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My heart will grow on

posted Jan 27, 2017, 7:03 PM by Vondriska Lab   [ updated Jan 27, 2017, 7:04 PM ]

Developmental biology provides new promise for organ transplantation

 

A combination of genetic engineering and stem cell biology could revolutionize treatment of multiple human diseases

 

When, on the back of Pegasus, Bellerophon encountered the Chimera, the beast was doubtless the stuff of nightmares: a body part lion and part goat, whose tail was a serpent. In contemporary times, a chimera is considerably less frightening, referring in biology to an organism that arises from multiple parts of genetically different organisms. This can happen naturally, for example when two sperm fertilize one egg during sexual reproduction, or in the laboratory, when pluripotent cells, rather than germ cells, are combined with a developing blastocyst (the early structure which has just begun to commit to the distinct lineages that will in turn generate the organs and tissues of the animal). In the laboratory, however, chimeras are usually not made in the Homeric sense: that is, typically the cells, which are mechanically injected into the blastocyst, are from the same species as the blastocyst. In recent years, however, scientists of have figured out how to get cells from one species to incorporate into the developing blastocyst of another species, but until recently this has been an inefficient process and was limited mostly to rodents and lower organisms.

As they report this week in the journal *Cell, Professor Juan Carlos Izpisua Belmonte at the Salk Institute in La Jolla California and colleagues have potentially revolutionized experimental chimerism by combining two recent technological innovations: the first is CRISPR-Cas9, which enables rapid and precise genome editing, and the second is induced pluripotency, which generates—from a small sample of somatic cells—pluripotent cells (called iPS cells) which can give rise to all cells in the body. Unlike the mythical chimera, the chimera generated in the laboratory does not have body parts solely from the cells (and thus resembling the features of) one organism or another: experimental chimeras do not have the head of a pig and the feet of a man. Instead, each body part is a mosaic of cells from each organism. To circumvent this issue, Professor Izpisua Belmonte and his team used CRISPR-Cas9 to selectively delete in the mouse blastocyst genes controlling the development of a given organ and then injecting into these mouse blastocysts pluripotent cells from a rat. In this scenario, if chimerism occurs, the targeted organ should be made up of cells from the rat, not the mouse: remarkably, the investigators demonstrate that they have pulled this off for both the pancreas and the heart.

But a mouse is not a man. So in a separate set of experiments, the researchers attempt to extend these observations to larger animals, choosing the pig to provide the blastocyst. Here the investigators employed the second tool—induced pluripotency—to generate iPS cells from human fibroblasts (taken from the foreskin, incidentally, although in principle any adult cell will work). When these induced pluripotent stem cells were injected into the pig blastocysts and the blastocysts subsequently implanted into a surrogate sow, resultant pig fetuses had organs containing human cells. At this point the process is very inefficient, with only a vanishingly small number of the cells in the pig being of human origin, although with further technical innovation, these numbers should be increased substantially.

If these two advances can be combined, the results would be potentially ground breaking for biomedical research. iPS cells, which are experimentally generated in the lab from normal adult skin cells, obviate ethical concerns incumbent with the use of human embryos or embryonic stem cells. If CRISPR-Cas9 can be perfected in pigs, the possibility exists that human organs and tissues could be grown in these animals.

The most provocative use for such human-pig chimeras would be organ transplantation. How might this work? Say your doctor informs you that your heart is failing and you need a transplant. Rather than get on a waiting list, you would instead donate some skin cells and have a heart—your heart, in fact, because since it comes from your cells it would be genetically identical to you—grown up in a pig over a few months, after which a surgeon would transplant your new heart from the pig to you.

Substantial technical hurdles remain before such practices will be a reality, but there are many other nearer-term uses for this technology, including drug screening and disease modeling. After slaying the Chimera, Bellerophon’s arrogance led him to challenge the gods, with predictably tragic results. How researchers advance these new findings towards helping mankind will determine whether they share his hamartia.

*Link to the paper: http://www.cell.com/cell/fulltext/S0092-8674(16)31752-4

 

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