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With this training, Vassar created a transgenic mouse expressing a mutation in the K14 gene, which is responsible for building a keratin network in the innermost layer of the epidermis. But the transgenic mouse with the K14 mutation seemed to be normal in appearance, health, and behavior—in other words, the mutation showed no distinct phenotype. “We were very disappointed,” Fuchs recalls. “We thought it was a complete failure, a good idea but bad luck.”
After a few litters of K14 mutants were born with no apparent defects, Fuchs's lab manager, Linda Degenstein, noticed a mother mouse eating a newborn pup with an apparent skin defect. Might Degenstein have stumbled on nature's way of taking care of deformed offspring—and also an explanation for why all the transgenic pups in the litter appeared normal? Clearly, they thought, close observation of the mice in the immediate hours after delivery was needed.
“We essentially had a stakeout all night long,” recalls Vassar, now a professor of cell and molecular biology at Northwestern University in Chicago. “We would bring the mice into the lab, and then camp out the entire evening waiting for them to give birth.” The stakeout revealed that some of the K14 mutations were so severe that the very act of birthing stripped the epidermis off the newborn. The mouse pups were unlikely to survive in this way, so the mother was instinctively cutting her losses, eating the doomed mutants so she didn't have to waste energy caring for them. A less attentive team would have missed it altogether.
Vassar and a postdoc, Pierre Coulombe, now chairman of biochemistry and molecular biology at the Bloomberg School of Public Health at Johns Hopkins University in Baltimore, managed to remove the mutant newborns from the cage in time to assess the damage. “The severe blistering was due to mechanical fragility in these mice,” Vassar says. Without a proper keratin network, the skin cells were as fragile as eggshells, ready to break under the mildest strain.
After a trip to the medical library, Fuchs and Vassar uncovered two rare human diseases that looked much like the mouse disease: epidermolysis bullosa simplex (EBS), which involves blistering of the inner epidermal layer, and epidermolytic hyperkeratosis (EH), which manifests in the outer layers. Within a year, they had worked out the genetic basis for both EBS and EH, building on a discovery Fuchs had made as a postdoc, that as epidermal stem cells differentiate, they switch off two keratin genes, K5 and K14, and switch on two others, K1 and K10.
These studies established a paradigm for what are now 89 distinct genetic disorders of intermediate filament proteins. This work also led to a greater understanding of normal skin. When Fuchs moved her lab to Rockefeller in 2002, she continued to focus on skin stem cell differentiation.
Fuchs's research today looks at the signaling pathways that help a skin stem cell decide whether to become an epidermal cell or a hair follicle. For a stem cell to become a hair follicle, at the right moment, the pathway known as Wnt must be turned on, and another, known as BMP, must be switched off. In the absence of these opposing signals, the stem cell becomes skin. While such research at some point could lead to the elusive cure for baldness, Fuchs is focused on its less commercial, more profound implications for human health. She and her colleagues are now investigating the relationship between the process of stem cell activation and defects that cause cell proliferation and cancer.
Fuchs and Hansen spend most weekends exploring New York, often ending up at one of the city's many art museums, standing for long stretches at a time in front of their favorite paintings. A few in particular at the Metropolitan Museum of Art—Virgin and Child by Murillo, Vermeer's Young Woman with a Water Pitcher—really hold their attention, as well as several Picassos at the Museum of Modern Art. “We can stand in front of a painting for an hour,” Hansen told me, “and even though we've seen it dozens of times before, we see something new in it.”
The same is true, it seems, of the way Fuchs looks at a skin cell—like a work of art that reveals new insights every time she studies it, no matter how many times she's looked at it before. Like Picasso in his cubist period, she continues to focus her kaleidoscopic view on familiar questions in search of surprising answers.