An interview With Elaine Fuchs

Discovering the Wonders of Skin Cells

Q. OVER THE YEARS, WHAT HAS BEEN THE DISCOVERY YOU ARE MOST PROUD OF?

A. We pioneered an unconventional approach to solving the genetic basis of human disease. In the past when geneticists were researching an inherited disease — cystic fibrosis, breast cancer —they would systematically study large families where it occurred and then search the DNA to find the defective gene. Eventually, they’d identify the culprit, let’s say BRCA1. But this didn’t tell them how encoded mutant proteins contributed to a person getting breast cancer.
In the early 1990s, in my lab, we took a reverse direction by studying what the proteins did and then figuring out what diseases they caused when defective. Our first breakthrough came while we were studying a rare inherited blistering skin disorder. Because it is rare, there were no large families to study. You couldn’t use the conventional methods to identify it.
What we did was to begin by studying keratins, the major proteins of the skin. When we engineered mice to express mutant keratins, we discovered that their skin blistered. Moreover, we were able to show how the mutation caused the blistering. So the next step was to compare the skin pathology of the mice to all the known blistering skin diseases in humans. We teamed with dermatologists to study skin samples from patients. This led us to the genetic basis of this inherited blistering disorder in humans. Since, our method has become a paradigm for guiding scientists to the genetic basis of other human diseases.

Q. YOUR LABORATORY CURRENTLY FOCUSES ON SKIN STEM CELLS. WHAT ABOUT THEM FASCINATES YOU?
A. Skin stem cells have special properties that the ordinary skin cells lack. They can develop tissue that can become outer skin or hair follicles or sweat glands. I’d like to know how one stem cell can create tissues so different from one another.

This may, ultimately, prove helpful in treating burn patients. Right now, we can give them skin grafts, though the transplanted skin won’t grow hair and won’t sweat, which people need to regulate their body temperature. Once we fully understand how skin stem cells work, we may be able to engineer better skin grafts. We may even be able to create tissue that helps with corneal blindness. I hope so.

Q. AS PART OF THAT RESEARCH, YOU ENGINEERED AN UNUSUALLY HIRSUTE MOUSE. WHY?

A. We wanted to understand the function of a protein that skin stem cells produce: beta-catenin. It helps genes switch on and off and it helps cells adhere to each other. So we expressed the protein and put it into mice. To our surprise, we saw that the protein seemed to coax the stem cells into making hair follicles.

Q. WAS THAT A CLUE TO HOW SKIN STEM CELLS MAKE HAIR?

A. Exactly. The protein issued instructions to the switch that takes a stem cell and says to it, “Make a hair.” What we were doing by expressing high levels of beta-catenin was saying to the epidermal cells, “Make a hair.” And they said, “O.K.” Hence: the hairy mouse.

Q. DID YOU ALWAYS WANT TO BE A SCIENTIST?

A. I’ve always been interested in how things work. When I was child in 1950s Chicago, there weren’t many women scientists. So to ask the kinds of questions that interested me was unusual. I remember as one of three females among 200 male chemistry majors at the University of Illinois, I was terrified that if I did well in class, the professors would think I’d cheated. That’s how much I didn’t think I belonged. So I studied like crazy and routinely got the best grades on examinations because if I was No. 1, then who could I have cheated from?

When I entered graduate school at Princeton in 1972, one of three women in biochemistry, I had difficulty finding a thesis adviser. The first person I talked to about the possibility of working in his laboratory was Bruce Alberts. He said, “I only take the best students.” To me, it was an indication “out the door.” I then wrote to Art Pardee, who indicated he wasn’t taking on new students. The next year, he took two male students. The thesis adviser who accepted me was Charles Gilvarg. I was happy until his lab technician said, “It’s surprising that you work for him because he had indicated that women don’t belong in science.”

I took these things as an invitation to prove people wrong about women in science. It made me work harder.

Q. BRUCE ALBERTS WAS, UNTIL RECENTLY, THE HEAD OF THE NATIONAL ACADEMIES OF SCIENCES, WHICH YOU ARE A MEMBER OF. DID HE EVER TELL YOU HIS SIDE OF THE STORY?

A. Well, he claims no recollection of the event. But these days, all of these gentlemen are supportive of women in science. They’ve come around.

I have to tell you that now that I’m in a position of authority, I feel that it’s vital for me to pave the way for other women to get into the ranks. It’s true of many of the successful women of my generation. One of my closest friends is Susan Lindquist of the Whitehead Institute. She feels the same. I don’t think any of us view our success as an indication we can quit now. It is no longer fashionable to say out loud that you don’t believe that women should be scientists, but the attitudes remain.

Q. GETTING BACK TO STEM CELLS. DOES IT TROUBLE YOU THAT YOUR PARTICULAR AREA OF RESEARCH, SKIN STEM CELLS, IS CONSTANTLY TOUTED AS AN ALTERNATIVE TO EMBRYONIC STEM CELL RESEARCH, WHICH IS CONTROVERSIAL?

A. We have to keep using embryonic stem cells because they provide a gold standard for learning about how all cells function. We have to understand what embryonic stem cells do — how they work. Why can they give rise to every single cell of our body, some 220 different types of cells? The adult skin stem cells I work with can only make three different tissues, which is minuscule by comparison.

Q. BUT KYOTO UNIVERSITY’S SHINYA YAMANAKA HAS REPROGRAMMED ADULT SKIN CELLS SO THAT, LIKE EMBRYONIC STEM CELLS, THEY APPARENTLY CAN MAKE MANY OTHER TISSUES, NOT JUST THOSE THREE. HE JUST RECEIVED AN AWARD FROM THE MARCH OF DIMES, WHICH SAID IN AN ANNOUNCEMENT, “HIS METHOD ELIMINATES THE NEED TO OBTAIN STEM CELLS FROM HUMAN EMBRYOS.” IS THAT RIGHT?

A. At the moment, Yanamaka’s discovery doesn’t replace human embryonic stem cells. What it does is give hope that we might eventually replace them. One reason we still need them is that Yamanaka’s own work is actually based on human embryonic stem cells! If he’s trying to coax a skin cell to become an embryonic one, he can’t do that without first knowing what an embryonic stem cell does. And we haven’t learned all of that yet.

Besides, people who work on reproduction will always need to work on the embryonic stem cells. So that’s never going to entirely go away. Once some of this is solved, I will favor focusing on adult stem cells. We’re not at that point yet.

Elaine Fuchs, 60, a cellular biologist at the Rockefeller University and a Howard Hughes Medical Investigator, studies the biochemistry of skin tissue. She is the new president of the International Society for Stem Cell research. Some of her work is aimed at transforming the treatment of burn and wound victims.