Women in STEM with Michelle Arkin
Join us for our monthly Women in STEM series where we showcase and celebrate the achievements of inspiring women in the field. Step into the world of scientific innovation with Michelle Arkin, a visionary chemical biologist who leads the way as a Professor and Chair of Pharmaceutical Chemistry at UCSF. As the Director of the Small Molecule Discovery Center (SMDC), Michelle’s groundbreaking research delves into the development of cutting-edge methods and molecules that unlock the potential of “undruggable proteins.” Her expertise encompasses protein-protein interactions and dynamic or intrinsically disordered proteins, pushing the boundaries of what’s possible in the field.
Can you tell us about your journey in the field of STEM and the challenges you encountered along the way?
I started out as an art history major at Bryn Mawr College, a women’s college in Pennsylvania, US. I was ‘pre-med’ and got really interested in the science and especially the integration of chemistry and art. Art is made of chemistry (as paintings are made from pigments, oils, and other materials) and we were interested in what about the chemistry made a work of art change over time. Colours can get lost or change and things interact with each other. Thus, understanding how a painting was made meant you can learn a lot about how it might have looked originally and the uniqueness of how painters worked.
That’s how I got into chemistry. When it came time to graduate, I thought I wanted to go to graduate school in chemistry, but first I took a year abroad and worked as a teacher at the international school in Israel. I struggled with going to graduate school in art conservation science, ie, the science of art, or more general chemistry, and I decided to do chemistry because it had broader opportunities. I went into my PhD at Caltech as an inorganic chemist. On the side, I kept working on the colours of inorganic chemistry, studying how gemstones are built and how their colours arise. For my PhD project, I chose an advisor who worked on DNA and I started working with her on the physical properties of DNA.
Could you share an example of a specific project or some research that you have worked on and its impact in your field?
I worked with Jackie Barton in the early days of what’s now called DNA-mediated electron transfer. This is the premise that the DNA double helix is built by the electronic interactions of heterocyclic bases. Because of this electronic interaction, it is easier to transmit information in the form of electrons through this DNA helix. Jackie thought that maybe biology can use this idea to transmit biological information, like mutations in the DNA. I was really focused on the physical properties of DNA; ie, how to demonstrate that DNA can transmit this electron conductance, sort of a wire. And that was a very controversial idea.
I’m not sure that it was controversial just because it was new and because the field of electron transfer theory wasn’t that interested in things that were new, or if the data weren’t there yet and they just weren’t convinced. But it had a personal quality to it that, looking back, I wonder if it had to do with Jackie and me being women. I don’t know. It’s hard to tell. But you hear African Americans and other underrepresented groups talking about this issue; it’s hard to know whether I’m being treated with less respect or with less benefit of the doubt and so the disagreements were more personal. I once had a reviewer say, “Congratulations, now you’ve done what everyone else can do. Go back into the lab and do something better.” Thus, when I left my PhD, I decided to get out of electron transfer. I didn’t think what was happening there was worth the pain personally.
I went to Genentech and postdoc-ed for Jim Wells in protein engineering. That was a very hot field and a really exciting area. I didn’t know anything about proteins or display technologies or screening technologies. And that was very exciting. I recall that the reviews from the first paper we submitted said, “This is good. Fix this, consider this. This is overstated on this.” I couldn’t believe how straightforward the reviews were and Jim couldn’t understand why I was so surprised. Anyway, after my postdoc, I helped Jim start a biotech company. There’s something about startup companies that’s just all hands-on deck all the time. They provide a good opportunity to create a culture from scratch and to foster a culture of inclusiveness. The culture is: bring everything you have, and we’ll use as much of it as we can. It afforded great opportunities as a scientist, and I learned so much.
They say that people get Nobel prizes for work they did when they were below 40, which I used to find really depressing because I’m in my fifties. But when I think about it more conceptually – what I did before I was 40, how much Sunesis and graduate school and my postdoc affected the way I think about science, what I think is interesting, what I think is important, in the way we prosecute a project – a lot of that did come from those early startup days.
How has your research in STEM contributed to advancements or improvements in your field, and what potential future applications or implications do you foresee based on your work?
The goals for Sunesis had such an impact on my current research, as did the early days of thinking about what we call fragment-based drug discovery. Steve Fesik’s and Phil Hajduk’s lab at AbbVie had published a paper in 1996 on SAR by NMR (structure-activity relationships by nuclear magnetic resonance) and then we started Sunesis in 1997. The idea of discovering tiny molecules that had low affinity but high ligand efficiency was very stimulating to our work on addressing so-called undruggable target classes.
Jim’s work with mutagenesis had shown that the functional interface, or the residues that really contribute to binding affinity, is a subset of the structural interface between two proteins. Thus, you don’t have to find a molecule that fills that whole interface, which is much larger than a drug-like molecule. Instead, you just have to bind to the functionally relevant hotspot at the interface. And when you look at protein interfaces, they tend to have one to three of these little hotspots. That’s where fragment discovery was so appealing; finding these little pieces that fit in these different sub spots that you could then link together. The practice of binding fragments has become a mature field, and one of the key reasons for its success is the use of methods that measure binding instead of function. Binding methods tend to be higher resolution and have lower false positive rates because they’re based on a physical interaction.
Now, linking fragments or optimising fragments is not that mature a discipline, despite many years. It’s still highly structure-based, highly empirical, iterative. I think the next stage could be developing systematic ways that are less reliant on high-resolution information. In the academic lab, we have focused on covalent molecules, which have become acceptable – even stylish. The technology that we use was developed at Sunesis by my colleagues Dan Erlanson, Andrew Braisted, and Jim Wells called disulfide tethering.
