Beginning with her first insight into the stem-cell niche, Kimble and her colleagues have made a series of startling findings that seem to apply to most, perhaps all, multicellular organisms. First, she and HHMI investigator Iva Greenwald at Columbia University found in parallel that the distal tip cell works partly through Notch signaling. Notch is a protein that plays major roles in cell-to-cell communication in many animals, including humans. Without Notch protein, all worm germline stem cells differentiate; with excess Notch, they fail to differentiate and instead form a tumor.

In the 1990s, Kimble's explorations led her to examine the role of RNA regulation in stem-cell development. Although RNA is the middle step in the “central dogma” of molecular biology (“DNA makes RNA makes proteins”), it was long considered a delivery boy that simply carried DNA's instructions to the cell's protein factories. In 1997, Kimble and her husband Marvin Wickens, an expert on RNA at Wisconsin (whom she met at the MRC), collaborated to identify a protein called FBF that binds to RNA and controls whether a germline stem cell in the nematode forms a sperm or an egg. In 2002, she and Wickens proceeded to show that these stem cells also require an FBF signal to divide into more stem cells. Otherwise, they differentiate into a sperm or an egg.

Like Notch, FBF and related “PUF” proteins now appear to be utility players in regulating animal development. PUF proteins, for example, establish the front-and-back orientation of the fruit fly embryo and are active in the planaria's neoblasts, which enable a tiny fragment of this flatworm to completely regenerate. Neoblasts, like their kindred stem cells in germlines and embryos, are totipotent—able to form any cell type. Thus, if RNA regulation is a general requirement for controlling totipotent cells, the “delivery boy” may deserve a promotion, Kimble proposes. “The idea, not proven, is that the PUF RNA-regulatory proteins may be responsible for maintaining totipotency.” It's suggestive, she adds, that PUF proteins are also found in human embryonic stem cells.

Espousing the radical notion that some stem cells are regulated through RNA in addition to DNA shows Kimble's comfort with flouting convention. Further evidence came in 2006, in a Nature review she wrote with HHMI investigator Sean Morrison at the University of Michigan. The subject was the link between stem cells and asymmetric cell division, the splitting of a stem cell into one stem cell and one differentiated cell. “A lot of people have talked as though asymmetric cell division is the defining characteristic of stem cells,” says Morrison. “But when you look at the data, there are many systems where this is not true, and others where it has not been adequately tested.”

If stem cells always divided asymmetrically, they could never increase their numbers, but they do. “The issue was the elephant in the room,” Morrison says, “so we agreed it would be useful to write a review article” showing that stem cells actually divide symmetrically and asymmetrically. Kimble turned out to be “a really great collaborator,” he adds. “It's not very often that you run into someone who cares just as deeply about the topic as you do and is always there when you pick up the phone to talk it over.”

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