Episode 60: Dr. Jonathan Sessler on Cancer Therapy and Texaphyrins

Introduction to Dr Sessler

0:00Hi, you're listening to Let's Talk Chemistry, a podcast by Chemtalk. On today's episode, we interview Dr. Jonathan Sessler, professor of chemistry at the University of Texas at Austin. He is a three-time Hodgkin's lymphoma cancer survivor and shares how his personal experience led to his incredible discovery of expanded porphyrins, or as he cleverly names, texifrins after the state flag of Texas. These molecules are useful for medical imaging, cancer therapy, and more.

0:33We hope you enjoy. Hello, and welcome back to another episode of Let's Talk Chemistry by Chemtalk. I'm your host, Neil, and today I'm joined by my co-host, Jason. Today, we have a very special guest, professor of chemistry at the University of Texas at Austin, Dr. Jonathan Sessler. Throughout his career, Dr. Sessler has amassed over 600 publications and 70 patents. He also co-founded the biopharmaceutical company, Pharmacyclics, based on his work on polyphorins. Let's hear how he got to this point.

Dr Sessler's Background

1:04My name is Jonathan Sessler, and I'm a professor at the University of Texas at Austin in chemistry department. I'm affiliated with the organic and inorganic divisions. So, I did my undergraduate work at Berkeley, University of California, and then I did my PhD across the bay at Stanford. And for the locals, that's kind of like going from Texas A&M to Texas and big rivalry schools.

1:36From there, I went to France and worked with Professor Jean-Marie Lane at Université Louis-Pastille de Strasbourg, which is now just the Université de Strasbourg. And that was before Jean-Marie, four years before he won the Nobel Prize. I then, after a year and a half there, spent all five months or so in Japan before I started my job as an assistant professor here at Texas.

2:08And I sort of moved up the ranks with time. And I'm now the Doherty Welch Chair Professor in Chemistry here at the University of Texas, which we often call UT. It seems like Dr. Sessler was always involved in academia and science. He was. Dr. Sessler explains his early influences that have propelled him into academia. I grew up in a very strange household. So, I'm proud of the fact that my mother was the first woman to have an advanced degree

2:44in physics from Columbia University. And my father was a hotshot young physics. I was a graduate student there. And after postdoc with Hans Bethe, Nobel Prize winner in physics, my dad started first Ohio State. And after four years, moved to Lawrence, now what's called Lawrence Berkeley National Lab. And he actually renamed it Lawrence Radiation Lab. And he was early on in broadening policy for Department of Energy.

3:19Wow. So, the Sesslers were an academic family? Yeah.

Early Influences on Dr Sessler

3:23He speaks more about how his early impact propelled him into academia. So, my childhood dinner conversation would consist of him having read Science Magazine that day and talking about interesting articles and no reading at the table, no fidgeting, but just discussion. And so, from the earliest days, it was, what do you think about this? And my dad, being trained in physics, loved family problems. So, he'd had us working story problems in our head.

3:55Like, okay, look at that tree. Do you think there are more leaves on that tree than that kind of tree in the whole world? How would you figure this out? How much energy? More energy is it taking you to ride your bike up the hill than down the hill? Well, the sky is blue, what's Planck's constant, and that kind of problem. So, I had a very strange upbringing because my dad was such a physics genius. I couldn't possibly do math or physics in a competitive way.

Choosing Chemistry

4:23I'm curious, what made Dr. Sessler choose chemistry specifically? Yeah, me too. Dr. Sessler explains. I remember in high school, we were trying to take physics as a sophomore or something. I remember I couldn't do some problems, so I asked him, okay, you know, things jumping off of, you take a ball, it goes down a ramp, and how far does it go? And I asked him, can you please help me? And he looked at it and goes, well, I think the answer is about 14. You do the next one. So, he was the world's worst teacher.

4:56So, chemistry was something he didn't understand at all. But he was wise enough to give my older brother and me a little back room with a sink and a Bunsen burner. And in those days, as a faculty member, he could order some chemicals until we could just mess around. So, I started doing that starting in seventh grade. And I couldn't do any of these physics problems very well. But I could make new esters, and they'd have beautiful smells, they're bombs, and fun things.

