Michelle Arkin: All Things are One Thing

SLAS2016 Drug Target Strategies Track Chair Michelle Arkin, Ph.D., likes a good puzzle. Not only does she enjoy deciphering complicated connections and matching up contrasting ideas, she refers to it as her "personality super power."

Even more powerful to her is the sharing of ideas between like-minded professionals in the life sciences discovery and technology community. "People think of scientists as nerds, loners and introverts, but it's more of a team sport," laughs Arkin, who is an associate professor in pharmaceutical chemistry and associate director of biology in the Small Molecule Discovery Center at the University of California, San Francisco (UCSF) and an author of several papers published in the Journal of Biomolecular Screening (JBS), one of two SLAS MEDLINE-indexed scientific journals. "The social aspect of science, working together and getting ideas and energy from each other influenced my whole career."

Arkin's background in biophysics, biochemistry and spectroscopy shapes much of the work in her high-throughput screening (HTS) lab and helps to address challenging problems in chemical biology and early-stage drug discovery using small molecules.

Arkin's lab and collaborative network draw from cross-sections of the UCSF community that have a common interest in small molecule discovery. As the director of UCSF's HTS lab, Arkin consults with many labs and suggests how their biology might convert into small molecule projects either for probes or drug discovery; she sees this broad spectrum of ideas and sometimes the primary source that joins them. To sum up all the associative activity that goes on, Arkin coined a phrase that her students have grown accustomed to hearing: "All things are one thing."

"In the community of ideas, taking two things that look pretty disparate and seeing how they connect to each other is something I have always enjoyed doing," Arkin says. "After doing this job for a few years, you start to see what people are thinking about and make connections between their points of view. It makes science much more interesting and gives your own research a different flavor and vision. If you can have a different perspective, it helps you talk to people creatively about their projects."

Arkin and her team pick valuable targets and use model systems in HTS that help her to be thorough in the earliest stages of drug discovery. "In the early days of HTS, scientists tried to simplify the system so it would fit in a little well and be done a million times. This process sometimes simplified the biological relevance right out of the system," she notes. "We make an effort to simplify the system down to its relevant biology and no further." Arkin adds that SLAS's focus on innovation in drug discovery has been a big help in accomplishing their work.

One example of how Arkin's team works to develop novel screens is the assay they developed using live schistosomula that was a finalist for the SLAS Innovation Award in 2014. "The study of the Shistosoma parasite had been qualitative and low-throughput. In collaboration with Conor Caffrey and Rahul Singh (at University of California, San Diego and San Francisco State), we thought to give schisto biology a high-throughput, quantitative view so we could identify new drugs and learn something about parasite development, genetic variation in schistosomula and their responses to drug treatment," Arkin says. "This is an example of how we try to dig into a hard problem without giving up on it. We try to make it a quantitative science."

The lab also works with purified proteins to study their structure and function. While studying how proteins work isolated in solution, Arkin explains that the scientists must also keep in mind how that information fits back into the complex environment of the cell. "For example, what might look like a small change in an isolated protein may have a much bigger knock-on effect within a multi-protein complex," she says. "Then we consider whether we can make small molecules that are really context-specific modulators of biological function."

During the eight years that she has been at UCSF, Arkin remarks that the notion of academic drug discovery has greatly expanded and now includes collaborative research agreements with pharmaceutical companies, licensing, company formation and 'pre-competitive' sharing. She adds, "In a sense, the macro-experiment of our lab is how to do team science in academia. We are helped a lot by the collaborative culture of UCSF and the culture of the national/international academic drug discovery community exemplified by the Assay Guidance Manual (an NIH e-book outlining best practices in early discovery) and the Academic Drug Discovery Consortium."

"It's been fun to be part of and to help build the academic drug discovery community," she says, noting that the single lab, sole principal investigator model doesn't work well in drug discovery. Tweet The best solutions merge the best of industry and academia, but it means understanding their opposite challenges. "Scientists function the same regardless of where they perform their research," she says. "The constraints on scientists come from how the institutions in which they perform are organized."

Merging Disparate Ideas

Arkin has always enjoyed doing things that other people think of as different. In high school, she mixed up her schedule with theater, science and advanced placement (AP) classes. In college she studied art history and chemistry. "While those things look different on the outside, they don't really feel different on the inside. They are all creative endeavors," she continues.

At Bryn Mawr College, Bryn Mawr, PA, Arkin found the blend of art and science within art conservation particularly appealing. The use of biophysical methods, such as spectroscopies, helped art historians determine artist attributions, how a piece might have changed and how to get it back to its original state. "Studying art history through that lens was satisfying," Arkin comments. "It made me feel close to the art object, the artist and how the object moved through time."

Despite the fascinating work, when class scheduling became a challenge, Arkin decided one major would have to take a backseat to the other. "As I thought about which of these two paths to pursue," she says. "I decided chemists could enjoy art in their free time, but if an art historian tried to enjoy off-hours chemistry, they might burn down the house!"

