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Expanding Research with Mini Brains Elicits Ethicists' Questions

ARTICLE IN BRIEF

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ORGANOIDS used in Zika virus research (from left to right) before exposure to Zika, after exposure to Zika, and after treatment.

A new paper about cerebral organoids, or mini brains, raises discussion about whether they are ‘sentient’ beings, leading to questions about ethical issues and concerns that will need to be addressed.

The advent of cerebral organoids, sometimes called “mini brains,” has led to lofty hopes for neurological research. What could hold more promise than a three-dimensional model representative of the human brain, derived from human stem cells, with which researchers can assess the effects of diseases and then devise ways to overcome or reverse those effects?

Already, the organoids are being used to investigate the effects of the Zika virus, Parkinson's disease, and other conditions. But as research interest involving cerebral organoids continues to expand, so too have concerns about the ethics of that research.

Ethicists tend to agree that there are no major concerns with the miniaturized and simplified cerebral organoids that are used in research now. But ethical considerations are important to consider sooner rather than later, they say, so that the field can be vigilant and not overstep ethical boundaries before it's too late.

Labs are busy trying to make the organoids more complex — and therefore more scientifically useful — and it stands to reason that they'll succeed. Already, cerebral organoids have been implanted into lab rats and mice, and other researchers, it has been reported, have connected the tiny brain organoids to blood vessels, a step toward providing a blood supply to keep them from quickly rotting.

“It is hard to underestimate the importance of organoids in general and brain organoids in particular,” two neuroethicists wrote in a paper published in the February 28 online edition of the Journal of Medical Ethics. “So, it is likely that investments and research on the topic will increase, leading to knowledge and techniques able to create more ‘evolved’ mini-brains.” The authors pointed out that, today, cerebral organoids have “dendritic spine-like structures” similar to mature neurons and have been shown to have differentiation of photoreceptor-like cells that can respond to light-based stimulation.

“I do not think there is an adequate discussion of the ethical implications of organoids as such, and of cerebral organoids in particular,” said lead author Andrea Lavazza, MA, a research fellow in neuroethics at Centro Universitario Internazionale in Arezzo, Italy, who wrote the paper with Marcello Massimini, MD, PhD, of the University of Milan. “If, as we hypothesize, the cerebral organoids will be able to show some forms of sensitivity in the future, important issues will arise, and they won't be easily addressed.”

THE INTEGRATED INFORMATION THEORY

The authors proposed using the so-called “Integrated Information Theory” to think about the potential consciousness of cerebral organoids. The theory, introduced by Giulio Tononi, MD, PhD, director of the Wisconsin Institute for Sleep and Consciousness, is an attempt to explain what conscious experience actually is. It proposes that a conscious experience has to be “informative,” or distinct from other experiences, and that each experience has to be “integrated” and can't be split into individual parts.

A system has “subjective experience,” then, “to the extent that it is capable of integrating information,” the authors wrote. The theory also proposes a way to quantify a system's ability to integrate information.

A useful way to assess whether a cerebral organoid satisfies this definition of conscious experience, they said, might be the Perturbational Complexity Index, introduced by Dr. Massimini and colleagues, which can be calculated by using local transcranial magnetic stimulation of the cerebral cortex. It has been used to assess brain-injured, unresponsive patients.

“If cerebral organoids were to show levels of complexity that are somehow comparable with the ones detected in the residual cortex of a minimally conscious patient, it would be necessary to start an ethical debate on their use in clinical research and practice,” Dr. Lavazza said. “Could we produce a sentient mini brain and use it for destructive experiments? Would it be better to use a minimally ‘sentient’ human ‘brain’ or an animal model, for example, a mammal? Such questions may be premature today but may not be so in the (near) future.”

POINTS OF CONSENSUS

Joshua Shepherd, PhD, assistant professor of philosophy at Carleton University in Ottawa, wrote in an editorial in the March 18 online edition of the Journal of Medical Ethics that, rather than finding one winning theory of consciousness, it might be best to find points of consensus on the “kinds of biophysical architecture likely to support conscious process of moral interest.”

“Her conscious state may include perceptual consciousness, and more determinate varieties of conscious perception (vision, proprioception, etc.), or it may include cognitive consciousness, and more determinate varieties of conscious cognition (anticipation, mental action, judgment or whatever),” he wrote. “Arguably, not all phenomenal properties are morally on a par.”

