Lab Meeting: Pamela Silver
“How do we engineer biology, faster, cheaper and more predictably?”
Child math phenom, 60’s teenage rebel, polymer chemist, sailboat builder, cancer drug discoverer, biotech founder, engineer, and admirer of The Wire, Dr. Pamela Silver brings the productive creativity of her native Silicon Valley to the staid halls of East Coast academe.
Emphasis on productive. Trained as a chemist and molecular biologist, Silver’s post-doctoral work (in Mark Ptashne’s group at Harvard) uncovered how proteins move from cytoplasm to nucleus. Identification of these “nuclear localization sequences” had profound consequences for studying cell biology in model systems like yeast, and ultimately human cancer. After a brief stint as faculty at Princeton, Silver moved her lab to the Dana Farber Cancer Institute. She performed one of the first high throughput screening efforts to uncover molecules that block nuclear transport of cancer-causing proteins. Based on her work, the biotech Karyopharm was founded—a company that now has two FDA-approved therapies for use in certain blood cancers.
Despite this “feel good” moment of translating her work, the lifelong sailor felt the need to change tack: I was getting kind of restless about whether I wanted to continue in cancer biology or do something different. I had the good fortune to meet bioengineers and computer scientists from MIT,” reflects Silver (Q#1). Inspired by this interdisciplinary crew, she helped found the “synthetic biology working group” in the early 2000s. Together they created a roadmap of how to translate basic biology findings into solving real-world problems: “How do we engineer biology, faster, cheaper and more predictably?” To pursue these types of questions, Silver was one of the first members of the Department of Systems Biology at Harvard Medical School. She also became the first Director of the Harvard University Graduate Program and has helped mentor hundreds of trainees.
Still eager to innovate, Silver’s lab at Harvard and the Wyss Institute is currently building synthetic cells that act as sensors, engineering proteins (e.g. that can block apoptosis) for therapeutic use in conditions like pancreatitis and ALS, and using systems approaches to study how viral genes block host immune responses. Among her group’s more recent inventions include bacteria that can sense and respond to gut inflammation, and the Bionic Leaf (Nocera Lab collaboration), which couples sunlight capture to highly efficient bioproduction. She has helped found the synthetic biology hive at HMS, aimed at pursuing big, collaborative projects that have the potential to substantially improve life on Earth. Along the way, she has helped co-found companies like 64-x and Kula Bio, in collaboration with Pillar VC.
Silver is a fellow of the American Academy of Arts and Sciences, an NIH MERIT awardee, a Fellow of the Radcliffe Institute, one of the top twenty Global Synthetic Biology Influencers and was the Joseph Henry Lecturer at the Washington DC Philosophical Society. She is currently the Elliot T. and Onie H. Adams Professor of Biochemistry and Systems Biology at Harvard.
When asked about her interests, Silver says: “[I am interested in] everything! I read broadly. I am not focused. I've been unable to focus on one thing my whole life.” Countless trainees, the disciplines of molecular and synthetic biology, biotech, patients and perhaps the environment itself, are the ultimate beneficiaries of this singular “lack of focus.”
Below is an interview with Dr. Pamela Silver, from September 2022:
1. What was your first taste of science? Briefly, what about this initial experience drew you in?
I'm a child of Silicon Valley. I grew up in Atherton, California before it was the richest town in the world. My parents were early settlers there. Even back then, it was a very high tech and science-based world. Both of my parents were psychotherapists, which made me a strange child. But in my house and community, there was always an emphasis on science and asking questions. But let's face it, I grew up in the coastal elitist world.
I had precocious math ability when I was very young, which I don't have any more, just to be clear. But because of that [ability], I was encouraged to pursue math and science. At that time it was considered unusual for girls to be good at math. I went to the public schools, but there was just a huge emphasis on science and math. I am really a product of the 60s and all the investments that were made in science education [around that time]. As a young teen, I won the IBM math contest. I remember that the prize was a slide rule—so that kind of dates how old I am. Most people today may not even know what a slide rule is.
There is a great book [What the Dormhouse Said by John Markoff] that talks about the synergy between the psychedelic hippie culture and the advent of personal computers. It's a great book, and I encourage you to read it. But that [synergy] was kind of my early life.
[On what it was like in the 60s Silicon Valley and decision to train in science]
In the early Silicon Valley, the people I went to high school with, and my best friend to this day, had fathers that founded some of the major companies in Silicon Valley. So, I had one of the first Hewlett Packard programmable calculators, and I was exposed to science all the time. You couldn't get away from it. It was just natural to end up doing something in science.
When I went to college, I started out as a math major. But eventually, I switched to physics. I also considered briefly doing high energy stuff at SLAC. But the problem then was, things were not really digitized. So, if the pen broke on the printer broke, your experiments could get derailed for a year. So that was not very appealing as I was more of an experimentalist than a theorist.