The idea of undrugability is really a tautology. It’s just a phrase for things that haven’t yet been drugged. If we think, “well, these haven’t been drugged yet, why not? To what extent is it a target problem and to what extent is it a methodology problem?” I think drug discovery is going through a very exciting period for that reason. For instance, our newest research incarnation is in stabilising protein interactions by discovering molecular glues. We’re using our technologies as a systematic means of pulling two proteins together. Molecular glues have taken on a huge part of the mental landscape in new drug discovery, and systematic approaches have been lacking. So this work can have a valuable impact.
As a woman in STEM, what unique perspectives or strengths do you believe you bring to your work?
Well, it’s hard to generalise, but for me, it’s the breadth of work and projects I’ve been involved in and being able to draw parallels between seemingly disparate problems. When you see a lot of things and each one seems separate, it can be overwhelming. But when you see how they’re connected to each other and a project you did a couple of years ago has a technology or actually a similar problem to the one you’re currently focused on, the ability to see connections that provide solutions is something that I really enjoy and something people say women are good at.
Also, I’ve always felt that working with others has been important. In the last few years, academic science has turned towards the importance of teamwork and team science.
You see so many more grants now that are based on team science or ‘dream teams’, things like this. When I started in academics 16 years ago, I heard the question, “how can I evaluate your work if you are not the last author? If you are collaborating with all of these different people, if you’re providing the small molecule tools for lots of different projects, how can I evaluate you as an independent scientist?” And my answer to that has changed over the years. I used to try to answer the question; later I would think, “Well, this is the future, get on board.” And now nobody even asks that question.
I really appreciate the idea of teamwork and it’s more fun to work with people than to compete with them. It’s more fun to be happy for other people’s success and to build your career such that people are happy when you do well too, because you build a network of positive interactions rather than competitive interactions. That’s an important feature of my work philosophy. And as department chair and in other leadership roles, I really appreciate transparency: that we don’t own knowledge, we don’t use knowledge as power or control, who gets to know something or decide what people shouldn’t know. Just try to be transparent in how you’re making decisions, where they come from and how they may affect people.
What advice would you give to young women who are considering a career in STEM but may be hesitant due to societal stereotypes or perceived challenges?
I think many young women may not have experienced any women in their professional education thus far, which might make them nervous. So it’s helpful to see women in leadership positions around just so they see that they can do it. But it’s also important not to let people who don’t look like each other off the hook. You should be supportive of anybody you see with talent or who wants to succeed and help them and see them. It really comes down to people wanting to be seen. And part of that is not accepting them as the stereotype that they bring, but really what their specific unique gifts, talents and concerns are. When you approach people that way, you do sometimes hear from women that they’re worried about having families and how the perceived intensity of being a professor or being a scientist is incompatible with that.
And that makes me sad. The way in which it makes me most sad is that I can travel a lot and I can have this career and happy family life because my husband contributes. It’s not my responsibility. I didn’t take a hit during COVID because of my childcare responsibilities. We adjusted our lives so that we could have a successful family and keep our careers going. So I’m very blessed in that way, but I encourage women to think about it that way. Not as whether they can do something, but whether their family unit can accommodate everybody’s goals.
In your opinion, what can organisations and institutions do to create a more inclusive and supportive environment for women pursuing STEM careers?
Europe is far ahead of the US in terms of laws and the amount of time that women and men can take off. But there are better protections than previously. And this is a situation in which we need laws because people encounter such a vast difference in workplace expectations. From hourly workers who have to take a vacation day to vote, to people like me who have a tremendous amount of flexibility in where and how we spend our day. It’s just so different for different people. Providing a good environment for employees means accommodating them and their needs and helping them grow to be the fullest representation of themselves.
We work in a creativity-driven field where you need to feel safe and have some life experience to know what problem are important to solve. We need to encourage both safety and life experience. And if that’s the starting point that we use to base decisions, we’ll come to better decisions.
Looking ahead, what exciting developments or advancements do you foresee in your field of STEM, and how do you envision your own research contributing to those future innovations?
In chemical biology, we are in a golden age. We have amazing technologies coming from biology and big data and machine learning, computer science that allows us to collect a tremendous amount of information and to help filter it and integrate it. Integration is really the key. We’re past the time where you can just do one technique. Information must be integrated and used to decide what problems to solve, how to solve them.
The intersection of biology and omics, computer science and chemistry, pharmacology and clinical medicine; being able to speak to that wide variety of people is incredibly important in this phase. And if you can listen, learn from all of these different disciplines and integrate these different disciplines into your own thinking, then there’s an amazing number of problems we can address.
Michelle Arkin is a chemical biologist, Professor and Chair of Pharmaceutical Chemistry, and Director of the Small Molecule Discovery Center (SMDC) at UCSF. Michelle’s research focuses on developing methods and molecules that target currently ‘undruggable proteins,’ including protein-protein interactions and dynamic or intrinsically disordered proteins. The SMDC engages in collaborative drug discovery research, capitalising on tools and expertise in high-throughput screening, fragment-based drug discovery, and medicinal chemistry.
Michelle is a cofounder and Director of Ambagon Therapeutics and cofounder of Elgia Therapeutics, and sits on the advisory boards for several private and public biotech companies. Prior to UCSF, Michelle was Associate Director of cell biology at Sunesis Pharmaceuticals, where she helped discover inhibitors of protein-protein interactions for IL-2/IL-2R and LFA1/ICAM (lifitegrast, marketed by Novartis). She earned her PhD in chemistry at Caltech and held a Damon Runyon postdoctoral fellowship at Genentech.
UC San Francisco (UCSF)