Local experts critical of proposed mouse chimera project

A proposed US experiment to produce a mouse for testing the organ- or tissue-forming capacity capabilities of human embryonic stem cells should not proceed -- at least, not with totipotent human ES cells, according to a leading Australian stem cell expert.

Dr Peter Mountford, CEO of Melbourne based biomedical company Stem Cell Sciences, said the outcome of the mouse-human chimera experiment would be impossible to predict

He said he expected US legislators would outlaw such an experiment "to prevent the obvious", but also to avoid experiment that "would not be understood by the wider community."

But Mountford said he could foresee a more limited type of experiment being done, using ES cell lines with carefully restricted capacities for organ or tissue formation.

Such experiments would be a prelude to growing replacement human organs in other species, such as the pig, or would provide basic information about the complex cascade of genetic events involved in organ formation.

The New York Times this week reported this week that the proposal arose out of a meeting of nine stem cell experts at the New York Academy of Sciences on November 3, organised by Rockefeller University biologist Dr Alu Brivanlou.

Brivanlou said he called the meeting to discuss quality standards for new human ES stem cell lines around the world. Details of the meeting were reported in Nature this week.

A standard test of the totipotency of mouse ES stem cells by involves injecting them into mouse blastocysts to see if they contribute to the normal development of organs and tissues in the resulting embryo.

The New York Academy of Sciences meeting discussed an experiment in which human ES cells would be injected into a mouse blastocyst to product what the New York Times described as a "human-mouse hybrid".

The mouse would not, in fact, be a hybrid, because no direct mixing of the mouse and human genomes would be involved.

The mixing would involve whole cells, to create a chimeric mouse in which a few human ES cells, under the control of the mouse embryonic development program, would team up with mouse cells to otherwise normal mouse organs or tissues.

'Too horrible to contemplate'

According to the New York Times, Stanford University stem cell expert Dr Irving Weissman described the experiment as potentially "enormously important" -- but warned that carelessness could result in outcomes that would be "too horrible to contemplate".

Weissman said an extreme example of such an outcome might be an accidental mating between a male mouse making human sperm, and female a mouse producing human eggs.

Scientists in the New York meeting differed in their views -- some warned it was premature and unethical, and could provoke policy-makers to further restrict or even ban embryonic stem cell research.

Others felt the experiment would be of great value, and unwanted outcomes could by avoided by using 'knockout' human ES cells incapable of giving rise to human reproductive or brain cells in the chimaeric mice.

Stem Cell Sciences' Mountford said he could envisage such an approach being used to grow human organs in pigs.

The approach would involve crossing two lines of transgenic pigs, engineered so that when crossbred, their embryos would not have the capacity to grow a normal pig heart.

Mixing human ES cells containing heart-forming genes into the blastocysts would lead to the development of pigs with fully human hearts, to solve the critical shortage of donor human hearts.

Mountford other similarly restricted human ES cell experiments would have other clinical and research applications -- the approach would involve ensuring these cells could not contribute to the full diversity of cell types in the normal embryo.

He said such experiments could be done tomorrow, were it not for the Federal government's ban on human cloning.

"It will soon be very evident that the extremists in the human stem cell debate who have pushed for a ban on therapeutic cloning have made a great error, on behalf of all Australians," he said.

"The Australian community has shown more support than any other for human embryonic stem cell research, and for the prospect of human therapeutic cloning, but their elected government representatives, under pressure from a tiny minority of colleagues with extreme views, have blocked these prospects."

Monash University stem cell expert Assoc Prof Martin Pera, of the Centre for Reproduction and Development, said he would be against undertaking the chimera experiments.

"If they were to fail, it would not be terribly informative, and if they succeeded, there could be a substantial contribution of the human cells to organ and tissue development, and no way to predict the outcome, or how we should regard it," Pera said.

"The key thing is that there are alternatives to these sorts of experiments, such as combining human ES cells with fragments of developing embryonic tissue to see if the embryonic environment directs them down a particular developmental pathway.

"Later on, perhaps during foetal development, or in adult animals, there might be good experimental reasons to introduce embryonic stem cells or their derivatives in a locally restricted way to treat diseases."

On whether it would be possible to produce human ES cells with limited development potential, Pera said it was very difficult to see how such a controlled result could be achieved.