A first at Salk: human stem cells in brains of mice
By Bruce Lieberman-Union-Tribune Staff Writer
December 13, 2005
In a first, San Diego scientists have created mice with mature and active brain cells grown from human embryonic stem cells.
Their achievement, announced yesterday, is an important step forward for researchers studying Alzheimer's disease, Parkinson's and other brain disorders.
K.C. ALFRED /
Biologist Fred Gage led the stem cell study at the Salk Institute in La Jolla.
Their work also deepens ethical discussions about engineering animals with the biology of more than one species.
There was no chance any of the mice would have acquired human traits, said scientists nationwide. Mickey Mouse these mice were not.
But biologist Fred Gage showed that human embryonic stem cells can grow to look like mouse cells in the brain and, most importantly, communicate with the mouse cells.
"This was an initial study to see if we could get the human cells to differentiate into neurons (that are) physiologically active," said Gage, who led the study at the Salk Institute in La Jolla. The paper appeared yesterday in the Proceedings of the National Academy of Sciences.
By combining human and mouse cells, Gage and his colleagues created a type of chimera a creature that contains tissues from two or more kinds of animals.
Although common in biomedical research and even medicine surgeons have long transplanted pig heart valves into humans patients mixing brain cells generates new ethical concerns.
"If you said this animal has a human liver, I don't think people are going to be as worried about that as they are about the brain," said Michael Kalichman, director of the Research Ethics Program at UC San Diego. "We have this worry (that) those cells will somehow make connections to form a consciousness that is somehow analogous to human consciousness."
Scientists are trying to better understand diseases by studying how undeveloped cells in embryos grow into brain, heart, lung and other adult tissues.
By learning how these stem cells build an animal, they hope to discover where and how genetic defects contribute to the onset of disease.
Biologists routinely examine stem cells in a petri dish in the lab, but they also want to more closely track those cells "in vivo" in other words, inside a living animal.
With mixed success, they have transplanted human stem cells into adult lab animals.
For example, a team at UC Irvine found that such cells injected into the spines of paralyzed mice promoted healing and helped them walk again. Other scientists have injected stem cells into the brains of adult mice, but until now they weren't able to show whether the cells communicate with surrounding "native" cells.
Gage and his colleagues thought the stem cells would have a better chance of incorporating into the mice's physiology if they were implanted very early in the rodents' life.
In their experiment, Gage's team injected human embryonic stem cells into mouse fetuses only 14 days old. Each fetus received about 100,000 human cells. The fetuses were then reimplanted in their mothers' wombs.
Most of the injected cells died as the mice grew. But about 100 to several hundred of them survived into adulthood in each mouse.
The rodents' brain cells apparently prompted the human embryonic stem cells to morph into cells approximating the size and shape of typical mouse neurons, Gage said.
Somehow, communication between the two species' cells prompted the human ones to suppress genes that would have otherwise led to the growth of human-looking brain cells.
"We were surprised by this," Gage said.
His team's success gives Gage hope that scientists can make inroads into studying how Alzheimer's and other neurological conditions start.
In one approach, researchers might implant healthy human embryonic stem cells in mice that are engineered to display symptoms of Alzheimer's. They would then examine whether and how the disease crosses over from the mouse's native brain cells to the cells of human lineage.
In a second approach, scientists might put diseased human embryonic stem cells into healthy mouse fetuses. They would try to determine if the human cells cause the rodent ones to become diseased.
Gage's study is one of many involving the injection of human cells into rodent brains. Some are more controversial than others.
At Stanford University, for instance, stem cell researcher Irving Weissman aims to engineer a mouse with neurons that are completely human.
His project and others have prompted the National Academies of Science to call for ethical guidelines on how to engage in such work.
"The idea that human neuronal cells might participate in 'higher-order' brain functions in a nonhuman animal, however unlikely that may be, raises concerns that need to be considered," wrote the authors of a report published in April by the National Academies.
"Studies on the brain are proceeding rapidly, but there is clearly a need for more investigation, and (human embryonic stem) cell research in this field should proceed with due care."
The report did endorse research that commingles human and animal tissues. It recognized such efforts as vital to ensuring that experimental drugs and new tissue replacement therapies are safe for people.