A Nobel Prize For Chemistry Work ‘Totally Separate From Biology’

In a conversation from 2022, Dr. Carolyn Bertozzi discusses bioorthogonal chemistry, which could have applications in chemotherapy.

Speaker names marked ? are inferred from speaking time and the show’s known hosts — they are not voice-verified.

• 0:00Speaker 00

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• 0:18Speaker 01

  Research that won a Nobel Prize a couple of years back could specifically target cancerous tumors much better than traditional chemotherapy can.

• 0:25Speaker 02

  So you get this burst of toxic drug only in the tumor and nowhere else in the body, and it kills the tumor without these toxic side effects.

• 0:34Speaker 01

  It's Monday, December 2, and you're listening to Science Friday.

• 0:40Speaker 01

  I'm Sci-Fry producer Dee Peterschmidt. We're continuing to celebrate our 33rd anniversary with some of our listeners' favorite segments. And you know what? High on that list was this 2022 conversation with Nobel Prize-winning chemist Dr. Carolyn Bertozzi. Here's her conversation with Arifato.

• 0:57Ira Flatow?

  Today, bio-orthogonal chemistry is a staple in biological research and a promising tool for medicine. These reactions involve two chemicals that can bond with each other, even in an environment as complicated as the human body. And they don't interfere with the normal chemical reactions in the body. Its pioneer won the Nobel Prize in Chemistry for her research. Let me bring her on now. Dr. Carolyn Bertozzi, 2022 Nobel Prize laureate and professor of chemistry at Stanford in Palo Alto, California. Congratulations and welcome to Science Friday.

• 1:29Speaker 02

  Thank you so much. It's really wonderful to be here.

• 1:32Ira Flatow?

  Nice to have you. OK, let's start with the basics. What does it mean for chemistry to be bio-orthogonal? Pretty big word there.

• 1:40Speaker 02

  Yes, it's a bit of a mouthful, but you can break it down into its two parts. So the word orthogonal is one that we usually use when we're trying to describe two things that don't interact with each other. When someone is really thinking outside the box or in a very different way, we like to think of that as orthogonal thinking. So bio-orthogonal means not interacting with biology, totally separate from biology.

• 2:10Speaker 02

  And we invented that concept because we had ideas for how such a chemistry could be useful in biology and medicine.

• 2:17Ira Flatow?

  Give me your idea of how useful it is.

• 2:19Speaker 02

  Well, it started with a very specific application in mind. And what the backstory is, is that I had a longstanding interest in the biology of complex carbohydrates. And people might think of that term as having to do with food that you eat, but there's a whole different world of biology of complex carbohydrates, which is that they're basically like a forest that decorates the entire surface of every cell in your body. And we wanted to be able to study those complex carbohydrates and we wanted to image them. We wanted to be able to see them in microscopes or see them in a magnetic resonance imaging

• 3:04Speaker 02

  scan or a PET scan. And there was no way to see them. So the very early genesis of bioorthogonal chemistry was as a tool to be able to study and to visualize those cell surface sugar molecules.

• 3:18Ira Flatow?

  And why do you want to know so much about how the sugar molecules are working on the cell surface?

• 3:24Speaker 02

  Well, even back in the 1990s, which is when I started this whole area of research, people knew that the structures of cell surface sugars change during diseases. And the area in which this had been studied most extensively was in cancer. So people knew that if you looked at the surface of cancer cells, the sugars had changed compared to the normal cells around them. And anytime there's a change in molecules between healthy tissue and cancerous tissue, you might be able to exploit that as a means to visualize those disease cells and to detect the disease.

• 4:07Speaker 02

  But the problem was, at that time, the only way to study those sugars was on cells and tissues that you took out of the body and ground up into bits and pieces and destroyed. And there was really no way to look at the sugars on the cells when they were alive and in the body. And that's what you need to do if you want to be able to detect these changes for cancer detection or cancer diagnosis.

• 4:32Ira Flatow?

