Seeing the Need for a New Kind of Chemistry
Today she is a Stanford University Professor of Chemistry and a 2017 Inductee to the U.S. Patent and Trademark Office’s National Inventors Hall of Fame, but Carolyn Bertozzi initially wanted to major in music. Only to appease her parents—who had lived through The Great Depression and preferred she pursue a more practical and financially stable career—did she agree to take pre-med requirements at Harvard University while she explored her other interests. There, she found herself drawn to biology, and later, “unexpectedly,” to organic chemistry, ultimately earning her A.B. in Chemistry from Harvard. Dr. Bertozzi went on to do graduate and post-doctoral work at the University of California, Berkeley, and University of California, San Francisco, and then took her first faculty position at UC Berkeley. In 2015 she moved her lab of about 35 researchers to Stanford University. Cumulatively, across her career, she is named on 50 U.S. patents.
Her recent induction into the National Inventors Hall of Fame was for her work on bioorthogonal chemistry—a field Dr. Bertozzi developed in response to “a practical need” she encountered during her Ph.D. and post-doctoral research. Bioorthogonal chemistry allows researchers to chemically modify molecules within living systems without interfering with the surrounding biology. The approach requires a level of precision that was previously unprecedented in synthetic chemical reaction methodology, because most experiments are conducted in laboratory environments under highly controlled “non-biological” conditions. Although she initially developed the technique to image the sugar coating on cells, she also patented an application of it that involves attaching drug molecules to antibodies to combine their cancer-fighting properties. In 2008, she founded Redwood Biosciences, a startup company that was acquired in 2014 by Catalent, who commercialized this patented technology under the name SMARTag™.
I tell my own students that if you’ve invented something and people are going to profit from it, you should be among them.
Dr. Bertozzi spoke with Innovator Insights about her experience as an inventor and patent owner in academia, and how carving out her own space in the science community helped her to succeed.
Can you explain what bioorthogonal chemistry is, how it works, and what its uses are?
It actually started because of a very practical need in the field of glycobiology, which is the biology of sugars. I was interested in this area of biology in my Ph.D. work and during my postdoctoral training, and I continue to study it to this day. When I started my own independent lab at Berkeley in 1996, I had an interest in understanding the sugar coating on cells. These sugars constitute a very complex molecular coating that contains information about the biology of the cell. I wanted to study that, but there were no good experimental tools at the time to visualize these sugars as they appeared on cells. So I set out to develop a tool to image them. That was the original motivation for inventing bioorthogonal chemistry, but immediately once we started publishing on it, people identified all kinds of other interesting applications and it went viral outside of the field of glycobiology.
“Orthogonal” is a term that scientists use to mean two things that don’t interact with each other at all. So bioorthogonal chemistry is a type of chemical reaction that does not in any way interact with anything in biology. And because of that, you can actually perform these chemistries in a biological system, and that turns out to be incredibly useful for tagging molecules with imaging probes and chemically altering molecules in a biological setting without disruption. Just like a traditional chemist in a lab creates chemical reactions in flasks, we wanted to do chemistry in the body of an animal, which is a completely uncontrolled environment. Since you can’t control the environment, the chemistry itself has to be incredibly precise and pristine and insensitive to all of the other stuff surrounding those reacting molecules. That was an unprecedented quality in chemistry at the time; there would be no motivation to develop reactions so precise if you could just control the environment, but once you let go of the control and do the chemistry in a live animal, that’s when you need a whole new level of specificity and precision.
What are the most common uses for it?
Originally, we developed these reactions so we could tag sugars on cells inside the bodies of animals, particularly cancer cells, with fluorescent probes that we could then visualize to see how they change in the body of that animal. But now, people use it for all kinds of interesting experiments. For instance, if you take a complex mixture like a blood sample, which has 100,000 molecules, and you want to follow just one molecule to see what it’s doing, you can use bioorthogonal chemistry to do that. It’s a way to interrogate a needle in a haystack in a very clean way. It opened up new experimental platforms from which biologists can ask questions in a new way. But for me, the motivation originally was for the very explicit purpose of trying to image cell surface sugars. And we invented some reactions along the way that weren’t known before.
What do your patents cover?
I have a number of patents covering different bioorthogonal reactions. Some of them have been licensed by biotech companies that are using them to make chemically modified protein therapeutics today. My own company licensed a bioorthogonal chemistry patent to develop antibody-drug conjugates; again, that wasn’t why we invented this 20 years ago, but it’s certainly an interesting practical application that came of it 10 years later.
I also have some nanoscience-related patents. With a physics collaborator at Berkeley, I developed a device called the nanoinjector that uses carbon nanotubes to drive cargo into cells past the plasma membrane, which is a barrier that’s hard to breach for certain molecules. I have a filing in the provisional patent application stage for a diagnostic test for tuberculosis, and I have a platform technology for ultrasensitive detection of autoantibody disease biomarkers for early detection of Type 1 Diabetes and HIV infection. We’re also working on an application of this for allergy-related antibodies.
What has your experience been like with the patent system?
