Human tissues in a dish: The research and ethical implications of organoid technology
Ethics of organoid research
Growing functional human tissues and organs would provide much needed material for regeneration and repair. New technologies are taking us in that direction. In addition to their use in regenerative medicine, stem cells that grow and morph into organ-like structures known as organoids can be used in drug development and toxicology testing. The potential developments and possibilities are numerous and affect not only biomedicine but also areas of ongoing ethical debate, such as animal experimentation, research on human embryos and fetuses, ethics review, and patient consent. Bredenoord et al. review how organoids affect existing ethical debates and how they raise novel ethical dilemmas and professional responsibilities.
Science, this issue p. 10.1126/science.aaf9414
Structured Abstract
BACKGROUND
Organoids are stem cell–derived structures generated in vitro that display the three-dimensional architecture and physiology of intact organs. They offer unique possibilities for modeling and studying normal development and disease processes and open up innovative approaches to medical research, drug discovery, and toxicology testing. Together with reprogramming technology and gene editing methods, organoids hold the promise to influence the innovation cycle in biomedical research, including fields that historically have been the subject of intense ethical debate. In this Review, we discuss the ethical implications of organoid technology and the impact on biomedical research.
ADVANCES
Owing to their great potential, organoids are likely to affect ongoing ethical debates over subjects ranging from the role of animal experiments and the use of human embryos and tissues in biomedical research to precision medicine, stem cell transplantation, and gene therapy. Most societies have formulated public policies to balance the advancement of biomedical science with the various concerns regarding the use of animals and human embryos and tissues for biomedical research. Organoids may necessitate a recalibration of these ethical and legal policies. However, they should not be presented as a simple solution that can abrogate controversial technologies. We suggest that the use of organoids is complementary to, rather than in competition with, these classical research methodologies.
In addition, organoids should not be seen as a morally neutral alternative. They are grown from cells and tissues obtained from human individuals, and establishing the moral and legal status of human organoids requires ethical discussion and empirical research, particularly for sensitive cases such as brain organoids. The storage and use of organoids in so-called living biobanks raise ethical and governance challenges—for example, questions about the type of donor consent and ethics review needed for long-term storage and use and for feedback of clinically relevant findings to the patient. Personalized drug testing in organoids may close the gap between preclinical drug development and clinical trials. It will further blur the line between research and care and will challenge policies for drug reimbursement by insurance companies. Cautious ethical approaches are needed for the first clinical transplantations of organoids, particularly when organoid technologies are combined with gene editing. Last, the strong public interest in organoids, together with the immature nature of the field, requires particular attention regarding public (media) communication to avoid inaccurate or incomplete representations and excessive expectations.
OUTLOOK
Organoid research holds considerable potential for investigating human development and disease and for advancing precision and regenerative medicine. Despite these promising applications, there are several layers of complexity, not only in a technological sense, but also with regard to the ethical introduction in research, clinical care, and society. By engaging scientists, clinicians, patients, ethicists, policy-makers, and the public in constructive interdisciplinary collaborations and dialog around the challenges discussed in this Review, we strive for responsible research and innovation and long-term acceptance of this exciting technology.
Ethical considerations of organoid models.
Organoids are likely to affect policies for research using animals and human embryos. They also have implications for biobanking and patient consent policies and require particular responsibility in communicating results to the public.
Credit: K. Sutliff/SCIENCE
Abstract
The ability to generate human tissues in vitro from stem cells has raised enormous expectations among the biomedical research community, patients, and the general public. These organoids enable studies of normal development and disease and allow the testing of compounds directly on human tissue. Organoids hold the promise to influence the entire innovation cycle in biomedical research. They affect fields that have been subjects of intense ethical debate, ranging from animal experiments and the use of embryonic or fetal human tissues to precision medicine, organoid transplantation, and gene therapy. However, organoid research also raises additional ethical questions that require reexamination and potential recalibration of ethical and legal policies. In this Review, we describe the current state of research and discuss the ethical implications of organoid technology.
