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."
Many women want non-hormonal birth control. A 22-year-old's findings were used to launch a company that could, within the decade, bring a new kind of contraceptive to the marketplace.
Now a scientist with NextVivo, Shrestha is not directly involved in the development of the contraceptive that is based on her research. But, back in 2016 when she was going through her own problems with hormonal contraceptives, she “was very personally invested” in her research project, Shrestha says. She was coping with a long list of negative effects from an implanted hormonal IUD. According to the Mayo Clinic, those can include severe pelvic pain, headaches, acute acne, breast tenderness, irregular bleeding and mood swings. After a year, she had the IUD removed, but it took another full year before all the side effects finally subsided; she also watched her sister suffer the “same tribulations” after trying a hormonal IUD, she says.
For contraceptive use either daily or monthly, Shrestha says, “You want the antibody to be very potent and also cheap.” That was her goal when she launched her study.
Shrestha unshelved antibody research that had been sitting idle for decades. It was in the late 80s that scientists in Japan first tried to develop anti-sperm antibodies for contraceptive use. But, 35 years ago, “Antibody production had not been streamlined as it is now, so antibodies were very expensive,” Shrestha explains. So, they shifted away from birth control, opting to focus on developing antibodies for vaccines.
Over the course of the last three decades, different teams of researchers have been working to make the antibody more effective, bringing the cost down, though it’s still expensive, according to Shrestha. For contraceptive use either daily or monthly, she says, “You want the antibody to be very potent and also cheap.” That was her goal when she launched her study.
The problem
The problem with contraceptives for women, Shrestha says, is that all but a few of them are hormone-based or have other negative side effects. In fact, some studies and reports show that millions of women risk unintended pregnancy because of medical contraindications with hormone-based contraceptives or to avoid the risks and side effects. While there are about a dozen contraceptive choices for women, there are two for men: the condom, considered 98% effective if used correctly, and vasectomy, 99% effective. Neither of these choices are hormone-based.
On the non-hormonal side for women, there is the diaphragm which is considered only 87 percent effective. It works better with the addition of spermicides — Nonoxynol-9, or N-9 — however, they are detergents; they not only kill the sperm, they also erode the vaginal epithelium. And, there’s the non-hormonal IUD which is 99% effective. However, the IUD needs to be inserted by a medical professional, and it has a number of negative side effects, including painful cramping at a higher frequency and extremely heavy or “abnormal” and unpredictable menstrual flows.
The hormonal version of the IUD, also considered 99% effective, is the one Shrestha used which caused her two years of pain. Of course, there’s the pill, which needs to be taken daily, and the birth control ring which is worn 24/7. Both cause side effects similar to the other hormonal contraceptives on the market. The ring is considered 93% effective mostly because of user error; the pill is considered 99% effective if taken correctly.
“That’s where we saw this opening or gap for women. We want a safe, non-hormonal contraceptive,” Shrestha says. Compounding the lack of good choices, is poor access to quality sex education and family planning information, according to the non-profit Urban Institute. A focus group survey suggested that the sex education women received “often lacked substance, leaving them feeling unprepared to make smart decisions about their sexual health and safety,” wrote the authors of the Urban Institute report. In fact, nearly half (45%, or 2.8 million) of the pregnancies that occur each year in the US are unintended, reports the Guttmacher Institute. Globally the numbers are similar. According to a new report by the United Nations, each year there are 121 million unintended pregnancies, worldwide.
The science
The early work on antibodies as a contraceptive had been inspired by women with infertility. It turns out that 9 to 12 percent of women who are treated for infertility have antibodies that develop naturally and work against sperm. Shrestha was encouraged that the antibodies were specific to the target — sperm — and therefore “very safe to use in women.” She aimed to make the antibodies more stable, more effective and less expensive so they could be more easily manufactured.
Since antibodies tend to stick to things that you tell them to stick to, the idea was, basically, to engineer antibodies to stick to sperm so they would stop swimming. Shrestha and her colleagues took the binding arm of an antibody that they’d isolated from an infertile woman. Then, targeting a unique surface antigen present on human sperm, they engineered a panel of antibodies with as many as six to 10 binding arms — “almost like tongs with prongs on the tongs, that bind the sperm,” explains Shrestha. “We decided to add those grabbers on top of it, behind it. So it went from having two prongs to almost 10. And the whole goal was to have so many arms binding the sperm that it clumps it” into a “dollop,” explains Shrestha, who earned a patent on her research.
Suruchi Shrestha works in the lab with a colleague. In 2016, her research on antibodies for birth control was inspired by her own experience with side effects from an implanted hormonal IUD.
UNC - Chapel Hill
The sperm stays right where it met the antibody, never reaching the egg for fertilization. Eventually, and naturally, “Our vaginal system will just flush it out,” Shrestha explains.
