Brain coral metaphorically represents the concept of growing organoids in a dish that may eventually attain consciousness--if scientists can first determine what that means.
Few images are more uncanny than that of a brain without a body, fully sentient but afloat in sterile isolation. Such specters have spooked the speculatively-minded since the seventeenth century, when René Descartes declared, "I think, therefore I am."
Since August 29, 2019, the prospect of a bodiless but functional brain has begun to seem far less fantastical.
In Meditations on First Philosophy (1641), the French penseur spins a chilling thought experiment: he imagines "having no hands or eyes, or flesh, or blood or senses," but being tricked by a demon into believing he has all these things, and a world to go with them. A disembodied brain itself becomes a demon in the classic young-adult novel A Wrinkle in Time (1962), using mind control to subjugate a planet called Camazotz. In the sci-fi blockbuster The Matrix (1999), most of humanity endures something like Descartes' nightmare—kept in womblike pods by their computer overlords, who fill the captives' brains with a synthetized reality while tapping their metabolic energy as a power source.
Since August 29, 2019, however, the prospect of a bodiless but functional brain has begun to seem far less fantastical. On that date, researchers at the University of California, San Diego published a study in the journal Cell Stem Cell, reporting the detection of brainwaves in cerebral organoids—pea-size "mini-brains" grown in the lab. Such organoids had emitted random electrical impulses in the past, but not these complex, synchronized oscillations. "There are some of my colleagues who say, 'No, these things will never be conscious,'" lead researcher Alysson Muotri, a Brazilian-born biologist, told The New York Times. "Now I'm not so sure."
Alysson Muotri has no qualms about his creations attaining consciousness as a side effect of advancing medical breakthroughs.
(Credit: ZELMAN STUDIOS)
Muotri's findings—and his avowed ambition to push them further—brought new urgency to simmering concerns over the implications of brain organoid research. "The closer we come to his goal," said Christof Koch, chief scientist and president of the Allen Brain Institute in Seattle, "the more likely we will get a brain that is capable of sentience and feeling pain, agony, and distress." At the annual meeting of the Society for Neuroscience, researchers from the Green Neuroscience Laboratory in San Diego called for a partial moratorium, warning that the field was "perilously close to crossing this ethical Rubicon and may have already done so."
Yet experts are far from a consensus on whether brain organoids can become conscious, whether that development would necessarily be dreadful—or even how to tell if it has occurred.
So how worried do we need to be?
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An organoid is a miniaturized, simplified version of an organ, cultured from various types of stem cells. Scientists first learned to make them in the 1980s, and have since turned out mini-hearts, lungs, kidneys, intestines, thyroids, and retinas, among other wonders. These creations can be used for everything from observation of basic biological processes to testing the effects of gene variants, pathogens, or medications. They enable researchers to run experiments that might be less accurate using animal models and unethical or impractical using actual humans. And because organoids are three-dimensional, they can yield insights into structural, developmental, and other matters that an ordinary cell culture could never provide.
In 2006, Japanese biologist Shinya Yamanaka developed a mix of proteins that turned skin cells into "pluripotent" stem cells, which could subsequently be transformed into neurons, muscle cells, or blood cells. (He later won a Nobel Prize for his efforts.) Developmental biologist Madeline Lancaster, then a post-doctoral student at the Institute of Molecular Biotechnology in Vienna, adapted that technique to grow the first brain organoids in 2013. Other researchers soon followed suit, cultivating specialized mini-brains to study disorders ranging from microcephaly to schizophrenia.
Muotri, now a youthful 45-year-old, was among the boldest of these pioneers. His team revealed the process by which Zika virus causes brain damage, and showed that sofosbuvir, a drug previously approved for hepatitis C, protected organoids from infection. He persuaded NASA to fly his organoids to the International Space Station, where they're being used to trace the impact of microgravity on neurodevelopment. He grew brain organoids using cells implanted with Neanderthal genes, and found that their wiring differed from organoids with modern DNA.
Like the latter experiment, Muotri's brainwave breakthrough emerged from a longtime obsession with neuroarchaeology. "I wanted to figure out how the human brain became unique," he told me in a phone interview. "Compared to other species, we are very social. So I looked for conditions where the social brain doesn't function well, and that led me to autism." He began investigating how gene variants associated with severe forms of the disorder affected neural networks in brain organoids.
Tinkering with chemical cocktails, Muotri and his colleagues were able to keep their organoids alive far longer than earlier versions, and to culture more diverse types of brain cells. One team member, Priscilla Negraes, devised a way to measure the mini-brains' electrical activity, by planting them in a tray lined with electrodes. By four months, the researchers found to their astonishment, normal organoids (but not those with an autism gene) emitted bursts of synchronized firing, separated by 20-second silences. At nine months, the organoids were producing up to 300,000 spikes per minute, across a range of frequencies.
He shared his vision for "brain farms," which would grow organoids en masse for drug development or tissue transplants.
When the team used an artificial intelligence system to compare these patterns with EEGs of gestating fetuses, the program found them to be nearly identical at each stage of development. As many scientists noted when the news broke, that didn't mean the organoids were conscious. (Their chaotic bursts bore little resemblance to the orderly rhythms of waking adult brains.) But to some observers, it suggested that they might be approaching the borderline.
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Shortly after Muotri's team published their findings, I attended a conference at UCSD on the ethical questions they raised. The scientist, in jeans and a sky-blue shirt, spoke rhapsodically of brain organoids' potential to solve scientific mysteries and lead to new medical treatments. He showed video of a spider-like robot connected to an organoid through a computer interface. The machine responded to different brainwave patterns by walking or stopping—the first stage, Muotri hoped, in teaching organoids to communicate with the outside world. He described his plans to develop organoids with multiple brain regions, and to hook them up to retinal organoids so they could "see." He shared his vision for "brain farms," which would grow organoids en masse for drug development or tissue transplants.