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References and Notes
1
M. A. Lancaster, J. A. Knoblich, Organogenesis in a dish: Modeling development and disease using organoid technologies. Science 345, 1247125 (2014). 10.1126/science.1247125
2
H. Clevers, Modeling development and disease with organoids. Cell 165, 1586–1597 (2016). 10.1016/j.cell.2016.05.082
3
A. Fatehullah, S. H. Tan, N. Barker, Organoids as an in vitro model of human development and disease. Nat. Cell Biol. 18, 246–254 (2016). 10.1038/ncb3312
4
J. T. Neal, C. J. Kuo, Organoids as models for neoplastic transformation. Annu. Rev. Pathol. 11, 199–220 (2016). 10.1146/annurev-pathol-012615-044249
5
P. H. Dedhia, N. Bertaux-Skeirik, Y. Zavros, J. R. Spence, Organoid models of human gastrointestinal development and disease. Gastroenterology 150, 1098–1112 (2016). 10.1053/j.gastro.2015.12.042
6
J. Z. Johnson, D. Hockemeyer, Human stem cell-based disease modeling: Prospects and challenges. Curr. Opin. Cell Biol. 37, 84–90 (2015). 10.1016/j.ceb.2015.10.007
7
A. S. Daar, H. L. Greenwood, A proposed definition of regenerative medicine. J. Tissue Eng. Regen. Med. 1, 179–184 (2007). 10.1002/term.20
8
N. H. Franco, Animal experiments in biomedical research: A historical perspective. Animals 3, 238–273 (2013). 10.3390/ani3010238
9
R. Franco, A. Cedazo-Minguez, Successful therapies for Alzheimer’s disease: Why so many in animal models and none in humans? Front. Pharmacol. 5, 146 (2014). 10.3389/fphar.2014.00146
10
M. van de Wetering, H. E. Francies, J. M. Francis, G. Bounova, F. Iorio, A. Pronk, W. van Houdt, J. van Gorp, A. Taylor-Weiner, L. Kester, A. McLaren-Douglas, J. Blokker, S. Jaksani, S. Bartfeld, R. Volckman, P. van Sluis, V. S. Li, S. Seepo, C. Sekhar Pedamallu, K. Cibulskis, S. L. Carter, A. McKenna, M. S. Lawrence, L. Lichtenstein, C. Stewart, J. Koster, R. Versteeg, A. van Oudenaarden, J. Saez-Rodriguez, R. G. Vries, G. Getz, L. Wessels, M. R. Stratton, U. McDermott, M. Meyerson, M. J. Garnett, H. Clevers, Prospective derivation of a living organoid biobank of colorectal cancer patients. Cell 161, 933–945 (2015). 10.1016/j.cell.2015.03.053
11
J. F. Dekkers, G. Berkers, E. Kruisselbrink, A. Vonk, H. R. de Jonge, H. M. Janssens, I. Bronsveld, E. A. van de Graaf, E. E. Nieuwenhuis, R. H. Houwen, F. P. Vleggaar, J. C. Escher, Y. B. de Rijke, C. J. Majoor, H. G. Heijerman, K. M. de Winter-de Groot, H. Clevers, C. K. van der Ent, J. M. Beekman, Characterizing responses to CFTR-modulating drugs using rectal organoids derived from subjects with cystic fibrosis. Sci. Transl. Med. 8, 344ra84 (2016). 10.1126/scitranslmed.aad8278
12
F. L. B. Meijboom, E. N. Stassen, The End of Animal Life: A Start for Ethical Debate (Wageningen Academic Publishers, 2016).
13
P. Sandoe, N. H. Franco, T. B. Lund, D. M. Weary, I. A. S. Olsson, Harms to animals – can we agree on how best to limit them? ALTEX 4, 28–32 (2015).
14
S. Festing, R. Wilkinson, The ethics of animal research. Talking Point on the use of animals in scientific research. EMBO Rep. 8, 526–530 (2007). 10.1038/sj.embor.7400993
15
N. Gjorevski, A. Ranga, M. P. Lutolf, Bioengineering approaches to guide stem cell-based organogenesis. Development 141, 1794–1804 (2014). 10.1242/dev.101048
16
M. A. Lancaster, N. S. Corsini, T. R. Burkard, J. A. Knoblich, http://biorxiv.org/content/early/2016/04/19/049346 (2016).
