Fishing for Answers with Robert Tjian

The professor of biochemistry on the intersection of science and entrepreneurship
By Pat Joseph

The surname is cognate with Chen, Chan, Tsien, etc., but almost everyone calls Bob Tjian “Tij”—like teej. He picked up the nickname in junior high in New Jersey, where his family had arrived from China by way of Brazil. He and his eight siblings, of whom he is youngest, spoke a polyglot mash-up of Chinese, Portuguese, and English. “We’d start a sentence in the first language and end in the third,” he says. “No one could understand us except us.”

It was as an undergraduate at Cal in the late ’60s that Tij discovered biochemistry and first met the late Dan Koshland, whose lab he talked his way into, despite having taken no courses in the subject. Koshland became not just his professor but, as Tij later wrote in a memorial, his “hero and best friend” as well. 

After graduating from Cal, he left for Harvard, where he earned his doctorate, and Cold Spring Harbor Laboratory, where he did postdoctoral work under Nobelist James Watson, famous for his role in elucidating the molecular structure of DNA. He returned to Cal as faculty in 1979. 

In addition to being a professor and preeminent scientist—winner of the Passano Award, the Louisa Gross Horwitz Prize, and the Charles-Léopold Mayer Prize, among other honors—Tij has also distinguished himself as both an administrator and an entrepreneur. As president of the Howard Hughes Medical Institute from 2009 to 2016, he oversaw a multibillion-dollar endowment in support of biomedical research. As cofounder of drug development companies Tularik Inc. (later acquired by Amgen) and, more recently, Eikon Therapeutics, he has long been at the leading edge of the biotech industry. 

On top of everything else, Tij is a devoted fisherman who has traveled the world with his fly rod. Tularik took its name from a stream in Alaska’s Bristol Bay watershed that boasts world-class fishing for rainbow trout. He was first introduced to the sport by Horace “Nook” Barker, of Barker Hall fame, who took him fishing in the Sierra. As he says in the conversation that follows, fly-fishing, to him, is like science. 

This interview has been edited for length and clarity. 

Why did you first come to Berkeley from the East Coast? 

Probably because I was naturally rebellious. In the high school that I went to in South Jersey, not that many people would go to college, and it was assumed that if you got into the University of Pennsylvania, which was right across the river, or MIT or Princeton, that you would go there. I did get accepted to all of those, but I decided on Cal. 

So you were already aware of Berkeley’s reputation as a radical campus? 

No, not particularly. I would say I was curious about coming to California. I’d had it with the East Coast, I guess, from the standpoint of both weather and culture, and I was looking for something new. It didn’t hurt that I already had a couple of siblings who had gone to Cal: Two of my sisters had just graduated, and my brother was just starting grad school.

Did any of your siblings become scientists?  

Nobody. They were either in business or architects and designers. And that’s definitely the genetic predisposition in my family; there’s a very strong tendency towards art and design.

And you? Did you come to Berkeley with plans to study science? 

I started off thinking I was going to go into math because I had a great math teacher in high school—the usual story. The best experience one has in coming to Cal is realizing that there are a lot of people out there way smarter than you. I lived in the Cloyne Court co-op, which was all about engineers and mathematicians and scientists. Very quickly, I realized that the level of talent here was so much higher and that math was definitely not my forte.

So, how did you find your way to biochemistry?

Even in junior high, when I first started taking biology, I seemed to have a knack for it. Chemistry, too, came to me very naturally. I really discovered that at Cal. My first research experience was with Dr. Jorgenson, the only female professor of chemistry at Cal at the time. And then I worked with a famous organic chemist, Henry Rapoport. But I didn’t find chemistry that challenging, so I started looking at biochem and molecular biology. That’s when I ran into Dan Koshland, and that accidental collision just changed my whole life.

Koshland led the restructuring of biological sciences at Cal and helped make it a hub for the field. How central has Berkeley been to the emergence of the biotech industry?

I would say UCSF and Berkeley were the beginnings of biotech, because the first two companies to form were Cetus, from Berkeley, and Genentech, from UCSF, very quickly followed by Chiron (Berkeley/UCSF). And, so, that’s two out of three. You can’t get much more in front of it than that.  

And yet I think Berkeley’s success there tends to get overshadowed in the public imagination by Stanford’s role in the tech industry …

They certainly weren’t first or dominant [in biotech] during that early period. That’s not to say that they haven’t absolutely done a great job of leveraging it since then, entrepreneurially, more effectively than we have.  

There does seem to be a real push at the University now to create a start-up culture around the life sciences. 

I think it’s happening, and I think it’s happening from the bottom up. A lot of students, from undergraduates all the way through graduate students and postdocs, want to see that happen. I think the junior faculty certainly are more prone to go into that translational side of things. 

But Berkeley is also different. We still strongly believe that fundamental discoveries are the best way to move technology forward, actually letting biology guide us. The CRISPR story is a classic example of that. Jennifer [Doudna] didn’t go into it thinking she was going to revolutionize biotech. She was more interested in RNA structure and function. 

