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Human brain cells working in mice

Thursday December 15, 2005

Rick Weiss

12/13/05(Washington Post) - By injecting human embryonic stem cells into the brains of fetal mice inside the womb, scientists in California have created living mice with working human brain cells.

The research offers the first proof that human embryonic stem cells — vaunted for their potential to turn into every kind of human cell, at least in laboratory dishes — can become functional human brain cells inside a living animal, reaching out to make connections with surrounding brain cells.

The human cells had no apparent impact on the animals’ behavior. About 100,000 cells were injected into each animal; just a fraction survived in their new hosts. The animals’ brains were still more than 99 percent mouse — a precaution that helped avoid ethical objections to creating animals that were "too human."

The finding that the human cells are working in their new environment provides encouragement for those who hope to develop stem-cell-based therapies for neurological diseases such as Parkinson’s.

More immediately, mice with humanized brains could provide a living laboratory where scientists can study human brain diseases and drug companies can test the safety of experimental medicines.

"Let’s say you’re in the last stages of research before testing a new drug in humans," said lead researcher Fred Gage of the Salk Institute for Biological Sciences in La Jolla, Calif. "This could help tell you what effect it will have on human neurons inside a brain."

The work, published in today’s issue of the Proceedings of the National Academy of Sciences, is the latest in the ethically challenging field of human-animal "chimera" research — a reference to the Chimera of Greek mythology, which had a lion’s head, a goat’s body and a serpent’s tail.

In previous studies, scientists had injected brain cells from aborted human fetuses into the brains of rodents and shown that the human cells could survive and migrate to various brain regions.

But because those human brain cells were relatively mature, they were larger than their rodent counterparts and it often was unclear whether they were working.

The new work, which started with human embryonic stem cells instead of cells that had already become brain cells, showed that those human cells developed into all the major kinds of cells normally found in mammalian brains, namely neurons and nerve-nurturing glial cells. It also showed that the neurons are biologically active and make what appear to be good connections, or synapses, with adjacent mouse cells.

"It’s the best evidence yet that they are integrating and functioning," said Irving Weissman, a Stanford University stem-cell scientist.

Reflecting growing concerns about the ethics of making animal-human hybrids, the National Academy of Sciences earlier this year released voluntary guidelines on chimera research that have been adopted by major research institutes and have been made mandatory in California for state grant recipients.

The rules aim to limit the extent to which animals — especially primates — get humanized and to prevent the creation of human embryos inside animal wombs through the mating of animals bearing human eggs or sperm.

Those rules were not drawn up when the Salk experiments were conducted, but the experiments’ protocol was approved by the institute’s ethics board. Moreover, before the results were published, the team asked for a new review, which concluded the work would have been approved under the new guidelines, Gage said.

Gage estimated that in the latest work, as few as 100 of the 100,000 injected human cells survived and became integrated with the mouse brains, which typically contain 75 million to 90 million mouse cells.

In painstaking surgeries, Gage and his colleagues partially removed 14-day-old mouse fetuses from the womb, being careful not to disrupt the placenta that provides maternal nourishment. After injecting the human stem cells into curved cavities of the brain called the lateral ventricles, they tucked the pups back in for their last week of development.

The human cells, taken from days-old human embryos by a San Diego company, CyThera, had been engineered to emit a green fluorescence. That helped them stand out against the background of mouse cells when the animals’ brains were later analyzed under the microscope.

The cells migrated into the forebrain, where they grew only to the size of mouse neurons. Most extraordinary, Gage said, was that they connected to others and were firing — though it is still unclear if they fire in electrical patterns typical of mouse or human cells.