5:26So, like, he used to joke, well, you're not a very good chemist, Jonathan, because all chemists start by trying to blow themselves up, and you haven't yet succeeded. Whether it be chemistry or physics, it seems that Dr. Sessler had a very early engagement in STEM. Yeah. Those early experiences were very formative in his decision to pursue the field. He also found academia to be very enriching. I like the academic life. We had the benefit of traveling around a lot, as my dad attended conferences and sabbaticals.

5:59And so, I like that. I always loved history and politics and languages. So, I think in a different reality, I probably would have joined the diplomatic service as an area specialist or one of the non-political appointees that sustained the government. And I actually had a chance to have dinner at some fundraiser with Professor Galbraith from the LBJ School of Public Affairs. And he was one of the, or still travels around all over, doing these sorts of policies.

6:34He was there early on when meeting Chuan Lai, when China was being opened up. So, in a different life, I would have been doing what he does. But science, science family, science background. So, I did chemistry.

6:51Differentiation from what my parents could do. My poor younger sister, she just couldn't stand it. Wait to get out and go talk to her friends on the phone. So, my older brother and I, we lived that reality and learned a lot. Dr. Sessler also has some crazy early chemistry experiments that contributed to his interest in the field. Behind us was Hans Mark, who is some political kind of administrative person. And I remember one Sunday, we were so excited.

7:22We had made this new, at 8 a.m., we put it up, blew up this big rock. And he got out, I guess, woke him up, and he started yelling at us. And then he became UT's chancellor. Fortunately, he didn't remember me, because I came as an assistant professor. He greeted all the new professors. Fortunately, he didn't remember me. So, that was a pretty good one. And, yeah, fun stuff. Yeah, that's quite the start to chemistry.

Texaphrin and Porphyrins

7:52That's a great point. It's amazing how personal experiences can shape scientific research. Speaking of experiences, I'm curious to know more about Dr. Sessler's journey at UT. Me too. Let's hear what he has to say. So, when I came here, I spent all of two days in Texas interviewing for a job here. So, I started in 1984, and I'd been in Texas all of two days. At that time, they were a little worried about Californians and non-Texans.

8:23So, we had to take a four-day class on how to teach to Texans. And this was Texas being rich in those days. So, they paid me $1,000 to sit in this session on how to teach to Texans. And, of course, I'm a brat then. I'm still a brat, but I was even more bratty then. So, I was going, okay, well, how do I explain inverse electron demand deals all there? Normally, Homo, we want to lower the Lumo dienophile, but sometimes you do it the other way.

8:54How do I explain this to Texans as opposed to other people on the planet? And, of course, these were people with masters of education going, whatever. But I learned something in that class, that there's a lot of subnationalism in Texas. Texas people are really proud of Texas, more so than California people were proud of California where I grew up. And I learned that in Texas, everything is bigger. And I had been doing research on blood pigments for my PhD.

9:27In fact, actually, most of my education. And those are the technical name for those porphyrins because of their purple color. They were named porphyrin and porphyria or diseases with these. But then I realized I should probably make something that's more local. So we set out to make one that was bigger. And we finally did that. And that was really the first structurally characterized, a larger version of a blood pigment.

9:59So people had worked on these a little bit, including the famous R.B. Woodward, who had made one as a byproduct during his Nobel Prize with earning or winning synthesis of vitamin B12. But nobody was really playing with them. And so this was kind of a moderate big deal. And we were contacted by Chemical Engineering News, which is kind of a professional rag. And, of course, in the primary literature, we couldn't call it that.

10:30So we call it an expanded porphyrin. And they said, well, what's the real pet name? And I said, well, texaphrin. And all papers are subject to what's called peer review. And they said, well, please get rid of this name. But fortunately, we were able to get it into the literature. And then it stuck.

10:48Wow. Who knew adopting the everything is bigger in Texas mentality would lead to the groundbreaking development of texaphrin? Yeah. And the fact that texaphrin molecularly resembles Texas is also a nice touch. Hey, Dr. Sessler mentioned that texaphrin was an expanded porphyrin. Do you mind breaking down exactly what a porphyrin is and what makes an expanded porphyrin special? Yeah, for sure. So porphyrins are a group of organic compounds that play a vital role in biology, and especially in our own biology. Porphyrins are the building blocks for heme, which is a component of hemoglobin,

11:23the protein that carries oxygen in our blood and also gives our blood its red color. These molecules are characterized by a ring-like structure that allows them to bind metals, which is crucial for their function. Got it. So porphyrins are essential for aerobic life due to their key role in oxygen-related processes. Exactly. Now, an expanded porphyrin is essentially a larger version of these molecules. By increasing the size of the ring-like structure, scientists can explore new properties and potential applications to porphyrins.