Muotri holds a spider-like robot that can connect to an organoid through a computer interface.
(Credit: ROLAND LIZARONDO/KPBS)
Yet Muotri also stressed the current limitations of the technology. His organoids contain approximately 2 million neurons, compared to about 200 million in a rat's brain and 86 billion in an adult human's. They consist only of a cerebral cortex, and lack many of a real brain's cell types. Because researchers haven't yet found a way to give organoids blood vessels, moreover, nutrients can't penetrate their inner recesses—a severe constraint on their growth.
Another panelist strongly downplayed the imminence of any Rubicon. Patricia Churchland, an eminent philosopher of neuroscience, cited research suggesting that in mammals, networked connections between the cortex and the thalamus are a minimum requirement for consciousness. "It may be a blessing that you don't have the enabling conditions," she said, "because then you don't have the ethical issues."
Christof Koch, for his part, sounded much less apprehensive than the Times had made him seem. He noted that science lacks a definition of consciousness, beyond an organism's sense of its own existence—"the fact that it feels like something to be you or me." As to the competing notions of how the phenomenon arises, he explained, he prefers one known as Integrated Information Theory, developed by neuroscientist Giulio Tononi. IIT considers consciousness to be a quality intrinsic to systems that reach a certain level of complexity, integration, and causal power (the ability for present actions to determine future states). By that standard, Koch doubted that brain organoids had stepped over the threshold.
One way to tell, he said, might be to use the "zap and zip" test invented by Tononi and his colleague Marcello Massimini in the early 2000s to determine whether patients are conscious in the medical sense. This technique zaps the brain with a pulse of magnetic energy, using a coil held to the scalp. As loops of neural impulses cascade through the cerebral circuitry, an EEG records the firing patterns. In a waking brain, the feedback is highly complex—neither totally predictable nor totally random. In other states, such as sleep, coma, or anesthesia, the rhythms are simpler. Applying an algorithm commonly used for computer "zip" files, the researchers devised a scale that allowed them to correctly diagnose most patients who were minimally conscious or in a vegetative state.
If scientists could find a way to apply "zap and zip" to brain organoids, Koch ventured, it should be possible to rank their degree of awareness on a similar scale. And if it turned out that an organoid was conscious, he added, our ethical calculations should strive to minimize suffering, and avoid it where possible—just as we now do, or ought to, with animal subjects. (Muotri, I later learned, was already contemplating sensors that would signal when organoids were likely in distress.)
During the question-and-answer period, an audience member pressed Churchland about how her views might change if the "enabling conditions" for consciousness in brain organoids were to arise. "My feeling is, we'll answer that when we get there," she said. "That's an unsatisfying answer, but it's because I don't know. Maybe they're totally happy hanging out in a dish! Maybe that's the way to be."
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Muotri himself admits to no qualms about his creations attaining consciousness, whether sooner or later. "I think we should try to replicate the model as close as possible to the human brain," he told me after the conference. "And if that involves having a human consciousness, we should go in that direction." Still, he said, if strong evidence of sentience does arise, "we should pause and discuss among ourselves what to do."
"The field is moving so rapidly, you blink your eyes and another advance has occurred."
Churchland figures it will be at least a decade before anyone reaches the crossroads. "That's partly because the thalamus has a very complex architecture," she said. It might be possible to mimic that architecture in the lab, she added, "but I tend to think it's not going to be a piece of cake."
If anything worries Churchland about brain organoids, in fact, it's that Muotri's visionary claims for their potential could set off a backlash among those who find them unacceptably spooky. "Alysson has done brilliant work, and he's wonderfully charismatic and charming," she said. "But then there's that guy back there who doesn't think it's exciting; he thinks you're the Devil incarnate. You're playing into the hands of people who are going to shut you down."
Koch, however, is more willing to indulge Muotri's dreams. "Ten years ago," he said, "nobody would have believed you can take a stem cell and get an entire retina out of it. It's absolutely frigging amazing. So who am I to say the same thing can't be true for the thalamus or the cortex? The field is moving so rapidly, you blink your eyes and another advance has occurred."
The point, he went on, is not to build a Cartesian thought experiment—or a Matrix-style dystopia—but to vanquish some of humankind's most terrifying foes. "You know, my dad passed away of Parkinson's. I had a twin daughter; she passed away of sudden death syndrome. One of my best friends killed herself; she was schizophrenic. We want to eliminate all these terrible things, and that requires experimentation. We just have to go into it with open eyes."
A new study provides key insights in what causes Alzheimer's: a breakdown in the brain’s system for clearing waste.
A new study provides key insights into what’s causing the disease. The research, published in Nature Communications, points to a breakdown over time in the brain’s system for clearing waste, an issue that seems to happen in some people as they get older.
Michael Glickman, a biologist at Technion – Israel Institute of Technology, helped lead this research. I asked him to tell me about his approach to studying how this breakdown occurs in the brain, and how he tested a treatment that has potential to fix the problem at its earliest stages.
Dr. Michael Glickman is internationally renowned for his research on the ubiquitin-proteasome system (UPS), the brain's system for clearing the waste that is involved in diseases such as Huntington's, Alzheimer's, and Parkinson's. He is the head of the Lab for Protein Characterization in the Faculty of Biology at the Technion – Israel Institute of Technology. In the lab, Michael and his team focus on protein recycling and the ubiquitin-proteasome system, which protects against serious diseases like Alzheimer’s, Parkinson’s, cystic fibrosis, and diabetes. After earning his PhD at the University of California at Berkeley in 1994, Michael joined the Technion as a Senior Lecturer in 1998 and has served as a full professor since 2009.
Dr. Michael Glickman