I ended up in chemistry, which I found to be really interesting. I liked working with my hands and just seeing what I could make. I want to be clear. I never had a ‘career plan.’ And I know that's easy for someone who comes from coastal elite to say, but I really didn't have a concrete plan. I never consciously thought: ‘I'm going to be a professor’ or ‘I'm going to be x.’ I just went for the ride and did a lot of different things. After college, I worked as a polymer chemist in a startup. Finally, I went to grad school, around the time when molecular biology was really taking off. It was just clear to me that [molecular biology] was the place to be. So, I retrained as more of a biochemist before coming East for my postdoc. [Out East] I was inundated with the revolution in molecular biology. Companies were also being founded. My postdoc advisor [Mark Ptashne] and Tom Maniatis, founded Genetics Institute, which later was bought by Wyeth.
It was a really exciting field—there was this opportunity to combine molecular biology with questions in cell biology. For example, I articulated a question about how things move in and out of the nucleus. This is one of the lessons [in science]—there very few others working on this question at the time. When I wrote my first NIH grant, I had only 10-20 references [to other papers]. So, I discovered one of the first nuclear localization signals [on GAL4 N-terminus] and used that as the foundation for my first research program.
I had the privilege to move my research group to the Dana Farber Cancer Institute. I was doing kind of fundamental and basic work and thought: ‘I should really try to do something a little more applied to cancer.’ I searched for molecules that would affect nuclear transport in tumors. It was at the time that the ICCB had just formed [at Harvard], so it was a great time to do a high throughput screening. We successfully found compounds that blocked nuclear export of key cancer-causing molecules.
This project led to the founding of Karyopharm, which was based around my work. Since then, this company has developed FDA-approved drugs that block nuclear export of tumor suppressors and oncogenes. That was a real ‘feel good’ moment—that I did something with real world application. At the time, I was also getting kind of restless about whether I wanted to continue in cancer biology or do something different. I had the good fortune, this is what's great about being in Boston, to meet bioengineers and computer scientists from MIT. They were forming this ‘Synthetic Biology Working Group’ and I had the luxury of being their token biologist. Since then, I ended up switching my whole field and interests [to synthetic biology].
2. How do you define synthetic biology, and what was your first exposure to this field?
I had the realization that a lot of the things in molecular biology could fit under the rubric of ‘synthetic biology.’ For example, we were making synthetic proteins for tracking nuclear transport and other aspects of cell biology. In a way, I already had an affinity for [synthetic biology]. The way I define it is: how do we engineer biology, faster, cheaper and more predictably? Synthetic biology tries to achieve those goals. About 20 years ago, we [the synthetic biology working group] articulated a roadmap for the field. What’s exciting is that we have now achieved a lot of the goals on that roadmap.
You can compare synthetic biology to synthetic organic chemistry, which was the revolutionary technology at the beginning of the last century. [Organic chemistry] brought you all these new materials, plastics, nylon, etc. So you can now ask: is synthetic biology the new technology that will grow the next economy? And is this actually an industrial revolution, which is happening now?
[On why synthetic biology is such a ‘hot’ field currently]
I think it is a matter of asking: how do we take this enormous amount of biology knowledge, and start predictably engineering this biology to solve real world problems? And I want to really emphasize, for me, it's about engineering at scale to solve problems. There are many people in synthetic biology that are, building ‘toy systems,’ which are great, because it is a proof of concept. But I am more interested in going beyond that [to scale].
3. Name an overlooked scientist, whom you feel strongly that every grad student (or med student) should know and be able to describe their major findings. What were the killer experiments?
I don’t like identity politics, and I don't like identity science. So, I don't think in those terms. With the advent of the internet and being able to search PubMed, you find that there are many ‘unknown’ scientists. I love being able to access all their work, read a paper and look up the authors. I’ll often look what they did in the past. I love to go back and research their trajectory: How did this person get there? Who are they? So, for me most scientists I encounter are ‘unknown.’ And we should all be known. In a way we're getting there because of PubMed and tools like that. We should not care about identity science and who's the ‘big shot’. In time, some of these ‘big shots’ turn out to be wrong anyway.
[On trends related to open access publication]
I'm encouraged by getting rid of journals because they slow things down. They also create this identity cult. I have little patience for anyone who says to me: ‘I want to come to your lab because I want to publish papers in Nature.’
I feel like [publishing] stalled out parts of my life, and it made me depressed and was largely unnecessary. So, the normalization of things like preprints is a great trend. [Preprints help] get rid of the status of ‘publishing in X.’ I think it's happening, because only so many papers can get published [in the ‘top’ journals] anyway. So that's all great. Social media can be an asset but also a danger. I love seeing discussions, and things like that, but the misuse [of social media] in terms of disbelief in science and whacky hypotheses and things like that is huge. So, it's a balance—take the good with the bad.
