In 2011, Dr. Anthony Atala of the Wake Forest Institute for Regenerative Medicine stepped onto the stage at the TED conference and delivered his talk on the promising future of regenerative medicine. He spoke about his and his colleagues’ recent discovery: a machine that could print a human kidney scaffold. This discovery built on his previous work, published in the 2006 issue of the Lancet, describing the creation of laboratory-grown bladders and their transplantation in patients suffering from congenital bladder defects. The Lancet report was a milestone in a journey to combat organ shortage that had begun decades earlier. Dr. Atala had toyed with the idea of engineering organs, or making them de novo, since the early 1990s. At the time, his idea was considered “science fiction” by many of his colleagues and the public alike.
By the time of Dr. Atala’s TED Talk (another sign of how mainstream and normalized his work had become), the concept of laboratory-synthesized organs had shed its heretical label and the torch of abstraction had passed to the domain of interspecific chimeras. Less than a year prior to this talk, Dr. Hiromitsu Nakauchi’s group, a powerhouse in stem cell biology, published the results of their rat-mouse chimeras in Cell, where they had grown a rat pancreas in a mouse by injecting rat pluripotent stem cells (PSCs) into a Pdx1-deficient mouse blastocyst incapable of pancreatogenesis. The implications of this work were powerful, intoxicating, and as clear as they were nebulous. The findings reverberated within the regenerative medicine community eliciting such comments as “Viable Rat-Mouse Chimeras: Where Do We Go from Here?”
In the early days of 2017, the group of Dr. Juan Carlos Izpisua Belmonte of the Salk Institute published the successful generation of yet another interspecific chimera in Cell – this time, it was human PSCs that were injected into a pig blastocyst and implanted in a host pig. Embryos were allowed to develop for 28 days in utero, at which point the embryos were analyzed for the presence of human cells. Out of the 2075 chimeric embryos that were implanted, only 186 had developed – a fraction of the initial input. And within the 186 developing embryos, the level of contribution of human cells to the overall embryo was very low. Although the presence of human cells, and therefore their ability to engraft, was confirmed, these embryos were slow to grow and smaller than expected. The authors speculated that these results could be attributed to the evolutionary distance between humans and pigs, differences in corporal size and disparity in gestation periods (114 days in pigs versus 280 days in humans). Additionally, the pig blastocysts in which the human PSCs were injected were not genetically altered to be deficient in any organs, a trick that can provide a competitive advantage for engrafting human cells as they take over the physical niche of the absent pig organ. Optimizing experimental conditions to reach higher engraftment levels could lead to chimeric models for the study of early human embryology, the pathophysiology of heritable human diseases where implanted human PSCs carry deleterious mutations and drug screening.
The experiments performed in the study were terminated after only 28 days of gestation, and therefore the viability of the chimeras was not assessed. However, this work raises significant ethical and legal concerns. As the new frontier in regenerative medicine, human interspecific chimeras are being subjected to scrutiny, controversy and claims of “futurology”. While the ability to grow human organs in pigs or cattle could revolutionize transplantation medicine and arguably end organ shortage permanently, there are legitimate concerns that require the attention of the scientific community and society at-large. The introduction of human PSCs at such an early stage in development sets the stage for two hypothetical scenarios that demand consideration.
First, if these human PSCs, capable of giving rise to any cell type in the body, contribute to the neurological development of the chimeric embryo, one runs the risk of creating chimeras capable of higher thought. Proponents of the work argue that the human contribution to these animals is so low that this would be an infeasible outcome. The study by Dr. Izpisua Belmonte’s group assessed the presence of human cells in the brain and, phenotypically, found none. However, while many professions operate by the adage “seeing is believing”, in science, function is believing – not phenotype. So, while the apparent lack of human neurons in these chimeric embryos is comforting, it is certainly not definitive.
The second unsettling consternation of allowing chimeric animals to come to term is the possibility of human cells contributing to the chimera’s germ cells – an outcome which many argue would bring us closer to The Island of Doctor Moreau. These concerns led the National Institutes of Health to impose a moratorium on funding research “in which human pluripotent cells are introduced into non-human vertebrate animal pre-gastrulation stage embryos” until further review of the bioethical implications.
If the downside of unregulated chimeric studies gone rogue seems so cataclysmic, then surely, organ printing seems like a more palatable alternative. However, in all likelihood, 3D-printing alone will not be able to end the organ shortage crisis. Although certain organs like the bladder and skin can be printed with remarkable success, other organs have much more complex functions and architecture that is difficult to recapitulate through 3D-printing. For example, the primary role of the bladder, a hollow muscular sac, is to store and release urine. The kidneys, on the other hand, are structurally complex, highly vascular organs made of multiple cell types that filter out waste, reabsorb nutrients, produce hormones, govern acid-base homeostasis, and regulate blood pressure and water levels. This physiological difference makes printing a functional kidney a much more Herculean task than printing a bladder, an undertaking that lends itself better to the use of a host species as a vessel for natural organ generation.
Amidst the simultaneous fanfare and denunciation of Dr. Izpisua Belmonte’s work, exactly two weeks after the publication of the first human-pig chimeras, Dr. Nakauchi (who in 2010 grew a rat pancreas in a rat-mouse chimera) made another seminal contribution to the field and to the debate of interspecific chimeras as a potential source of organs. Seven years after his initial finding, Dr. Nakauchi grew a mouse pancreas in mouse-rat chimeras, transplanted the chimeric pancreatic islets into streptozotocin-induced diabetic mice, and cured them of their diabetes.
As it turns out, Doctor Moreau may have been on to something.
- Atala A et al. Tissue-engineered autologous bladders for patients needing cystoplasty. Lancet, 367(9518):1241-6 (2006).
- Kobayashi T et al. Generation of rat pancreas in mouse by interspecific blastocyst injection of pluripotent stem cells. Cell, 142(5):787-99 (2010).
- Wu J et al. Interspecies Chimerism with Mammalian Pluripotent Stem Cells. Cell, 168(3):473-486 (2017).
- Yamaguchi T et al. Interspecies organogenesis generates autologous functional islets. Nature, 542(7640):191-196 (2017).
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