New York Times
November 27, 2002

Stem Cell Mixing May Form a Human-Mouse Hybrid

By Nicholas Wade

A group of American and Canadian biologists is debating whether to recommend stem cell experiments that would involve creating a human-mouse hybrid.

The goal would be to test different lines of human embryonic stem cells for their quality and potential usefulness in treating specific diseases. The best way to do that, some biologists argue, is to see how the cells work in a living animal. For ethical reasons, the test cannot be performed in people.

But if the human stem cells are tested that way in mice, any animals born from the experiment would be chimeras - organisms that are mixtures of two kinds of cells - with human cells distributed throughout their body. Though the creatures would probably be mice with a few human cells that obey mouse rules, the outcome of such an experiment cannot be predicted. A mouse with a brain made entirely of human cells would probably discomfort many people, as would a mouse that generated human sperm or eggs.

Dr. Irving L. Weissman, an expert on stem cells at Stanford University, said that making mice with human cells could be "an enormously important experiment," but if conducted carelessly could lead to outcomes that are "too horrible to contemplate." He gave as an extreme example the possibility that a mouse making human sperm might accidentally be allowed to mate with a mouse that had made its eggs from human cells.

At least two biologists in the group that is discussing the experiment said they believed that it was premature or unethical and could stir policy makers to limit further stem cell research or ban it.

Stem cells are a kind of universal clay, so responsive to local cues that they can morph into blood, skin, bone or any other replaceable tissues. They retain the gift of self-renewal, which, to curb the risk of cancer, is withdrawn from all the body's mature cells. Stem cells, when they divide, usually produce one mature cell and one stem cell.

They hold high promise as an all-purpose material for repairing many degenerative diseases of old age like Parkinson's, cancer and heart disease.

Other scientists say such experiments would be of great value and could be conducted with human stem cells engineered so that they could not produce brain or reproductive cells. That group acknowledged that even an experiment drawn up with such precautions should first undergo scientific review and public debate.

The proposal for the experiment grew out of a meeting on Nov. 13 at the New York Academy of Sciences sponsored by the academy and Rockefeller University. It was organized by Dr. Ali H. Brivanlou, a Rockefeller biologist who studies embryology.

Dr. Brivanlou invited eight other experts and, as observers, two editors of scientific journals and Dr. James F. Battey Jr., director of the National Institute of Deafness and chairman of the stem cell task force of the National Institutes of Health. The meeting was not intended to be public, Dr. Brivanlou said, and at one point, the nine experts held a closed session at which the observers, including even Dr. Battey, were asked to step outside.

One journal editor wrote of the meeting in the current issue of Nature, reporting that Dr. Battey "criticized participants for what he regards as excessive secrecy." Dr. Battey did not return telephone calls to his office.

The purpose of the meeting, Dr. Brivanlou said yesterday in an interview, was to discuss quality standards for several new lines, or colonies, of human embryonic stem cells being developed around the world.

In one test that they discussed, human embryonic stem cells would be injected into an early mouse embryo when it was still a small ball of cells called the blastocyst. Scientists would then see whether the human stem cells showed up in all the mouse's tissues. That ability, known as pluripotentiality, is the hallmark of a true embryonic stem cell.

Injection into another mouse's blastocyst is the standard test for mouse embryonic stem cells. Those cells, like human embryonic stem cells, come from a small pool of all-purpose cells a few days after the fertilized egg has started to divide.

No one knows whether human embryonic stem cells would survive in a mouse blastocyst. If they did, and they contributed to all the tissues, that would be a useful test for the many claimed human embryonic stem cell lines being developed, Dr. Brivanlou said.

One participant, Dr. Janet Rossant of Mount Sinai Hospital in Toronto, said that she did not consider the test necessary and that if the injected human cells made major contributions to the mouse, "I think that is something that most people would find unacceptable."

Dr. Weissman of Stanford, who was not at the meeting, said the experiment could help scientists follow the behavior of human cells with genetic diseases. Studying how the diseased human cells develop in a mouse could offer treatment insights.

Dr. Weissman said undesirable outcomes like a mouse with a brain made of human cells or a mouse that generated human sperm could be avoided by deleting certain genes from the human cells before injecting them into a mouse. He added that such procedures should be carefully reviewed by a body like the National Academy of Sciences.

"You must assure yourself and the public," he said, "that it's ethical. It's not for scientists alone to decide."

A biologist at the meeting here, Dr. Fred H. Gage of the Salk Institute, said that the question of making mice with human cells deserved further consideration and that scientists and the public "should listen to each other more" before reaching a conclusion to go ahead.

In using mice simply to test the pluripotentiality of human embryonic stem cells, it would not be necessary to let the mice grow to term, Dr. Gage said. The earlier the mice were killed the smaller would be the ethical issue, in his view.

Dr. Richard M. Doerflinger of the National Conference of Catholic Bishops, who has long opposed research with human embyronic stem cells, said his primary objection remained with the first step, that of killing a human embryo to obtain embryonic stem cells. Dr. Doerflinger's initial reaction to the proposed experiment was that as a test for pluripotentiality it might not be objectionable.

"If you end up with one human cell per organ of a mouse, I don't think it raises a new problem," he said. "The amounts of human material in an animal would have to be pretty substantial to start talking about a human hybrid, and I don't think this raises that specter."

The nine participants at the conference are drafting a white paper to lay out proposed standards to test human embryonic stem cells. The mouse injection test is on the list, Dr. Brivanlou said, with the wording under discussion.

Federally financed researchers can work only with "presidential cell lines," the human cell lines established before Aug. 9, 2001, which President Bush declared as the cutoff for permissible stem cell work. The guidelines prepared by Dr. Brivanlou's group could be applied to those stem cells, as well as the nonpresidential ones.