By David N. Leff
The operetta singer who crooned, "Ah, sweet mystery of life, at last I've found you," was idolizing love, not stem cells. But a case could be made for linking the two.
It's usually love that brings about the union of a woman's ovum and a man's sperm, to form the first cell in embryogenesis. Nine months later, the outcome is a human infant comprised of several trillion cells, parceled out among the organs of the body. Packaged within that founder cell are the machinery and the messages that jump-start the geometric multiplication of all the succeeding cells.
Early on, that primordial pluripotent stem cell gives rise to purpose-designed next-generation stem cells, each programmed to produce one of those prototypical organs and tissues.
It was only a matter of time before scientists zeroed in on organ-specific stem cells, beginning two decades ago with those dedicated to replenishing the hematopoietic blood-forming cells. And since the bone marrow produces these particular stem cells, the favored treatment to rectify blood-borne diseases is now bone-marrow transplantation (BMT). (See BioWorld Today, June 3, 1999, p. 1.)
As for diseases of the brain, pointed out neonatologist and pediatric neurologist Evan Snyder, each such local disorder is currently treated piecemeal to restore whatever neuronal component is missing or degenerate - for example, dopamine replacement for Parkinson's disease (PD).
Now, within the past couple of years, Snyder and other neuroscientists have put neural stem cells (NSCs) on the map as potential therapy not only for site-specific cerebral ailments such as PD, but also for diseases than affect the entire brain. (See BioWorld Today, Jan. 12, 1999, p. 1.)
Snyder cited multiple sclerosis (MS) and the leukodystrophies as "fairly famous global [i.e., brain-wide] human diseases. These all lack basic myelin protein, the white-matter sheath that enwraps neuronal cell projections, much as insulation protects electric wires.
"The idea of there being solid-organ stem cells," Snyder pointed out, "is dramatically new. In fact, the brain is the first solid organ from which a stem cell has been isolated. So diseases that affect the entire brain, and are characterized by the absence of a neural stem cell type, can now be addressed therapeutically.
"In other words," he continued, "it's somewhat equivalent to saying one can now do a bone-marrow transplant to the brain. When you've had a disorder that affects the entire body, a blood-borne disease, or a cancer that's spread all over, most of the time now, clinicians would say, 'Well, let's do a BMT. It can replace the missing red cells all throughout the body, or hit the disseminated metastatic cancer, or here's an immunodeficiency, or an enzyme deficiency - one of these inherited storage diseases - let's do a BMT.'"
Snyder continued: "You can then go on by analogy and say, 'Well, most neurological disease is not PD, which is one area where you can take something like dopamine and try to fix it.'" But most neurologic disease is really extensive, often multifocal, or scattered throughout the brain. And sometimes it affects every cell of the entire brain.
"The idea that those kinds of global diseases can ever be addressed," Snyder went on, "was thought to be a bit unattainable. And certainly not to be obtained by any kind of neural transplantation paradigm. Maybe you could address it with a drug that gets distributed systemically. Or maybe you could try BMT and just hope that some of the cells made it up above the neck.
"None of those really has been successful for most neurological diseases," he observed. "What we have done is take a cell from the brain that had stem-cell qualities, and used it as our graft material. We put it into cerebral germinal zones, which by definition incorporate immature cells and then facilitate their distribution throughout the brain. What we've demonstrated is that these NSCs can distribute themselves throughout the brain, and replace a missing or dysfunctional cell type of neural origin."
It Worked In Trembling Mutant Rodents
Snyder is an assistant professor of pediatric neurology and neurosurgery at Harvard-affiliated Boston Children's Hospital. His NSC demonstration appears in today's Proceedings of the National Academy of Sciences, dated June 8, 1999. It's titled: "'Global' cell replacement is feasible via neural stem cell transplantation: Evidence from the dysmyelinated shiverer mouse brain."
"The particular animal model that we used to test this hypothesis," Snyder told BioWorld Today, "happened to be the mutant shiverer mouse. The neural cell that is dysfunctional all throughout its brain is called the oligodendrocyte, a glial cell, which makes myelin. Those neural SCs that we inserted became the missing oligodendrocytes all throughout that mouse's brain."
Here's how the co-authors weaned those tremulous animals off their myelin deficit.
"We would take a newborn shiverer mouse," Snyder recounted, "inject cloned neural stem cells into its brain ventricles, then let the animal grow up. When it reached maturity, we assessed whether we had replaced its missing basic myelin protein, and looked to see if the cells were distributed throughout the brain, which was the case. They did become oligodendrocytes, an even greater percentage, in this abnormal environment where those glial cells were dysfunctional, than you would expect even in a normal environment. And those oligodendrocytes were really making good myelin, which was wrapping around the host nerve processes. What's more, 60 percent of our tested transplanted shiverers evinced near-normal behavior."
Snyder made the added point that, "These mutant mice do not have any MBP of their own, so any myelin had to have come from our donor neural stem cells."
Monkeys Next, Then Kids, Grown-Ups Maybe
With a view toward eventually trying the stem cell therapy on children with myelin-deficiency disease, initially leukodystrophy, Snyder observed: "The intervention by which we implant neural stem cells into the brains of neonatal mice is very quick, very simple, non-traumatic, and something that can actually be done in kids, in real humans, without any difficulty.
"The most famous of these nine inherited early childhood disorders," he pointed out, "is adrenal leukodystrophy - 'Lorenzo's Oil disease.' They are all absolutely neurodegenerative and crippling, in fact fatal, for kids."
If all goes well with impending preclinical studies in monkeys, he envisages applying human neural stem cells to newborns, "ideally, as early as the diagnosis could be made. If it couldn't be made until the first year of life, one would administer the treatment, as we did with the shiverer mice, to newborns or infants."