By David N. Leff

Generations of neurologists have long known, and taught, that the 100 billion neurons in the human brain begin dying off soon after birth, and can never be replaced. They associated this accelerated cell demise in old age with the onset of neurodegenerative diseases.

Neuroscientist Fred "Rusty" Gage, at the Salk Institute for Biological Studies, in La Jolla, Calif., recalls that the great Spanish pioneer of studies in brain function, Ramon y Cajal (1852-1934), wrote of neurodegeneration, "After the fonts of development have dried up, nothing remains."

Gage told BioWorld Today why he believes the dogma emerged, and flourishes.

"Neurons are complex cells, and they have long connective processes," he said. "To think that that cell could somehow de-differentiate, divide, and give rise to another one of itself, seemed almost impossible. In fact, it likely is impossible. What probably promulgated this dogma was that idea."

He continued: "Now we know that there are persistent, proliferating populations of either stem cells or early progenitor cells that remain in the adult nervous system. It's from those cells that the new ones are being formed, not from division of a fully mature cell. So, what encouraged the dogma was the lack of information demonstrating that these primitive cells persisted.

"In fact, to my way of thinking, the neuronal-death dogma is right," he went on. "We are simply thinking new things, based on our new knowledge, that these primitive cells remain, and differentiate."

The dying-neuron dogma began taking hits about a decade ago, when Gage and others reported apparent brain-cell survival in rodents, guinea pigs and primates. But most neurologists rejected these findings, some on the grounds that the human brain - given its superiority over other mammals - must be in a class by itself.

Gage pointed out that "with bird song, there is a seasonal loss of neurons, which is replenished each year as a new song is born." He himself reported two years ago discovery of "two areas of the adult brain, long hidden in the literature, which still behave as their immature progenitors did during embryonic development." (See BioWorld Today, Oct. 17, 1996, p. 1.)

However, those adult brains belonged to rats and mice. Then, Gage came upon a unique opportunity to verify that neurogenesis does indeed take place in the adult human brain.

"Four or five years ago in my lab," he recalled, "we were working on animals, using a drug called bromodeoxyuridine (BrdU) to detect the growth of brain neurons. And we came to the realization that this procedure was being used clinically to assay tumor growth. So, we began looking for cancer trials already under way that we could link to, get patient approval, and become part of the study."

A 'Prehumous' Bequest of Brain Cells

Gage's Swedish postgraduate student discovered a clinical study of throat cancer cases in Sweden, at the Gvteborg University Hospital. "These patients," Gage recounted, "were given BrdU, and biopsies taken of their tumors. Counting the BrdU cells was a way to measure how aggressive the tumors were. BrdU decorates the nuclei of cells that have undergone division. They could assay at a given moment in time how many tumor cells were dividing, and in what proportion to non-cancerous tissues."

The Salk team gained permission from five of these terminal patients, who had received one dose of BrdU for diagnostic purposes, to look for signs of possible new neuron growth in their brain autopsies. A sixth, who had not had the drug, served as a control.

The results of their search appear in the November 1998 issue of Nature Medicine, under the title "Neurogenesis in the adult human hippocampus."

"The hippocampus is the brain structure," Gage explained, "that is highly touted as the learning and memory area. That concept is important when arguing that neurogenesis cannot occur in the adult human brain, or even in mammals, because by adding new neurons in a complex structure like this in the brain, you would disrupt existing memories."

Back in La Jolla, the co-authors quantified BrdU-labeled cells in the dentate gyrus, which comprises half of the hippocampus, as well as in other brain regions. They strongly resembled the round to oval nuclei of cells found in the dentate gyrus of adult rodents and primates. But no such telltale signs of neuronal growth were found in the cell nuclei of the BrdU-free control patient's brain.

Clinical Applications Still 'Fairly Theoretical'

The Nature Medicine paper concluded that "cell genesis occurs in human brains - as in rodents - and that the human brain retains the potential for self-renewal throughout life."

As for practical implications of this counter-dogma finding, Gage observed, "They are fairly theoretical at this point."

Animal experiments, he said, were "trying to find out the mechanisms underlying neurogenesis. But, because people didn't think neuron renewal occurred in humans, the implications of it hadn't been taken very seriously in terms of the clinical applications.

"Now," he said, "we can begin to look at these experimental animal studies as real models of what is going on in humans. If we have a homologous process that occurs in both, we can take a biopsy or an autopsy of mammalian adult brain, extract these primitive cells, grow them up in culture and expand them. Then transplant them into the adult human brain, where they can differentiate into a variety of cell types.

"So one practical consideration," Gage suggested, "is an alternative source of proliferating populating cells that are not from an embryonic or fetal source, but rather from an adult source."

He concluded, "I think that among the new strategies that are evolving from this kind of study is the idea that, in addition to transplantation of cells from the outside into the brain - where we believed that there was no capacity for self-renewal or regeneration - these studies suggest that with the appropriate knowledge of how neurogenesis occurs, what molecules are involved in the process, we might be able to pharmacologically induce or facilitate or encourage the central nervous system to do its own repair." n

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