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David MacMillan: A catalyst for discoveries

Chemist won the Nobel Prize in 2021 for important innovations in the pharmaceutical industry

In São Paulo, David Macmillan found a 40-minute break in his schedule to give this interview

Léo Ramos Chaves/ Revista Pesquisa FAPESP

In April, science enthusiasts had the opportunity to meet three winners of the Nobel Prize, the world’s most prestigious science award. There were two days of scheduled activities with Scottish chemist David MacMillan, of Princeton University, USA, awarded in 2021; Norwegian neuroscientist May-Britt Moser, of the Norwegian University of Science and Technology, awarded the 2014 Nobel Prize for Physiology or Medicine; and French physicist Serge Haroche, of the Collège de France, a winner in 2012. The idea was to bring scientists, students, and entrepreneurs together to talk about how science can help make a better world. The Nobel Prize Dialogue Rio and São Paulo 2024 was organized by the Brazilian Academy of Sciences (ABC) in partnership with the Nobel Foundation and with support from FAPESP.

Pesquisa FAPESP spoke with MacMillan during the two-day program, in a rare break in the busy schedule of meetings and lectures. He runs a laboratory in the area of catalysis, which focuses on molecules capable of accelerating or enabling chemical reactions. His award recognized the importance of asymmetric organocatalysis, an area he created in the 1990s when he was a professor at the University of California, Berkeley, which had a huge impact on the pharmaceutical industry.

Since then, the chemist has forged other equally significant paths. “If photocatalysis establishes itself like organocatalysis, experts in the field consider that he is a candidate for a second Nobel prize,” says chemist Fernanda Finelli, of the Federal University of Rio de Janeiro (UFRJ), who did a postdoctoral fellowship in MacMillan’s laboratory 15 years ago. She says that the chemist leads his group closely, with a mixture of seriousness, passion, and charm. “I learned from him to consider what the impact of implementing an idea will be.”

MacMillan was the founder of the Princeton Catalysis Initiative, in which companies invest and can develop projects in conjunction with researchers from a wide range of areas, harvesting innovation and new knowledge. It currently involves 15 departments, 95 teaching staff, and six industrial partners. He hopes to see this type of partnership between academia and business gain space in Brazil, which would give a greater dimension to the excellence of the country’s scientists and would contribute towards strengthening the pharmaceutical sector.

This interaction exists even within his family. His wife, Korean chemist Jean Kim MacMillan, today a pharmaceutical industry consultant, keeps a keen eye on discoveries for the development of drugs and participates in the trips, contributing with her applied vision in discussions with specialists. The couple have three daughters.

Passionate about soccer, David MacMillan, 56 years of age, took advantage of the trip to Rio to visit the headquarters of soccer team Botafogo and watch Fluminense tie with Bragantino at the Maracanã stadium. These are the rare moments in which he forgets about chemistry.

How is it to be in the Nobel Dialogues?
It has been very interesting. I had a chance to meet with students, professors, and people in business, and see what they are thinking about science, politics and the relationship between academia and industry. Brazilians are excited about the science they do. I’m Scottish, and we are the same. It’s a different style of culture, but also very authentic.

You rely heavily on students. How do you foster excellence and creativity?
I honestly believe that the vast majority of people can be successful, and that can be amplified if you put them in the right circumstances. In my lab, I put people in projects that can be successful. When they suddenly realize that they can do it, it is like watching a flower bloom right in front of you. Fernanda [Finelli] is one of the best examples of that. When she first came to my lab she was shy, intimidated. But we got her on a great project, she published in one of the best journals in the world. When she came back to Brazil she had this confidence of what she could accomplish. Everyone is different, you have to spend time with people and understand what is going to bring that out of them. Once you do this, the science will take care of the science.

What changed after the Nobel Prize?
I was a successful chemist, people respected me. But I was a chemist. And then you win the Nobel Prize. All of a sudden, you have to represent your country, your field, your university, your group. Suddenly many people want to talk to me, which is a privilege but at the same time it’s a different situation. For 12 months, I just enjoyed the whole experience. Then I did a self-analysis about what do I love. I love chemistry. This year has probably been the most productive of my group ever. I’ve never been more proud of what we are doing, and that’s because chemistry is what got me here in the first place, it’s what I love to do.

