December 13, 2005
Tuesday

Researchers have designed mice containing fully functional human nerve cells as a novel way to study and potentially treat neurodegenerative diseases such as Parkinson's and Alzheimer's.

The neurons were formed in the brains of mice that had been injected with human embryonic stem cells as 2-week-old embryos.

Studies at the Salk Institute for Biological Sciences showed that the human cells migrated throughout the mouse brain and took on the traits of their mouse-cell neighbors. The results present direct evidence that primitive human stem cells can be cultured in the lab, be injected into an animal, and then develop into a particular type of desired cell.

The report appears in this week's Proceedings of the National Academy of Sciences.

Scientists said it was the first time cultured human embryonic stem cells have been shown to develop into a particular type of cell in the body of another living species.

Creation of a so-called "mouse-human chimeric nervous system" stops well short of spawning a mouse with a human-like cerebral cortex. In fact, all the brain structures of the four mice used in the Salk experiments had been formed before the human cells were injected, and less than 0.1 percent of the mice brain cells were found to be of human origin.

Yet the new experiments approach an ethical divide that makes some observers squeamish.

The term chimera comes from a creature in Greek mythology that had the head of a lion on the body of a goat. Such monstrous connotations have been tamed somewhat in the modern era of pig valves for heart patients and protein drugs manufactured in hamster cells.

Still, some critics of human embryonic stem cell research argue that more attention should be paid to the ethics and potential dangers of cutting-edge biomedical research.

"Where are the lines, and how do we decide where the lines are?" wondered Jennifer Lahl, a bioethicist at the Center for Bioethics and Culture Network in Oakland. "What if someone decides to start doing this for art? I'm glad science has progressed to the level that we can do this incredible stuff, but we also have to be a lot more thoughtful about it."

The bioethical implications aside, the findings may have broad interest in the stem cell field because they suggest that stem cells respond to much the same signals in mice as in humans - if not all mammals. Previous development or "differentiation" studies of stem cells into the various cell types of the body have been done primarily in laboratory dishes.

Researchers now hope to discover how brain disorders develop out of the mysterious interaction of neurons and their surroundings.

Two types of experiments are envisioned: Healthy human cells might be injected into animal brains carrying human-like genetic disorders; and cells carrying disease traits, perhaps derived through cloning techniques from cells of living patients, might be put into normal animal brains.

"Is it a diseased environment that influences nondiseased cells, or are diseased cells hurting a healthy, intact environment?" asked Fred Gage, a Salk Institute professor and co-head of the institute's Laboratory of Genetics, who was senior author of the new study.

Similarly, if a drug candidate is found, it might first be given to chimeric mice to study the drug's effect on human cells in a living system before proceeding to human trials.

Gage said care was taken to ensure that the human-mouse brain experiments were done ethically and noted that the experimental design was approved in advance by an independent ethics review board sponsored by the Salk Institute.

Begun in 2003, the work predated the appearance of a National Academies report on stem cell ethics, which has become the tentative guideline of stem cell programs including the California Institute for Regenerative Medicine, created by Proposition 71 in 2004. Gage said a special embryonic stem cell ethics review panel was set up at Salk as suggested by the National Academies, and approved the experiments after they were done.

Also, in accord with the guidelines, the mice in the experiments were isolated in separate cages so they couldn't breed, to avoid the possibility of creating lines of chimeric animals. This was done even though it would be highly unlikely that human cells - which in this case were injected directly into the fluid-filled ventricles of the mouse brains - would alter mouse reproductive cells.

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