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'Humanised' organs can be grown in animals

It's bad news, says your doctor. Your liver is failing. So he extracts stem cells from your bone marrow and injects them into a sheep fetus while it is still in the womb. When the sheep is born, much of the animal's liver will consist of your own cells - ready to be harvested and given back to you.

This dream therapy is still years off, if it happens at all, but the first steps have already been taken by a team led by Esmail Zanjani at the University of Nevada, Reno. "Esmail has some pretty startling results," says Alan Flake of the Children's Hospital of Philadelphia.

Zanjani's team hopes the animal-human chimeras they are creating will one day yield new cells genetically identical to a patient's own for repairing damaged organs, and perhaps larger pieces for transplantation.

It might even be possible to transfer whole organs, since in some cases having at least a partly human organ would be better than a purely animal xenotransplant. Immune rejection of the animal portion would still be a problem, but it is not insurmountable, says Flake. "I don't think that in 10 to 15 years that's out of the question."

Growth factors

If perfected, the technique could overcome some of the big stumbling blocks facing researchers who want to make tissues and organs for implants. It might yield significant quantities of just about any kind of cell or tissue, for instance, with no need to fiddle about with different culture conditions or growth factors.

Instead, the host animal's own developmental program guides the injected human stem cells into their final roles. "We take advantage of the growing nature of the fetus," Zanjani says.

It would also allow doctors to obtain immune-compatible cells without having to create human embryos by therapeutic cloning. Human cells could be separated from the animal ones simply by modifying existing cell-sorting machines.

Providing the method really does produce normal human cells, they would not be rejected. And any stray animal cells would be killed off by the recipient's immune system.

Of course, the idea of using part-human, part-animal chimeras as living factories for producing cells or organs raises a host of ethical and safety issues. There is the risk of transferring animal diseases to humans, for a start. And the creation of such chimeras has long been controversial. Is a sheep with human cells making up part of its brain no longer just a sheep?

Stem cell jab

Zanjani's original goal was to see if unborn children with genetic defects could be treated by injecting healthy stem cells into the fetus. This is still his main aim, but while doing animal experiments he realised the technique could also be used to grow "humanised" organs.

The first hint this might work came from work done by Flake a few years ago (Nature Medicine, vol 6, p 1282). He showed that when human mesenchymal stem cells extracted from bone marrow are injected into sheep fetuses, the human cells become part of the heart, skin, muscle, fat and other tissues. But the numbers of human cells were very low. Zanjani's team has now managed to produce sheep-human chimeras with a surprisingly high proportion of human cells in some organs. According to results presented at a conference earlier in December, in some cases between seven and 15 per cent of all the cells in the sheep's livers are human.

The human cells must be injected around halfway through gestation - before the fetus's immune system has learned the difference between its own and foreign cells, so that the animal does not reject them, but after the body plan has formed.


Clustering together

In some cases the human liver cells cluster together to form functional, fully human liver units, says Graca Almeida-Porada of the Nevada team. These units could be transplanted whole as auxiliary organs, says Zanjani.

What is more, human albumin - a blood protein produced by the liver - has been detected in the host animals' blood. The work has been submitted for publication.

Meanwhile, results of similar experiments on the heart will be published early in 2004. "The type of stem cells we use make a lot of heart cells," is all Zanjani will say about these experiments.

If he is right, it would be an important advance because it would open the door to creating fetal heart cells for therapy. For example, a kind of fetal heart cell called a cardiomyocyte has been shown to be especially good at repairing hearts in rats or mice, but there is one big obstacle: at the moment the only source of human fetal heart cells is human fetuses.

Robert Kloner, a heart expert at the University of Southern California in Los Angeles, says an approach like Zanjani's would get around this ethical issue.

Time and place

Zanjani says it might also be possible to grow a wide range of other tissues, such as insulin-producing islet cells for treating diabetes. And he hopes it will be possible to increase the proportion of human cells in organs still further.

The team is now trying to identify subpopulations of stem cells that might be better at producing one organ or another. Their results also hint that the timing and site of the injection make a difference.

But all members of the Nevada team stress that the technique is years, if not decades away from being tested in humans. For starters, it will be crucial to make sure the human cells really are functional. Recent experiments have suggested that some stem cells fuse with other cells when injected, rather than forming normal heart cells or liver cells.

A key question is whether the human cells fuse with sheep cells, says Philip Noguchi, head of the Center for Biologics Evaluation and Research at the US Food and Drug Administration. It would not necessarily be the death knell if the cells do fuse, but it would be important to know what problems it presents, Noguchi says.

Zanjani is optimistic, however: with human cells making up such a large proportion of some chimera organs, he thinks the sheep would die if these cells were dysfunctional fused cells.

Lurking viruses

All the same, there is widespread opposition to xenotransplantation in countries such as the UK and Canada. One big worry is that retroviruses lurking in animal DNA could mutate into forms that infect people.

The US is more open to the idea, and a few clinical trials are under way, but health concerns mean Zanjani's technique would be expensive to develop.

What is more, companies are unlikely to invest in the method because he has not tried to patent it. And it could even be unpatentable: in 1998, the US Patent Office declared it unlikely that it would grant any more patents on part-human inventions.

Then there is the moral issue. Some people oppose the creation of all human-animal chimeras on religious grounds, and many more would join them if there were the slightest chance that sheep with human brain cells might be more than just sheep.

Zanjani doesn't rule out the possibility entirely. "There is no way for us to know," he says. "But at the level we're working with the animal, it's still a sheep."



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