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Chemist Carolyn Bertozzi on Biology’s Dark Matter

Intelligencer 11/29/2022 Intelligencer Staff

Tech journalist Kara Swisher admits she is not a science person, but she believes it’s essential to have conversations with scientists in order to better understand the complex and critical work they do. In the latest episode of On With Kara Swisher, Kara talks to Stanford chemist Carolyn Bertozzi, who just won the 2022 Nobel Prize in Chemistry for inventing the promising new field of bioorthogonal chemistry, which consists of chemical reactions that scientists can use to study molecules in a living biological environment without interfering with the natural processes of that environment. As Stanford noted in its celebration of her award, these methods have since been used by Bertozzi and other researchers “to answer fundamental questions about the role of sugars in biology, to solve practical problems, such as developing better tests for infectious diseases, and to create a new biological pharmaceutical that can better target tumors, which is now being tested in clinical trials.”

In their wide-ranging conversation, Swisher spoke with Bertozzi about the field she founded and its potential to treat illnesses as well as her thoughts on mentorship, biotech start-ups, and Mastodon (which even Nobel Prize–winning scientists are apparently having trouble figuring out). In the excerpt below, Bertozzi explains how cells are like M&Ms — and how bioorthogonal chemistry offers insights and potential treatments that target their shell.

Carolyn Bertozzi: So M&Ms I like to think of as kind of like a simple rendition of what your cells look like. M&Ms have a sugar coating, and so do your cells, but the sugars are way more complicated on your cells than on that M&M.

Kara Swisher: Not as delicious, but go ahead.

Bertozzi: Not as yummy. And sometimes they’re bad guys. You wanna get rid of it.

So the reason we made these medicines was to take the sugar off of cancer cells, and when you strip them of their sugar coating, it turns out your immune system is able to see the cancer cells as bad guys and kill those cells.

Swisher: I see. So the sugars were protecting them.

Bertozzi: That’s right; they were using the sugars to confuse your immune system is what we learned. But that’s more recent work. The Nobel Prize is actually recognizing just the chemistry that we use to kind of get to the bottom of this.

Swisher: The detection.

Bertozzi: Yeah, right. The detection method.

Swisher: So why sugars? … Why is that so interesting to you?

Bertozzi: You know, because sugars are — they were like the dark matter of biology, in a way.

Swisher: So you’re doing a little physics reference there.

Bertozzi: A little bit, yeah. So, you know, you interviewed Jennifer Doudna, you interviewed the scientists at BioNTech and so on, and they talked about DNA and RNA. And you’ve maybe had people talk about proteins. So there’s a fourth important biological molecule. Those are the sugars, but nobody was talking about them.

Swisher: Why not?

Bertozzi: Because it was the dark matter — no one really knew much about them. And they were difficult to study because you couldn’t see them. So since everybody else was working on those other molecules, when I was trying to figure out what would I do in my lab, I thought sugars would be the place to go because nobody was studying them. And it was a big mystery.

They’re all over every single cell, and they’re involved in a lot of really important biology for human health and human disease. But no one could study them, and people didn’t even know they were there for the longest time. Turns out we’ve learned they’re really important in the immune system and in the process of cancer.

Swisher: When you talk about that idea of looking at them and understanding them, one of the things I did talk about with both Jennifer and the couple from BioNTech was the idea of the worst things that it could unleash. Obviously, any science, whether it’s vaccines or whatever, has implications. How do you look at that when you’re shedding a light on this important biology? What’s the things you think about?

Bertozzi: You know the kind of work we do is a little less fraught with ethical conundrums, and the reason is that the molecules we study, they’re not programming the cell for all eternity. They’re players in a more transient way in biology. They don’t have the same permanence that the DNA has. So we don’t have the same ethical issues, but we do have problems that we think about that go beyond the science.

For example, when we discover that these sugars are contributing to diseases, and we wanna make medicines to treat those diseases based on that learning, we have to convince people that, even though they’ve never heard of sugars before, sugars are really important in biology and they should invest in making new medicines that target them. So I think just educating people about this new area of biology is our rock that we have to push up the hill.

