According to Pamela Silver, “if more than 10 percent of your experiments work, you’re doing the wrong experiments”—a sentiment that summarizes her overall philosophy of science. For Silver, the Elliott T. and Onie H. Adams Professor of Biochemistry and Systems Biology, it's all about risk. Not only can big risk lead to big payoff (if you’re lucky), but it’s also where all the fun is. From her childhood in the then-fledgling Silicon Valley where she rubbed shoulders not only with technology luminaries but also with members of the Grateful Dead, to her current work as a pioneer in the field of synthetic biology, Silver’s career can be best described as one long pursuit of her scientific fascinations. Here, Silver discusses her approach to running a lab, her thoughts on the future of science, and why we should be able to engineer biology the same way we engineer electronics.
HMS: How did you get into science?
SILVER: That’s a long story. I was born in essentially the Silicon Valley area in a small town called Atherton. It’s now one of the richest towns in the world because lots of Google people live there. My father was one of the founders of the Palo Alto Medical Clinic and on the psychiatry faculty at Stanford. Both my parents were psychiatrists, actually. My father would take me to the Stanford Hospital with him. I would get to sit in the doctor’s lounge or see the research labs.
But there was this atmosphere of science and engineering in the whole area. One of the developers of sonar lived down the street. Children of the founders of the burgeoning computer industry were among my friends. When I had minor surgery as a kid, the doctor who operated on me was the guy who did one of the first heart transplants. Douglas Engelbart, inventor of the computer mouse, was a neighbor. Incidentally, another neighbor was Bob Weir, of the Grateful Dead. And when I was a kid Jerry Garcia taught me guitar, although I didn’t realize who he was at the time.
HMS: What?!
SILVER: Yep. He lived in the area, and when he was broke and trying to make money he was teaching kids guitar.
HMS: Do you still play guitar?
SILVER: No. I hated it. But you have to understand, this was the community. The area, the whole San Francisco scene, was full of people like this.
HMS: What were you like as a student?
SILVER: I had precocious math ability. I don’t have it anymore, but as a young girl I was extremely talented at math, and not so much at things that girls are supposed to be good at, like reading. I would always test really high on these math tests, and that was at the time considered unusual. I think I was probably the subject of someone’s PhD thesis at Stanford, because I was so unusual. I was a nerd before there were nerds and I didn’t feel very popular.
I won the IBM math contest when I was either in the seventh or eighth grade. The prize was a slide rule, and it was the coolest slide rule in the world. This one had a beveled edge on it so you could use it as a straight edge also. I didn’t appreciate it then, and eventually lost it, and ever since I’ve been looking the world for one. I look on the Internet all the time and just found one!
But I knew back then pretty much that science was my thing. I didn’t know what aspect of science, and I never thought about medical school. I went to UC Santa Cruz because you could basically design your own major. I really wanted to go to Hampshire College, but my father refused to pay for a school that was full of only hippies and was a firm believer in the public UC system (despite the fact that he went to Harvard).
At Santa Cruz I went from math to physics to chemistry. I even had the opportunity to help solve the structure of proteins by NMR [nuclear magnetic resonance] and got to work at Stanford.
HMS: What was it like being a woman in the sciences at a time where it was still heavily male dominated?
SILVER: I actually often think, “I wonder if I had been a male would I have been more of a risk taker?” because I think there really was a stigma (perhaps self-imposed) about being a woman in the sciences. When I went to college and was a physics major, there was only one other woman. And from my all-girls high school nobody went into science except me and my best friend who went into marine biology.
HMS: How did you make the jump to biology?
SILVER: I worked in industry for a while where I was more of a chemist, and then when I went to graduate school at UCLA it was sort of in the heyday of molecular biology, and so it was just the obvious thing to do. But I can legitimately say that I had almost no biology training until I went to graduate school at UCLA. But they let me finish my PhD in three years.
HMS: What have been the key defining moments for you?
SILVER: Well, there was my insect collection that I made in eighth grade. Seriously! I think all the insects in that part of California must have been decimated because every kid tried to have a bigger, better insect collection. Probably that IBM math thing, too, was defining.
HMS: More recently?
SILVER: One of those kind of “oh wow” moments, and this is going to sound old-fashioned because it’s now textbook stuff, but when I was a postdoc, I was kind of an outlier because I had this idea that proteins could be specifically targeted to the nucleus, and at the time many people just thought everything diffused in and out. And also I thought I could approach this in yeast, which was the trendy organism to work on, because it had molecular biology.
And so I discovered that my hypothesis was right and that I could take a small piece of a nuclear protein and fuse it to something else and see it go into the nucleus, and this involved using fluorescence microscopy. And the “aha!” moment was when I looked under the microscope and saw that it worked. Chills went down my spine.
It was a risk. It sounds standard now, but back then it was a risky thing to do. I now tend to get myself into environments where I am always kind of the outlier doing something that is more risky or different, and this was an example of that. So I guess I did achieve what had eluded me when I was younger.
HMS: Probably everything that is standard now started out as something risky.
SILVER: Yes. And I wasn’t the only one to discover this, but I was one of the first. It was a reasonable hypothesis, but it hadn’t been proven, but it also countered another prevailing view at the time.
The other thing though is that although I was a postdoc, I didn’t have a plan. All these kids now have a plan. They have a career ‘path’. When I went to college, I didn’t have a plan. When I went to graduate school, I didn’t have a plan. When I was doing my postdoc, I always had this sense that, “Well, I have this idea. If it fails I’m just not going to get a job or I’ll do something else. I’ll go back to building sailboats.”