  And so how does looking at sugars connect to the idea of this orthogonal model? How did you apply it?

• 4:39Speaker 02

  Well, you know, it's funny because science usually has a backstory of accidents and serendipity, and this story has an element of that. So way back when I was a postdoctoral fellow, and so this is before I was a professor. Instead, I was a researcher in someone else's lab at the time. And I was thinking about the sugars and frustrated that there was no way to visualize them. And other molecules, like proteins and DNA and RNA, other stuff that you find in cells and in animals and humans, there were actually some really nice technologies to look at those other molecules, but there was just a gap. There was nothing for the sugars.

• 5:20Speaker 02

  And then I happened to go to a conference in Southampton, England, of all places, as a postdoctoral fellow, and I heard a lecture from a German biochemist named Werner Reuter. And in that lecture, he talked about the fact that you could feed cells chemically altered versions of very simple sugars. And as long as the alterations were very subtle, not too dramatic, those altered sugars would get metabolized by the cells and they would be incorporated into the cell surface complex carbohydrates. So you could actually make the cells turn into what they eat. You've heard the phrase, "You are what you eat," right? And these cells actually were putting altered sugars on the surface just because they were

• 6:05Speaker 02

  eating the little simple precursors. And so that gave me an idea for how you could sneak a little bit of chemistry into cell surface sugars and then use the chemistry to attach probe molecules for imaging. And it was a very simple idea at the time, but there was a huge problem with the idea because you would need the simple chemistry to be what we later termed bioorthogonal.

• 6:31Speaker 02

  And there really wasn't a chemistry that existed at that time that would allow you to do such a thing. So that was where the motivation came from. And if I hadn't seen that lecture by Professor Reuter, I'm not sure I would have had this idea anytime soon.

• 6:46Ira Flatow?

  Well, how do you guarantee that your bio-orthogonal chemistry is only going to react with the one specific thing you want it to?

• 6:56Speaker 02

  Well, that is the central challenge in the whole area is to find these magical chemistries that even though there's thousands of other chemicals in your body, that somehow they're willing to ignore all of that and yet still react with something else that's bio-orthogonal. And we spent many years engineering the chemical groups so that they would have exactly this sort of thread the needle capability. And you have to do a lot of experimentation. So when we made new functional groups, which is what we call chemical groups, we would test them. We would test them in cells in a dish, first and foremost. And we would do a lot of experiments to see whether they were attaching themselves unwittingly to

• 7:40Speaker 02

  some of the biological molecules. And if they did, we threw them in the garbage can and went back and try a different type of chemical. And once we got them to be very clean in cells, then we would test them in animals. And enough of that has now transpired over the last 25 years that we now are very confident that we have a toolkit of bio-orthogonal chemistries that are so safe that some of them are now being tested in human clinical trials. They're inside the body of human patients.

• 8:13Ira Flatow?

  Well, that brings me to the meat of my next question, so to speak. Give me some ideas of how you might apply this chemistry.

• 8:19Speaker 02

  Well, right now, the two leading applications have to do with drug delivery.

• 8:27Speaker 02

  Right, so especially for cancer. And we all know that the types of medicines people are traditionally treated with for cancer, which we call chemotherapies, they can be really toxic and hard to handle. And the way that those medicines work is they kill cancer cells, but they also kill some of your healthy cells at the same time. And that's why people on chemo have these side effects, like losing their hair and being very nauseated and sometimes having organ damage. And, you know, on a bad day, the drug might do more harm than good to a cancer patient. So one of the challenges is to figure out, how do you send that toxic drug to the cancer cell specifically,

• 9:12Speaker 02

  like a guided missile, and keep it away from all the other cells in the body? And bioorthogonal chemistry has turned out to be useful for this. And so as a case in point, there is a biotech company here in the Bay Area, outside San Francisco, that I am an advisor for. And they have a protocol to treat patients with soft tissue sarcoma. That's a particular type of cancer in bones. And the way they do this is they inject into the tumor area a material. It's a hydrogel polymer, and it's actually quite similar to the same material that's injected cosmetically for people who want filler. If you've ever heard of cosmetic fillers,

• 9:55Speaker 02

  there's literally a polymer that gets injected into the face where a person wants to fill a wrinkle, for example.