Can you briefly explain asymmetric organocatalysis?
If you look at your hands, they look identical. But they are not, because if you take a glove for the left hand, it doesn’t fit on the right hand. They are mirror images of each other. In organic chemistry, molecules also exist in mirror images. But your body is made up of one mirror image, and not the other one. To this day, we don’t know why. As it happens, most medicines are made of molecules that can be mirror images, and one mirror image could be the medicine, and the other could be dangerous, toxic, have side effects. If I try to tell them apart in the lab, it takes me 40 minutes, with very expensive equipment. But if I gave it to a child, she could smell the difference between the molecules, because your body recognizes them. You have to be able to make one for medicine, and not the other one, but that is very difficult to achieve. So what we did was to come up with a way. Now people use it to make medicines, perfumes, shampoo, polymers and all these different things, using organic molecules to do the catalysis, instead of using non-sustainable ways of doing it.

When you started and named the field, you didn’t know how to do it. Why was it so hard?
At that time, the only ways known in the world were to use metals, which can be toxic, or biocatalysis, using the enzymes that are the catalysts of life. There were not any general principles for using organic molecules. I knew I wanted to do it, just did not know how to. This is one of the things I believe: it is better to have a great question than a great solution. Then you become focused, maybe obsessed with the idea. When you are surrounded by great students, really gifted people, they are going to solve that problem with you. In this case, it worked quite quickly. To this day, I remember the moment of finding out that it worked, it was an incredible experience. I was at Berkeley at the time, I remember thinking that I was going to get tenure. When you are an assistant professor, the biggest worry is to keep the job.

Did you think it might not be possible?
Absolutely. We recently published in Science a paper which I’m very proud of. We worked on the project for 17 years. For probably 16 years I thought I was not going to solve it in my career. And then we got it.

Léo Ramos Chaves/Revista Pesquisa FAPESP Tickets sold out at USP: Adam Smith, of the Nobel Prize Outreach, MacMillan, Serge Haroche, and May-Britt MoserLéo Ramos Chaves/Revista Pesquisa FAPESP

What is it?
Some molecules are readily available in nature, we call them feedstocks. The number one functional group is alcohols—OHs. Typically, you can bond the oxygen to other things, but you cannot remove the oxygens to do carbon-carbon bond formations. We wanted to figure out ways to take any two alcohols, lose the oxygens and connect them. At first it seemed completely crazy, but now we solved how to do it. It is just fantastic. I wondered if the world would care, and people really did. Pharmaceutical companies are now using it.

What do they use it for?
In drug discovery, you have to make three-dimensional molecules and test them. Typically, we have to make 8,000 molecules to get to one that will get to the clinic and be tested in humans. In many cases, the person in the pharmaceutical company wouldn’t even make the effort of doing it, as it would be the equivalent of having a lottery ticket. But if you can use alcohols, that are three-dimensional, you can build molecules. Instead of needing maybe a month, we can do it in one reaction, so it accelerates the way in which you can get access to these molecules for testing. For us, it is fantastically satisfying.

When you have a problem that takes 17 years to solve, how do people get their degrees on the way?
You can’t keep working on it all the time. If someone works on it and it doesn’t work, you move them to another project. You almost have to wait for that class of students to graduate, because if you don’t, they will tell the next person: “Don’t work with that, it doesn’t work.” You have to wait for that memory to go away, and when the next group comes, you put someone on it. What happened this time was that a first-year graduate student solved the problem. In chemistry, being naive about something really helps, because you’ll do things that people with more knowledge would not do. But chemistry is much more nuanced than yes-no answers. I am a big fan of not being skeptical, because when you are, nothing works. Every time you don’t run a chemical reaction, it has 0% chance of working. But even with a 2% chance, if you run it 50 times, one may work. There is definite value in getting past what you think is possible or not possible.

You work very close to the pharmaceutical industry, right?
I do. And I am very influenced by watching what they do. They don’t ask us to do specific things, but, as a neutral observer, I think of how I can invent ways to change the way they do things. Fortunately for us, things we have done were useful, and people have started to adopt it. A student can literally invent a reaction on Monday, and people will start using it in a pharmaceutical industry by Friday. When a student sees it happen, it’s amazingly empowering, it is one of the best ways to get people motivated and excited about the science they’re doing.

