We met with Dr. Carolyn Bertozzi to discuss the thrill of scientific discovery, COVID-19, drug development, and much more. Enjoy!
Pioneering biologist/chemist Dr. Carolyn R. Bertozzi discusses glycobiology, bioorthagonal reactions, drug development, COVID-19, the thrill of scientific discovery, and working with students and postdoc researchers. Anne T. and Robert M. Bass Professor in the School of Humanities and Sciences at Stanford University and investigator at the Howard Hughes Medical Institute, Dr. Bertozzi talks with Dr. Jed Macosko, academic director of AcademicInfluence.com and professor of physics at Wake Forest University.
Once we got to see how powerful these chemistries were, it naturally sort of fostered other ideas for how to use the chemistry. And so in my own lab, we've used those reactions to make new kinds of chemically modified protein therapeutics. We make antibody drug conjugates using those chemistries.” – Dr. Carolyn Bertozzi
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(Editor’s Note: The following transcript has been lightly edited to improve clarity.)
Jed Macosko: Hi, this is Professor Jed Macosko at Wake Forest University and at Academic Influence, and today, I have an old friend from back in the California days, visiting us here on this show, Professor Carolyn Bertozzi who is at Stanford University and is rated highly both in biology and in chemistry.
So I just wanted to ask you a little bit, do you remember sometimes referring to your research and the sugars on the outside of the cell as the peanut M&M? Was that one of your analogies that you used at one point?
Carolyn Bertozzi: Yeah, it sure is, and I still use it today. [chuckle] I think it’s a great...
Jed: I love that analogy.
Carolyn: Yeah, it’s something everybody immediately conjures up in their imagination when you say that. It’s a common...
Jed: So when did you get into studying the sugars on the outside of the cell?
Carolyn: I started thinking about that area in graduate school. So I worked with a young carbohydrate chemist at UC Berkeley, whose name was Mark Bednarski, and he was my thesis advisor. And he had gotten interested in sugars and glycobiology as we call it, as a post-doc himself, with George M. Whitesides at Harvard.
So he kind of brought that sensibility into his brand new lab at Berkeley, and I was one of his first students. And he gave me some papers to read about sugars, and I just got hooked. It was so fascinating.
Jed: So what were some of the most exciting discoveries you’ve made in your career, just a couple of them, and how did they go down?
Carolyn: Well, of course, the reality is that the discoveries are not really made by me. [chuckle] Those discoveries are made by my students and postdocs in the lab. And usually, if I’m lucky, when they get their first hint of a discovery, they immediately come running to my office and show me the data. Nowadays with COVID, they’ll text me and email me, but some of the big moments of that type that I remember were, for example, the first time one of our so-called bioorthogonal reactions worked on living cells.
That was kind of a big moment, and the student, I knew she was doing the big experiment and it was a big question, would it work? And I knew she was doing the experiment that week, but I wasn’t sure exactly when. And all of a sudden one afternoon, she just kinda threw the door open to my office carrying her ice bucket with tubes in it in one hand, and the data printed out on the other hand.
And she was covered in sweat ’cause she had run into my office from a different building on campus. And Berkeley has a hill, so she had run up from the bottom of the hill to the top of the hill where the chemistry buildings are, soaked in sweat and she just looked at me with her big eyes and she said, "It worked." [chuckle] I was like, "What worked?"
And all these other students started flocking in behind her. I guess, the energy was in the air, and so that’s the kind of moment that you just love. So she had made this discovery that you can do chemistry on cells, and it was a big deal at the time.
Jed: That that is an amazing story about a cool discovery and one that you had been building towards. It wasn’t like she just randomly thought of something one weekend and tried it. You obviously had been putting the pieces together in your mind and assigned her the project to trying it out. So yeah, even though she did the discovery, you were the one masterminding it, which is great.
You hash it out late at night on some whiteboard in the hallway, and then you patch together what are the early experiments and you piece by piece, build the molecules and test them in simple systems and then systems of higher complexity.” – Dr. Carolyn Bertozzi
Carolyn: We had hashed it out. Mastermind, I think would be a generous term. I think, you know how it is with research projects. You hash it out late at night on some whiteboard in the hallway, and then you patch together what are the early experiments and you piece by piece, build the molecules and test them in simple systems and then systems of higher complexity. So this had been going on for many weeks, building up to this one really important experiment.
But I’ve had now enough of those moments with different students and different postdocs that I’ve gotten pretty good at seeing the moment where I know that that person that that’s gonna be their career. You know what I mean? I now can recognize when a student has a really critical experiment that’s a really new thing, breaking some ground.
