William Reville
Using organ transplants to replace failing human organs and tissues saves and improves the quality of many lives every year. Up until now suitable organs for transplantation have been available only from human donors, and donor organs are in very short supply. The number of people currently waiting for transplants significantly exceeds the supply of available organs. In the USA there is a requirement for about 120,000 transplants every year, but only 30,000 people receive them.
About 150 organ transplants are carried out annually in Ireland and about 650 people are currently waiting for transplants.
Two areas of research are currently trying to solve this supply problem. The latest research, aimed at growing human tissues and organs in pigs suitable for transplantation to human patients, is only in its early stages of development and involves the creation of human-pig chimera embryos. Chimera means the embryo contains cells from both pig and human.
Research
The second area of research is now well developed and is aimed at modifying pigs so that their organs are suitable for transplantation into humans. It is hoped that such organs will soon become available on a large scale.
Both types of research are attended by ethical issues but such issues are greater in the case of the chimera research. The aim of this work is to eventually grow human organs in pigs on a routine basis. This work was done at the Salk Institute in California and is just published in the journal Cell. http://www.cell.com/cell/fulltext/S0092-8674(16)31752-4
Scientists removed embryos at the blastocyst stage (several days old embryo) from pigs, injected the embryos with induced pluripotent stem cells (iPSC) prepared from humans and returned the embryos to the sow for gestation. These stem cells are undifferentiated cells that have the potential to develop into any of the over 200 types of specialised adult human tissue cells.
After 28 days it was seen that some of the iPSC in the embryos had developed into precursors of various human tissue types including liver, neurons and heart. This result is an essential first step along the road to eventually growing transplantable human tissues and organs in the pig.
There are significant ethical issues associated with this animal-human chimera work, including the risk of accidentally creating animals with human consciousness or of accidentally releasing animal-human chimeras into the wild.
But, in addition, many people will find these animal-human chimera experiments intrinsically disturbing, seeing them as somehow going against nature itself and imitating the clumsy fumblings of Dr Frankenstein. On the other hand, some bioethicists see no problem with this work and enthusiastically justify it on the basis that it will relieve the chronic shortage of transplantable human organs.
The second approach to solving the human organ transplant supply problem is xenotransplantation, the transplantation of nonhuman organs or tissues into humans, but this approach has not been feasible to date. However, recent developments promise that it will soon be possible to harvest largescale supplies of organs from genetically engineered pigs that are suitable for transplantation into humans.
Pigs seem to be the optimal choice as a source of non-human organs for transplantation into humans, although baboons are also a possibility. The physiology of pigs is quite similar to human physiology and the general biology of the pig is well understood. Pigs are also about the same size as humans, have big litters, are easily raised and mature quickly.
Baboons are genetically closer to humans than the pig and people would naturally feel more squeamish about harvesting baboons for spare parts than using pigs for this purpose. They are also more difficult to raise and reproduce more slowly than pigs.
Until now it has not been possible to transplant pig organs into humans because viruses that could not be treated or neutralised are embedded in the pig genome and would probably cause disease in humans.
Furthermore, the human immune system would also strongly reject pig organs. However, it seems that these difficulties have been overcome and there is great optimism that xenotransplantation from pigs to human will soon become a reality.
George Church, geneticist at Harvard Medical School, is developing pigs that will make suitable organ donors for pig to human xenotransplantation.
He recently announced (http://www.nature.com/news/gene-editing-record-smashed-in-pigs-1.18525) the successful inactivation of 62 virus locations in the DNA of pig embryos using a powerful new gene-editing technique. Church’s team also modified more than 20 other genes in another set of pig embryos that would cause immune rejection or blood clotting when pig organs are transplanted into humans.
These gene modifications and virus deletions will be incorporated into the pigs eventually used for xenotransplantation. Church is now ready to implant the genetically modified pig embryos into surrogate sows, and he has co-founded a biotech company to produce the genetically engineered pigs on a large economically viable scale.
Objections
Objections to this breakthrough will undoubtedly arise on ethical or religious grounds. Animal rights philosophy objects to using animals as a source of tissues and organs for humans, believing that this reinforces the notion that animals exist merely to satisfy human needs.
The genetically modified pigs may also have to be reared in isolation to keep them sterile and healthy. Isolation and frequent monitoring could be hard on pigs because they are social animals.
Other groups would object on the grounds that it is wrong to use animals for ‘unnatural’ purposes.
And on the religious side, many Muslims and Jews would object and would not avail of this new transplant technology.
However, on balance, this work will almost certainly be widely welcomed by both medicine and the general public as a major advance in the field.
William Reville is an emeritus professor of biochemistry at UCC. http://understandingscience.ucc.ie
