The paper trail

The paper trail By Kerry Grens ARTICLE EXTRAS Growing a New Antidepressant A Harsh DecreeBrain Cells Video 1928 Histologist and Nobel laureate Santiago Ramon y Cajal writes in Degeneration and Regeneration in the Nervous System, "In adult centers the nerve paths are something fixed, ended, immutable. Everything may die, nothing may be regenerated." Santiago Ramon y Cajal 1965 Joseph Altman and Gopal Das at the Massachusetts Institute of Technology are the first to describe neurogenesis in adult rat hippocampus, but Ramon y Cajal's dogma remains intact. 1977 Using radioactive thymidine labeling and electron microscopy, Michael Kaplan and James Hinds at Boston University find evidence of neurogenesis in the olfactory bulb and dentate gyrus of rat. Kaplan later writes in a 2001 Trends in Neurosciences article: "In the midst of a revolution one must chose allegiance, and during the 1960s and 1970s, those who chose to support the notion of neurogenesis in the adult brain were ignored or silenced." Fernando Nottebohm 1983 Fernando Nottebohm at the Rockefeller University publishes evidence of neurogenesis in adult female canaries. 1997 While a postdoc with Bruce McEwen at the Rockefeller University, Elizabeth Gould shows that neurogenesis occurs in tree shrews, and that stress decreases the number of new neurons in the dentate gyrus. "I think it really was a turning point in the acceptance of the phenomenon as being real and relevant," Gould says. Rusty Gage 1998 Using brains from cancer patients who had been injected with the dividing-cell marker bromodeoxyuridine, Rusty Gage at the Salk Institute and his colleagues publish the first evidence of neurogenesis in human brains. Date undisclosed Mitsubishi Pharma conducts clinical trials on a drug, later known as BCI540, to treat a nonpsychiatric neurological disorder. The drug passes safety trials but fails for efficacy. Barry Jacobs 2000 After his own findings in 1998 that serotonin increases neurogenesis, and evidence from Ron Duman's group at Yale that antidepressants increase neurogenesis, Barry Jacobs proposes a theory of depression in which the "waning and waxing of neurogenesis" contributes to the development of, and recovery from, the disease. 2003 René Hen at Columbia University and his colleagues show that blocking neurogenesis prevents antidepressants from changing behavior in mice. René Hen 2004 Jacobs's theory goes to the laboratory as Hen, Gage, and others found BrainCells, Inc., in La Jolla, Calif. The company aims to find potential new antidepressants by screening compounds for neurogenic qualities. 2006 After screening hundreds of compounds, BrainCells finds BCI540 to be neurogenic, effective in animal models of behavior, and mechanistically novel as a potential antidepressant. 2007 After the company has raised $37 million to proceed, BrainCells will conduct Phase IIA clinical trials on BCI540's efficacy as an antidepressant. 2008 Results are expected from BCI540's clinical trials, which will be the first test of whether BrainCells' neurogenesis screening platform could succeed.