I still think that’s the strength of Berkeley, but now it’s more balanced, with faculty realizing that just getting a publication may not be the ultimate endgame. 

Was there ever anything taboo about academics becoming entrepreneurs in your field? 

Oh, absolutely. I would say the vast majority of my colleagues were either uncomfortable with it or outright antagonistic to the idea. I never felt that way, because my father was a chemical engineer, and he combined science and engineering and the private sector his entire career. I didn’t see that as a morally bad thing to do. 

You’re known for studying gene expression and transcription control. Can you explain that for readers? 

It’s conceptually pretty straightforward. You know that DNA carries all the genetic information that makes any individual organism, right? And DNA is a double-stranded, long molecule. You have to somehow translate that information into usable molecules that keep you alive. You gotta make proteins, you gotta make RNA, you gotta make membranes … everything. It’s kind of like this little blueprint. The question is: What the heck is the machine that knows how to read that blueprint and make all the right pieces? That’s what I’ve been studying since I was a grad student. How does this process that has to go on in the entire lifetime of an organism—every minute, every hour, every day—how does that work? It’s the biggest puzzle imaginable. 

And does that puzzle relate to disease?  

In every way you can imagine. Name any disease, and I can show you why it ultimately comes down to the following: You’re making too much of something, you’re making too little of something, or you’re making the wrong version of something at the wrong time. That’s pretty much disease, right there.

So, how far have we come in our understanding of this?

I’ve been at it for 47 years, and I feel like I’ve learned a huge amount and like I know very little. I’ve slowly been putting together the parts list and their relationships to each other, but it still doesn’t tell us how the machine works.

One of the great things about a place like Berkeley is that, with the help of my physics friends, my engineering friends, my computation friends, my cell biology friends, I can start to address this question of not only “what” but “how.” 

Now, for the first time in the history of biology, I have a microscope that allows me to see individual molecules moving in real time. I went from looking at either dead cells or cells that are frozen, or snapshots of live cells, to all of a sudden having high-speed movies of what a cell is doing while alive. More importantly, I have resolution that allows me to look at individual molecules. I’m seeing something I could never see or measure before. That is what Berkeley is all about: allowing people like me to expand my horizons. I literally, completely changed the technological platform that my lab works on. It was transformational and disruptive. 

And now, with your lab partner, Xavier Darzacq, and Nobel laureate Eric Betzig, whom you recruited to Berkeley, you’ve founded a new start-up called Eikon Therapeutics, which will use this technology to screen for new drugs. If Eikon is successful, what will it look like? 

What I really care about is not only using my science to discover new therapies. I’m even more interested in developing methods that will set the course of drug discovery on a different path. If Eikon is successful, five years from now every pharmaceutical company will want to do what we’re doing. Right now, Eikon is so far ahead technologically that nobody’s doing what we do. Nobody would know how to. So, we’re going to have to somehow democratize that.

And this all hinges on this new microscope technology? 

It’s gone way beyond that. It’s a situation where big data analytics, machine learning, incredibly sophisticated microscopy, and the most sophisticated molecular genetics, including CRISPR, all have to come together with medicinal chemistry. And no one’s ever done it that way. We’re the first, and, of course, it’s extremely challenging, but that, to me, is what’s worth doing. And that defines a lot of what Cal does because we started at a very fundamental level, and then we’ve got to take it all the way to practice. That’s a very long road.

And it sounds like it would be tough for the private sector alone to accomplish.

Impossible. I mean, all the money and effort that Eric and Xavier have already spent in the last decade, getting our microscope technology to the point where we could even begin to imagine commercializing it—no company would ever do that on a regular basis.

I’d like to change subjects now from vocation to avocation. I understand that you’re a committed fly fisherman. What is about fishing that hooks you?

I’m a complete fanatic. Fly-fishing, to me, is like science: You never perfect it, you always learn more, and it’s highly unexpected. There are so many parts to it. There’s the fact that you’re almost always in beautiful, remote places. And then there’s something about that moment when that fish strikes your fly and you get that jolt. It’s like a drug.

There’s a line in A River Runs Through It about how it’s not fly-fishing if you’re not looking for answers to questions.

Exactly right. And you never completely find your answers either. I’ve been fishing for 60 years now, and I’m still learning. I just came back from a trip in British Columbia, and I, yet again, improved my casting in a way that was incredibly subtle yet made a huge difference—just a small change in the angle of my arm.

So, what about retirement? Are you going to fish your twilight years away or are you going to keep working at the bench? Or some combination thereof?

I like to joke with my students that they’re either going to carry me out of the lab in a box or I’m going to drop facedown in a river somewhere. Short of that, I’m not giving up. 

I think retirement is great if you’re working on a job that you think is a job. But if what you do is what you really want to do, even if you’re not getting paid, then why would you retire? 

I’ve never felt like I had a job. It was always what I really wanted to do. 

From the Winter 2021 issue of California.
Filed under: Science + Health
Image source: Courtesy of Robert Tjian
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