17
R. J. Perry, L. Peng, N. A. Barry, G. W. Cline, D. Zhang, R. L. Cardone, K. F. Petersen, R. G. Kibbey, A. L. Goodman, G. I. Shulman, Acetate mediates a microbiome-brain-β-cell axis to promote metabolic syndrome. Nature 534, 213–217 (2016). 10.1038/nature18309
18
I. A. S. Olsson, A. K. Hansen, P. Sandøe, Ethics and refinement in animal research. Science 317, 1680 (2007). 10.1126/science.317.5845.1680
19
D. V. Hansen, J. H. Lui, P. R. Parker, A. R. Kriegstein, Neurogenic radial glia in the outer subventricular zone of human neocortex. Nature 464, 554–561 (2010). 10.1038/nature08845
20
T. J. Nowakowski, A. A. Pollen, E. Di Lullo, C. Sandoval-Espinosa, M. Bershteyn, A. R. Kriegstein, Expression analysis highlights AXL as a candidate Zika virus entry receptor in neural stem cells. Cell Stem Cell 18, 591–596 (2016). 10.1016/j.stem.2016.03.012
21
H. Retallack, E. Di Lullo, C. Arias, K. A. Knopp, C. Sandoval-Espinosa, M. T. Laurie, Y. Zhou, M. Gormley, W. R. Mancia Leon, R. Krencik, E. M. Ullian, J. Spatazza, A. A. Pollen, K. Ona, T. J. Nowakowski, J. L. DeRisi, S. J. Fisher, A. R. Kriegstein, http://biorxiv.org/content/early/2016/06/15/058883 (2016).
22
A. L. Bredenoord, G. Pennings, H. J. Smeets, G. de Wert, Dealing with uncertainties: Ethics of prenatal diagnosis and preimplantation genetic diagnosis to prevent mitochondrial disorders. Hum. Reprod. Update 14, 83–94 (2008). 10.1093/humupd/dmm037
23
B. Steinbock, Life Before Birth: The Moral and Legal Status of Embryos and Fetuses (Oxford Univ. Press, ed. 2, 2011).
24
The Congregation for the Doctrine of the Faith, Donum Vitae. Instruction on Respect for Human Life in Its Origin and the Dignity of Procreation (1987); www.vatican.va/roman_curia/congregations/cfaith/documents/rc_con_cfaith_doc_19870222_respect-for-human-life_en.html.
25
A. L. Bredenoord, P. Braude, Ethics of mitochondrial gene replacement: From bench to bedside. BMJ 341, c6021 (2010). 10.1136/bmj.c6021
26
I. Hyun, A. Wilkerson, J. Johnston, Embryology policy: Revisit the 14-day rule. Nature 533, 169–171 (2016). 10.1038/533169a
27
International Society for Stem Cell Research, Guidelines for Stem Cell Research and Clinical Translation (2016); www.isscr.org/docs/default-source/guidelines/isscr-guidelines-for-stem-cell-research-and-clinical-translation.pdf?sfvrsn=2.
