“If you are intent on accomplishing something, then the most important thing is to develop the resilience to deal with the setbacks in whatever form those appear because they’re going to be there. Don’t give up in the face of obstacles.”
How did you get into science?
When I was in grade school, science was not part of my bringing up. I had to transfer from a classics-oriented high school to a suburban high school where you couldn’t graduate without taking a laboratory science, so I took chemistry as a senior and loved it. Chemistry was unlike anything I had encountered. I loved the idea that it was about the world and matter and stuff, the idea that this table here is made of molecules that have mostly empty space in them. I also loved my teacher; he was a real role model for me. So I went into college thinking, I’m going to major in chemistry, and I did.
My aspirations at the time were to be a high school chemistry teacher. That worked until my junior year in college when I fell in love with ATP. I went to a lecture where a guy talked about scientific theory. You get this perception in school that you read something in a textbook, and it’s truth. I hadn’t been exposed to the idea that scientists disagree on what the correct explanation or model for something is. He laid out these theories about oxidative phosphorylation, and I thought it was the coolest thing ever, and I decided this is what I want to do. So I switched over to a cell/molecular/biochemistry focus. I ended up not working on ATP until my philosophy graduate dissertation when I went back to ATP and outlined all of the different theories of truth and how all the theories developed in what I think is a really cool epistemic archaeology where I delved into all of the arguments that were going on in the 40s and 50s. So that’s how I got into biochemistry.
I went to grad school at Stanford. Stanford biochemistry was at the time a DNA department, and I had never got as far as DNA in my biochemistry courses, so I came there pretty ignorant. I had read some of the historical stuff, but I ended up doing my dissertation on DNA replication and then quit science, went to grad school again in philosophy, taught philosophy at Caltech for three years. Then my job ended, and I got into Lee Hood’s lab, then worked on the Human Genome Project for the entirety of the time it was being sequenced.
What are some of your long-term goals?
You know, that’s such an interesting question. I’m 67, and Carl Jung had this interesting theory where he says in the first third of your life you have to grow up: you have to learn to develop an ego, you have to learn to function as an autonomous being; then in the second third you do what the Buddhists call the housholder thing: you establish your career, you establish your relationships, you raise a family, you buy a house–this is all stereotyping of course, but the idea is that you make your mark on the world; then in the last third of your life you start to develop the capacities that were latent, that you didn’t have time for when you’re busy making your mark on the world. And I think I’m in that stage. I don’t have long-term goals anymore. I’ve become much more present-tense oriented, focused on what is appearing before me right now, and just to be able to enjoy that and appreciate it is my current goal. Honestly, it’s a really good goal for anyone in any stage of their life. We spend so much time anticipating the future and planning the future and conjuring up all these future scenarios, most of which never come to pass, and miss what’s right in front of us. Aside from that, I’m interested in art, spending time with my friends, helping out the institute, staying healthy. When I was your age, 67 seemed so grandmotherly to me.
I’m going to go on a tangent now. In the late 80s, I was very much involved in an HIV support community. People died, as there were little no effective treatments at the time, and I knew a lot of people who died, and I remember thinking I’m 40, I know how to be 20, I’m learning in this group how to be 60, but I have no idea how to be 40. It was really strange, but that experience has stuck with me. It was a really transformative chapter of life. Looking ahead to different ages, you realize that you don’t’ know. People develop at different paces based on what life presents to them. Right now you’re at the stage where you’re taking in a lot of information and deciding how you want to live your life when you grow up and you’re emancipating yourselves from the values of your parents and looking at them, choosing which ones to adopt. And that’s cool. That’s where you are. And it gets different with every decade.
As a female in science, how has the gender bias changed throughout your career?
When I went to Stanford as a graduate student, I was an affirmative action candidate–this was in 1972–and in 1972, the National Institute of Health had informed the biochemistry department that they needed to admit more women, and if they didn’t, NIH was going to pull their graduate student training grant. The reason for this was that the biochemistry department had somewhere between 30 and 35 graduate students, of which one was female. No female faculty, the only females were the female technicians working for the male principal investigators. They admitted a class of 6 and there were 3 males and 3 females. The sexism was very overt. That’s another thing that has changed; the sexism is a lot more subtle now than it was back then. My advisor said to me when I wanted to join his lab–Stanford had a rule that if I wanted to join his lab he had to let me–he tried to talk me out of it, saying he didn’t know whether women had different hormones that made them less able to withstand stress in research, and I worked for the guy anyway.
Was it a mistake? I don’t know. I was his first female grad student, or postdoc, or technician, and I got the sexism left, right, up, down, and around. In a situation like that, I had to make a decision: am I going to let this affect me or am I not, and I decided to go the thick-skin route and ignore it as a survival strategy. One of my other female classmates—it just got to her.