Ariane Lewis, MD, assistant professor of neurology at New York University, who specializes in neurocritical care and neuroethics, said that “it will certainly take quite some time to get to the point where a model of a brain reaches the level of a mature human brain in terms of functionality, with synapses established and connections made such that the brain could formulate thoughts.”

“I don't think that we're there right now, and I don't think it's happening around the corner, but I think it's good to think about it at this point,” she said. “Appropriately, the research that's being done right now is spurring the questions of what could happen going forward, and could this potentially lead to something that could be ethically gray or unethical, and how should we think about that? And how should that frame the direction in which research goes?”

Karen Rommelfanger, PhD, assistant professor of neurology and program director of Emory University's neuroethics program at the Center for Ethics, said that our views regarding cerebral organoids are likely to change as our understanding of them improves.

“As we learn more about what these organoids actually are, then I think it could be possible that our values around them change. And I think that's what the [Lavazza] article tries to ask,” she said. “Is there something more we need to learn about what these organoids are, and might that change the way we think about their capacity and how we should use them?”

She said the Integrated Information Theory approach might be a helpful starter tool but pointed out that it's fairly nebulous. Any model for assessing consciousness has to be as explicit as possible, she said.

“Those models have to be very precise in their definitions and the behaviors to which they correlate, and right now there's a lot of wiggle room.”

And even if “consciousness” is established, she asked, what then?

THE IMPACT ON SOCIETY

“To suggest that there are these levels of consciousness doesn't really solve the problem, because you still have to assign what those levels mean, and which ones were meaningful enough to impact our behavior toward organisms with those assigned levels of consciousness,” Dr. Rommelfanger said.

Part of the equation has to involve the views of society at large, she said.

“If I donate tissue from my beloved grandmother or myself even and I see that the tissue is responding to light, and it responds to sound, and then I start to tell you there's the beginnings of memory formation in there, and it's having experiences, that it remembers the tests that are being done on them, you might start to feel queasy about that,” she said. “You might not think it's appropriate to trash it and put it in a biohazard bag and be done when the experiment is over.”

Sylvie Janssens, PhD, a post-doctoral fellow in developmental and regenerative biology at Icahn School of Medicine at Mount Sinai, who uses cerebral organoids to study Zika virus' effects, said the organoids have filled a “critical gap in methodology” because they overcome the ethical hurdle of using primary human brain tissue and the limited applicability of rodent models. They also offer a fast and reliable model for studying merging public health crises, she said.

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DR. ARIANE LEWIS: “Appropriately, the research thats being done right now is spurring the questions of what could happen going forward, and could this potentially lead to something that could be ethically gray or unethical, and how should we think about that? And how should that frame the direction in which research goes?”

She has not yet encountered any ethical issues using the organoids but said she would “pause to reflect on potential ethical issues in the use of organoids in chimera models, i.e. implanting human-derived organoids directly into other species.” She added, “I believe that just because something is possible, that does not necessarily make it good.”

A dialogue between the scientific community and the general public will help guide what is appropriate, she said.

“I also believe that scientists, in general, are deeply attuned to this dialogue and that there is an extraordinary amount of transparency on the part of the scientific community,” Dr. Janssens said. “Thus, I do not believe any fundamental ethical boundaries would be violated without prior public engagement.”

Dr. Lewis said there are likely to be ongoing questions about what is appropriate with regard to cerebral organoids research. “I see this as an offshoot of stem cell discussions,” she said. “I think that there's obviously a wide range of debates about whether stem cells can be used for research and how they can be used for research, and I think to me this is a niche subtopic associated with that topic.”

Dr. Rommelfanger said the issue is about doing the type of science “that people want” to be done. “Nobody wants to have a disease or an illness that benefits from something that was studied in an unethical way,” she said. “So these are shared interests.”

But she also suggested that it might be difficult to find firm answers.

“I think there's this desire that there will be someone who can tell us what's right and wrong and that's what the ethicist will do,” she said. “But the reality [is] we kind of live in this gray zone and [ethicists] often help people choose between the least wrong things. It's not always so simple.”

LINK UP FOR MORE INFORMATION:

• Lavazza A, Massimini M. Cerebral organoids: Ethical issues and consciousness assessment http://jme.bmj.com/content/early/2018/02/28/medethics-2017-104555. J Med Ethics 2018: Epub 2018 Feb 28.
    • Shepherd J. Ethical (and epistemological) issues regarding consciousness in cerebral organoids http://jme.bmj.com/content/early/2018/03/12/medethics-2018-104778. J Med Ethics 2018; Epub 2018 Mar 13.