28
H. Tang, C. Hammack, S. C. Ogden, Z. Wen, X. Qian, Y. Li, B. Yao, J. Shin, F. Zhang, E. M. Lee, K. M. Christian, R. A. Didier, P. Jin, H. Song, G. L. Ming, Zika virus infects human cortical neural progenitors and attenuates their growth. Cell Stem Cell 18, 587–590 (2016). 10.1016/j.stem.2016.02.016
29
X. Qian, H. N. Nguyen, M. M. Song, C. Hadiono, S. C. Ogden, C. Hammack, B. Yao, G. R. Hamersky, F. Jacob, C. Zhong, K. J. Yoon, W. Jeang, L. Lin, Y. Li, J. Thakor, D. A. Berg, C. Zhang, E. Kang, M. Chickering, D. Nauen, C. Y. Ho, Z. Wen, K. M. Christian, P. Y. Shi, B. J. Maher, H. Wu, P. Jin, H. Tang, H. Song, G. L. Ming, Brain-region-specific organoids using mini-bioreactors for modeling ZIKV exposure. Cell 165, 1238–1254 (2016). 10.1016/j.cell.2016.04.032
30
J. Dang, S. K. Tiwari, G. Lichinchi, Y. Qin, V. S. Patil, A. M. Eroshkin, T. M. Rana, Zika virus depletes neural progenitors in human cerebral organoids through activation of the innate immune receptor TLR3. Cell Stem Cell 19, 258–265 (2016). 10.1016/j.stem.2016.04.014
31
F. R. Cugola, I. R. Fernandes, F. B. Russo, B. C. Freitas, J. L. Dias, K. P. Guimarães, C. Benazzato, N. Almeida, G. C. Pignatari, S. Romero, C. M. Polonio, I. Cunha, C. L. Freitas, W. N. Brandão, C. Rossato, D. G. Andrade, Dde. P. Faria, A. T. Garcez, C. A. Buchpigel, C. T. Braconi, E. Mendes, A. A. Sall, P. M. Zanotto, J. P. Peron, A. R. Muotri, P. C. Beltrão-Braga, The Brazilian Zika virus strain causes birth defects in experimental models. Nature 534, 267–271 (2016). 27279226
32
S. N. Boers, J. J. M. van Delden, H. Clevers, A. L. Bredenoord, Organoid biobanking: Identifying the ethics: Organoids revive old and raise new ethical challenges for basic research and therapeutic use. EMBO Rep. 17, 938–941 (2016). 27296278
33
A. Deglincerti, G. F. Croft, L. N. Pietila, M. Zernicka-Goetz, E. D. Siggia, A. H. Brivanlou, Self-organization of the in vitro attached human embryo. Nature 533, 251–254 (2016). 10.1038/nature17948
34
M. N. Shahbazi, A. Jedrusik, S. Vuoristo, G. Recher, A. Hupalowska, V. Bolton, N. M. Fogarty, A. Campbell, L. G. Devito, D. Ilic, Y. Khalaf, K. K. Niakan, S. Fishel, M. Zernicka-Goetz, Self-organization of the human embryo in the absence of maternal tissues. Nat. Cell Biol. 18, 700–708 (2016). 10.1038/ncb3347
35
M. Mostert, A. L. Bredenoord, M. C. Biesaart, J. J. M. van Delden, Big Data in medical research and EU data protection law: Challenges to the consent or anonymise approach. Eur. J. Hum. Genet. 24, 1096 (2016). 10.1038/ejhg.2016.71
36
J. F. Dekkers, C. L. Wiegerinck, H. R. de Jonge, I. Bronsveld, H. M. Janssens, K. M. de Winter-de Groot, A. M. Brandsma, N. W. de Jong, M. J. Bijvelds, B. J. Scholte, E. E. Nieuwenhuis, S. van den Brink, H. Clevers, C. K. van der Ent, S. Middendorp, J. M. Beekman, A functional CFTR assay using primary cystic fibrosis intestinal organoids. Nat. Med. 19, 939–945 (2013). 10.1038/nm.3201
37
N. A. A. Giesbertz, A. L. Bredenoord, J. J. M. van Delden, Inclusion of residual tissue in biobanks: Opt-in or opt-out? PLOS Biol. 10, e1001373 (2012). 10.1371/journal.pbio.1001373
38
S. N. Boers, J. J. M. van Delden, A. L. Bredenoord, Broad consent is consent for governance. Am. J. Bioeth. 15, 53–55 (2015). 10.1080/15265161.2015.1062165
39
K. C. O’Doherty, M. M. Burgess, K. Edwards, R. P. Gallagher, A. K. Hawkins, J. Kaye, V. McCaffrey, D. E. Winickoff, From consent to institutions: Designing adaptive governance for genomic biobanks. Soc. Sci. Med. 73, 367–374 (2011). 10.1016/j.socscimed.2011.05.046
40
E. Bender, “Science pic: Reprogramming a retina” (Novartis, 16 July 2015); www.nibr.com/stories/nerd-blog/science-pic-reprogramming-retina.
