New Prospects for Growing Human Replacement Organs in Animals

By NICHOLAS WADE JAN. 26, 2017

For the first time, biologists have succeeded in growing human stem cells in pig embryos, shifting from science fiction to the realm of the possible the idea of developing human organs in animals for later transplant.

The approach involves generating stem cells from a patient’s skin, growing the desired new organ in a large animal like a pig, and then harvesting it for transplant into the patient’s body. Since the organ would be made of a patient’s own cells, there would be little risk of immune rejection.

The human-organ-growing pigs would be examples of chimeras, animals composed of two different genomes. They would be generated by implanting human stem cells into an early pig embryo, resulting in an animal composed of mixed pig and human cells.

One team of biologists, led by Jun Wu and Juan Carlos Izpisua Belmonte at the Salk Institute, has shown for the first time that human stem cells can contribute to forming the tissues of a pig, despite the 90 million years of evolution between the two species.

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Another group, headed by Tomoyuki Yamaguchi and Hideyuki Sato of the University of Tokyo, and Hiromitsu Nakauchi of Stanford, has reversed diabetes in mice by inserting pancreas glands composed of mouse cells that were grown in a rat.

The two reports together establish the feasibility of trying to grow replacement human organs in animals, though such a goal is still far off.

Many technical and ethical barriers have yet to be overcome, but the research is advancing alongside the acute need for organs; some 76,000 people in the United States alone are awaiting transplants. Creating chimeras, especially those with human cells, may prove controversial, given the possibility that test animals could be humanized in undesirable ways. One would be if human cells should be incorporated into a pig’s brain, endowing it with human qualities. Almost no one wants a talking pig.

Another untoward outcome would be if human cells should come to compose the pig’s reproductive tissues. Few people want to see what might result from the union between a pig with human sperm and a sow with human eggs.

In 2005, Senator Sam Brownback of Kansas introduced a bill imposing a $1 million fine on anyone creating and profiting from a chimera with human cells in its brain or reproductive tissues. That bill went nowhere, but in deference to public concerns the National Institutes of Health in 2015 instituted a moratorium on using public funds to insert human cells into animal embryos. The ban is still in place, and it’s unclear whether the Trump administration would continue to consider lifting the moratorium or whether new objections would be raised to using public funds for this line of research. Insertion of human stem cells into the early embryos of monkeys was prohibited in 2009, and remains so because monkeys, given their evolutionary closeness to humans, might easily have their brains altered by human cells.

Biologists’ interest in chimeras has been prompted by the limited success in coaxing medically useful tissues from stem cells grown in glassware. All-purpose human stem cells were first derived from human embryos in 1998 and from ordinary adult tissue cells in 2007. After each discovery there were hopes of converting the cells into therapeutic tissues by exposing them in glassware to the sequence of natural chemicals that in the living embryo directs them into constructing the heart, brain, lungs and other organs.

But no one knows exactly what sequence of chemicals is required for the generation of each different tissue or organ. This may be why glassware experiments with stem cells have not yet lived up to their full promise. Some biologists believe a better approach may be to grow stem cells not in glassware but in a developing embryo, where they will be exposed to the natural sequence of chemicals required to induce each type of organ.

Generating inviting homes for the donor cells may reduce the risk that they will be incorporated in nontarget tissues like the brain or reproductive tissues. Also, an organ made purely of donor cells can be transplanted into the donor animal with minimal fear of rejection.

In practice, about 10 percent of the mouse pancreases generated in rats was composed of rat cells, because the rat supplies the blood vessels for the organ. But the rat blood vessels seem to be quickly replaced when the organs are transferred to mice.

The mice with their new pancreases lived in good health for a year after the transplant. They came from the same inbred strain as the donor mice, so they did not reject their new organs.

The result provides proof of principle that Type 1 diabetes can be treated by growing a pancreas from an individual’s cells in another animal.

The next step is to repeat the experiment in pigs, which produce organs of a more suitable size for use in humans.

To achieve the goal of growing human organs for transplant, researchers must first engineer pigs that cannot make the organ of interest. In mice, this has already been done for the pancreas, heart and eye. They must then show that human stem cells can construct such an organ in a pig. Since the pig will supply the blood vessels and nerves, these will need to be replaced by the recipient’s cells after transplant without triggering immune rejection.

If rejection does occur, the researchers will have to knock out the pig’s vasculature genes and arrange for these too to be humanized. Complex organs, like the heart, will be harder to grow than those like the pancreas which has a single kind of progenitor cell. All these steps, though they seem feasible, will require several years to develop and test.

Both scientists expressed confidence that ethical concerns about chimera research could be addressed. Chimeras are typically mosaics in which each organ is a mixture of the host and donor cells.