11:53And Dr. Sessler used this idea to create texaphrin by taking the foundational design of a porphyrin and giving it a texaphrin-sized upgrade. So the bigger the molecule, the more room there is for innovation and creativity? Yep. Expanded porphyrins can interact differently with metals and other molecules, opening up new possibilities in fields like medical imaging and cancer treatment. Wow. Thanks for the help. No problem. Hey, Dr. Sessler mentioned that he studied blood pigments for the majority of his education.

12:23Do you think that's where he got the inspiration to create texaphrin? Yeah, that's a great question. I'm also curious about what drew Dr. Sessler to study porphyrins in the first place and how that journey led to texaphrin. So all this came about in part because when I was a Ph.D. student, I went to Stanford not just for chemistry, but for the potential need for chemotherapy. So when I was a senior at Cal Berkeley, I was diagnosed with stage 3B, Hodgkin's lymphoma.

12:56So I spent my senior year doing radiation therapy. I barely graduated because by the end I was not so strong. And then I, at the time, M.D. Anderson had not really come on the scene. And there were two major cancer centers in the United States. One was Memorial Sloan Kettering in New York, and the other was Stanford Medical Center. So I decided I would go to either to Columbia, where I got to meet the famous Gilbert Stork once, famous for his endamine chemistry and for his art collection and all that.

13:34And, but Stanford was closer to home, so I decided I would go there. And it was right across the street from the medical center, just in case. Sadly, my third year, I, disease relapsed. I spent a year now on chemotherapy, under the guidance of Richard A. Miller, who was a fellow, which is a young, somewhat independent doctor and researcher. And his research was on anti-idiotype antibodies, which led to foundation of IDAC that then got bought by Biogen.

14:12And that led to first antibody drugs, and something like 60% of new cancer drugs are now biologicals. So that all, but he was number two at that company. His big boss, Ron Levy, who's really one of the greats in biotechnology, not just for that, but for many other cycles. And he kept asking me when I was in grad school, you're doing all this research on blood pigments. How are you going to cure cancer with that? You have cancer. How are you going to cure cancer with that?

14:43And when we made these bigger texifrens, we thought it would be useful for that. And I went and talked to him about it. And it was actually pretty funny because the proposal on the topic had been rejected. And I was crying out of his shoulder during one of the follow-up checkups right before Thanksgiving. So I wouldn't miss teaching, go home, see my mom, who was still alive. The next day, Thanksgiving evening, calls on the phone.

15:13Got to talk to Jonathan. Your tests are fine. I read your proposal. We're going to start a company. So that led to the start of Pharmacyclics, which originally was based on that technology. Eventually, Pharmacyclics pivoted and developed Ibrutamide, which is seeing increasing competition. But a few years ago, it was the number four or five best-selling drug on them. So Pharmacyclics ended up being a big success, even though our compound initially did not get through the FDA.

15:48And now we're starting a new company. I'm trying to bring it back. Not so much as a standalone drug is, but a tumor-localizing carrier. So what's known to the porphyrin community, but maybe not to you, Neil, is that these larger amphiphilic molecules are taken up by cancer. And the teleological rationale or evolutionary rationale can be debated, but maybe it's they need these. They catabolize them, get the nitrogen, get the amino acids, get little pieces.

16:22But anyway, they're taken up well into cancer, and that proved true for the texaphrin. So the new company is based on using that as an alternative to an antibody drug conjugate. And we'll see how far that gets. It's truly inspiring how Dr. Sessler's personal battle with cancer fueled his scientific journey. Battling cancer while finishing his degree definitely took a lot of effort and determination. Yeah, no doubt about that. And Richard A. Miller's role in Dr. Sessler's exploration of expanded porphyrins was also pivotal.