41
T. Ulrich, “Building brain organoids to shed light on disease” (Novartis, 20 May 2016); www.nibr.com/stories/nerd-blog/building-brain-organoids-shed-light-disease.
42
A. Ranga, N. Gjorevski, M. P. Lutolf, Drug discovery through stem cell-based organoid models. Adv. Drug Deliv. Rev. 69-70, 19–28 (2014). 10.1016/j.addr.2014.02.006
43
V. Marx, Tissue engineering: Organs from the lab. Nature 522, 373–377 (2015). 10.1038/522373a
44
M. Hild, A. B. Jaffe, Production of 3-D airway organoids from primary human airway basal cells and their use in high-throughput screening. Curr. Protoc. Stem Cell Biol. 37, IE.9.1–IE.9.15 (2016). 27171795
45
S. Yui, T. Nakamura, T. Sato, Y. Nemoto, T. Mizutani, X. Zheng, S. Ichinose, T. Nagaishi, R. Okamoto, K. Tsuchiya, H. Clevers, M. Watanabe, Functional engraftment of colon epithelium expanded in vitro from a single adult Lgr5+ stem cell. Nat. Med. 18, 618–623 (2012). 10.1038/nm.2695
46
M. Huch, H. Gehart, R. van Boxtel, K. Hamer, F. Blokzijl, M. M. A. Verstegen, E. Ellis, M. van Wenum, S. A. Fuchs, J. de Ligt, M. van de Wetering, N. Sasaki, S. J. Boers, H. Kemperman, J. de Jonge, J. N. M. Ijzermans, E. E. S. Nieuwenhuis, R. Hoekstra, S. Strom, R. R. G. Vries, L. J. W. van der Laan, E. Cuppen, H. Clevers, Long-term culture of genome-stable bipotent stem cells from adult human liver. Cell 160, 299–312 (2015). 10.1016/j.cell.2014.11.050
47
E. W. Kuijk, S. Rasmussen, F. Blokzijl, M. Huch, H. Gehart, P. Toonen, H. Begthel, H. Clevers, A. M. Geurts, E. Cuppen, Generation and characterization of rat liver stem cell lines and their engraftment in a rat model of liver failure. Sci. Rep. 6, 22154 (2016). 10.1038/srep22154
48
S. F. Boj, C. I. Hwang, L. A. Baker, I. I. Chio, D. D. Engle, V. Corbo, M. Jager, M. Ponz-Sarvise, H. Tiriac, M. S. Spector, A. Gracanin, T. Oni, K. H. Yu, R. van Boxtel, M. Huch, K. D. Rivera, J. P. Wilson, M. E. Feigin, D. Öhlund, A. Handly-Santana, C. M. Ardito-Abraham, M. Ludwig, E. Elyada, B. Alagesan, G. Biffi, G. N. Yordanov, B. Delcuze, B. Creighton, K. Wright, Y. Park, F. H. Morsink, I. Q. Molenaar, I. H. Borel Rinkes, E. Cuppen, Y. Hao, Y. Jin, I. J. Nijman, C. Iacobuzio-Donahue, S. D. Leach, D. J. Pappin, M. Hammell, D. S. Klimstra, O. Basturk, R. H. Hruban, G. J. Offerhaus, R. G. Vries, H. Clevers, D. A. Tuveson, Organoid models of human and mouse ductal pancreatic cancer. Cell 160, 324–338 (2015). 10.1016/j.cell.2014.12.021
49
M. G. J. L. Habets, J. J. M. van Delden, S. L. Niemansburg, H. L. Atkins, A. L. Bredenoord, One size fits all? Ethical considerations for examining efficacy in first-in-human pluripotent stem cell studies. Mol. Ther. 24, 2039–2042 (2016). 27966562
50
FDA should stand firm on stem-cell treatments (Editorial). Nature 535, 7–8 (2016). 10.1038/535007b
51
S. H. Woolf, The meaning of translational research and why it matters. JAMA 299, 211–213 (2008). 10.1001/jama.2007.26
52
S. L. Niemansburg, T. H. Tempels, W. J. Dhert, J. J. M. van Delden, A. L. Bredenoord, Societal impacts of regenerative medicine: Reflections on the views of orthopedic professionals. Regen. Med. 10, 17–24 (2015). 10.2217/rme.14.69
53
