Tens of millions of Americans suffer each year from neurological and psychiatric disorders. While scientists’ understanding of the human brain continues to advance, effective treatments remain hobbled by the models researchers use to study neurological diseases.
A report, released April 8 by the National Academies of Sciences, Engineering, and Medicine, considers the ethical considerations of three emerging models for studying the human brain: human neural organoids, cell transplants, and chimeras. Neural organoids are in-vitro, three-dimensional collections of human brain cells that mimic many features of the fetal brain. Both transplants and chimeras involve the introduction of human brain cells into nonhumans animals, but while transplants can be done during many phases of development, chimeras are created when human stem cells are injected into an animal very early in its development, such that they integrate more fully and grow in parallel with the host’s cells.
Joshua Sanes, a neurobiologist at Harvard University, and Bernard Lo, a professor emeritus of bioethics at the University of California, San Francisco, and the president emeritus of the Greenwall Foundation in New York, cochaired the committee that produced the report. The two spoke to The Scientist about the group’s findings, which were informed by a review of the scientific literature and subsequent discussions with lawyers, ethicists, social scientists, science and religion scholars, and representatives of the public, among others.
The Scientist: What makes the brain a more contentious issue with respect to the ethics of some of these tools?
Bernard Lo: Many people believe the brain is the seed of characteristics that set us apart from nonhuman animals—higher consciousness, complex problem solving, things like that. So the type of research that our report talks about raises concerns about blurring distinctions between humans and animals and upsetting human dignity.
Another issue is getting consent from patients to have their cells used in this way. We pointed out that, under current US regulations, biomaterials that are outside the patient’s body and have been deidentified can be used in other research without additional consent for research like this. There’s an active discussion as to whether the current oversight system is appropriate for this kind of research that, for some people, is quite sensitive.
TS: Moving into the technologies themselves, you state in the report that it is extremely unlikely, for now, that organoids would possess consciousness, emotions, or heightened sensitivity to pain. What is the evidence that supports this?
Joshua Sanes: Just to clarify, we’re saying that with the current state of technology, we believe it isn’t happening, and it’s unlikely to happen in the near future. But the whole essence of the report was to get out ahead of the curve, because it’s such a fast-developing technology that we honestly can’t predict where it’s going to go.
With organoids, for example, it’s very difficult to define [consciousness], but to the extent that people have a sense of the neural correlates of consciousness, it seems to involve very complex circuitry that includes long-distance connections between whole brain regions. But any organoid will only have the characteristics of one or a few brain regions. There aren’t those long-distance connections that would suggest they’re going to have consciousness. In addition, the level of maturation of the organoids, and the degree of patterning in their connections is, at this moment, rather low.
TS: One of the other tools you talk about, chimeric animals [with human brain cells], do not yet exist. What will it take to make these models viable?
JS: The scientific reason to think that it would be hard to get a viable, by which I mean a postnatal chimeric animal with human neurons populating its brain, are multiple. But probably the main one is the tempo of the development of neurons . . . in utero. A human neuron gets to a neonatal stage in nine months, whereas a mouse gets to a neonatal stage in twenty-one days. So that mismatch is viewed as a major problem.
TS: How does the language that scientists use to describe these technologies influence peoples’ perception of them?
BL: We singled out the term ‘mini brains,’ which you see in press releases and media stories. And really, these organoids, which are four millimeters in size at this point, are so much smaller in terms of their volume, number of cells, and the complexity of their neural circuits. So it’s misleading. The report also discusses the term chimera, which is widely used in other fields of science and has roots in popular literature and mythology going back centuries. Do those other connotations flow over in this context?
We think that a good term for describing this research would be descriptive, it would be scientifically accurate, and it would be neutral in the sense that it wasn’t designed to either push people towards acceptance of the technology or to pull them into rejecting it. And we suggest that there’s a big responsibility on scientists, and also [on] institutions where the research is being done, to put out press releases that use language which is scientifically accurate and leads the audience to say, ‘I don’t know much about that, but I’d like to learn more.’
TS: You said in the report that at present, existing regulatory oversight is sufficient for these tools. What will need to change to prompt a reexamination?
JS: It’s hard to say, because I know as a biologist that you can’t really predict the direction or the speed of research. Sometimes things are just roaring down the track, and then they come to a blockade and nothing happens for several years.
In vague and abstract terms, if organoids become much more complex and mature, that would be a checkpoint. But if you [wanted to know] how much more complex and how much more mature, I don’t think we’re in a position to say. For chimeras, if it does become possible to make chimeras with human embryonic or iPS [induced pluripotent stem] cells and nonhuman animals, that would be another check. That’s not currently allowed by NIH funding, but that doesn’t mean it’s not allowed by private sources or internationally.
For transplants, it’s a little hard to say. The transplants that have been done have introduced fairly modest numbers [of neurons] into a brain. Now, if some technology were developed . . . in which transplants could introduce very, very large numbers of neurons, that would be another checkpoint.
BL: But we shouldn’t be waiting for something to happen before we start to talk about this and bring together scientists and nonscientists and the public and legislators. We should really start those discussions now and plan for them to continue. Because as Josh points out, science is unpredictable. We should be proactive and really plan that there’s going to be developments. And we should keep ahead of those developments as best we can.