Another transformative moment happened at Dana-Farber Cancer Institute. I had an amazing grad student, and this was at the time that the green fluorescent protein had just been discovered, and we realized that we could put it in cells and then make movies watching different things move around in cells. And so we were one of the first to make a movie of watching cells divide and watching a certain part of the nucleus, how it behaves and how cells behave.
And when I saw that movie I thought, “This is the coolest thing in the world.”
I have to confess that I’m not good at focusing on just one thing, which people in our field often say you have to do. I was always dabbling around in other stuff. My big thing was supposed to be this study of the nucleus and how things moved in and out, but I was getting bored with it. You get the sense there are problems that are just going to be solved, regardless of whether you work on them or not. When you realize that someone published a paper and it’s exactly like yours, the excitement goes away. I was actually really lucky when Marc Kirschner invited me to join this “brand new” Department of Systems Biology a decade ago. I was the fourth member.
HMS: What about synthetic biology? How did you get into that?
SILVER: That would actually be from what I consider another transformative moment. A bunch of bioengineers and computer scientists formed what was called the Synthetic Biology Working Group at MIT. And they invited me to come as sort of the token biologist, and that was just transformative for me. I got to spend time with these people and we really articulated this question of: Why can’t biology be faster and more predictable to engineer?
That became the foundation of synthetic biology. I believe that biology is the technology of this century and that you should be able to engineer biology the same way that you can engineer electronics.
HMS: Why do you believe that?
SILVER: Because we know so much about it and some of it has parallels to electronics. We know that it’s modular. We know that it can do a lot of things well. It’s very sensitive. Olfaction can detect a single molecule. We know it can make patterns. We know about gene expression. So I think that the fruits of what came from 30 years of molecular biology should now allow us to make a more predictable way to engineer biology. Also we’ve got tons of information. We have sequenced genomes being deposited every day, so that gives us so much material to engineer biology with. This forms the basis of what we call synthetic biology.
The working group formed around 2001, and the government also became very interested in synthetic biology, for defense and economic reasons. And so we became part of a group that started working with DARPA. As a result of this group, I changed my research direction. Now my whole lab works in synthetic biology.
HMS: How would you describe your overall approach to doing science?
SILVER: Risk taking. It’s all about risk. I mean I get mad at myself if I think I’m not taking enough risk. There is a saying that if more than 10 percent of your experiments work, you’re doing the wrong experiments. Now, this can be a problem because funding agencies don’t like risk. They want sure things. But my personal philosophy is to find a strategy where you can take as much risk as possible.
HMS: How do you do that?
SILVER: Many labs train young scientists by teaching them that you should only publish in the fancy journals and that’s your life, but I don’t see that as what science is about. And I feel that somebody has got to speak up and change things. I don’t think it’s going to be people in my generation, and that’s why I think it’s important to convey to younger people that they should be thinking about what kind of world they want to work in, because right now they’re running in the other direction. But maybe I’m an enigma. I don’t know. I really tell them to think outside the box.
HMS: How do you run a lab?
SILVER: It’s extremely informal. My door is almost always open. People sit right outside there and eat lunch every day.
It’s called ‘management by walking around’. I’m also very egalitarian. I don’t think the postdocs are somehow better than the grad students or the techs. Everybody has a say. And also, part of my lab is at the Wyss Institute and part is here, and my husband, Jeff Way, works at the Wyss and keeps an eye on them over there. [laughs] The other secret is: get good people.
HMS: What does “good” mean?
SILVER: People who live and breathe science. People from completely different backgrounds who all find this so cool that they’re going to really engage in it. I have one postdoc who came from Stanford computer science, and he could have gone to Pixar, but he said, “No, that was too boring. Biology is way cooler.” And he has done these simulations about protein movement that he thinks is just way more exciting than making planes and cars fly around the movie screen.
I also hate conflict. I always tell people who join my group that if there ever is conflict they should come tell me all about it, because there is nothing they can tell me that I haven’t seen. I’ve trained over 30 grad students and I don’t know how many postdocs, and I’ve lived with conflict. I let them know that I can resolve anything. That helps create community.
HMS: How important is community for science?
SILVER: Very. Within the synthetic biology community, we started what we’re calling the SB meetings, so we had SB 1.0 in Boston, and we just finished SB 6.0 in London. We’re trying to make a global community of synthetic biologists, and it’s working, but it’s the people that say you shouldn’t take any risk who are getting in our way. The more traditional people, I think, are holding back these younger people who want to go out and try stuff and do whacky things, and they’re running up against this very regimented publication and granting system that makes it difficult for somebody who is a free thinker.
I sometimes ask myself, “Would Steve Jobs make it in the way we do things?” No way. He would go out and do it himself, and there actually is a DIY bio community now which I think was born out of the synthetic biology community. There are also spaces, open laboratories, where people are just starting up their own thing and not relying on the infrastructure of academia or industry to try to do biology. The trouble is we bring promising young scientists through these graduate programs and they get exposed to this still very traditional environment.
But, to be honest, I feel like I’m walking on the edge, because I just don’t know how much longer I’m going to be able to pull this off sort of. And I’m really lucky. I’ve got great people, and I always feel like someone is going to catch up with me and say, “Wait a minute, what is going on there at the Silver lab anyway?”
HMS: What keeps you up at night?
SILVER: I actually worry a lot about people, the people in my group, because I want them to succeed, because I feel like I’ve had my moment. At this point in my career, it’s really about making sure they get what they want, and if I feel like something is going wrong or maybe I put them down the wrong path or something like that, that really does keep me up at night. But mostly, I’m trying very hard not to keep up at night.