4. What are you reading in your free time?
I'm a big believer in free time. I just finished an amazing book called The Fall of the Ivory Tower [by George Roche]. It really captures from post-World War II to now, what's gone wrong with universities, and why we are in the current political situation. [Our current troubles] are connected to the growth in the universities post- WWII through the GI Bill and defense spending. The book also shows how cuts in public education that started with Ronald Reagan, gets us to the bad place we are now. The book discusses what happens in State Universities and how student loans impact young people. It's just a mess.
I usually read about five books at once. But I want to give a shout out to the ‘third golden age of television.’ Shows like The Wire, Breaking Bad and The Sopranos. I am fascinated by amazing television. I think The Wire is like reading Dickens. [TV] is a different art form that has just had this incredible moment. These types of shows are amazing.
5. What has been your scientific high point? — What do you consider to be the most exhilarating discovery or set of discoveries you have been involved in throughout your career?
As a grad student, getting anything to work was amazing. [As a post-doc in Ptashne’s lab] when I first saw the localization [of GAL4] induced by the nuclear localization signal, I was blown away—I had a hypothesis and it was right. And I showed that it worked. Also, in the early days of the green fluorescent protein—we were one of the first groups to work on it. I had an amazing grad student [Kahana] who built a microscope, and we could film cells with GFP and watch their mitotic spindles moving around. And that was amazing. I would say it was a slower process, but helping develop drugs was also amazing. And then, very recently, our co-invention of the bionic leaf has just been a terrific ride.
6. What set of research questions or projects has you most excited about coming into lab today?
I'm trying to move into a different style of doing science. We’re building the synthetic biology hive at HMS, which is meant to be a community where people can work on problems that are bigger than an individual.
What we are thinking about is: how do we apply biology? The bionic leaf is an example of how to make food from air. We are thinking about projects that can get groups of people excited enough to get up, beat COVID, come in and work together to solve something with real-world application. And there's just a ton of projects. These types of projects can range from medical to environmental in flavor. I've kind of been fixated on environmental projects right now—in part because I grew up in California and I love the ocean. So, I'm kind of obsessed with things focused on the ocean and the environment. I want to grow and engineer coral--but I may not get there.
7. Which areas of science, outside of your direct field, are you most excited about seeing develop in the next 5-10 years?
Everything! I read broadly. I am not focused. I've been unable to focus on one thing my whole life. I was reading some of the other interviews and said: ‘oh, you should stay focused.’ That's not me. You know, I'm interested to see what happens with space travel. Do we get there? And then, of course, I'm interested to see if all the amazing precision and gene therapies that medicine seems like it's on the cusp of utilizing—do these actually work? I think we don't know. We’ll know in 10 years.
8. Who are a couple up-and-coming scientists (lab < 10 yr old) in your area, or more broadly, whom you think we should watch? Why is their work so exciting to you?
One person from my own group is Dave savage. He's a little more established. He's at Berkeley and just got HHMI. I think he's amazing. He started the cyanobacteria work in our lab, and has carried on to do to really do amazing things with regard to enhancing photosynthesis. Another former group member, who's just starting her own lab is Rebecca Sherbo, at Northeastern. She actually did some of the work to make bacteria capable of generating food from CO2. One person who's not from my lab, who I love, is Jen Brophy. She just started her lab at Stanford, and I think she's going to do some amazing stuff with synthetic biology and plants.
9. What is one piece of advice for a young scientist aspiring to have a career in academia, and make some important discoveries?
My first piece of advice is to not follow the herd. Secondly, advice from old people, is sometimes useless but interesting to hear. Following the herd - you might miss interesting stuff. If you can find that space, like I found, where you can work on something novel and where there aren't many things known, that can be really exciting. It can also be scary because you are by yourself. Depending on your personality, working as part of a group can be very good, because you can tackle problems that are bigger [in scope]. But again, it's an individual choice—I don't want to discourage the person who wants to really drill down and do something on their own. We need all kinds of research and people.
10. How did you get involved with Pillar VC? What are the things that you're excited about working on with them?
It was really fun to get involved with Pillar and the venture capital process, and just learn about it. I believe I got involved with Pillar through the founding of Kula bio, but I'm now involved in a couple of others [company builds]. Part of my interest [in company formation] is that I grew up in Silicon Valley. I grew up in that culture of startups—Kleiner Perkins was right down the street from where I lived. So, it's been part of my life for a long time.
I'm actually involved in another effort, called Science for America that seeks to change funding models, in order to tackle bigger, longer-term problems. But the ‘frenzy’ for startups is great for young people, or someone who wants that experience. In some ways it can beat starting an academic lab. A couple years ago, it was easier to secure a few million to start your company than [it was] to get an NIH R01 grant. It’s good to have lots of options for young scientists and engineers.