Chuan He on The Pulse Podcast: Epitranscriptomics & Biotech

Full Transcript

0:11Tanner

From the Gordon Center for Integrative Science at the University of Chicago, this is the Pulse Podcast. I’m your host, Tanner Baldwin. The Pulse dives deep into the most interesting biotech stories and features world-class biotech leaders. This podcast is brought to you by the Harvard Biotech Club, a trainee-led organization on a mission to bridge the gap between academia and industry.

Today’s guest is Dr. Chuan He. Chuan is the John T. Wilson Distinguished Service Professor in the Department of Chemistry and in Biochemistry and Molecular Biology at the University of Chicago. He is also an investigator of the Howard Hughes Medical Institute, and his research sits at the intersection of chemistry, biology, and medicine. He is widely recognized as one of the pioneers of the field of epitranscriptomics. Chuan received his Bachelor of Science in Chemistry from the University of Science and Technology of China in 1994. He earned his PhD in Chemistry from MIT in 2000 and then completed postdoctoral training at Harvard before joining the University of Chicago faculty in 2002. Over the course of his career, Chuan has transformed our understanding of how chemical modifications on RNA regulate gene expression. His work showed that RNA methylation is reversible — a discovery that opened an entirely new area of biology and has had major implications for cancer development, plant biology, and other fields. In recognition of these contributions, he was awarded the highly prestigious Wolf Prize in Chemistry, as well as the Tetrahedron Prize and the Falling Walls Science Breakthrough of the Year in Life Sciences Prize. We are thrilled to have Dr. He with us today.

Chuan, thank you for joining us!

1:48Chuan

Well, it’s great to see you again, Tanner.

1:50Tanner

This is a special episode of the Pulse, because we’re here in the beautiful Gordon Center for Integrative Science on the campus of the University of Chicago. This is our first episode taking place outside the greater Boston area, and we feel really lucky to have you as a guest. It’s a testament to how far the Pulse Podcast has come in such a short time, thanks to the hard work of the Pulse team.

But before we start discussing your scientific accomplishments and your future plans for translating that science into biotech advances, I’d love for you to start by telling us a little about your background — specifically your upbringing, and what originally inspired your interest in science.

2:30Chuan

Yeah. Well, first of all, Tanner, thanks for involving me in this program. It’s really a pleasure. I get asked that quite a bit.

I grew up in the mountain areas in the southwest of China. My parents graduated from college back in the ’60s, and they were assigned to work for, I would say, the manufacturing industry deep in the mountains, because that was during the Cultural Revolution. There were tensions between the Soviet Union and China, so the Chinese broke many of their manufacturing operations in half. One half stayed in the city, the other half they moved into the mountains just to back up whatever was in the city. So that’s where my parents went.

It turned out that many, many college graduates were assigned to work in these different units, so the average education level there was way above the rest of China. And I think growing up there, having an environment filled with intellectuals and diverse people from different backgrounds — that’s what was stimulating, I think, early on. You hear about Einstein, you hear about physics, the Big Bang. We’re talking about the ’70s and ’80s, right? With limited exposure to any other kind of entertainment.

So that kind of shaped my early days. I was like, “Ah, I want to be a scientist.” From there it became pretty much a straight line. I went to college and was determined to come to the US, because that’s where the most exciting frontier science was done. I came to get my PhD training at MIT, did a postdoc at Harvard — so I lived in Boston for seven years. And I started my career in Chicago, and I’ve stayed in Chicago since. So that’s a simple, interesting path, I guess.

4:58Tanner

It sounds like from an early age you were in a very intellectually stimulating environment. Were your parents academics? Did they have any sort of scientific affiliation?

5:11Chuan

Not really, but my dad is a physician — he graduated from med school. My mom was a chemist, but the facilities we were in were really manufacturing plants, so my mom did not really practice her own science. It was a very bizarre system, I would say. People were not very happy; they were just basically packed there.

