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"Once a stroke occurs, there's no good way to repair it," says Steinberg, who has no affiliation with Layton other than the study. "With the advances in molecular biology and stem cell biology, the potential for repairing damaged tissue in stroke patients has become a reality. It's just that nobody knows which cell is going to be the best transplant. This is the first clinical trial to test it."
But if the patients aren't apprehensive, many doctors in the stroke-studying community are. And Steinberg is well-acquainted with his colleagues' skepticism. The same August 2000 issue of Neurology that published enthusiastic findings from the first Layton trial phase also featured an editorial headlined, "Cell transplant therapy for stroke -- hope or hype?" The editorial, by Dr. Justin Zivin of the University of California at San Diego, cautioned against the conclusion that patients' functional improvement was due to Layton's cells, and hinted that the company expedited the article's publication to attract potential investors. Zivin's central concern, reiterated in an interview with SF Weekly and shared by many of his colleagues closely watching the Layton trial, is that the study has progressed into humans without proving its central thesis: that Layton's cells are legitimate neurons.
"Are these even neurons they're implanting?" Zivin says. "You're not at all sure they're going to hook up properly. The article you should be writing is how much hype this study is getting when it's still a long way from proving its worth."
"We don't know how the cells are working," Steinberg admits. "We don't know whether they're making connections and acting like replacement neurons or whether they're secreting some kind of neurotransmitter, trophic factor, or growth substance that enhances the activity of the neurons that survived the stroke."
Steinberg's counterpart at the University of Pittsburgh, Dr. Douglas Kondziolka, is equally honest about the study's unknowns. But, like Steinberg, he points to brain scans that show a slight increase in patients' metabolic activity to suggest the Layton cells are wiring properly into the brain. If the stroke-damaged brain areas are using more sugar after the surgery, he says, it could mean the injected cells are surviving and fueling their repair efforts with glucose.
"There's no direct proof of anything," says Kondziolka. "But a duck looks like a duck. These cells look like neurons. They behave like neurons, they release the appropriate transmitters, they have the potential to talk to each other. They do all these things that we expect neurons to do."
Skeptics say that's an optimistic interpretation of the study's findings. They argue that the brain surgery itself might be responsible for stimulating existing neurons, that the uptake in metabolic activity could be due to inflammation following the insertion of a needle.
"You can't say that has anything to do with the cells that were transplanted. If they tell you that, they're bullshitting you," says Scott Whittemore, a professor of neurology at the University of Louisville. "They could put any cell in there, and it might give them the same effect. There's a general sense among researchers that the clinical trials were premature and that we don't understand what the effects are yet."
The source of Layton's cells is another concern. If these cells were once cancerous, who's to say they won't revert to a tumorigenic state after they've been implanted?
"In the 25 years this cell line has been studied, there has never been a tumor formed in animals or in people," says Steinberg, adding that embryonic or fetal stem cells probably have more potential to become cancerous. "These are pure neurons. They are primitive neurons. They will differentiate, mature into different neuronal types, but they don't mature into other cell types that divide," the way stem cells do.
Dr. Gregory del Zoppo, a professor at the Scripps Research Institute in La Jolla, Calif., and a spokesman for the American Stroke Association, says the scientific community needs more and varied animal studies to be convinced of the cells' viability. "There's a concern that perhaps enthusiasm is taking the upper hand here," del Zoppo says. "If I were involved in the study, I'd be excited, too. I don't think anyone is saying we shouldn't explore this, but I think human experiments are beyond where we should be right now. It's over the top. I would encourage the company to proceed with caution."
"Maybe we're wrong," says Layton CEO Gary Snable, a 64-year-old with a thicket of white hair and the habit of winking when he's trying to drive home a point. "Here we've purposely implanted tumor cells in someone's brain expecting they'll be benign, and they turn out not to be. Even though everybody knows this is not a risk-free procedure, we'd feel just awful."
The window in Snable's office looks out on shrubbery and parking spaces. For the first five years, when Layton was based in tiny facilities in Atherton and Gilroy, Snable's was the only name on the payroll. Now the company has about 30 employees, who work in a low brick building at the rear of a Sunnyvale research park, tucked deep into the shade of trees.