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Published On September 21, 2018

POLICY

First Thoughts

Tiny models of the brain are becoming more complex. When should the ethicists step in?

When Thomas Hartung presented his neurological research at a conference in 2016, he expected the feedback to be technical, not philosophical. A toxicologist at Johns Hopkins University, Hartung was talking about his work with cerebral organoids, tiny assemblages of neurological tissue grown from human stem cells. His organoids would be used to test chemical safety, revealing harms that go undetected in tests on animals.

But one of the biggest reactions to his talk came in response to a chance comment. “I said our organoids are ‘thinking,’ ” he recalls. By that, he meant that his organoids displayed spontaneous electrical activity, with neurons firing and stimulating each other.

A resulting tsunami of publicity anticipated a growing debate about the ethical implications of brain organoids, a powerful new tool for studying brains and their problems (“Tiny Marvels,” Winter 2018). For many in the general public, Hartung’s research conjured up an image from science fiction— a disembodied brain suspended in a vat—raising questions about selfhood, experience and the ethical boundaries of science. People wondered what kind of “thinking” the organoids could do, to which Hartung would respond: “They have nothing to think about.”

Electrical activity in the current generation of brain organoids, including Hartung’s, is far from the complex, sustained patterns found in human and other animal brains. Today’s organoids possess neither perception nor memory, can’t interact with the world outside of their containers and lack anatomical complexity. Hartung was quick to tell critics that although his organoids resemble brains, they are not minds.

That distinction, however, may eventually become harder to make. “We can’t create that level of sophistication yet,” says Christof Koch, president and chief scientific officer at the Allen Institute for Brain Science in Seattle. “But in a decade or more? We may get to the level of a simple mind, say that of a mouse.”

While Hartung’s organoids were no bigger than “a fly’s eye,” labs have rapidly made them larger and more sophisticated. In April, researchers at the Salk Institute in San Diego showed how they had transferred human brain organoids into mouse brains, which helped the organoids survive for as long as 233 days—much longer than previous methods. Researchers have learned to connect organoids with blood vessels, a critical step in enabling them to develop more complex structures. Soon brain organoids might be joined to hearts, eyes or other mini-organs.

“The closer the proxy gets to a functioning human brain, the more ethically problematic it becomes,” wrote Nita Farahany, a bioethicist at Duke University, in an April Nature article that she co-authored with Koch and 15 other prominent ethicists and scientists. The authors warned that future organoids might be capable of experiencing “pleasure, pain or distress; being able to store and retrieve memories; or perhaps even having some perception of agency or awareness of self.”

Such brain organoids would demand a profound re-evaluation of research practice, the authors said. What moral duties would they be owed? How should organoid tissues be disposed of? Would they be preserved in some way, like chimpanzees sent to live in sanctuaries after they were no longer needed for research?

Even now, some researchers worry that existing regulations may not be up to the task of dealing with this new, fast-moving field. In a cautionary paper published last year in the journal eLIFE, geneticists John Aach and George Church at Harvard Medical School recalled asking for guidance from their research oversight committee about a new technique they had developed that could have led to the connection of, for instance, a brain organoid to heart and eye tissue. That kind of complexity may approach that of a developing embryo, and “such entities might be morally concerning,” they wrote.

But after careful study, the Harvard committee found that current federal guidelines didn’t apply to this new work. A rule that actual embryos can’t be grown past the age of 14 days, for example, was insufficient to regulate innovations that would allow brain organoids to reach much greater levels of complexity—potentially becoming, as Aach and Church designated them, “synthetic human entities with embryo-like features.”

In the eLIFE paper, Aach and Church called on the biomedical community to dive into the ethical and conceptual issues for such research, and argued against using timelines as a guide—depending, rather, on the presence of anatomical features concerned with physiological functions that are morally compelling. Marcello Massimini, a neurophysiologist at the University of Milan, and philosopher Andrea Lavazza at the International University Center in Arezzo, Italy, have proposed looking at electrical activity. They note that tests measuring neurological complexity are already in use, for example to determine whether a patient who appears to be in a coma may be conscious and aware. In the future, similar measures could be applied to assess brain organoids.

Hartung is preparing a bioethics course for medical scientists that will probe such issues, and Koch urges researchers and ethicists to look ahead to questions they could one day face. “We’re still far away,” he says, “but we need to think about it now so we can get ready to deal with the ethical issues.”