S. van der Burg, Taking the “soft impacts” of technology into account: Broadening the discourse in research practice. Soc. Epistemol. 23, 301–316 (2009). 10.1080/02691720903364191
54
S. L. Niemansburg, M. Teraa, H. Hesam, J. J. M. van Delden, M. C. Verhaar, A. L. Bredenoord, Stem cell trials for cardiovascular medicine: Ethical rationale. Tissue Eng. A 20, 2567–2574 (2014). 10.1089/ten.tea.2013.0332
55
J. Kimmelman, Ethics, ambiguity aversion, and the review of complex translational clinical trials. Bioethics 26, 242–250 (2012). 10.1111/j.1467-8519.2010.01856.x
56
G. Schwank, B. K. Koo, V. Sasselli, J. F. Dekkers, I. Heo, T. Demircan, N. Sasaki, S. Boymans, E. Cuppen, C. K. van der Ent, E. E. Nieuwenhuis, J. M. Beekman, H. Clevers, Functional repair of CFTR by CRISPR/Cas9 in intestinal stem cell organoids of cystic fibrosis patients. Cell Stem Cell 13, 653–658 (2013). 10.1016/j.stem.2013.11.002
57
H. H. Bauer, Scientific Literacy and the Myth of the Scientific Method (Univ. of Illinois Press, 1992).
58
T. Kuhn, The Structure of Scientific Revolutions (Univ. of Chicago Press, 1962).
59
T. Swierstra, A. Rip, Nano-ethics as NEST-ethics: Patterns of moral argumentation about new and emerging science and technology. NanoEthics 1, 3–20 (2007). 10.1007/s11569-007-0005-8
60
T. Caulfield, D. Sipp, C. E. Murry, G. Q. Daley, J. Kimmelman, Confronting stem cell hype. Science 352, 776–777 (2016). 10.1126/science.aaf4620
61
E. Caldwell, “Scientist: Most complete human brain model to date is a ‘brain changer’” (The Ohio State University, 18 August 2015); https://news.osu.edu/news/2015/08/18/human-brain-model/.
62
D. B. Resnik, A. E. Shamoo, The Singapore statement on research integrity. Account. Res. 18, 71–75 (2011). 10.1080/08989621.2011.557296
63
S. Chakradhar, New company aims to broaden researchers’ access to organoids. Nat. Med. 22, 338 (2016). 10.1038/nm0416-338
64
A. Astashkina, D. W. Grainger, Critical analysis of 3-D organoid in vitro cell culture models for high-throughput drug candidate toxicity assessments. Adv. Drug Deliv. Rev. 69-70, 1–18 (2014). 10.1016/j.addr.2014.02.008
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Volume 355 | Issue 6322
20 January 2017
20 January 2017
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Copyright © 2017, American Association for the Advancement of Science.
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Published in print: 20 January 2017
Acknowledgments
We are grateful to the members of our research groups for numerous discussions that led to the ideas expressed in this Review. J.A.K. thanks U. Körtner and C. Druml for insightful discussions on the ethics of organoid and human embryonic stem cell research. We also thank M. Lancaster, H. Gehart, and N. Sachs for providing images and T. Kulcsar for graphics support. The work of A.L.B. is supported by The Netherlands Organization for Health Research and Development (ZonMw, grant 731010020). Work in J.A.K.’s laboratory is supported by the Austrian Academy of Sciences, the Austrian Science Fund (grants I_1281-B19 and Z_153_B09), and an advanced grant from the European Research Council.
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