But I did get exposed to all kinds of interesting people and different thoughts. When we were young, there were telescopes — we would look at the stars, this type of thing. You definitely got that exposure.

6:04Tanner

Did you ever consider following in your dad’s footsteps and going to medical school, or did you always know you wanted to do science?

6:11Chuan

Well, the first thing my dad told me is: don’t be a physician. Back then, physicians in China were respected, but it was more of a service role. I think the young kids there always had this desire to get into science and be the next Einstein or something. It’s every kid’s dream, right?

6:44Tanner

Absolutely. You mentioned being drawn to the States and the cutting-edge research done here. Of course, you conducted research at MIT and at Harvard, and ultimately you ended up at the University of Chicago. Is there a specific reason you ended up here?

7:07Chuan

I was actually toward the end of my first year of postdoc, and my PhD advisor just wrote me an email that said, “Go find a job.” I was like, “Okay, if you think so, let me go find a job.” And I always joke that the University of Chicago made a mistake when they hired me.

I ended up here, but I want to say — I’ve said this a few times — I really regretted my decision, because I should have stayed as a postdoc for an extra year or two. When I came out after 20, 22 months of postdoc, I didn’t feel like I was experienced enough in biochemistry or biology. My PhD training was pretty much in synthetic inorganic chemistry and organic chemistry, but in my postdoc I had started doing biochemistry, structural biology, a little bit of molecular biology. So I was not ready. But I was also lucky I was able to come to Chicago and grow in this wonderful environment.

8:14Tanner

I can imagine that having a diverse background at times can be a strength. Have you found that’s true, or did you feel like maybe a few more years as a postdoc specializing in chemical biology would have been more productive?

8:31Chuan

I think it would have been more productive. Back then, there were far fewer people with cross-disciplinary experience than today — it’s very common now. We’re talking about 26 years ago. I think I did not receive enough biological training during my postdoc, just because it was short. There was a lot more I could have learned from that lab.

So when I started at the University of Chicago, I really went back to synthetic chemistry and played with structural biology and a little bit of microbiology. It took me five, six years to get tenure. Only after tenure did I make the decision that it was time for me to switch. But I think in those five, six years I’d learned enough biology by working on microbiology, biochemistry, and DNA damage repair in my own lab. I gained enough confidence and background to tackle bigger questions.

9:33Tanner

Yeah, absolutely. Whatever lack of experience there might have been at the outset, I think you’ve certainly been able to make up for it and then some.

Now you’re at the University of Chicago — at what point did you become interested in nucleic acid modifications? At what point did you begin researching this question of RNA modifications? These were known previously for many decades, but your work opened up this whole new idea that they were reversible and dynamic. Can you tell us a little about how you got interested in that question?

10:20Chuan

Yeah. When I did my postdoc work, I was working on DNA damage repair. I basically picked Professor Gregory Verdine’s lab and learned all the DNA methylation repair. I was working on the Ada protein, a transcription factor in E. coli that regulates ada itself, alkA, alkB, and aidB. That was my postdoc work, and I became very interested in AlkB, because at the time computational analysis suggested this was a metalloprotein — an iron protein that may perform oxidation. With a metals-in-biology background — my PhD training was as a synthetic inorganic chemist interested in mimicking enzymes, particularly iron and copper enzymes — I was drawn into this, and I wrote a job proposal to study DNA damage repair, particularly oxidative demethylation repair. At the time that was something very new.

My lab spent the next five, six years really adding different pieces into this very novel DNA damage repair mechanism. So we’d been doing interesting DNA modification chemistry and biology from 2002 to 2008.

2008 was the time I got my tenure, and I always say this — it’s actually true. The day I got tenure, I thought about it and made the decision to close many parts of the lab: pretty much shut down the entire program. That takes time, because you have students and postdocs. But I made a decision that I was just going to shut down pretty much all the programs. We had done very well, I would say, in structural biology of DNA damage repair, microbiology, metalloproteins, and some synthetic work.

