Lift NIH restrictions on chimera research.

INSIGHTS Arun Sharma, 1,2 Vittorio Sebastiano, 1,3 Christopher T. Scott, 4 David Magnus, 4 Naoko Koyano-Nakagawa, 5 Daniel J. Garry, 5,6,7 Owen N. Witte, 8 Hiromitsu Nakauchi, 1,9,10 Joseph C. Wu, 1,2,11,12 Irving L. Weissman, 1,13 * Sean M. Wu 1,2,11 * Institute for Stem Cell Biology and Regenerative Medicine, Stanford University School of Medicine, Stanford, CA 94305, USA. 2 Cardiovascular Institute, Stanford University School of Medicine, Stanford, CA 94305, USA. 3 Department of Obstetrics and Gynecology, Stanford University School of Medicine, Stanford, CA 94305, USA. 4 Center for Biomedical Ethics, Stanford University School of Medicine, Stanford, CA 94305, USA. 5 Lillehei Heart Institute, University of Minnesota, Minneapolis, MN 55455, USA. 6 Stem Cell Institute and Paul and Sheila Wellstone Muscular Dystrophy Center, University of Minnesota, Minneapolis, MN 55455, USA. 7 Cardiovascular Division, Department of Medicine, University of Minnesota, Minneapolis, MN 55455, USA. 8 Broad Stem Cell Research Center and Department of Microbiology, Immunology, and Molecular Genetics, University of California, Los Angeles, Los Angeles, CA 90095, USA. 9 Department of Genetics, Stanford University School of Medicine, Stanford, CA 94305, USA. 10 Center for Stem Cell Biology and Regenerative Medicine, The University of Tokyo, Tokyo, Japan. 11 Division of Cardiovascular Medicine, Department of Medicine, Stanford University School of Medicine, Stanford, CA 94305, USA. Department of Radiology, Stanford University School of Medicine, Stanford, CA 94305, USA. Department of Pathology, Stanford University School of Medicine, Stanford, CA 94305, USA. *Corresponding author. E-mail: [email protected] (I.W.); [email protected] (S.M.W.) REFERENCES 1. NIH Notice Number NOT-OD-15-158 (https://grants.nih.gov/ grants/guide/notice-files/NOT-OD-15-158.html). 2. H. T. Greely, M. K. Cho, L. F. Hogle, D. M. Satz, Am. J. Bioeth. 7, 3. O. Brustle et al., Nat. Biotechnol. 16, 1040 (1998). 4. S. C. Zhang, M. Wernig, I. D. Duncan, O. Brustle, J. A. Thomson, Nat. Biotechnol. 19, 1129 (2001). 5. H. Lee et al., Stem Cells 25, 1931 (2007). 6. National Research Council (U.S.), Committee on Guidelines for Human Embryonic Stem Cell Research, Institute of Medicine (U.S.), Board on Health Sciences Policy, Guidelines for Human Embryonic Stem Cell Research (National Academies Press, Washington, DC, 2005). 7. O. Gafni et al., Nature 504, 282 (2013). 8. J. Wu et al., Nature 521, 316 (2015). 9. H. Masaki et al., Development 142, 3222 (2015). Making sense of the troubles at NEON IN HIS 25 September News Feature “Ecology’s tough climb” (p. 1436), J. Mervis detailed the problems that have plagued the National Science Foundation’s (NSF’s) National Ecological Observatory Network (NEON). The severity of NEON’s troubles recently led to a congressional hearing in which James Olds, head of NSF’s Biological Sciences Directorate, said that NEON Inc. would be replaced as NEON’s contractor sciencemag.org SCIENCE 6 NOVEMBER 2015 • VOL 350 ISSUE 6261 Published by AAAS Downloaded from www.sciencemag.org on November 10, 2015 Lift NIH restrictions on chimera research in NOT-OD-15-158 serve to impede scien- tific progress in regenerative medicine and should be lifted. PHOTO: HIROMITSU (HIRO) NAKAUCHI the Guidelines for Human Embryonic Stem Cell Research that animals in which human pluripotent stem cells (hPSCs) have been Edited by Jennifer Sills introduced during development should not breed and that hPSC chimerism with non- human primates is restricted (6). Research involving hPSC complementa- tion in non-human, pre-gastrulation–stage vertebrate embryos represents a special MANY OVERSIGHT MECHANISMS exist for topic with tremendous potential to elucidate research involving human subjects and early human development. Development cells, as well as the transfer of materials of stem and progenitor cells from pre- into other vertebrates, partly to reassure the gastrulation embryos occurs over the weeks public that biomedical research is ethically following blastocyst implantation into conducted. In the recently posted notice appropriate hosts. Currently, it is impos- NOT-OD-15-158, the NIH stated that it “will sible to accurately recapitulate human not fund research in which human pluripo- development in vitro, and there is no ethical tent cells are introduced method to obtain post- into non-human implantation–stage vertebrate animal pre- human fetal tissue for gastrulation–stage isolating tissue and embryos while the organ stem cells for agency considers a regenerative medi- possible policy revision cine. Although early in this area” (1). This chimera studies involv- notice encompasses ing hESCs/iPSCs and human pluripotent non-human vertebrate stem cells (hPSCs), animal blastocysts have including human shown some capac- induced pluripotent ity for contribution stem cell (hiPSC)– to host tissues (7–9), based human/ much work remains to non-human chimera unravel key differences studies. We believe in early development Engraftment of hiPSC (red) into mouse blastocyst-stage embryo that this notice poses between humans and a threat to progress in other vertebrates. If we stem cell biology, developmental biology, succeed in inducing significant chimerism and regenerative medicine. We hope the between hPSCs and pre-gastrulation–stage guideline recommendations that emerge embryos from non-human vertebrates, from the NIH Workshop on 6 November tremendous potential exists to develop will accelerate the decision to reinstate humanized disease models for studying NIH funding for this research area, which drug pharmacology. Similarly, implantation has tremendous promise. We strongly of hPSCs derived from patients with herita- believe that a continued dialogue between ble diseases could illuminate genetic disease scientists and bioethicists regarding pathogeneses in an appropriate in vivo human/non-human chimera studies context. It may even be possible to generate is critical for advancing human health an unlimited supply of therapeutic replace- through basic science. ment organs using porcine or sheep models, Much of the bioethical concern in regard an effort that we (H.N.) have undertaken to human/non-human chimerism arises with support from the California Institute from the possibility of chimeric animals har- for Regenerative Medicine. By eliminating boring human neurons and germ cells. Can federal funding for this research, the NIH human neural cells coexist with those from casts a shadow of negativity towards all animals and establish “humanized” cerebral chimerism studies regardless of whether anatomy and circuitries? Furthermore, human cells are involved. would such chimeras be elevated to a higher Ultimately, we believe that human/ metaphysical state and “think” more like non-human chimerism studies in pre- us (2)? Current scientific data have not sup- gastrulation embryos hold tremendous ported such possibilities, despite hundreds potential to improve our understanding of xenotransplant studies introducing of early development, enhance disease human neurons into the mouse brain (3–5). modeling, and promote therapeutic With regard to germline transmission, the discovery. Given that the objective of the National Academy of Medicine and the NIH is to enable discoveries that advance National Research Council have stated in human health, the restrictions presented LET TERS