A new study promises new paths to research mental illness, but raises questions about whether so-called organoids could develop consciousness
Alysson Muotri was dumbfounded when the pea-sized blobs of human brain cells that he was growing in the lab started emitting electrical pulses. He initially thought the electrodes he was using were malfunctioning.
Muotri was wrong. What the cells were emitting were brain waves — rhythmic patterns of neural activity. “That was a big surprise,” he says.
The 3D blobs of brain cells, known as organoids, are commonly used in disease and drug research to replicate organs. But no “mini-brain” had ever shown signs of brain waves before.
That was in 2016. Now, Muotri and his colleagues at the University of California, San Diego, have detailed their findings on the organoids in a new study in the journal Cell Stem Cell.
Scientists are a long way from understanding the human brain. Organoids that emit brain waves could open up new opportunities for research. But as mini-brains become better replicas for real brains, they raise ethical questions about where sentience begins, and whether these blobs of tissue need protections of the sort offered to animals and humans in research.
Muotri’s team grew organoids by first programming adult skin cells into stem cells that have the ability to specialize into any cell type. With the right cocktail of chemicals and growth factors to stimulate cell growth, Muotri and his team were able to coax the cells into becoming different types of neurons. With this recipe, they grew hundreds of organoids that were more mature than previous models.
Using electrodes, they first detected bursts of brain waves at about two months. As the organoids grew, they produced brain waves at different frequencies, and the signals became more regular, suggesting the neurons were forming connections. Then, at about 10 months, the neural activity plateaued. Muotri says that might be due because additional neurons are needed to continue development or that some of the cells in the organoids start to die off after 10 months.
“The more accurate the brain surrogate is, the more ethically complex it is, too.”
The researchers then developed a machine-learning algorithm based on data from newborn humans to see if they could predict the age of brain development in the organoids. The algorithm analyzed signals from an electroencephalogram, or EEG, which detects electrical activity in the brain using electrodes, and found that the organoids emitted similar brain waves as infants born prematurely. The study is the first time such brain activity has been shown in organoids.
“One might assume that for the brain to really form these sophisticated networks it would have to be an intact brain,” Muotri says. “You actually don’t need that.”
The organoids, which have been kept alive for a few years, could help better study early brain development. Such work has been challenging, in part, because fetal brain tissue is hard to come by. Organoids are also valuable for testing drugs.
Jennifer Erwin, a molecular geneticist and neuroscientist at the Lieber Institute for Brain Development in Baltimore, Maryland, says the UC San Diego team’s organoids are a major advance that will allow researchers to better study psychiatric disorders, such as schizophrenia, which afflicts more than three million Americans and has stubbornly resisted treatment.
“For many neurological and psychiatric disorders, we know the neural circuit activity is disrupted,” she says. For instance, in autism, epilepsy, schizophrenia, bipolar disorder, and depression, there are no discernible structural changes to the brain that researchers can observe from cells grown in a dish. Instead, “the brain oscillations are the part that’s dysfunctional.” Now, researchers could conceivably study brain waves in a person with one of these conditions and compare them to brain waves seen in organoids.
“It’s good to see that a better brain surrogate is being developed,” says Nita Farahany, a professor at Duke University who specializes in the bioethics of emerging neurotechnologies. “But the more accurate the brain surrogate is, the more ethically complex it is, too.”
As mini-brains get more advanced, Farahany says researchers need to consider whether organoids could eventually gain consciousness, and if so, what guidelines might be needed on research involving organoids. Should scientists be allowed to transplant human organoids capable of conscious experiences into animals? Less developed versions have already been implanted in mice and rats.
“We need to start asking questions about whether or not it’s possible for these organoids to develop any sentient-like capabilities,” Farahany says.
In the brain organoids that Muotri and his team made, neural development stopped at a certain point, but in the future, scientists might find a way to keep organoids developing past extreme infancy in the lab. The human brain forms connections when it receives sensory inputs from outside stimuli. So far, scientists have only tested basic sensory inputs on organoids, such as shining a light on them, to measure the response.
Farahany says questions also arise about whether researchers should be able to “own” brain organoids like they do other types of tissue, as well as how they should dispose of these organoids after their research concludes. Muotri thinks imposing any restrictions on brain organoids at this stage would be premature, but acknowledges that “we don’t know the potential of this technology.” And scientists don’t even have a good idea of what consciousness is, which means it will be difficult to know when organoids might advance beyond blobs of cells to something that could actually feel.
Muotri stresses that organoids are still far from resembling the real thing. There are more than 100,000 cell types in a human brain. In the organoids he and his team made, there are just 18. “That’s the level of complexity,” he says. “It just shows how far away we are from the real tissue.”