Looking for new areas of interest, I was lucky to talk to my colleague Tao Pan, who’s an RNA biologist. We kept talking almost every other week and came up with several ideas. We thought about RNA imaging, and then we realized there were good people working on RNA imaging already. Then we thought about RNA modification. And the third topic was actually snoRNA — Tao brought that up, and just a few years ago we started to work on snoRNA.

But at the time, when I looked at that and at my expertise, I realized chemical modifications on RNA were a very interesting subject. So that was the area I put effort into. And in science you also need to be lucky. We were working on FTO at the time, because it had been proposed to be a DNA damage repair protein involved in obesity and diabetes. It took a couple of years for us to realize that its real substrate is RNA methylation — and then the rest is history.

13:49Tanner

It sounds like acquiring tenure in 2008 was a pivotal moment for the lab. On one hand you’re shutting down certain focuses, but on the other hand you maybe have more flexibility to take more risk and work on an area that fewer people are working on.

14:12Chuan

Yeah, I think there were two factors. Number one, of course, you get job security. That’s a big one. That’s important. You get that monkey off your back.

The second part was that back then there were mechanisms to support ideas with no preliminary results. We had the EUREKA grant from NIH — $200,000 a year, Tao and I. I also had a Keck Foundation grant, about a million for five years. We’re talking about almost 20 years ago, and the money went much further than today. With that financial support, we were able to spend three, four years working on something we didn’t know was going to pan out or not.

15:05Tanner

So, very long story short, it ends up that it does pan out. With this FTO discovery, I was wondering if you could expand on that a little and why it was such a big discovery?

15:21Chuan

I think this goes back to epigenetics, and back to the complexity of humans. We each have trillions of cells and 200 different cell types, depending on who you talk to. But we all came from a fertilized egg. What that means is that in the majority of our cells the genome shares pretty much the same sequence — that’s 3 billion base pairs. So we’re talking about 3 billion base pairs encoding the complexity of trillions of cells, 200 different cell types, and thousands of cell states, if you think about stem cells, progenitor cells, cells under stress, and so on.

Now, what encodes this complexity? It has to come down to certain modifications on DNA and histones. And on top of that, there are also RNA modifications. Before our work, we all knew DNA modifications and histone modifications are very important to encode the complexity of the genome, and that post-translational modification of proteins makes millions of different forms of protein. That’s where the complexity of life comes from. People tended to pay less attention to RNA modifications. The thought back then was that RNA modifications fine-tune RNA structure. We proposed in 2010 that RNA modifications can have similar regulatory functions.

And I think the discovery of FTO as a demethylase really showed that FTO is such an important protein — a gene with very significant phenotypes. If you knock it out in mouse, it can be lethal. Surviving mice have slower development. It’s associated with energy metabolism, and so on. So everything suggests this is a regulator of diverse physiological pathways, and yet it is actually an enzyme that removes an RNA modification.

I want to emphasize that the modification itself is also particularly interesting. This is N6-methyladenosine. It was discovered back in the 1970s and is the most abundant modification on mammalian messenger RNA. If you count, there are about two or three per messenger RNA. About 40% of messenger RNAs could be modified, so the modified ones carry four or five of these. But back in the ’70s and ’80s, because of the lack of molecular cloning and all the modern technologies we have, people didn’t really know what these modifications did. These are low-abundance RNAs.

And then later on, the fact that FTO reverses this suggests a broad regulatory function — and later we found this has a profound impact on pretty much every biological process. In the last four to six years, we’ve further shown modification on chromatin-associated RNA that shapes transcription, and so on. I would say this is a new way to look at gene expression regulation, and this new layer of regulation seems to impact pretty much every biological process.

18:46Tanner

It was definitely a profound discovery that introduces a whole new paradigm — the complexity and the diversity in regulation that is applied on the DNA level also applies to RNA. And with that FTO discovery, it introduced the idea that these modifications are highly dynamic and have very profound impacts on things like cancer and plant biology.

