Stem Cell Pioneers

Despite federal opposition to embryonic stem cell research, the promise of medical benefits, academic freedom and profits in California is luring scientists to the field

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Cell biologist Larry Goldstein of the University of California at San Diego, who worked closely with Weissman on the Prop. 71 campaign, started his first project with human embryonic stem cells in the summer of 2004. The research takes place in a small room that discreetly has no indication of what goes on inside.

Incubators in the room hold federally approved embryonic stem cell lines, one of which came from the Wisconsin researchers, and others made since August 9, 2001, by groups not using NIH funds. Little round red and green stickers dot all of the boxes on the shelves to indicate whether supplies were purchased with federal money, because strict penalties would be imposed if ever a researcher grew nonfederally approved cells using a petri dish that NIH paid for.

Goldstein wants to use his stem cell lines to study Alzheimer's disease. He plans to splice genes that are known to cause a rare type of inherited Alzheimer's into the cultured cells, and then test different hypotheses about what causes the disease. If a clear mechanism emerges, researchers may use the cell lines to screen various experimental drugs, to see which ones prevent the cells from developing characteristic signs of Alzheimer's disease. This use of embryonic stem cell lines "has been a completely underemphasized part of the discussion," he says.

For now, though, Goldstein's lab simply wants to figure out which lines grow best in which cell-feeding broths, which have odd-sounding names like Modified Eagle Serum and Leukemia Inhibitory Factor. "We're at the very, very beginning stages," says Nikole Kimes.

Kimes snaps on a pair of latex gloves and sprays her hands with disinfectant. She removes a clear, plastic petri dish from an incubator that's about the size of a dorm room fridge. The incubator is set at 98.6 degrees Fahrenheit—human body temperature. Kimes moves to a lab bench that's covered by a ventilation hood, and she slides the petri dish under the lens of a microscope. The magnified cells look like the tiny bubbles that cluster at the bottom of a pot of water just before it begins to a boil. Mouse connective tissue, which forms a platform for the cells to grow on, resembles long grains of rice.

Normal embryos take on a mulberry shape as they grow. Although initially there's a symmetry to the bubbles in the petri dish, they do not look like a mulberry, nor will they ever take on that shapeas they grow. For one thing, they lack placental cells that help form early embryos. As a normal embryo grows, its cells also change shape as they lose their "stemness"and commit themselves to becoming, say, muscle, liver or bone cells. Kimes, however, is doing everything she can to keep the embryonic stem cells in a state of perpetual bachelorhood in which they make no commitments.

Kimes picks up an instrument that resembles a toy gun with a foot-long glass straw, called a pipette, attached to it. She gently maneuvers the tip of the pipette into the petri dish, and when she pulls a trigger, dead cells and fluid rush up into the pipette. The back end of the instrument has a plastic tube that leads to a large flask that collects the detritus. She replaces the pipette with a fresh one that she takes from a box with a green dot—these are nonfederally approved cells—and then uses it to slowly add fresh medium, the color of pale cranberry juice, to the dish. She then slips the dish back into the incubator. She will do this again and again, most every day of the week, sometimes removing samples of cells to see if their chromosomes have become mutated.

Kimes and Goldstein still don't know which media best support the growth of these cells and yet prevent them from turning into a specific type of cell. These particular cells seem to like a cocktail that she concocts from certain serums, amino acids, growth factors and antibiotics. And in her more ambitious experiments, she changes the cocktail's ingredients to compel the cells to turn into neurons. (She finally succeeds after several months of tinkering.) The Goldstein lab has not begun to make its own cell lines from excess embryos or to make human lines using cloning technology. "We're just figuring out how to do this," Kimes says with a laugh. "We'll have our hands full for a while."

Given the dramatically polarized perspectives that proponents and opponents have of this research, the Goldstein lab's work with human embryonic stem cells is oddly mundane. Goldstein says the passage of Prop. 71 should speed the time it takes to answer nuts-and-bolts questions about how to manipulate embryonic stem cells in a lab. "Science moves quickly when lots of people work with a new technology," says Goldstein. "Lots of different tricks get worked out, little secrets get shared, lore gets passed around."

Robert Klein is a California real estate developer and lawyer who has movie star good looks and a winning smile. Klein, who worked on the legislation's language and the financing of Prop. 71 with bonds, became involved in the issue partly because his 15-year-old son has diabetes.


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