Human Neurogenesis

For this article, Jennifer Fisher Wilson interviewed Fred H. Gage, director of the Laboratory of Genetics at the Salk Institute for Biological Studies in La Jolla, Calif. Data from the Web of Science (ISI, Philadelphia) show that Hot Papers are cited 50 to 100 times more often than the average paper of the same type and age. P.S. Eriksson, E. Perfilieva, T. Bjork-Eriksson, A.M. Alborn, C. Nordborg, D.A. Peterson, and F.H. Gage. "Neurogenesis in the adult human hippocampus," Nature Medicine, 4:1313-7, November 1998. (Cited in more than 165 papers since publication)

Because of a long-established fact that human brains simply cannot replace dead neurons, scientists considered brain damage irreversible and neurological disease in the elderly unstoppable. In the research reported in this paper, however, investigators demonstrated that adult human brains generate new cells after all. Since then, scientists have been furiously studying the implications, and research in this area has accelerated.

It was the first time that researchers had ever demonstrated human neurogenesis. Prior evidence had suggested that human neurogenesis occurred, but it wasn't until publication of research showing neurogenesis in the hippocampus that most scientists believed it.

"Contrary to accepted knowledge, previous evidence existed that new neurons were born in restricted regions of the adult brain, but resistance existed that adult neurogenesis was generalizable to primates and humans. Our results proved that neuro-genesis does occur in humans," said Fred H. Gage, director of the Laboratory of Genetics at the Salk Institute for Biological Studies in La Jolla, Calif., lead investigator for the research.

Prior to studying the human brain, the paper's authors from the Salk Institute examined neurogenesis in mice and rats. This research indicated new neuron development in adult animal brains. Encouraged that this work might carry over into humans, Gage and first author Peter Ericksson, who was on sabbatical from Sahlgrenska University Hospital in Goteborg, Sweden, searched for a way to prove whether neurogenesis occurred not only in mice and rats, but also in humans. This required establishing the generalizable relevance of the phenomenon.

The investigators established procedures for isolating dividing progenitor cells from the adult brain and examining them in culture dishes. They reasoned that since the diagnostic marker bromodeoxyuridine was used to monitor tumor progression in human patients, they might be able to examine the brains of patients treated this way. It was difficult to obtain subjects for the research, but they obtained tissue from five (plus one control) fresh postmortem brains.

Courtesy Fred Gage, Reprinted with permission from Nature Medicine

Neurons in hippocampus (red) are surrounded by non-neuronal astrocytes (blue). Among these older neurons is a newborn neuron (green).

Gage attributes the new acceptance of neurogenesis in the adult brain to the ability to extract and propagate these cells in cultures. The cells that divide in the brain are now thought to be stem cells that persist in the adult brain, he said. But scientists are unsure still of the purpose or functionality of neurogenesis.

Gage presented his most recent research on the functional nature of these cells at the Society for Neuroscience meeting in early November. "We have theories as to the significance of their function but no proof yet," he said. He suggested that if cells can be obtained from the adult brain and expanded in vitro, they may be used for cell replacement. "Alternatively, if we learn enough about endogenous brain neurogenesis, we may be able to induce endogenous repair," he added.

Gage's lab is working to define the spatial and temporal conditions that permit functional regeneration of the adult nervous system. They are studying the cellular and molecular mechanisms that regulate neurogenesis and cell genesis throughout the brain and spinal cord. They are also studying the environmental factors that regulate neurogenesis and mechanisms through which they act.

Jennifer Fisher Wilson (jfwilson@snip.net) is a contributing editor for The Scientist.