Perspectives on pig human chimera paper

Image from Jun Wu, first author

A new paper focused on human and other chimeras just came out today in Cell reporting a number of findings, but most strikingly successful generation of human-pig chimeras in utero.

The paper, entitled, “Interspecies Chimerism with Mammalian Pluripotent Stem Cells” describes various chimeras including mouse-rat ones, although those have previously been reported. This work comes from a team led by Juan Carlos Izpisua Belmonte including first author Jun Wu, and also with important contributions 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 stem cells (induced pluripotent stem cells or IPSC) and early pig embryos. The authors were able to get post implantation forms of these chimeric embryos and they then studied these. They tested the ability of different kinds of human pluripotent stem cells to contribute to the human-pig chimeras and found interestingly that an intermediate type of stem cell had 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 in the other species with the latter unable to make that organ due to an induced genetic change. While they did not use this technology with human chimeras, in theory if one were in the future to try to use chimeras to make human organs for transplantation, the complementation method or something like it would be needed. A related, very important chimera paper came out in Nature yesterday from pioneer Hiromitsu Nakauchi reporting functional islets in rat-mouse chimeras.

Residual pig cells in hypothetical human organ grown in chimera. Even with blastocyst complementation, let’s say with a human pancreas being the target organ to make in a human-pig chimera, the pancreas within the chimera to be used for transplantation would certainly contain some pig cells. These porcine cells likely would come from multiple sources including possibly a few pig pancreatic cells, mostly pig blood cells, and possibly others such as fibroblasts. These pig contributions would be a challenge in terms of successful organ transplantation into a human due to the threat of immune rejection.

CRISPR comes into play? Another potentially complementary technology that could come into play is one to reduce the immunogenicity of pigs using CRISPR to remove antigens. For instance, George Church’s team published a paper last 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 pigs beyond those related to endogenous retroviruses.

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

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

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

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

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

12 thoughts on “Perspectives on pig human chimera paper”

  1. Apparently the creation of chimeras is a dead end road, it is unlikely that there will be a real breakthrough. The number of human cells that were ultimately incorporated into the pig embryo was not very high (“about 1 in 100,000 of the cells in the pig–human chimaeras were human”), and many of the chimeric embryos were underdeveloped. The greater was the number of human cells the more brighter expressions had the anomalies. According to the authors, there are several reasons why the human-pig experiments did not work as well as the mouse-rat ones. For one, mice and rats are much more related to one another than are pigs and humans, and the rodents have much more similar gestation periods (mice and rats differ by a few days, while pigs and humans are off by more than five months). Obviously for chimeras should be taken orangutans.
    There are another ways – to replace in the pig cell some genes on human genes. Or to organize in an adult pig selective apoptosis of certain cells and replace them with human iPSC. Or to grow preformed human organelles in the lymph nodes of newborn piglets.

  2. Any thoughts on the ethics of growing a human or human like brain in a pig’s body to study diseases of the nervous system? :p

    1. Isn’t this part of the ethical concern of the current study? The human cells contribute to the CNS as well.

      1. I wonder how the interaction between neuromeres of human origin and ectomesenchyme and other tissue types inside of a pig embryo would play out.

        It might be good enough for a disease model, but would it actually be possible to create a “human in a pig’s body”? I kind of doubt that. But I am definitely not a neuroscientist. Anyone have any take on this?

  3. stemcellrepairman

    I’m pretty sure Hiromitsu’s lab already has functional, high quality pig-human chimaeras for something close to this. Much better quality data, as in actual fetal pigs with non-pig organs. I have no idea when they’re publishing that, though.

    (Belmonte hype machine strikes again!)

    1. @repairman,
      Hopefully they are in the process of publishing it. Maybe it is in review somewhere?
      By actual fetal pigs with non-pig organs, do you mean human organs?

  4. This has been done before:

    Dev Biol. 2006 Jul 1;295(1):90-102.
    Contribution of human embryonic stem cells to mouse blastocysts.
    James D1, Noggle SA, Swigut T, Brivanlou AH.
    Author information
    In addition to their potential for cell-based therapies in the treatment of disease and injury, the broad developmental capacity of human embryonic stem cells (hESCs) offers potential for studying the origins of all human cell types. To date, the emergence of specialized cells from hESCs has commonly been studied in tissue culture or in teratomas, yet these methods have stopped short of demonstrating the ESC potential exhibited in the mouse (mESCs), which can give rise to every cell type when combined with blastocysts. Due to obvious barriers precluding the use of human embryos in similar cell mixing experiments with hESCs, human/non-human chimeras may need to be generated for this purpose. Our results show that hESCs can engraft into mouse blastocysts, where they proliferate and differentiate in vitro and persist in mouse/human embryonic chimeras that implant and develop in the uterus of pseudopregnant foster mice. Embryonic chimeras generated in this way offer the opportunity to study the behavior of specialized human cell types in a non-human animal model. Our data demonstrate the feasibility of this approach, using mouse embryos as a surrogate for hESC differentiation.

  5. I wondered about residual pig tissue, too. But I talked with some transplant immunologists, and they aren’t concerned. They think the pig blood vessels would be rapidly replaced by human cells. We should keep talking about this.

    1. That’s a good point. Over time post-transplant the porcine cell #’s would go down. I wonder how low (effectively zero?) and whether pig antigens not associated with living cells would also decrease?

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