Eager to tackle human biological problems, Fuchs pursued a postdoc in the Massachusetts Institute of Technology (MIT) lab of Howard Green, a pioneer in culturing human cells—specifically, skin cells derived from newborn foreskins. “I learned cell culture from a master,” she says. “Howard really paid attention to the kind of detail that, even now, very few people have the capacity to do.” He recognized, for instance, that to grow human epidermal cells, you have to co-culture them with fibroblast cells from the dermis, located just beneath the epidermis, thus reproducing the “cross talk” between cell types that occurs in nature.

At MIT, Fuchs started wearing makeup and nice clothes, partly to annoy a female colleague who said women scientists should avoid looking too feminine. Today she still dresses carefully and elegantly, and her long blonde hair is always permed. With bright blue eyes, a long oval-shaped face, and a dazzling smile, she has skin so wrinkle-free that it makes you wonder whether studying skin cells is its own fountain of youth.

In 1980, Fuchs became an assistant professor of biochemistry at the University of Chicago and once again found herself in a man's world. As she was setting up equipment on the first day in her lab, the department chairman's lab technician dropped by. “Are you Dr. Fuchs's new lab technician?” he asked.

“Umm... I am Dr. Fuchs,” she replied.

Things got better a few years later when a departmental reorganization brought a cohort of three strong female biologists together into the new Department of Molecular Genetics and Cell Biology: Fuchs; Janet Rowley, already a member of the National Academy of Sciences; and another assistant professor, Susan Lindquist, now a lifelong friend and fellow HHMI investigator. Fuchs and Lindquist designed and co-taught a course called Gene Expression in Cell Biology, which they continued until Lindquist left for MIT and the Whitehead Institute for Biomedical Research. And their friendship went beyond the classroom. They were neighbors in Hyde Park, and their husbands were also good friends—in fact, Lindquist introduced Fuchs and Hansen—so the two couples got together often for dinner and conversation.

“Every New Year's Eve we would go out together to a restaurant, and then to a dance party sponsored by the Chicago Symphony,” says Lindquist. Getting to know her professionally and socially, Lindquist says, showed her that Fuchs is “both a phenomenally good scientist and a phenomenally good human being.”

One of Fuchs's goals when she got to Chicago was to make a cDNA library (a collection of DNA fragments used to help identify genes and the proteins they produce) of the major structural proteins she'd been characterizing at MIT. In those early days of recombinant DNA technology, such a goal was ambitious. Eventually, Fuchs and her colleagues not only determined the DNA sequences encoding these proteins but also defined the two basic subunits required for the most important structural protein, keratin, to self-assemble into filaments. And they discovered that the filaments, in turn, were essential for the skin's protective and hydrating functions, forming an elaborate cytoskeletal network that provides mechanical integrity to the cells at the skin surface.

By the mid-1980s, Fuchs moved on to investigate what happens when the genes involved in making keratin proteins are damaged. At the time, geneticists approached such a question using a technique known as positional cloning. An investigator would choose a disease of interest and then find a large family with affected members. Then the scientist would collect DNA samples from everyone in the family and study the differences in DNA sequences between the affected and the unaffected, hoping to find the relevant mutation.

“This strategy did not divulge how or why the defect in the protein caused the tissue abnormality, which was what I was interested in,” Fuchs says. “So we started at the reverse end and worked our way back.” This process involved a relatively new kind of laboratory model, developed in the early1980s: the transgenic mouse. It was a backward approach, since the idea was first to create a mouse with a specific mutation of interest, then analyze the pathology of the tissue defects, and finally find a resemblance to a human genetic disorder.

Not many scientists were making transgenic mice in 1986. Fuchs contacted one of the few in the Midwest—Susan Ross at the University of Illinois—and asked about sending a graduate student, Robert Vassar, to train in the Ross lab.

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