Skin has fascinated Dr. Elaine Fuchs for nearly four decades. After studying keratins, the major building blocks of epidermal cells, in her postdoc, she pioneered the use of reverse genetics to effectively break keratin proteins and uncover genes that cause human skin disorders. Using this approach, she hit on the genetic basis of a blistering skin disease called Epidermolysis bullosa simplex. Skin stem cells possess innate genetic programs, but the type of cell that they ultimately become – say, hair or skin – is influenced by signals that they receive from their environment. Fuchs talks about the outside factors that shaped her own development; the opportunities passed up, risks taken, and discoveries made that led her to where she is today, an HHMI investigator and the Rebecca C. Lancefield Professor of Mammalian Cell Biology and Development at Rockefeller University.
This article appeared in the Spring 2014 issue of Current Exchange Magazine.
I think it had a tremendous impact. There weren’t many kids in the neighborhood and my sister was four years older, so I was required to have resources that were self-supportive. My mom made me a butterfly net and I would go off in the fields and catch butterflies. She would give me all her old strainers and bowls from the kitchen and I would go out in the swamps and catch tadpoles and crayfish, and my parents would buy me very rudimentary science books. I remember once reading about an experiment that had been done on accelerated metamorphosis using thyroid hormone so I would beg my father for thyroid hormone and he would get some from Argonne National Lab (where he worked), and I would do experiments on the animals that I had accumulated in the neighborhood.
You’re digging up the haphazard aspects of my life! I thought I would be a biology major; I had been appointed a James scholar at the University of Illinois which was for a certain percentage of students who had done well in high school, and I’m probably the only person who’s ever turned down a James Scholarship. It wasn’t monetary, but it was an honorary title and allowed you to take accelerated courses. And my father said, “Why don’t you wait and see how you do.” I don’t think my father really thought I was going to do very well in school. And so I turned it down.
When I looked at the biology programs they had biology either for honors students or for teachers, and I thought, “Well I don’t want to be a teacher.”
When I looked at the chemistry program you could just be a chemistry major, so I just selected to be a chemistry major. And so before I ever got to do biology I realized that I really liked chemistry, math, and physics. I never got around to doing biology during the time that I was an undergraduate.
My aunt was definitely supportive. She wanted to go to medical school but was turned down. Later on, she worked as a technician at Argonne National Labs. And she was very strongly feminist, always supportive of women. When the National Organization for Women formed, she and her husband would march in the streets. My sister and I were the beneficiaries of her strong feminist attitudes.
It really wasn’t until I was on the faculty at the University of Chicago. My aunt would come into Chicago regularly, and I remember one time we were out to dinner and I had been at the University maybe two or three years and she asked me if I had ever felt discriminated against in going through my career. And I said, “No, not at all.” And she said, “Oh that’s strange, your sister has.”
And it never occurred to me. I did know that my sister had not gotten into the University of Michigan graduate school because they had told her that they didn’t like to accept women they thought would get pregnant and quit school, and so she ended up going to MIT.
There were aspects that I was cognizant of that were blatant, but then the more I started to think about it I thought about it the more I started to realize that my advisor from graduate school didn’t think women belonged in science, and the last advice he gave me before leaving is that if I got married and there were two jobs available in different cities that he hoped that I’d go to the one that my husband was going to.
I think it was because I always felt that I needed to work harder. I just took them as pieces of advice that I didn’t have any reason to question or think weren’t rooted in genuine advice for me. I just thought this was the assessment of my advisor and that I should work harder.
When I was at MIT as a post doc I began to really love what I was doing. Howard Green, my post doc advisor, wanted me to look at protein assembly, and I thought I really want to isolate messenger RNAs and look at gene expression using other approaches. So he let me do that without paying any attention to me, and that was very helpful. For the first time, nobody was telling me what to do, and it was do or die.
It really wasn’t until that point that I realized I had to be resourceful. Nothing was available; there were no biotech companies at the time so you had to do everything on your own, but the resources were available. For me working with the cell biologists and deciding that I wanted to do more molecular experiments, when all of these great labs were around me, taught me the value of interacting with a lot of other people. It was really that MIT experience that gave me that breadth of ability to be resourceful and interact with other people that I think has carried me along the way.
We had really gotten to the point where we had identified critical residues that were necessary for the filament assembly process. We were doing filament assembly in test tubes and getting defects by putting mutant genes into cultured cells and looking at how that affected in a dominant negative fashion the overall cytoskeletal architecture. We really got to the point where these were the major proteins that were expressed by skin.
