Written by Sarah Asbury, Biochemistry Class of 2019, McMaster University
When scientists discovered how to reprogram skin cells into neurons, research on neurological disorders broadened. Disorders of the brain have been historically difficult to study because brain tissue cannot be taken from a living person; human brain tissue can only be collected post-mortem.1 Following the discovery of induced pluripotent stem cell (iPSC) technology, skin samples from patients with neurological disorders could be reprogrammed into neurons and used to observe how living neurons are altered in disease states.2 While reprogrammed human skin cells have provided novel models of neurological disorders, the approach has always been limited because neurons are grown in a dish, a markedly different environment from how they exist within the body.1
Chang and colleagues recently provided the groundwork to produce an improved model compared to neurons in a dish: the ability to recreate an entire portion of the brain in vivo.3 The blastocyst complementation technique was utilized in this process, involving the injection of donor embryonic or induced pluripotent stem cells (iPSC) into the developing blastocyst, followed by host DNA modification to halt the development of a specific organ. This allows the donor stem cells to form the targeted organ instead. The animal resulting from blastocyst complementation is born chimeric, meaning that its tissues consist of a mixture of cells with either host or donor DNA. However, the targeted organ of the chimeric animal is composed almost entirely of donor stem cells, due to the aforementioned DNA modifications performed on host cells. Chang et al. successfully used blastocyst complementation to target the forebrain, producing mice with forebrains exclusively formed from donor embryonic stem cells.3
Blastocyst complementation is powerful because it allows researchers to edit genes to study their function in particular brain regions, without having to generate a non-chimeric transgenic mouse that is composed solely of donor cells.4 Traditional generation of a non-chimeric transgenic mouse requires germ line transmission of the donor cells and the breeding of chimeras to produce a fully transgenic mouse —a process which is incredibly time-consuming.5 Blastocyst complementation speeds up the timeline of creating a transgenic mouse; however, the resulting mouse will only have one region of their body composed solely of cells with the edited genes.3
Scientists have previously used blastocyst complementation to produce chimeras with interspecies organs; specifically, a rat pancreas in a mouse.6 Hence, Chang and colleague’s results insinuate the possibility of human brain organogenesis in other species.4 Human-animal chimeras have also been generated, where human embryonic stem cells injected into early pig embryos produced a human-pig post-implantation chimeric embryo.7 Notably, the human-pig embryo was sacrificed before birth due to ethical concerns. These discoveries have sparked ongoing research that uses blastocyst complementation in interspecies human-pig chimeras to produce human organs in pigs for organ transplants.8 Based on Chang and colleagues’ new study, it may also be possible to create an interspecies chimera with a portion of the brain that is entirely human, which could be used in conjunction with gene editing to study the gene’s function in specific brain regions.3,4 Additionally, researchers could theoretically take a skin cell from a patient with a neurological disorder, reprogram it into an iPSC cell, and use blastocyst complementation to produce an interspecies chimera with a live brain region, that is essentially a re-creation of part of the patient’s brain.4
While this model is an incredibly alluring tool for studying neural disorders, it may never come to fruition because of the ethical implications surrounding human-animal chimeras.4 Chimera tissue would contain a mixture of both the host and donor cells. This means that tissues derived from a human-animal chimera would be composed of both the host species cells and human donor cells.8 Human cells would contribute to the chimera’s brain, which has the horrifying potential of producing a human-like consciousness.9 The ethical implications of this possibility have prompted most countries to strictly regulate or outright prohibit the injection of human pluripotent or embryonic stem cells into animal embryos.9 Moreover, a human-animal chimera with an entirely humanized brain region would be unlikely to pass ethical standards in any country due to the even greater likelihood of human-like consciousness. So while an interspecies chimera with a human brain region would be an ideal model for studying in vivo cellular changes in human neurological disorders, it would never be justifiable under the premise that the chimeric animal could be, in part, a person.
1. Dolmetsch R, Geschwind DH. The human brain in a dish: The promise of iPSC-derived neurons. Cell. 2011;145(6):831-4. Available from: doi:10.1016/J.CELL.2011.05.034.
2. Russo FB, Cugola FR, Fernandes IR, Pignatari GC, Beltrão-Braga PCB. Induced pluripotent stem cells for modeling neurological disorders. WJT. 2015;5(4):209-221. Available from: doi:10.5500/wjt.v5.i4.209.
3. Chang AN, Liang Z, Hai-Qiang D, Chapdelaine-Williams AM, Andrews N, Bronson RT, Schwer B, Alt FW. Neural blastocyst complementation enables mouse forebrain organogenesis. Nature. 2018. Available from: doi:10.1038/s41586-018-0586-0.
4. Andersen J, Pașca SP. Absent forebrain replaced by embryonic stem cells. Nature. 2018. Available from: doi:10.1038/d41586-018-06933-w.
5. Kumar TR, Larson M, Wang H, McDermott J, Bronshteyn I. Transgenic mouse technology: Principles and methods. Methods Mol Biol. 2009;590 :335–362. Available from: doi:10.1007/978-1-60327-378-7_22.
6. Kobayashi T, Yamaguchi T, Hamanaka S, Kato-Itoh M, Yamazaki Y, Ibata M, Sato H, Lee YS, Usui JI, Knisely AS, Hirabayashi M. Generation of rat pancreas in mouse by interspecific blastocyst injection of pluripotent stem cells. Cell. 2010;142(5):787-99. Available from: doi:10.1016/J.CELL.2010.07.039.
7. Wu J, Platero-Luengo A, Sakurai M, Sugawara A, Gil MA, Yamauchi T, Suzuki K, Bogliotti YS, Cuello C, Valencia MM, Okumura D. Interspecies chimerism with mammalian pluripotent stem cells. Cell. 2017;168(3):473-86. Available from: doi:10.1016/J.CELL.2016.12.036.
8. Levine S, Grabel L. The contribution of human/non-human animal chimeras to stem cell research. Stem Cell Res. 2017;24:128-134. Available from: doi:10.1016/J.SCR.2017.09.005.
9. Bourret R, Martinez E, Vialla F, Giquel C, Thonnat-Marin A, De Vos J. Human–animal chimeras: Ethical issues about farming chimeric animals bearing human organs. Stem Cell Res Ther. 2016;7(1):87. Available from: doi:10.1186/s13287-016-0345-9.