• 10:01Ira Flatow?

  Yeah, we're not talking Botox here, right?

• 10:03Speaker 02

  No, not Botox. This is a different substance. It's harmless. It just kind of puffs up your skin, okay? So what this company has done is they have modified that same material with a bioorthogonal chemical. And they inject that material into the tumor. And it does nothing but fill up space. It's harmless. That bioorthogonal chemical has no interaction with the human body, just sitting there. But then, the next day, they inject the chemotherapy drug systemically. They put it, you know, in the typical way, in an IV bag. So the patient sits there and they have an IV infusion of chemotherapy. But the chemotherapy is rendered harmless by attachment of another bioorthogonal chemical.

• 10:49Speaker 02

  And it floats throughout the body, throughout circulation, doing nothing. It's totally harmless. But when it encounters that material that was injected on the previous day, the two bioorthogonal chemicals see each other, and they react. And that reaction releases the active chemotherapy right there, locally, in the environment of the tumor. So you get this burst of toxic drug only in the tumor and nowhere else in the body, and it kills the tumor without these toxic side effects. And they are now performing this procedure on patients in what's called a Phase 1 clinical trial. So they're looking to make sure that it's safe and to figure out what are the right doses of the two components.

• 11:33Speaker 02

  And if everything goes well, they'll start a next phase where they look for reduction of the tumor burden and benefit to the patient.

• 11:43Speaker 01

  After the break, how this approach to targeting tumors could be used to help treat other diseases.

• 11:54Ira Flatow?

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• 13:35Ira Flatow?

  Are there other drug applications or other diseases, tumors, you name it, that this might work with?

• 13:41Speaker 02

  Yes, there's another group in New York that is gearing up for a clinical trial to target radioisotopes to cancers. And these are like nuclear particles that release radiation that's damaging to the tumor. Also, it's a way of basically delivering the radiation very specifically to the tumor and keeping the damage away from other tissues. And it's kind of a similar strategy. They put one molecule in first, and it's actually an antibody that's armed with a bioorthogonal chemical. And that antibody is like a heat-seeking missile, which goes to the tumor and latches onto it. And then, in a second step, they add the radioactive particle, which has the other bioorthogonal partner on it.

• 14:26Speaker 02

  And it will then find that antibody and do the reaction. And now, that radioactive particle is also concentrated in the tumor. So that's, it's kind of a similar approach, but instead of a chemotherapeutic drug, it's a radioactive particle. And instead of a polymer that gets injected, it's an antibody that finds its way. But I think that theme is one that you'll find being tested again and again and again. And it's something you really couldn't even conceive of doing without the availability of bio-orthogonal chemistries.

• 14:58Ira Flatow?

  I've heard the work your co-Nobelist did called click chemistry. Is this, is this kind of a click chemistry you're talking about?

• 15:05Speaker 02

  Yes, you know, there, there are many overlapping concepts between bio-orthogonal and click chemistry. And that's why I think the Nobel Foundation kind of put us together into this one prize. The click chemistry term was coined by Barry Sharpless, and he shares the prize with myself and another chemist named Morton Meldahl. Barry was interested in reactions that have the property that they're very reliable. They form products in very high yield, and they do so without interference by other functional groups on the same molecules. So you can see how that's a similar, you know, challenge to our own thinking about

• 15:49Speaker 02

  bio-orthogonal chemistry. The big difference is that when Barry was conceiving of click chemistries, he was thinking about them as tools for the synthesis of complex molecules, which is another big challenge in the chemical sciences. And Morton Meldahl had a similar motivation. You know, both he and Barry are synthetic chemists. They like to make big, complicated molecules. And having these click chemistries can get you to those big, complicated molecules much more easily.