The globin genes were the major genes that were expressed by erythrocytes and at that point, it was known that sickle cell anemia and thalassemia were due to mutations in globin. So that was the point where it seemed to me that there ought to be patients walking around with keratin mutations and we had these mutations that disrupted filament assembly but looking in a petri dish at a disrupted cytoskeletal architecture didn’t give us a clue as to what human disease we should be looking at.
Irwin Freedberg, probably the most famous dermatologist at the time, (the chair of the NYU Dermatology) later told me that he had a list of fifty potential human skin disorders that were likely disorders of keratin and Epidermolysis bullosa simplex wasn’t on the list. So it wasn’t obvious what human disease to look for. And again, naively talking to my students and post docs, I thought that if there are patients walking around with these diseases, and the mutations are acting in a dominant negative fashion, if we put these genes into mice using transgenic technology we would maybe end up having mice tell us what we should be looking for.
It was probably naïve at the time, I was not a member of HHMI when I made the commitment to do transgenics. I was hoping that maybe 10 mice would be about all I needed, and I had no clue how expensive mouse work was.
It would have very quickly been one, but I was appointed to HHMI in 1988, and at that point I had the resources needed to support my pie-in -the-sky ideas. Hughes is more or less the same kind of challenge that I really enjoy, “You’re successful, here’s the money, now go do something that is different from what you would probably do, different from what other people are doing and come come back and see us in five years.” So you’re constantly being challenged, and I’ve always enjoyed that kind of challenge.
I encourage people to think broadly about the approaches to take to solve a problem. You have a question in science and you want to come up with the best way of getting there. Not, “These are the skills I know, now what questions can I ask?”
Safety is a natural instinct, I think. The natural instinct is “here are the skills I know how to do, and I’m really good at those skills, so I’ll just keep on doing them.” And it’s much less comfortable to take the strategy of saying “these are the skills I know how to do, but I’d really like to do this; I’d really like to know the answer to this question.”
For me it took a long time to develop the ability to think through what it is that I wanted to do because I was going in so many different directions and somehow managed to work out. In retrospect, that was a gift because I had gone through really quite dramatic changes in my approach and in my career. When I realized “I can do this”, that gave me the confidence to say, “I don’t know if I can do the next step, but I know I want to try.”
I think one has to somewhat develop that fearlessness. Everything has been a gift; to be paid to work in a laboratory and be surrounded by students and post docs that are smart and to be able to ask these questions – it’s such a gift. Maybe one day the funding will run out, or I’ll have to do something else, but if I have to go paint or draw or do something else, I’ll figure that out when I have to.
I guess I’ve always felt that way; I never really thought about a job at the University of Chicago. I thought of finding a small school with a few smart people and some students, and then this would be great. Maybe it’s that short-term sort of sense… I’ve always been comfortable with that. I guess I’m still comfortable with the notion that if I have to do something different someday, I have plenty of things I want to do with my life.
I pick the science, but if I had to tomorrow do something else, I could do it. I tell people not to worry so much about funding, not to worry so much about “What if it’s not going to work out?” That’s what I tell people in my group, worry about what you’re going to do if you do what you like doing. Just let it play itself out.
I think it is helpful just so that there has been this misperception that if a woman is going to go into science and really take a route of really doing the top state-of- the-art science that she can’t have children, it’s just too much for her to do.
A close friend of mine, Susan Lindquist, is an example that shows this conception is completely false. I make a point of saying that I believe just the opposite. It’s important to stand back from your science from time to time, and it’s also important to decide personally, “What’s going to make me happy? What’s going to make me excited about coming in to the lab everyday to do my experiments?”
And sometimes the answer to that is just not to put blinders on. Some people can completely burn out by doing that or be very unhappy and that’s going to affect how well they do their experiments and how well they think. For me, it’s been traveling, opera, ballet, whatever; but it’s always the need to do something.
If I hadn’t have spent so much time rationalizing when the right time to have children was and then crafting a life for ten years without children and then one day realizing that my life was completely incompatible with having children.
My husband and I spent about a month talking about well now is a good time to have kids, and we just looked at each other after that and said there’s no way we wanted to do that. I thought at the time that maybe I’d regret it when I’m older, but so far I’ve never had any regrets.
Positional cloning… It’s hard to say whether we would take the approach we had taken. It’s a lot simpler now but it doesn’t inform you about physiological relevance, whereas the approach we took allowed us to understand the biology of what was going on, we just didn’t know which genetic disease we should be applying that to. But as soon as we did, we understood the whole biology of the system. Even if you say, “Well it’s easy to do positional cloning”, what’s the protein doing? And that’s the challenge that I find exciting.
You have to say what drives you. For me being trained as a biochemist I wanted to know how things work, how does this happen? I love the icing on the cake with the relationship to genetic disease, but I guess I’m a hardcore basic scientist, and I always will be.