By David N. Leff

Monday, on a presidential visit to Pope Paul II, the pontiff exhorted Bush ¿to reject practices that devalue and violate human life at any stage from conception until natural death.¿

When will President Bush decide whether to allow or ban federal funding of human embryonic stem cell research? After the papal admonition, he told the press, ¿I¿m taking my time.¿ The latest official prediction is sometime in August, after the congressional recess.

Today¿s issue of Science, electronically released July 26, 2001, carries a timely story titled: ¿Segregation of human neural stem cells in the developing primate forebrain.¿ Its co-senior authors are neonatologist and pediatric neurologist Evan Snyder, at Harvard-affiliated Children¿s Hospital in Boston, and neuroscientist Curt Freed, at the University of Colorado, Denver. Freed is known for experimentally treating Parkinson¿s disease patients with brain implants of human fetal tissue.

Because of their paper¿s political sensitivity, Snyder and his immediate co-authors agreed to be interviewed anonymously.

¿Our findings,¿ one co-author told BioWorld Today, ¿provide a new method for looking at cell behavior in the developing brain.¿

The team injected human neural stem cells ¿ a subset of embryonic stem cells ¿ into the brains of fetal monkeys, early in their gestation. ¿We had cloned a line of genetically identical human embryonic neural stem cells now commercially available,¿ the co-author said, adding, ¿It¿s an established cell line, supplied by Layton BioScience Inc., of Atherton, Calif. We don¿t go back to human fetuses to do experiments. It¿s a cloned line we maintain in tissue culture, and draw on supplies taken from our freezer. The original source was from a human fetus that had been aborted for other reasons ¿ not for our purposes. It was going essentially into the wastebasket.¿

Dramatic Migration¿ Seeds Cell Differentiation

¿At Freed¿s facility in Denver, three unrelated pregnant macaque monkeys (Macaca radiata) were palpated to locate the in utero positions of their fetuses. Freed provided the monkeys,¿ the co-author recounted, ¿monitored them for the stage of gestation, participated in the surgical steps to expose the monkeys in the female wombs, and checked the cells. One of Dr. Snyder¿s colleagues brought the cells to Freed¿s lab. Together they injected them directly into the ventricular space of their brains. Then Freed monitored the monkey hosts¿ surgery until the experiment terminated.

¿The human cells migrated quite dramatically from their point of placement,¿ the co-author recalled. ¿They migrated to three cell-population sites, and participated in the ongoing behavior of the primate brain cells at each of them.

¿The cerebral cortex has six layers when it¿s mature,¿ the co-author explained. ¿They form by migration of cells from the central ventricle outward toward the cortex. Later cells migrate right past the earlier ones. Neurons in the cortex form earlier than glial cells ¿ the second population.

¿In our case, we injected the cells at a stage when neurons for the superficial layers were differentiating, and neurons of the deep layers had already formed. So we injected the human cells at the time that the host monkey¿s brain cells were making the superficial cortical layers. Many of the cells we injected joined in that activity and became neurons. Some of our injected cells went to the deeper layers of the cortex, and there they became glial cells ¿ the normal event for that particular site.

¿Thirdly,¿ the co-author continued, ¿some of the cells stayed in the walls of the ventricle, and did not differentiate into neurons or glia. They remained in a presumed self-repair reserve population. So the exciting point was that we could inject human cells that would take¿; they weren¿t rejected. They participated in the normal developmental events, dictated presumably by local environmental signals, yet to be identified. And they aged like the monkey¿s own cells in that given environment.¿

As for the therapeutic potential of implanted human neural stem cells, in the past, Evan Snyder mentioned the possibilities of gene therapy, cell replacement and cancer. (See BioWorld Today, June 8, 1999, p. 1.)

The present co-author outlined what this new work has done to advance those prospective clinical applications: ¿There are diseases of the brain, genetic and other, that affect the brain during its early development. So by the time a child is born, its brain is already compromised. This opens the potential to put genetically healthy cells into the brain, and hopefully modulate the bad effects of the ongoing disease process.¿

Unanswered Questions Defer Human Trials

¿The technology for injecting the human cells into the monkeys,¿ the co-author suggested, ¿could be translated quite directly into human diseases. The potential is there, but we don¿t know a lot of things yet: How many cells to inject? Exactly what kinds to inject? Whether to implant once or multiple times? And we don¿t know for sure about immune suppression. This was only a 30-day experiment, so we don¿t know whether in the longer term the cells might be rejected by the monkey host.

¿We¿d like to know more about all these things. We¿re not ready to go now to human trials, but this is a small step in that direction. The Old World primate is a close enough relative to people so that when we learn more from the monkeys we can go directly to humans.¿

Summing up, the co-author emphasized that ¿this approach offers the possibility of therapy in human fetuses who already have brain damage. I¿m stating it this way, given there is a lot of opposition to this kind of experimentation from people who claim to value human life from the moment of conception. I should think they would want to be optimistic and hopeful that it would produce something for human fetuses who are already suffering from disease.

¿Abnormalities of development in the fetus, and the availability of normal cells, might favorably modify such developmental disorders ¿ the number of human abnormalities that can be diagnosed by conventional amniocentesis, and recognizing the abnormal gene carried by the pregnant mother.

¿You¿d want to intervene then,¿ the spokesperson concluded, ¿because birth is too late; the disorder has already happened. So the methods we used in the monkeys will become directly applicable to such human diseases. It¿s an offer of potential therapy to a fetus that can¿t help itself.¿

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