Image from Jun Wu, first author

A new document focused on human and other chimeras just was released today in Cell confirming a number of findings, but most strikingly successful generation of human-pig chimeras in utero.

The paper, eligible, “ Interspecies Chimerism with Mammalian Pluripotent Stem Cells” describes various chimeras including mouse-rat ones, although those people have previously been reported. This work comes from the team led by  Juan Carlos Izpisua Belmont which includes first author Jun Wu, and also with important efforts from Pablo Ross’ s lab here at UC Davis

The big news is human-pig chimeras. The successful generation of chimeric embryos that were  generated from  mixtures of human originate cells (induced pluripotent stem cells or IPSC) plus early pig embryos. The authors were able to get article implantation forms of these chimeric embryos and they then examined these. They tested the ability of different kinds of human pluripotent stem cells to contribute to the human-pig chimeras plus found interestingly that an intermediate type of stem cell experienced the best ability. human-chimera

In the rodents, the team made the chimeras using a neat CRISPR-based technology called interspecies blastocyst complementation to get one species cells to make a specific organ within the other species with the latter unable to make that body organ due to an induced genetic change. While they failed to use this technology with human chimeras, in theory if a single were in the future to try to use chimeras to make human internal organs for transplantation, the complementation method or something like it will be needed. A related, very important chimera papers came out in Nature yesterday from pioneer Hiromitsu Nakauchi reporting practical islets in rat-mouse chimeras.

Recurring pig cells in hypothetical human organ grown within chimera. Even with blastocyst complementation, let’ ersus say with a human pancreas being the target organ to produce in a human-pig chimera, the pancreas within the chimera for use for transplantation would certainly contain some pig cells. These types of porcine cells likely would come from multiple sources which includes possibly a few pig pancreatic cells, mostly pig bloodstream cells, and possibly others such as fibroblasts. These pig efforts would be a challenge in terms of successful organ transplantation into a human being due to the threat of immune rejection.

CRISPR comes into play? Another potentially complementary technologies that could come into play is one to reduce the immunogenicity associated with pigs using CRISPR to remove antigens. For instance, George Church’ s team published a paper this past year on using CRISPR for removing endogenous retroviral genes (coding for strong antigens in some cases) in pigs as a method to reduce immunoreactivity in pig-human chimeras.   Of course , there are many antigenic proteins in domestic swine beyond those related to endogenous retroviruses.

Preferably, one could combine the chimera organ complementation and decreased antigenicity technologies to boost the odds of success.

Beyond technological challenges, thorny ethical problems are tightly interwoven into human chimera research. I wrote about these within a piece for Wired last year.

Even with complementation (where for example a pig chimera would certainly ideally only have human cells contributing to one organ like a kidney or pancreas) one of the ethical dilemmas is that the chimeras would have to be taken to term in order to get an usable human pancreatic. It is unclear if taking a human-animal chimera to phrase could be ethically permissible. In today’ s paper, the particular team isolated the human-pig chimeras for analysis extremely early in development.

Other ethical issues include avoiding excessive (however one defines that) individual cell contribution to chimeric brains and any human being contribution to germ cells. Potential safeguards for the second option include never letting the animals be bred or even always including a genetic change making them sterile or even both.

Overall, this is exciting research within an ethically challenging arena. The real hope right here long term for a new source of organs for transplants is extremely important given the massive need amongst individuals, many of whom die on the waiting list. This growth also makes starting to tackle the bioethical issues today rather than later a wise choice.

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