Because there’s so many more of us now, there’s more freedom. You guys have this idea that if you want to do something, you can do it. There are a lot fewer obstacles now than there were before. But there’s obstacles for anyone trying to pursue a career. There’s obstacles for guys too. If you are intent on accomplishing something, then the most important thing is to develop the resilience to deal with the setbacks in whatever form those appear because they’re going to be there. Don’t give up in the face of obstacles. And sexism unfortunately is still an obstacle.
Could you give us some details on what working on the Human Genome Project was like? What you guys did was revolutionizing.
It was an engineering challenge. Everyone was asking how do you do this? There was a lot of controversy at almost every stage over how to do it. Because Lee [Hood]’s group had invented the automated DNA sequencer, we got one of the earliest grants. We got a pilot project to prove the feasibility of generating long stretches of contiguous human genome sequence. We got the grant in 1989. We were supposed to sequence the human and mouse T-cell receptor genes, which turns out to be a hard region because there’s a lot of duplication. At the time, the longest sequence anyone had done was ~84 kilobases, which someone had done in Drosophila. In order to do the sequencing, you had to first do the mapping; you had to fish out the part of the genome that you intended to sequence, and that required you to generate a lot of clones in vectors that you would propagate in bacteria. And it was incredibly convoluted: you had to come up with ways of generating these clone libraries, then you had to screen them and pull out the clones from the region you wanted. And this was super labor intensive.
There were all these factors-of-two in technology improvement, where you could suddenly do double what you could do before. Ultimately, the process was still slow. I wrote a paper for Science in 1997 where someone wanted me to give a summary of where we were at. At the time, somewhere around 1.5% of the genome had actually been finished. I laid out a lot of the challenges. There was all this pressure from NIH. We had to do these monthly reports: how many bases did you sequence, what is your cost per base, what is your quality control?
And then Celera came along in 1998 and said, “Hey, we’re going to do the whole thing. We don’t need the public effort.” Craig Venter went to Congress to try to convince them to pull all the public funding because this company was going to be way more efficient, and of course everyone was afraid they were going to try to patent the genome. This was bad, bad, bad.
Plus, the Human Genome Project was an international effort. Different countries had planted their flags on various chromosomes. So the NIH changed the focus to generate the so-called draft sequence. It was such a mess. It was so horrible. We would have these annual strategy meetings at Cold Spring Harbor where the leaders of the international centers would give a report. At one of them, I think it was 2001, I held out this big, huge clone map where I had mapped out the different clones found in our region—everyone was claiming different parts of chromosomes; we were doing at this point part of chromosome 14, and then the French wanted chromosome 14 because Bastille Day on July 14 or something. So they switched us to chromosome 15, just one over. But the Consortium had a mandate that you were supposed to finish every clone you had started no matter where it was. And so all these different centers had clones in everybody else’s regions, and it was complete chaos—so at the meeting I held up a big map of about 20 megabases of chromosome 15 where I had tracked out which center owned every clone mapped to that region. It was ridiculous.
That changed the strategy. I was so proud of that moment; I had actually influenced it. People agreed to hand over the sequence data they had for the clones outside of their designated regions in order to help everyone finish their parts. But all the time throughout the project it was like that—people ferociously arguing that their strategy was the best—it was fun. The meetings were fun. They were entertaining. They usually had them at some beach resort. You would be in the hot tub at four in the morning arguing about whether the reads should be longer or shorter. It was a very crazy time but also a sense of accomplishment. And I loved it.
Of all the projects I’ve ever worked on, this was the one that played to my strengths. Because I was the overall project coordinator, I picked the path that produced the clones we were going to sequence and made sure the regions got finished. Basically, I had to know everything, and I was also involved in reporting to NIH. It was real systems integration stuff trying to figure out how to do this efficiently, and you always had some bottleneck or another that would slow the process down, and you would have to figure out how to speed that part up, and once you did that, it created a new bottleneck, rinse, repeat. It was cool. It was also really hard, and I had no life.
How do you feel you manage your personal life and your work life now? Do you feel you have a better balance than you once did?
It’s kind of swung the whole other way. When I was working on the genome—I worked on it from 1990 until it got done in 2004. It was amazing and really intense, and I used my apartment as a crash pad. I worked on weekends. I worked at night. I didn’t do anything else. I didn’t really have any friends except my work friends. And people at the time told me that I was working too hard, that I was going to burn out, that I could not sustain this level of intensity. And I never burned out while I was working on the Genome Project. And then once it was finished, I totally burned out.
