few systems. I would like to demonstrate that is also applicable to other systems, so that'll keep us busy for the next 10 years. I probably got 10 more years in my tank. And, at the same time, I, mentioned that I have started, I actually started four companies. And so, yeah, I would like to see the companies succeed and then generate a few products that will benefit, you know, the people with diseases, that's therapeutic companies, and also hopefully we can develop some agricultural products that can benefit everybody. You know, for example, you know, around my home we have fungal problems with my lawn. David Staley: Oh. Dehua Pei: And so I hope, hopefully, you know, some of the products will be able to deal with the fungal diseases that's [00:26:00] affecting my lawn. David Staley: Dehua Pei. Thank you. Dehua Pei: Thank you, David. Jen Farmer: Voices of Excellence is produced and recorded at The Ohio State University College of Arts and Sciences Marketing and Communications Studio. More information about the podcast and our guests can be found at go.osu.edu/voices. Voices of Excellence is produced by Doug Dangler. I'm Jen Farmer.