16:53Definitely. It marked the early beginning of Pharmacyclics, which became a huge success despite the initial expanded porphyrin not making it past the FDA. So Dr. Sessler mentioned using an expanded porphyrin like texaphrin to act as a tumor-localizing carrier for a drug conjugate. Why is he using the molecule as a carrier rather than a standalone drug? So cancer and expanded porphyrins, like texaphrin, have an interesting interaction in which the cancer cells tend to take up these larger molecules, possibly for growth or metabolism.

17:26Okay, I can picture it now. Since expanded amphiphilic porphyrins can interact with both water-loving hydrophilic and fat-loving hydrophobic substances, they're taken into the cancer well and super versatile for curing drugs or other therapeutic agents. Exactly. Molecules like texaphrin can act as a delivery truck, potentially transporting treatment directly into tumor cells while leaving healthy cells relatively untouched. Even though much preclinical and clinical testing will be needed to confirm or refute this expectation,

17:58it's still a cool concept to think about. Thanks for helping me break that down. Yeah, for sure. You know, Pharmacyclics is still on my mind. I think it was amazing how Dr. Sessler and Richard A. Miller conceptualized the drug and turned that vision into a company. Do you know if Dr. Sessler shared any advice on starting a biotech company? He does. He mentioned it in his interview. Let's hear what he has to say. So you need a few investors that really believe in you. And the investors, from my experience, they're first and foremost looking at personnel, whose management,

18:33because they figure good people will find a way to win. And Pharmacyclics with Richard Miller was a case in point. So the texaphrins didn't make it. But Darren Magdo has actually just texted me and will come in for the eclipse, I hope. He spent two years looking for backup compounds and found a way to make this a huge success. So they look first at that. Then they look at the upside potential. They're not worried about losing their money. But they want to know if this works, how will we make a billion dollars?

19:07Will this be a blockbuster drug that changes the landscape of science and medicine or if you're in the biotech? And only at the end, they look at what's your intellectual property, so what's the competitive risk, what's the technical risk. But these are way down compared to people. So investors prioritize leadership and potential for massive returns. It's a bit refreshing to know they are less concerned about the technical risk up front and more about the human element and market potential.

19:42Exactly. It's all about having a team of investors you can trust to navigate challenges and seize opportunities. An example being how Dr. Darren Magda spent two years searching for backup compounds when texaphrins initially didn't work. And pharmacyclics found a way to turn this to a massive success. One thing that Dr. Sessler said that stuck with me was, good people will find a way to win. It's a great reminder that in biotech, character and resilience are just as important as the science itself.

20:12Other than Dr. Sessler's current work in developing another biotech company, I'm curious about what kind of research projects he's currently doing in his lab. Yeah, same here. Let's hear about this straight from him.

Current Research Projects

20:22Yeah, so we have a whole bunch of these and almost every graduate student or postdoc, often they work in teams, have their own project. So one of them is really pushing this antibody drug conjugate or texaphrin drug conjugate alternative to antibody localization, where we're trying to use texaphrin to bring toxic species glorified rat poison, like platinum drugs, more specifically to a cancer environment.

20:55And that's a major theme, and that's been largely supported by the National Cancer Institute. We are trying to develop a new idea of small molecules that trigger the immune system. Matthew, one of my graduate students who's really, along with Sung Jung, pushing that idea. And we have found that a small molecule, that if you inject it along with cancer and come back a week later and give new cancer,

21:29largely the new cancer doesn't grow. And we think this is the best thing we've done. And that proposal, we've submitted that for funding to different agencies, including CIPRIT twice, NIH twice, and just completely hammered. And they say, oh, this will never work. It can't be done. And Pharmacyclics was founded because that was the reaction to texaphrin early on. And fortunately, Richard Miller believed in me and knew some VCs from contacts with IDEC. So I think that's the best thing that we're doing right now, but nobody else agrees with me yet.

22:05So either we're really visionary ahead of the world or we have something that's really bad. Time will tell. So that's the second major project.

22:16Critical materials are a big deal in our group. So we are looking, we have a project on trying to make lithium hydroxide, battery-grade lithium hydroxide from brine. And that's joined with my colleagues, Zach Page in chemistry and the great Benny Freeman in chemical engineering, who's really an expert on membrane technology. We're trying to figure out a way to make it more selective for lithium. And other critical materials include cobalt, nickel, things like that.