Poor Lee Hood was always trying to entice me to work on some biomarker project or whatever, then he tried to get me to learn how to write code, and it was like write code to do what? That’s how I morphed into administration. I was just intellectually burned out. But my whole life’s kind of been like that. I do these swings of super-intensity work, and then there are periods when there’s been an infusion of new people and new experiences in my life. I practically don’t do any work now. It’s all life.
I’m a pendulum person. That’s been my life. I don’t seem to do work-life balance well. It’s all unbalanced in one direction and then the other. I don’t necessarily advise this as a strategy, but that’s how it’s been working out. I like intensity; I never wanted to have kids. I had this intuitive sense that if I had a child, I would become mentally ill–I do believe that actually. Plus, my mother was such a horror in certain ways, I had a fear of inflicting the same emotional damage on any potential children. I also thought that if I had a child, that would destroy my ability to focus and immerse and concentrate. And I didn’t want to do that; I didn’t want to give that up.
I think work-life balance is really hard honestly because whatever you do, you want to do a good job at it if it’s worth doing, and when you have the commitment to a family or the commitment to a relationship and a commitment to work and a commitment to your friends and a commitment to your broader community and a commitment to yourself for your self-development, you can’t do it all. You just cannot do it all well. And so some people kind of do it in sequence. They say, these five years I’m going to focus on raising children, and these next five years I’m going to focus on developing my career. But society isn’t super supportive of that approach, so it makes it hard. Maybe there’s some people that can do it all, but I think most people can’t. So that forces choices, and I think for me what was most important was to have that freedom to thoroughly immerse myself in whatever it was I was interested in doing at the time.
Is there anything you wish you did differently in the course of your life?
I wish I had more self-confidence, especially in high school and college; I wish I had more self-confidence, but I’m not sure how you develop it. It helps if you’re in a supportive environment that develops it and nourishes it, and I was not. So I had to learn it the long, slow way. In terms of the choices I made, I don’t regret any of them. If I had to start over, I’m not sure I’d make the same ones.
One regret I do have about my life is that whatever it is I was meant to do or be, I don’t think I ever found it. I have this longing that I must have some special talent and if I was in the right environment, it would have become obvious. I never have felt adequate or good enough to do the various things that I got to do. Maybe that’s the human condition, and you go ahead and you do them anyway, but I think I’m someone who’s pretty good at lots of different things and super good and super talented at absolutely nothing. And I feel that as a loss. Maybe if I had made different choices, I would have locked into that groove and maybe not. But I don’t feel bad about any of the choices I made, and it’s made for a really cool and interesting life. It’s all good. If I died today, it’s good.
What advice do you have for students about to head to college?
It’s going to be hard. You’re going to be challenged. It’s probably going to be hard socially as well as intellectually unless you guys are super well adjusted. College for me was brutal socially; honestly, it was really, really hard. But I guess my advice would be: hang in. Know that at times, you’re probably going to feel self-doubt, and that’s okay. Sometimes I think that if you’re not insecure, there’s something wrong; you’re not paying enough attention.
What did you learn from your experience in grad school?
Failure. Failure is good for you. It’s really okay to fail. One of the best things you can do is fail and survive it. And take risks because it’s through taking risks that you develop your edge, and you develop your capacities for resilience and character. But the problem with taking risks is that if there isn’t a real possibility of failure, it’s not a risk. And so that means you could fail. And I failed in grad school majorly. I had this advisor, and he was really difficult. I thought maybe I should have picked a different advisor honestly. It was a high-pressure environment, and if you hadn’t published a paper by your third year of grad school, you were considered to be lazy, stupid, or incompetent, and my boss let me know often that he considered me to be all three of those things. I worked on a project that failed for three years, and then he threatened to kick me out of grad school if I didn’t change projects, but I did, and I picked a safe, low-risk, this is going to work, project, and it worked, and I graduated, and then I left science.
However, when I left science, my confidence was diminished, but my character wasn’t because I survived it. I had to learn that my worth as a person was not contingent upon accomplishing something. And that was a tough one for me because up until that project I always felt like if I persevered, and if I worked hard enough, and I was sufficiently dedicated, I would be able to accomplish that which I wanted to accomplish, and that had always been true, and there’s certain things I could write off like sports. I am not at all athletic. So I didn’t care. But I really cared about [my grad school project]. And I healed. And I survived. So that’s the biggest thing I think I learned from grad school.
What surprised you about science that you didn’t know before?
You have to deal with people. As an undergrad, I had this romantic idea of science. Back then the stereotype was the white man in a lab coat pouring over his microscope, discovering penicillin. The reality is that you’re working in groups of people, and there’s hierarchies, and people judging you all the time, and you have to decide whether to be competitive, cooperative, or both, and with who. You learn how to work with people because trying to get something done tends to be a collaborative effort these days.