It was your work that kicked off this whole journey. Can you tell us what it was like being there at the beginning and then following this field as it’s grown and matured? And maybe some of the challenges of pioneering a field when there are no established ways of studying these things — when not a lot is known. It was your work largely that built out a repertoire of tools to study these modifications. And also, what motivates you more: the biological question, or developing the tools that could unlock an unknown biological question?

20:09Chuan

These are very important questions. Very interesting questions. Early on, you get this excitement because you suddenly realize you’ve opened a door — there’s everything you can explore. The challenge is which one you really hold on to. Which one will have broad, long-lasting impact?

We went to the m6A binding proteins, the reader proteins, because we reasoned that by delineating regulatory pathways we could describe to the community how these modifications impact fundamental RNA processing, and then people could take this into their own fields — cancer, immunity, stress response signaling — and see how it plays out.

There were other challenges at the beginning. Because my training was not in RNA at all, we had to learn everything. That was a lot of challenge. We did not know the histories. We were not really familiar with the literature. That creates many challenges, and sometimes maybe confusion within the field, but I think we handled it well, and at the end of the day we were able to help build the field and really demonstrate the broad, profound impact of this regulatory pathway in diverse biological systems.

Regarding the last question, I think it really needs to start with the biology. But often the new biology is driven by new technology — we all know sequencing, mass spec, imaging. These are the things that really accelerate biology and open new areas of biology. I would actually emphasize both. My lab is absolutely a method development lab, but we often have our own biological questions. Because of that biological challenge, we go back and ask: can we develop methods to help us unlock it?

22:25Tanner

Do you think it’s a particular advantage of yours to have both of those under one roof? On one hand you have members of your lab who are experts in these new tools, but you also have those who are maybe more interested in focusing on the interesting new biology. How do you see that playing out in your work and in the collaborations between your lab members?

22:56Chuan

Definitely, definitely. As I said, sometimes you have a biological challenge and then you come back to develop methods. But there are also other cases. You know I’m a chemist. I dress like a biologist, but inside I’m a chemist — and a biologist too, I would say. Sometimes you just have a very interesting idea you want to test out, and you don’t know what it’s going to be used for.

For example, we developed this azide-modified click chemistry — I thought it would be cool for labeling single-stranded DNA. And then we developed KAS-seq, which can really map transcription. By the way, I think a lot of people should take a look at KAS-seq; it’s really good for transcription mapping. And we could never have imagined that it would become the key later on for us to study RNA–RNA interactions, which is now a major part of the lab.

So as you said, having both under one roof allows you to think, “Ah, I’ve got this method, and I’ve got this scientific challenge. Maybe I can modify the method further and use it to help me solve that challenge.”

24:13Tanner

Absolutely. And you’ve had a lot of success doing both — answering interesting biological questions and developing the tools that are pushing this new field forward for others to use and make important breakthroughs with. You’ve deservedly won many prestigious prizes, including the Wolf Prize, which is often thought to be a precursor to the Nobel Prize, the Falling Walls Prize, and many others.

After such an illustrious career as an academic, in recent years you’ve turned some of your attention toward translating these really important and exciting scientific breakthroughs into potential therapeutics and diagnostic tools. Could you tell us a little about some of those efforts, and what you’re most excited about?

25:09Chuan

In the last 10 years, we’ve shown that RNA modifications — epitranscriptomics pathways — regulate essential biological processes, and that their misregulation affects human diseases. In our hands, it really affects stem cell differentiation, development, proliferation, and also the immune system. We would like our research to add new knowledge, but on the other side, I also try to emphasize that you want to impact society. On that front we’ve spent a lot of effort lately. We’re trying to really show these discoveries can impact patients.

We ourselves have been looking at cancer therapies, immunotherapies, diagnostics as you said, and also plant biology. And there are other efforts in the community — clinical trials targeting METTL3, targeting m6A binding proteins and erasers. My prediction is that in the next three to five years we’re going to see a real burst of interesting clinical results that I hope will validate our basic research.

