It's no longer news that brain cells from a human fetus can be transplanted into the brains of Parkinson's disease sufferers. Nor that fetal pig cells are being groomed to take over this chore.
But what about the reverse: putting human brain cells inside the heads of non-human mammals — say, the rat (genus Rattus), for example?
Neuroscientist Ronald McKay is doing just that, but not in order to improve the rodents' I.Q. McKay, who heads the laboratory of molecular biology at the National Institute of Neurological Disorders and Stroke (NINDS), in Bethesda, Md., is motivated, rather, to get around a major shortcoming in the brain of Homo sapiens.
Like other neuroscientists, McKay deplores the fact that the living human brain acts like a black box. Except in the direst cases requiring open-brain surgery, this double handful of gray and white matter denies access to the inner workings of its neurons, astrocytes and oligodendrocytes. Their development, differentiation and degeneration can be studied only in vivo.
McKay's skeleton key to this master cerebral lock is to export those well-shielded human brain cells, and import them into the brains of rats, where they can be studied and manipulated at leisure, and in detail.
His paper, in the November issue of Nature Biotechnology, tells how: "Chimeric brains generated by intraventricular transplantation of fetal human brain cells into embryonic rats."
McKay and his co-authors took near-term rat embryos from their dam's womb, and shined a light on their heads. This revealed their brains, and outlined the fluid-filled cerebral ventricles that bathe the organ's solid cellular regions.
Into these cavities they injected sphere-shaped aggregates of human brain cells, taken (with their mothers' permission) from stillborn fetuses, 53 to 74 days into gestation. The co-authors had expanded these undifferentiated (not-yet-committed) stem cells in tissue culture, together with basic fibroblast growth factor (bfGF). They labeled these precursor cells with human-specific DNA and antibody markers — like military dog-tags — to distinguish them from rat cells, once they were implanted.
Human Cells 'Integrated Very Efficiently'
The bfGF acted like the starting gate in a horse race. It kept the human cells from starting to differentiate inside the rats' brains, until the timing was just right.
"When those human cells entered the rats' brains in very large numbers," McKay told BioWorld Today, "that was the most amazing finding. They integrated very efficiently into a particular rodent region. There, they showed a remarkable property to become part of the host tissue, continuing to generate in the subventricular zone of the adult rats.
"These chimeric animals," he said, "allowed us to ask very interesting questions about the properties of those human cells. It's sort of equivalent in the brain to putting entire human immune systems into transgenic mice."
To explore the feasibility of gene transfer into transplanted human cells, the co-authors infected cells with an adenovirus containing a reporter gene. "What that shows," McKay observed, "is you can use that to follow the cells. It's a nice result, and people will pick up on the practical uses of it — that the cells can be genetically changed and then grafted. Don't get me wrong. This is a rat, with just a few human cells in its head. Still, it's a very interesting technical system."
He continued: "There was no particular surprise with the behavior of those human cells. What these data suggested to us was that a lot of work being carried out on the rodent system is going to be reasonably rapidly applied to human systems, and that there will be no unexpected difficulties in growing human central nervous system stem cells."
The NINDS scientist foresees that "certain therapeutic applications are going to happen relatively fast, in terms of clinical trials in man. Say, in the next year or two."
Having reported this summer that neural stem cells corrected parkinsonism in rats, McKay has Parkinson's disease as first in line for the stem-cell therapy. But he added, "A number of groups are interested in applying this kind of technology to cerebral stroke, Huntington's disease and epilepsy." (See BioWorld Today, July 22, 1998, p. 1.)
Multiple Sclerosis A Target
And his own group has yet another entity in view: multiple sclerosis.
On this score, among the human differentiated cells they detected in rat brain regions were oligodendrocytes, a form of glial cell that wraps brain neuronal axons in protective myelin. "So we can use this system to look at the properties of human oligodendroglia, how they move and differentiate," McKay said. "That's of great interest to people who work on multiple sclerosis. (See BioWorld Today, Nov. 16, 1998, p. 1.)
But beyond embryonic stem cell (ESC) therapy, McKay sees a broader role for somatic cells.
"In the 1970s and 1980s," he said, "there was gene engineering. I think the next logical step is really cell engineering. And one sees that recognition now spreading quite widely. In fact, the work on embryonic stem cells is popular at the moment. What do they want to use ESCs for? To generate somatic precursor cells. Well, you can generate somatic precursor cells directly. You don't have to use ESCs. That's what our data say, basically. The ESC people know that. They cite our work as being good data for them."
McKay perceives "a very interesting and sudden shift going on in the field at the moment. People are really beginning to believe in cell engineering. There are different strategies for doing for doing it but, overall, it's going to be very successful." n