22:49And the same postdoc who really has been trying to launch the lithium is working on that. And then finally, Gabe Juarez is working on radioactive lanthanides and actinides. And so he makes molecules here, spends the summer in New Mexico at Los Alamos, trying to feed in radioactive elements, capture those. And those same sort of capture agents were trying to work with Brian Davies, Andy Ellington, Manish Kumar, to try and combine biological frameworks with small molecule capture agents as an alternative to polymers or liquid-liquid extraction.

23:35We think it might be cleaner. So those are major projects going on in the group. Wow, Dr. Sessler's lab is tackling a wide range of research projects. It's impressive how each one focuses on a different area, really highlighting how interdisciplinary and expansive chemistry can be. Yeah, I agree. Also, it's nice to see that one of his research groups is investigating texafrin as a localizing character for a cancer drug conjugate, a possible area of study he mentioned earlier. I found Matthew's project really fascinating.

24:05The idea of a small molecule triggering the immune system could be a game-changer. It's exciting that injecting these molecules into existing cancer cells seems to prevent new growth. I can see why Dr. Sessler compares this to texafrin and pharma-cyclics. The potential is insane. Dr. Sessler mentioned critical materials, like lithium, when describing one of his research projects investigating creating battery-grade lithium hydroxide from brine. Could you break down what critical materials are and how they relate to this lab?

24:36Yeah, of course. So beyond this discussion, you might have heard the term critical materials before, and it's for a good reason. They're essential for everyday technologies, and their demand is only increasing. That's exactly right. Critical materials are fundamental to clean energy technologies, like wind turbines and solar panels. You can't manufacture them without critical materials. They're called critical because their supply chain can be vulnerable to disruptions, whether due to political, social, or basic availability issues. Exactly. And this ties into Dr. Sessler's research group because lithium hydroxide is a vital component in lithium-ion batteries.

25:12By extracting it from brine, Dr. Sessler's research group is exploring a sustainable approach to obtaining this critical material. Right. This project isn't just about pushing technological boundaries. It's also about ensuring we have reliable access to these crucial materials while minimizing environmental impact. It's inspiring to see students doing their own research, like how Gabe Juarez is experimenting on radioactive lanthanides and actinides with capture agents. And the extension of this theme to developing an alternative to liquid-liquid extraction by integrating biological frameworks with capture agents is a massive plus two.

25:50Those projects that Dr. Sessler is currently working on are very creative and innovative. Is it something that he's actively trying to implement into his work? With Sessler's successful career in both the biopharma industry and academia, Dr. Sessler has been a strong advocate for innovation. I'm wondering if he speaks on this. He sure does. Here's his view on innovation in science. The world in science needs people who are very detailed orient, come along and figure everything out to the third decimal.

26:22And then you need people who are sort of creating ideas and that you can survive and succeed by being either first or best. And I was saying if you're first and best, and I've met a few people, then they're getting the call from Stockholm. And for me, it was always easier to try and be first. I guess I would emphasize there's so many ways to win. There are probably more ways to fail. But if you're be yourself, as I said, do what you love and do it well, you'll plot a path to success.

26:55And it may be different than anyone else, but you'll get there. It'll be fun. That's some good advice. I resonate with his words to be authentic in your work. I'm curious. Does Dr. Sessler have any more words of wisdom for our audience or those wanting to get into scientific careers? Yes, he does. Let's hear from him. Yeah. Do what you love and do it well. The other little bit of advice, which probably doesn't hold up to everybody, would be worry less and work more.

27:27And there are three real things that go into success.

27:32Your brain, which you probably inherited from your parents. Good luck, which comes from the man above or woman above. Allah, Elohim, whatever, Christ, whatever name you wish. And hard work. And of these variables, only hard work can you control. I agree with him. You can only control certain characteristics like your work ethic. So why not do it to the best of your ability? Now that this episode is coming to an end, we would like to thank Dr. Jonathan Sessler for giving his insights into porphyrin chemistry, biopharmaceutical industry, and his unique story and research.

28:08We would also like to thank you for tuning into this episode. This has been your number one source of talking chemistry. Let's talk chemistry. Until next time. Bye. Thank you for listening to Let's Talk Chemistry, a podcast by Chemtalk. We hope you enjoyed it. For more information on today's episode and countless chemistry resources, please visit our website at www.chemistrytalk.org.

28:38Let's Talk Chemistry, a podcast by Chemtalk.