• 16:18Ira Flatow?

  You know, people say chemistry is so boring, right?

• 16:23Speaker 02

  People are wrong.

• 16:26Ira Flatow?

  Well, this is, this is a great example of that. What sort of advice would you give people coming to you, you know, for future scientists? Would you, would you, I'm sure you would point them in your direction because as we say, chemistry is a lot less boring than you think it is.

• 16:43Speaker 02

  That's correct. I think the misconception of chemistry being boring might be our own fault because I think chemists teach students, and usually the first exposure is somewhere in high school. I think we teach those high school students in a kind of boring way.

• 17:04Ira Flatow?

  You think?

• 17:04Speaker 02

  I think so. I can only, and I, and I say this-

• 17:07Ira Flatow?

  As someone who took chemistry in high school, I can tell you that's the truth.

• 17:10Speaker 02

  It was true for me too, I hate to say. Um, I took chemistry in high school and I don't know that I hated it, but I didn't like it.

• 17:18Ira Flatow?

  Yeah.

• 17:18Speaker 02

  It's-

• 17:19Ira Flatow?

  Yeah, my worst subject.

• 17:20Speaker 02

  Yeah, it was boring and I didn't understa- it didn't seem relevant to me or the world at all. And then I went to college and I was, at first I was a pre-med. And so you have to take some chemistry classes if you're destined for medical school. So I did. Not because I wanted to, but because I had to. And even in freshman chemistry, I was not interested. Again, it didn't seem all that relevant or interesting to me. So you know, I'm, I'm just like you in that regard. And if I had not taken organic chemistry, I think I probably wouldn't have discovered the field as an exciting field. But organic chemistry turned things around for me. And that's when I realized that chemistry is so central in biology and biomedicine.

• 18:02Speaker 02

  And if you want to understand disease, you know, human disease and figure out how to treat diseases, you really need to be a chemist. So I'm really glad that I stuck with it long enough to discover organic chemistry because that sealed it for me. But I think if we did a better job teaching in the early stages, people wouldn't have this bias against chemistry. It's fascinating and there's so much we don't know and so many discoveries yet to be made. The field I think of is still very young.

• 18:30Ira Flatow?

  So now you have this huge stage. As a Nobel winner, you're in the spotlight. Are there things you want to use that power? Or visibility to try to do that maybe you couldn't just as a chemist?

• 18:43Speaker 02

  This is a really interesting question. You know, I certainly have philosophies that I would like people to think about and maybe even embrace. Um, having to do with the diversity of scientists needing some enhancement in order for us to do the best science we can do. Especially in the physical sciences like chemistry. There are many different- You know, underrepresented groups who have been historically excluded from the field and whose talent we haven't been able to avail ourselves of, which limits progress. Hopefully now people will pay attention to the importance of diversifying

• 19:24Speaker 02

  the chemical workforce so that we can take advantage of all the talent. That's one thing I would like to convey. And, you know, the interesting thing is lots of chemists, including myself, have been advocating for greater diversity among our ranks. But if you are awarded a Nobel Prize and your strategy for success has been to have the most diverse lab that you can have, I think that that gives, you know, some validation to the idea that diversity breeds success.

• 19:58Ira Flatow?

  Dr. Carolyn Bertozzi is professor of chemistry at Stanford University in Palo Alto and 2022 winner of the Nobel Prize.

• 20:06Speaker 02

  Thank you so much for having me.

• 20:11Speaker 01

  And that's all the time we have for today. Lots of folks helped make the show happen, including Sandy Roberts.

• 20:16Ira Flatow?

  Beth Ramey. John Dankoski. Emma Gomez.

• 20:20Speaker 01

  On tomorrow's episode, we'll do some time travel and figure out what it would have been like to witness the end of the dinosaurs. I'm Sci-Fry producer Dee Peterschmidt. Thanks for listening.