I never had any formal education around patents; I probably could have used it. Most of the time, I’m doing it on the fly. My Ph.D. advisor was entrepreneurial though, and he encouraged us to write patents. I’m co-inventor on a couple of patents from my Ph.D. work, and shortly after I started my job at Berkeley, I started a company with my postdoctoral advisor from University of California, San Francisco.
I think I’ve become better at knowing what’s “patent-worthy” over the years. When I first started my job at Berkeley, I filed many invention disclosures that had little chance of eventual licensing. Now, I ask our office of technology licensing to invest in patent preparation and filing only if I think there’s a good chance it will be licensed. Sometimes it’s for one of my own companies, so I’m pretty confident. My “hit rate” is much higher now.
How are patents viewed within the academic community in your experience?
Think about the role you’re going to play and whether the rules are so hardened already that you’re going to have to contort yourself to fit.
My view is heavily skewed because my career has been situated entirely in the Bay Area—this is of course an extremely entrepreneurial environment where academics are very involved in starting companies. It’s more the norm than the exception for professors to think about spinning out the research from their lab. We live in a very patent savvy environment. Our tech licensing offices are sophisticated compared to universities across the nation as a whole. So I think, overall, people are very positive about the idea of going through the effort to protect IP so that it retains its value and there’s a chance at a commercial translation.
The only negative language I hear around patents has to do with students’ participation in proprietary research. The people who do the work in our lab are not really employees; they’re students in a training environment and need to be able to publish their work, because that’s the currency they use to show the world their productivity. The students might sometimes feel it’s a conflict for them to be doing work that their PI [Principal Investigator] may want to patent and keep secret to some extent, whereas the student is under some pressure to publish. Many times, though, the student is a co-inventor on the patent, so they’re incentivized to protect that IP too. There are university rules that limit delays on publication so as to insulate students from such conflicts of interest. I have to be wary of this myself and make decisions that prioritize the needs of students. If the student needs their work published before we secure the European Union or Japanese patent rights, for instance, then we make those sacrifices.
For the most part though, patents are viewed very positively. I’ve never felt like patenting in any way interfered with publishing. When we’re ready to put a manuscript together, as soon as we have a cogent draft, we use that as a draft of the invention disclosure. I tell my own students that if you’ve invented something and people are going to profit from it, you should be among them. All of my patents have student co-inventors on them. Two of our bioorthogonal chemistry patents were exclusively licensed by biotech companies and in both cases the students who contributed to the invention received a portion of the patent income.
Did you have any negative experiences as a woman working in science, which remains largely male-dominated?
I was lucky because I grew up in a household where we were strongly encouraged to be scientists. My father was a professor of physics at the Massachusetts Institute of Technology. I wasn’t even aware of gender bias in science until I was at college. My older sister was very advanced in math and her elementary school teachers tried to tell my parents she didn’t have any friends because of it. My parents were often at the school advocating for her, and so teachers were wary of how they treated me when my turn came up. But in college, I did have to deal with it. When I wanted to switch my major from biology to chemistry there were some weird reactions to that idea. My college advisor told me I should consider teaching middle school rather than pursue a Ph.D., “because that’s where we need people to teach chemistry, that’s where you could make a difference.” Then, I noticed that I didn’t have a single female chemistry professor, and I hadn’t seen any women in the chemistry Ph.D. program (there were a few, it turns out, but so diluted they were hard to find). The good news was that by the time I had to face that reality, my confidence and self-esteem were already pretty secure; I was already 19 or 20. When a girl is younger and starts to internalize these messages, it can undermine her confidence and self esteem. I was shielded from that at the more vulnerable ages. That’s what having pro-science parents does for you. It bolsters your confidence, so by the time you get hit, you’re ready.
What advice do you have for other aspiring scientists and inventors hoping to achieve what you have?
It’s different for everyone I think. I just knew that I loved organic chemistry and I was good at it. I got it and I had ideas. And then it was about navigating the academic culture and finding an environment where the rules weren’t already written and cast in stone. In graduate school, there were certain areas of chemistry where I knew I’d never fit in because the culture was already firmly established and I would just be excluded. But there were other areas that were new and just forming and the rules weren’t really written yet, so you felt like there you had a shot of getting in early. For me, the opportunity area was the interface of chemistry with biology. The merger of these fields was new at the time and professors at the forefront were younger and a little less ossified by tradition. As a young graduate student I joined the group of an assistant professor who had just started and was building his group from scratch. That was good because, at the time, the percentage of women chemistry Ph.D. students at Berkeley was similar to what it had been at Harvard—about 10% or so. So in a group of 30 there would be two or three women, but in a new lab where the very first group is only three people, you’re the one woman in a group of just three. That was a good way to help build the culture from the ground up. I would say to aspiring scientists who find themselves in an environment where they are underrepresented, think about whether the rules governing success are so hardened already that you’re going to have to contort yourself to fit. And ideally, find an area of science that you are fascinated by and that differentiates you from the norms. My dual background in chemistry and immunology differentiated me in a way that was very helpful on the job market, and, more importantly, allowed me to identify interesting problems that no one seemed to be working on. For me, that was an important element of success.