What do you think of the dichotomy between basic and applied science?
The whole question is: are you more applied, or more basic? We need the full spectrum, or we would be missing great opportunities. If you look at papers from 100 years ago, people were doing organocatalysis. It was basic, and they had no idea that it would become useful for us in the future.

And what about photocatalysis, that’s another door you opened, right?
I think of organocatalysis as my first baby, and photocatalysis as my second baby. It has grown even bigger than organocatalysis, which is remarkable. In science, we have to dive in to see all the crazy directions you can take. That is when you have to rely on your instincts and intuition. We published papers on photoredox for three years. It was going ok. I had to make the decision of whether to move on to another area, but I thought there was something there, and we kept going. Two years later, it went huge. Now hundreds of research groups all over the world are doing this, every pharmaceutical, agrochemical, perfume company in the world uses it.

How does it work?
I can shine blue light on my hand all day long and nothing will happen. But if you shine one blue photon on this catalyst, it becomes the equivalent of 32,000 degrees Celsius. It can’t give off this heat, but it has to do something with the energy. One option is to selectively interact with a really stable molecule to remove or give electrons. And when it does that, it makes that molecule really reactive. You can literally take these feedstock chemicals that exist anywhere in the world, boring molecules, and make them do things that were previously really hard to do. It didn’t seem reasonable at the beginning.

And now you are putting that to biological use?
We are doing something called micromapping. A protein in a biological pathway interacts with lots of other things. In a cancer cell, it may interact with other things, we do not know which. So we took these photocatalysts, molecularly stitched them onto these proteins so they are still interacting inside the cell. Now, when we shine the blue photon on, the catalyst can leave a label behind wherever the protein goes. One of the things we just did: cancer treatments normally work for a certain period of time, and then humans will become resistant to that medicine. The question is why. We can study what the protein interacts with when everything is working, and what has changed when the cell becomes resistant. And we did find things that it has interacted with. Then we can take another small molecule—the medicine—to treat that pathway, and switch the medicine back on. Cells that had become resistant now are operative again. In vitro, we were able to do that shining blue photons on these catalysts, which does not damage the cell. On mice, we need to use red light, because it penetrates through the mouse tissues while blue light will not. The original paper was a collaboration with Merck biologists on a cancer treatment, and since then we have gone in other directions with it. Again, there is the naiveté. We are doing things that we probably shouldn’t, but in doing that, we are finding things that are surprising.

Is it possible to democratize chemistry?
When I first started doing organocatalysis, people would say that it was easy for me, being a Berkeley professor with all resources at hand. It is true, we did have resources and wonderful students. But the first idea was using an organic molecule in an experiment that cost 5 cents to perform. And it worked. So it was never about resources, it was about having a reasonably good idea. The good thing about organocatalysis is that we can see now people in all of these countries that have very low resources for science that can, first of all, teach organocatalysis, and then come up with their own ideas about it. That allows creativity and innovation without the need for large amounts of funding. Catalysis will become cheaper and cheaper based upon the types of reactivity that we have to find. Proteomics, on the other hand, is easily the most expensive thing that we do, it couldn’t be done in a place that is underresourced. If you democratize everything, you put yourself in a very specific regime, but along the way, if you can incorporate democratizing components, you absolutely should do it. The world is going to do it anyway.

Your wife, Jean, is also a chemist. Is she as driven as you?
She’s much more driven than me: she has two medicines that she put in the market. Most medicinal chemists don’t put one. The last one, which she made for a small biotech she was working for, sold for US$2 billion because of her molecule. People ask if I am one of the best chemists in Princeton. I say: “I’m not even the best chemist in my house.” She is an incredible chemist, and she loves traveling and interacting with scientists. It’s a dream come true for both her and me that we get to do this at this point in our careers.

And you have three daughters?
Yes. The youngest is 18 years old and is doing volunteer work in Africa. She was failing chemistry in high school, and we said she had to do well, having two chemists as parents. So I invited her to work in my lab during the summer. At the end I asked her what she thought, and she said: “Dad, the chemistry is ok, but what I really loved was the gossip.” She suddenly realized that labs are people, and she’s now leaning towards being a scientist, because of this human experience. The oldest one, at 26, is going to do a PhD in biomedical science, and the middle one, who is 24, has a sociology degree and is thinking about becoming a lawyer. They are very different, but make a great team together.