26:33Tanner

Your work follows a similar trajectory to the academic community as a whole, in the way that the barriers between academia and industry have broken down in recent years. Can you tell us a little about your philosophy for your students? Do you have any words of wisdom for trainees who want to do really interesting and exciting science, but of course also want their work to have direct impact on patients’ lives?

27:20Chuan

Yeah. First of all, when you receive academic training, you want to become an independent thinker. That’s number one. Number two, always keep in mind — you have to ask yourself — where is my value? Where is my innovation? You bring in value because you either have an innovative approach, an innovative idea, or you’re capable of catalyzing that. These come from your academic training and your research.

From there, you want to become open-minded, and keep in mind that research and translation are two connected but very different things. Research is about uncovering new knowledge and developing new tools. Translation is about directly solving medical problems. The second is much more targeted: you have to show you can solve a real-world problem, otherwise your program is going to die. Unlike the first one — as long as you’re doing interesting science, you’ll be supported — the second one is not the case. If you don’t have market value, you disappear. It’s a very simple game.

So you want to have your value from your training and your innovation, but when you go to the real world you really need to ask yourself: what are the problems or questions I can solve that have real market value?

27:20Tanner

Do you find it challenging at times to balance responsibilities relating to your work in industry with your work as an academic and as a mentor? Very different priorities.

29:17Chuan

Yeah, that’s a great question. We’re setting up a therapeutic discovery institute here at the University of Chicago. We’re known for basic discoveries; now we’re trying to make social impact. We ask exactly the same question.

From my point of view, there needs to be a wall in between. One side is the academic exercise, which is what we’re supposed to do. That’s innovation. What’s unique about you? Why you? What can you bring that leads to a new therapy? That’s the free-spirit innovation.

On the other side is translation, and the scope there needs to be defined by industry, not by professors. There are very few people who fully understand both academia and industry and can go back and forth. There are several in the Boston area — very good names everybody knows. But you have to really learn from failures and mistakes to understand.

Again, it comes back to everybody doing their own job. As a professor, as an academic researcher, you innovate new science. In industry, you execute, with a clear goal and a clear exit strategy — bringing this eventually to the bedside.

30:48Tanner

Absolutely. You definitely want some element of specialization. I think you’re right: if there’s too much blurring of the lines between academia and industry, there’s also a blurring of those different motives — motives that maybe shouldn’t be blurred. A profit motive versus a motive to pursue truth above everything else. I think that’s very wise advice.

31:15Chuan

I also want to say that there’s a trend of incubating biotech directly from university labs, and I think that’s going to be the future as well, because we’ve got everything. We’ve got the entire machinery set up for translation: we have VCs, early stage, mid stage; we have pharma. So incubating something is not that difficult anymore. And I think the days when you get $30, $40 million to start something completely new are also not financially feasible.

I think we’re going to see a lot more incubation in a very flexible mode, particularly because federal funding has been challenging. We’re going to see a lot of labs involved in early-stage validation of ideas and early-stage incubation of new ideas. That lab has to make the innovation, and then deliver that innovation to the next stage before a real biotech takes over. I think we’re going to see a lot of those.

32:31Tanner

Definitely. Almost as if there is a wall, and you want it to be semi-permeable to some degree.

32:40Chuan

At least communication between. Exactly. That wall is set up because there are two different mentalities. However, there needs to be flow — and there’s going to be a lot of flow. I think that wall is particularly important as we go into the next era, in which a lab is going to incubate projects and the professors need to realize what their research is versus what the real product is.

33:04Tanner

Definitely not always easy to know at the outset. A lot of these therapeutics — something like 10% ultimately get to approval.

33:14Chuan

More like 5%.

33:15Tanner

Yeah, maybe less. Is it safe to say that you see these issues with federal funding potentially leading to a new paradigm in the way academia relates to industry, with industry picking up more of the slack of the basic, foundational research? Is that something you see persisting and being good for the future of science and industry?