And I don’t say it ’cause it’s a lot of pressure to put on somebody, but I can see the experiment and say, "That’s your thesis project," or I can say, "That’s gonna get you a job. That’s your job right there." I can kind of see how it’s gonna unfold now.
Jed: That’s so exciting.
Jed: And do you sometimes see that with younger colleagues now that you’re a more senior faculty member? Do you sometimes see a young assistant professor come in, and when you hear about something they’ve done, you’re like, "That’s gonna get you tenure. That’s gonna keep you here at Stanford or wherever you are."
Carolyn: Yeah, sometimes. Yeah.
Jed: Yeah, that’s really exciting. Well, I do remember your lab there at Berkeley, and I know the hill that you’re talking about where your student had to run up the hill. And it’s exciting to think that she got it to work.
So what have you been able to do with these bioorthogonal reactions, and what kind of discoveries have you made in the biology world? That’s a huge accomplishment for a chemist, but it’s obviously very relevant in biology. So what have you been able to discover?
Carolyn: Well, you know, I mean, the early days of our motivations for bioorthogonal chemistry were all centered around using those chemistries as tools to study the biology of sugars. And that student who made that big result, the implications of that result were that we could actually do imaging experiments to visualize the sugars on cells, both in a dish, but also in an animal, to model different kinds of diseases, for example, in a mouse.
And so that was one of our early applications was for imaging of sugars in different settings and look at changes in their structures that correlated with a disease, so that’s a very basic research type of application over the years. So go ahead.
Jed: Yeah, you’ve applied it to cancer, sorry to interrupt you, you were gonna go ahead.
Carolyn: Yeah, so what started as a pretty focused application in imaging of sugars, then two things happened. One is that once we got to see how powerful these chemistries were naturally sort of fostered other ideas for how to use the chemistry.
And so in my own lab, we’ve used those reactions to make new kinds of chemically modified protein therapeutics. We make antibody drug conjugates using those chemistries, but then outside of my lab, lots of other academic groups had their own ideas for how those chemistries could be useful, having nothing to do with sugars.
And now the biopharma industry has been using these chemistries to do target discovery and target validation. And most recently, people have made actual therapeutics where the bioorthogonal chemistry happens inside the human patient as part of a therapeutic treatment. There’s a company that I advise here in the Bay Area that’s been doing bioorthogonal chemistry in humans to deliver drugs to the sites of a cancer, and they’re in a Phase 1 clinical study. So that’s really fun to see that.
Jed: Yeah, it’s so exciting. We’ve had a few Nobel Prize winners on this show…
and do you think that bioorthogonal chemistries are gonna win a Nobel Prize at some point?
Carolyn: Yeah, I couldn’t even speculate. But you know if we can improve some human lives.
Jed: I think they might and it seems to have done so many things.
Carolyn: If we can improve some human lives and some human health and help some patients, then I think that would be a very satisfying outcome of all of my research. Yeah.
Jed: That would be amazing.
And have COVID applications been involved in any of this research?
Carolyn: Well, like everyone, I think in the scientific community, once the pandemic started to rage and the global impact became more and more evident, many of us want to deploy our skills in some helpful way.
So yes, in fact, I have now a postdoc who works on SARS-COV-2, and he’s using bioorthogonal chemistries to label the sugars that are on the spike protein.
And of course, the spike is the famous protein on the surface of the particle that gives it its spiky look like the Corona. But that spike is covered in sugars, and it turns out that we can put bioorthogonal chemical groups into those sugars. And this has allowed us to track the viral particles during infection studies. So hopefully this will be yet another tool that researchers find helpful in their studies of COVID.
Jed: That would be amazing. Wow. Well, it’s really fun to hear all the things that you’ve been up to.
Are there any things in the future that you and your lab are looking to do, applications of research you’re doing on the sugars outside of cells or anything?
And my hope is that some of these technologies and some of the basic knowledge that we've learned using the technologies, eventually progresses to make medicines for people.” – Dr. Carolyn Bertozzi
Carolyn: Yeah, well, I’ve started simple companies from some of the basic science that started in my lab, but it got to the point where it was ready to translate into a drug development process. And my hope is that some of these technologies and some of the basic knowledge that we’ve learned using the technologies, eventually progresses to make medicines for people. So I think there’s going to be a focus to the last part of my career, and let’s hope it’s a big last part. I would like to see that it has a translational flavor to it. That’s the hope.
Jed: That would be amazing. Well, thank you so much for taking time to share about your research and about your discoveries and the fun of being a chemist with your foot firmly in the world of biology as well.
Carolyn: Well, thank you. I appreciate it.
Jed: Thank you so much Professor Bertozzi, it was really fun to see you.