Brainstorming Over Brain Organoids

By Insoo Hyun

This post is part of a series featuring authors who have received the Neuroethics R01 (Research Project Grants) supported by the NIH BRAIN Initiative. These research projects specifically address prominent ethical issues arising from emerging technologies and advancements in human brain research.

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Organoids are stem cell-derived 3D structures that self-organize into functional cell types and recapitulate basic organ functions. Organoids of various types (kidney, heart, lung, etc.) can be used to model diseases, screen and develop new drugs, and explore the mysteries of human organ formation and function¹.

One rapidly advancing area of human organoid research involves the creation and maintenance of small brain organoids in a dish². Although the advent of stem cell-based brain organoid research has allowed for realistic modeling of various human brain regions, current protocols do not allow for a full recapitulation of brain function. Currently, brain organoids lack mature neural networks, have no sensory input and output, and are therefore unable to interact with and react to the environment, making concerns about cognitive function or “thinking” of brain organoids unfounded at present³.

However, some of these limitations could be overcome through bioengineering strategies to refine spatial development and enhance maturation through vascularization and perfusion, resulting in afferent sensation and complex neural networks. These strategies could result the creation of larger brain organoids that can mimic human brain functions more realistically. If this were to happen, then research involving more complex brain organoids could begin to raise ethical concerns⁴.

This tipping point, from mere brain models to morally ambiguous entities, may come sooner than we think. Researchers are working hard to construct evermore realistic brain organoids in culture; thus it is important to understand what ethical boundaries may exist and where researchers and regulators should draw the line for research. Ethical considerations are needed both to reduce uncertainties over which projects to pursue in the lab and to address future concerns regulators and the public may harbor about whether this research, if left unexamined, could inadvertently undermine public trust in science. Given the quick pace of the science, what is the best way to identify and address new ethical concerns in this novel subfield of stem cell research?

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To respond to this question, I am pursuing a BRAIN Initiative-funded projected entitled The Brainstorm Organoid Project, together with Dr. Jeantine Lunshof, a philosopher ethicist at the Wyss Institute for Biologically Inspired Engineering at Harvard. Our project establishes ongoing and proactive ethical discussions among ethicists and the neuroscientists involved with this cutting-edge work, with the ultimate goal of developing greater awareness, understanding, and – beyond the duration of our project – guidance for future management of ethical issues that may be unique to new areas of brain organoid research. The Brainstorm Organoid Project is a close partnership between ethicists and scientists at the Church lab at Harvard Medical School, the Arlotta lab at Harvard  and the Pasca lab at Stanford – each informing the other through an unprecedented two-year process of joint deliberation.

Over the next five years or so, organoid researchers will attempt to build far more realistic human brain models by achieving key bioengineering advancements, chief among which are: (1) introducing perfusable vascular networks to maintain tissue viability and promote 3D brain model growth; (2) generating the full complement of missing cell types; and (3) building particular brain regions and exploring specific input and output signals. The latter point involves using brain models derived from human induced pluripotent stem cells (body cells engineered to become embryonic-like stem cells) with optogenetic channels for “writing” information/patterns into the laboratory models, connected with electrodes for “reading” the resulting electrical activity.

Our team’s exploration of these three areas together are likely to produce tractable new bioengineered tools for understanding functional interconnectivity of the human brain, dysfunction involved in many neurodegenerative diseases, and perhaps, even certain molecular mechanisms underlying cognition. The potential for these lines of brain research is significant because there are large gaps in current knowledge due to the relative inaccessibility of living brain tissue in the body and the ethical considerations that strictly limit in vivo brain research in human subjects. Our Brainstorm Organoid Project seeks to establish ongoing and proactive ethical discussions among ethicists and the neuroscientists involved with this cutting-edge work to examine (1) whether the emerging field of brain organoid research raises any unique ethical issues; and (2) whether existing stem cell research oversight committees are sufficient to manage the ethical issues related to this field. Our goal is to develop greater awareness, understanding, and future management of ethical issues that may be unique to this new area.

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Although we are still in the middle of our project, some enticing insights have already been generated, of which I will offer a small preview. The first insight is that, contrary to what many people suppose, the key ethical issue at the moment is not the threat of consciousness emerging in human brain organoid models. The science is simply not there yet for this to be a concern. Instead, much more salient issues are emerging at the bench-side that demand consideration now: For example, there are the issues of reproducibility and validation of brain organoids. Technical difficulties – such as growing brain organoids of consistent quality and speeding up the timeline of organoid development through bioprinting – are crucial to overcome if these brain models to serve as research tools for drug discovery and other scientific purposes.

However, strategies to achieve scalability, reproducibility, and controllability may also make it possible to create complex brain organoids for industrial purposes that the public may not be prepared to accept. Key questions involve whether there are any research uses of brain organoids in the future that would be ethically inappropriate given people’s sensitivities around human brain tissue. How are these no-go zones to be determined? Is there any brain organoid research that is simply out of bounds? Going back to the common worry about consciousness in brain organoids, would it ever be ethically permissible to attempt to generate consciousness or at least basic sentience in a complex brain organoid? As researchers look into a future of limitless possibilities for where the science could go, what self-imposed ethical limits ought there to be if any? This question requires ongoing communication between scientists and ethicists brainstorming together in the cutting edge of organoid research. We look forward to reporting our results a year from now.

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Insoo Hyun is Professor of Bioethics and Philosophy at Case Western Reserve University School of Medicine and Faculty Member in the Center for Bioethics at Harvard Medical School. As a Fulbright Scholar and Hastings Center Fellow, Dr. Hyun’s interests include ethical and policy issues in stem cell research and new biotechnologies.

Dr. Hyun has been involved for many years with the ISSCR (International Society for Stem Cell Research), for which he has helped draft all of the ISSCR’s international research guidelines and has served as their Chair of the Ethics and Public Policy Committee.

Dr. Hyun received his BA and MA in Philosophy with Honors in Ethics in Society from Stanford University and his PhD in Philosophy from Brown University. He is a regular contributor to Nature, Science, Cell Stem Cell, The Hastings Center Report, among many other journals. His book Bioethics and the Future of Stem Cell Research was published by Cambridge University Press in 2013.

References

1. Huch, M., Knoblich J.A., Lutolf M.P., & Martinez_Arias A. (2017). The Hope and the Hype of Organoid Research. Development 144: 938–941.
2. Lancaster, M., Renner, M., Martin, C., Wenzel, D., Bicknell, L.S., Hurles, M.E., ..., Knoblich., J.A. (2013). Cerebral Organoids Model Human Brain Development and Microcephaly. Nature 501: 373-379.
3. Bersenev, A. (2015). All About Organoids. Stem Cell Assays.  http://stemcellassays.com/2015/09/interview-madeline-lancaster/.
4. Cheshire, W.P. (2014). Miniature Human Brains: An Ethical Analysis. Ethics & Medicine 30: 7-12.

Want to cite this post?

Hyun, I. (2019). Brainstorming Over Brain Organoids. The Neuroethics Blog. Retrieved on , from http://www.theneuroethicsblog.com/2019/12/brainstorming-over-brain-organoids.html