Chemistry led her to graduate studies at the California Institute of Technology (Caltech). While working in the lab of her mentor, Jacqueline K. Barton, Ph.D., Arkin began to study something controversial. "We explored the electron transport properties of DNA based on an unusual observation that someone had made in the lab before me. I tried to figure out if it was real, how it worked, and to tease through the parameters from the early stages of this field," Arkin says. "Many people felt that the idea was just full-on wrong."

This became painfully apparent after a presentation of her findings at a conference. "People were vocally critical of our research," says Arkin, who returned home discouraged and told the story to a couple of her housemates who were Hollywood screenwriters. "I told them how everyone was talking. They said, 'Wait, everyone was talking about you? Nobody will remember why they were talking about you. They will just remember that they were talking about you.' It was nice to have had that distance and perspective from people outside the field of science."

Part of what makes the experience less painful to talk about now, Arkin says, "is that these properties of DNA are considered established." In fact, Barton went on to win some very prestigious awards, including the 2015 Priestly Medal and the National Medal of Science.

"Now looking back, and Dr. Barton talks about this, too, we were brave to explore this concept, especially in the face of opposition," says Arkin, who acknowledges that she was not comfortable being that far out at the front of an idea. "It took me a while to become confident and comfortable going public with my discoveries. Jackie Barton taught me to be a professional scientist and how to present information and carry myself."

Other relationships along her career path enriched her experience as well. A short post doc at Genentech introduced her to another mentor, Jim Wells, who later left the company to start Sunesis Pharmaceuticals. He invited Arkin to come along. "I went to this new company with him as a post doc. That was an opportunity that had never crossed my mind. I was planning to be a biochemistry professor, but he was doing great work in protein chemistry that influenced the work I do now," she comments.

Arkin describes it as an exciting time. "As one of the early scientists there as the company grew, I had the opportunity to mentor a lot of people. I had two or three experiences when women came to me and said, 'I don't know if you ever knew this, but it was great to see a woman succeeding in the profession. You were a role model,'" she explains. She adds with a laugh: "You don't go through life thinking of yourself as a woman scientist. You just try to make sure your shoes match and that you show up on time!"

With age comes wisdom, Arkin continues, adding that mentoring students at UCSF is a satisfying part of her job. Tweet She doesn't think that the post docs, staff scientists and graduate students in her lab benefit so much from what she says, but from the way she lives her life and offers examples of balancing life and work. She notes: "I try to be classy like Jackie and Jim were."

She adds, "This is really important. If you want to accomplish anything, people have to want to work with you. What makes them want to work with you? Knowing your stuff, being above-board, sharing. I'm a bit too impatient to be naturally diplomatic all the time, but I do like working with people and I try to focus on the relationship. I'll probably get mixed reviews, but that's my goal at least."

Getting Out into the World

To maintain a work-life balance, Arkin tries to continue her interest in art, but finds that she doesn't get to as many museums these days. She used to travel more for fun, and lived in Israel before starting graduate school. Now, she feels fortunate to live in San Francisco with its great local art opportunities and California with its diverse landscapes.

Arkin also enjoys a good read and pursues thought-provoking topics. A favorite was the book-turned-documentary, The Emperor of All Maladies: A Biography of Cancer by Siddhartha Mukherjee, M.D., Ph.D., which she thought encapsulated the researcher's quest to cure disease.

"I am also interested in meditation, but I spend more time reading about it than actually sitting down and doing it," she says. She recently read titles authored by what she calls "skeptic, modern writers," such as 10 Percent Happier by Dan Harris and The Antidote: Happiness for People Who Can't Stand Positive Thinking by Oliver Burkeman.

"Both of them write with a light hand and started these books with, 'I don't know about all this self-help stuff, but I went on a seven-day silent retreat that was pretty powerful...' They almost seem embarrassed by their own spirituality. I appreciate that. I think scientists can be like that; they are uncomfortable sometimes with metaphysics or being thought of as soft-headed."

Motivating Through SLAS

Back in the realm of drug discovery, Arkin's view is that scientists don't mind the unknown as much. "That's what we like to do as scientists, work on the edges of what's known," she comments. As SLAS2016 Drug Target Strategies Track chair, Arkin hopes to inspire participants and remind them of the innovation-driven research that powers drug discovery.

"Drug Target Strategies is meant to be next-generation and forward-looking," she explains. "We want to give a voice to state-of-the-art or emerging technologies at this meeting, working beyond what is standard practice now."

In past years, Arkin considered Drug Target Strategies to be one of the more science-y and less technical tracks. "Now I think the entire meeting has moved progressively in that direction," she says. "I think that there are a lot of innovative tracks this year, sessions that are outside the box, and things that will stimulate the life sciences professional's thinking." She eagerly anticipates broadening her involvement in the event with her recent appointment as a co-chair of SLAS2018, along with Timothy Spicer of The Scripps Research Institute. The event will be held February 3-7, 2018 in San Diego, CA.

Arkin appreciates the openness among event participants. "In the last few years, there has been a sea change in how people think about pre-competitive research, sharing best practices and helping those who someday might be competitors. They want to collaborate to waste less time and money. Everyone wants to apply good ideas toward drug discovery and get it out to patients faster," she comments. "SLAS has helped to bring a positive effect to the community."