Bird watchers can locate a songbird sight unseen by its species-specific melody.

Before a hatchling leaves its nest, the vocally naive youngster learnsto sing his tribal tune by listening to his parents run through theirinherited melodic repertoire of warbles, trills, chirps and tremolos.

Fernando Nottebohm, of the Rockefeller University, is a renownedspecialist in the neurology and neurogenetics of bird song. "He hasshown," said neuroscientist Fred "Rusty" Gage, of the Salk Institute,"that with bird song there is a seasonal loss of neurons, which isreplenished each year as a new song is born."

Human brains, so it seems, have no such luck. According to commonknowledge, cerebral neurons are laid down at birth, after which _without ever dividing _ they slowly, irrevocably, die off as ageadvances.

Now, a piece of uncommon knowledge finds welcome flaws in thisneuronal pessimism. It emerges from a paper in today's issue ofNature titled: "Differentiation of adult hippocampus-derivedprogenitors into olfactory neurons in vivo." Gage is the article'ssenior author.

He and his co-authors have rediscovered two areas of the adult brain,"long hidden in the literature," which still behave as their immatureprogenitors did during embryonic development.

"There are two major clusters of these proliferative zones in thebrain," Gage told BioWorld Today. "One is in the hippocampus,which is involved in learning and memory. The other occurs in thesubventricular zone, an area surrounding the fluid that bathes thebrain from the inside."

The first zone, he added, "gives rise to new neurons in the adult,which fill in or add to a particular hippocampal area called thedentate gyrus. Cells that arise in the second zone migrate out toanother important brain region, the olfactory bulb, which is involvedin smell. They add new neurons to that olfactory circuit throughoutthe adult animal."

Rat Cells Forsake Old Haunts, Adopt New Shapes

Gage's adult animal of choice is the rat. As he described in Nature,"the surprise in that paper is that when we take cells from the adultrat hippocampus and transplant them into the zone of proliferation,which leads to the birth and differentiation of olfactory-bulb (OB)neurons, those putative new hippocampal cells take on instead thecharacteristics of olfactory primordial cells. They migrate fivemillimeters out to the OB, turn tangentially, go into the bulb area, anddifferentiate into OB neurons. That is," he pointed out, "they are nowexpressing their phenotype of OB neurons rather than of thehippocampus, from where they came."

His experimental approach involved innovative methods for takingthe cells out of the adult rat brain, isolating them in vitro, andexpanding the culture greatly over two years of culture _ essentiallyindefinitely.

"We also developed techniques," Gage continued, "for geneticallyengineering them _ putting genes into the cells as markers. It was notnecessarily predictable that one could do that."

Then, transplanted back into the central nervous system of other rats,"we showed that they could differentiate into the variety of cells thatthey could differentiate into."

In effect, he pointed out, these immature, dividing, multipotentneurons _ for all the world like hemopoietic stem cells _ couldmigrate and function in two dimensions. Vertically, "they retain thecapacity for differentiation down all three of the major brain-celllineages _ astrocytes, oligodendrocytes and neurons. But in addition,[horizontally], in response to external cues or signals, they candifferentiate down neuronal pathways to produce a greater repertoireof neural phenotypes than would be predicted from where they'retaken."

While emphasizing that this is "a basic science study, trying toaddress issues of neurogenesis," Gage vouchsafes "thinking thoughtsthat we have about potential clinical applications, without saying thatwe have made a lot of headway toward any therapy."

In this context, he said that he is a scientific founder of twobiotechnology companies, Signal Pharmaceuticals Inc. in San Diego,and Somatix Therapy Corp. in Alameda, Calif.

"For Signal's purposes," he said, "they're interested in the fact thatwe can get these cells to grow for long periods of time in culture, andget them to differentiate down the lineages."

That firm's president and CEO, biochemist Alan Lewis, toldBioWorld Today: "We were recently awarded a Phase II technologytransfer business grant from the Salk Institute to work with Gage inthe human cell immortalization technique, which he and his lab, withSignal scientists, have been researching now for the past two andone-half years."

Lewis went on: "Our focus is better understanding the applicationsfor these neurons, and using them for drug discovery technologies, toidentify targets for neurodegenerative diseases, such as Parkinson'sand even Alzheimer's."

Regarding Parkinson's disease (PD), Gage observed: "One of theexciting phenotypes in the olfactory bulb is dopamine. And it turnsout that these are hippocampal cells which normally can't turn intodopamine cells." But when he engrafted these neurons into thesubventral proliferative zone, "they migrated out into the OB, wherethey did turn into dopamine cells."

Also pertinent to PD, Gage said, "the fact that we can culture thesecells for two years and more means that we may have a replenishablesource of dopaminergic neurons, rather than having to rely on fetaltissue, which must be taken and transplanted immediately. It takes 10or 11 fetuses per PD operation." n

-- David N. Leff Science Editor

(c) 1997 American Health Consultants. All rights reserved.

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