33:47Chuan

Yeah, I’ve thought about this for years. We rely so heavily on federal funding, and federal funding has played such a transformative role in advancing science and technology in the US, because basic research is really the key to everything. I think federal grants should continue to play that essential role.

In the future, I picture three funding sources. First, for the enterprise as a community, federal grants have to be strong — that’s the foundation. Second, philanthropy: foundations and gifts. I think that has kicked in a lot, like Howard Hughes and different foundations. And third — like Scripps and other institutes — we also need to have a portion of our labs, or a portion of our own research, directly connected to industry.

This just depends. There are PIs interested only in basic research — perfect. But we also emphasize heavily the PIs who are interested in bridging basic research to translation. There’s nothing wrong with that, and it will really show the impact of basic research. So I think everywhere we’re going to see the buildup of that type of hire and that type of lab, and in some of our own labs we’re going to have some projects working directly with industry to solve major questions there.

36:52Tanner

You raise a good point that we’ve faced some challenges recently with federal funding, but there’s an argument to be made that collaborations between academic and industry resources are at the very least an underutilized resource. So maybe these difficulties we’re having now are an opportunity to reevaluate the underpinnings of how science is driven.

Ultimately, you’ve had this amazing career as an academic, and in recent years you’ve made moves in industry as well. If you could go back and chart your course anew with hindsight, would you do anything differently?

36:28Chuan

I would like to have learned the industry part in a more gradual way. I was rushed into it in two cases — I don’t want to name them — almost against my own will, and neither of those worked out well. I’d like to have engaged more naturally.

I think our younger generation of faculty and PIs are different. They grew up in this era. They naturally started to embrace industry. There are opportunities for them: they talk to VCs, they watch how companies are set up. As I said, this is almost like research — if you don’t fail, you don’t learn. I would have liked the chance to sit on an advisory board or have direct interaction with industry in a minor role at the beginning, to learn and experience it for a few years before fully immersing myself in something.

36:28Tanner

I think that’s good advice. Just as you said, as the scientific enterprise becomes more interdisciplinary, it’s important for students to keep up with those changing times and to some degree have a diverse training experience.

Just to wrap up, I’d like to ask some more light-hearted questions. When you’re not doing science, what do you like to do?

38:09Chuan

Well, I like to travel a lot. My wife and I travel the world. We take our kids — we went to Iceland and Norway, hiking. Just experiencing the world. It’s the same curiosity as in science, but curiosity about the other part of the world: new science, the culture, how people live there.

36:28Tanner

Absolutely. If you couldn’t be an academic, what would you do for a living?

38:45Chuan

Not going to play soccer, as you know. Tanner is a great soccer player. No, I always joke that my ideal career would be coaching a football team. I’d love to do that.

38:58Tanner

Awesome. Do you watch a lot of soccer?

39:01Chuan

I watch soccer, but I watch a lot more football — American football. That’s my sport.

39:07Tanner

Do you have a favorite team?

39:10Chuan

I’m sorry to say I’ve been a Patriots fan for 30 years. And maybe the Chicago Bears come in as a close second. I bike down to watch their games, but they’re going to have a new stadium, so hopefully I can still go.

39:36Tanner

That’s great. Is there a book or any piece of media that you would recommend students listen to or read — something that had a profound impact on your career journey?

39:54Chuan

Not particularly, actually. I’m sorry to say that. But I do have a piece of advice: I advise undergrads to get into a lab as early as they can if they’re really interested. Hands-on experience is better than taking a hundred different classes.

40:13Tanner

Yeah, there’s really no book that could ever replace being in the lab.

40:18Chuan

And also, if you want to do translational work, just spend an internship in a company, or work on a project. Again, hands-on experience, real-world experience, is so important.

40:31Tanner

Yeah, absolutely. Well, thank you for taking the time to sit and chat with us. Really appreciated it.

40:39Chuan

Thanks, Tanner. It’s great to have you come back and great to see you again. Good luck.