“She showed in her early studies that [she] definitely got the sperm immotile, so they didn't move. And that was a really promising start,” says Jasmine Edelstein, a scientist with an expertise in antibody engineering who was not involved in this research. Shrestha’s team at UNC reproduced the effect in the sheep, notes Edelstein, who works at the startup Be Biopharma. In fact, Shrestha’s anti-sperm antibodies that caused the sperm to agglutinate, or clump together, were 99.9% effective when delivered topically to the sheep’s reproductive tracts.
The future
Going forward, Shrestha thinks the ideal approach would be delivering the antibodies through a vaginal ring. “We want to use it at the source of the spark,” Shrestha says, as opposed to less direct methods, such as taking a pill. The ring would dissolve after one month, she explains, “and then you get another one.”
Engineered to have a long shelf life, the anti-sperm antibody ring could be purchased without a prescription, and women could insert it themselves, without a doctor. “That's our hope, so that it is accessible,” Shrestha says. “Anybody can just go and grab it and not worry about pregnancy or unintended pregnancy.”
Her patented research has been licensed by several biotech companies for clinical trials. A number of Shrestha’s co-authors, including her lab advisor, Sam Lai, have launched a company, Mucommune, to continue developing the contraceptives based on these antibodies.
And, results from a small clinical trial run by researchers at Boston University Chobanian & Avedisian School of Medicine show that a dissolvable vaginal film with antibodies was safe when tested on healthy women of reproductive age. That same group of researchers last year received a $7.2 million grant from the National Institute of Health for further research on monoclonal antibody-based contraceptives, which have also been shown to block transmission of viruses, like HIV.
“As the costs come down, this becomes a more realistic option potentially for women,” says Edelstein. “The impact could be tremendous.”
This article was first published by Leaps.org in December, 2022. It has been lightly edited with updates for timeliness.
When all traditional therapeutic approaches fail for alcohol abuse disorder, a radical gene therapy might be something to try in the future.
In the U.S., more than 10 percent of people over the age of 12 are estimated to have AUD, and while medications, counseling, or sheer willpower can help some stop drinking, staying sober can be a huge struggle — an estimated 40-60 percent of people relapse at least once.
A team of U.S. researchers suspected that an in-development gene therapy for Parkinson’s disease might work as a dopamine-replenishing treatment for alcoholism, too.
According to the CDC, more than 140,000 Americans are dying each year from alcohol-related causes, and the rate of deaths has been rising for years, especially during the pandemic.
The idea: For occasional drinkers, alcohol causes the brain to release more dopamine, a chemical that makes you feel good. Chronic alcohol use, however, causes the brain to produce, and process, less dopamine, and this persistent dopamine deficit has been linked to alcohol relapse.
There is currently no way to reverse the changes in the brain brought about by AUD, but a team of U.S. researchers suspected that an in-development gene therapy for Parkinson’s disease might work as a dopamine-replenishing treatment for alcoholism, too.
To find out, they tested it in heavy-drinking monkeys — and the animals’ alcohol consumption dropped by 90% over the course of a year.
How it works: The treatment centers on the protein GDNF (“glial cell line-derived neurotrophic factor”), which supports the survival of certain neurons, including ones linked to dopamine.
For the new study, a harmless virus was used to deliver the gene that codes for GDNF into the brains of four monkeys that, when they had the option, drank heavily — the amount of ethanol-infused water they consumed would be equivalent to a person having nine drinks per day.
“We targeted the cell bodies that produce dopamine with this gene to increase dopamine synthesis, thereby replenishing or restoring what chronic drinking has taken away,” said co-lead researcher Kathleen Grant.
To serve as controls, another four heavy-drinking monkeys underwent the same procedure, but with a saline solution delivered instead of the gene therapy.
The results: All of the monkeys had their access to alcohol removed for two months following the surgery. When it was then reintroduced for four weeks, the heavy drinkers consumed 50 percent less compared to the control group.
When the researchers examined the monkeys’ brains at the end of the study, they were able to confirm that dopamine levels had been replenished in the treated animals, but remained low in the controls.
The researchers then took the alcohol away for another four weeks, before giving it back for four. They repeated this cycle for a year, and by the end of it, the treated monkeys’ consumption had fallen by more than 90 percent compared to the controls.
“Drinking went down to almost zero,” said Grant. “For months on end, these animals would choose to drink water and just avoid drinking alcohol altogether. They decreased their drinking to the point that it was so low we didn’t record a blood-alcohol level.”
When the researchers examined the monkeys’ brains at the end of the study, they were able to confirm that dopamine levels had been replenished in the treated animals, but remained low in the controls.
Looking ahead: Dopamine is involved in a lot more than addiction, so more research is needed to not only see if the results translate to people but whether the gene therapy leads to any unwanted changes to mood or behavior.
Because the therapy requires invasive brain surgery and is likely irreversible, it’s unlikely to ever become a common treatment for alcoholism — but it could one day be the only thing standing between people with severe AUD and death.
“[The treatment] would be most appropriate for people who have already shown that all our normal therapeutic approaches do not work for them,” said Grant. “They are likely to create severe harm or kill themselves or others due to their drinking.”
This article originally appeared on Freethink, home of the brightest minds and biggest ideas of all time.