Swisher: So the most important thing here will be these medications to let the immune system do its work. Definitely the people are talking about cancer vaccines, but these are for cancer treatments.

Bertozzi: Well, it’s one that we work on. There’s many other sugar-related diseases as well.

Swisher: Such as?

Bertozzi: Oh, gosh, everything. I mean, the sugars are involved in bacterial infections. Even COVID-19, there’s some sugar biology going on with that virus. In fact, sugars first kind of hit the mainstream in the pharmaceutical industry around the influenza virus.

So there’s flu drugs, and those drugs are sugars, basically. And they were designed based on the sugar biology that we know about influenza. The reason we work on cancer and these immune therapies is because the discoveries we happened to make relate to that area.

Swisher: You’re therapizing it, really — you’re trying to just get it until they figure out a way to completely get rid of it, correct?

Bertozzi: Well, you know, that’s what’s so exciting to me about immune therapies as opposed to other types of cancer medicines like chemotherapies, right? So, chemo: We’ve all heard of it. We know people who’ve taken it. That —

Swisher: Kills it.

Bertozzi: Kills the cancer — and you— at the same time, and it’s toxic and horrible, and very often the cancer comes back, and it becomes resistant to those drugs. And then the person has to try a new drug and a new drug and a new drug. And this can go on and on and on. Immune therapies have the promise of, you know, if you get your immune system to do the bad work, to do the killing, not only can you kill the cancer, but then your immune system has memory.

So if the cancer tries to sneak back, your immune system’s ready to go to kill it again, just the way that we get vaccinated against something and our immune system remembers that for a long time. So if you can do that for cancer, you could potentially cure the disease with your immune system.

Swisher: Meaning your immune system understands it, sees it, and kills it rather than externalized ways to treat it.

Bertozzi: Exactly.

Swisher and Bertozzi also talked about the challenges securing funding for such work, Bertozzi’s start-up-founding strategy, and why she’s hoping to the government will continue making massive investments in these new technologies.

Swisher: When you think about the impact of the pandemic, we’ve seen major advances in mRNA technology with COVID vaccines. Is there gonna be a next wave golden age of new drugs? ’Cause at the same time, we’re headed towards a recession. You think funding is gonna pull back … How do you look at that? Are we right on the cusp of something bigger, or is lack of funding gonna diminish and cause problems in that?

Bertozzi: We are in the beginning of an enormous wave of innovation in biotechnology and biopharma. Even five years ago, I was skeptical about medicines that are now making a huge impact. They’re completely new brands of medicine like mRNA vaccines. There’s live medicines like cell therapies. There’s gene therapies. There’s CRISPR-engineering therapies, right? And even five years ago you couldn’t believe it, and here we are.

So if ever there was a time to double down on the investment in biopharma, now is the time. Now the venture-capital community is a cyclical thing, right? So they have booms and busts, and right now it’s slow. A year ago, it was hot, right? And they’re gonna come back, and it’s already starting to come back. But I’m hoping that our public investment can keep pace.

Swisher: Right. Government investment.

Bertozzi: Right. The National Institutes of Health, the National Science Foundation — I’m hoping that these agencies can get the resources from the government and, with the support from the politicians and the taxpayers, double down at a time when that investment would have a huge impact.

Swisher: Throughout the pandemic, there’s been erosion of trust in science, in our institutions. Does that worry you?

Bertozzi: Yes, it does worry me. Because science has so much to offer humanity, right? Science has always been an amazing human creation. And it’s benefited people in so many ways. And I’m sure we could point to the bad things, too, but there’s so many more good things than bad things.

And so if people lose their trust in science, they’re leaving a lot of potential quality of life on the table. And you want people to benefit from science, so you want them to appreciate it. You want them to understand it. You want them to understand the basics of the scientific method and what scientists are trying to do for humanity.

This interview and transcript have been edited for length and clarity.

On With Kara Swisher is produced by Nayeema Raza, Blakeney Schick, Cristian Castro Rossel, and Rafaela Siewert with mixing by Fernando Arruda, engineering by Christopher Shurtleff, and theme music by Trackademics. New episodes will drop every Monday and Thursday. Follow the show on Apple PodcastsSpotify, or wherever you get your podcasts.

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