Biologists are Growing Mini-Brains. What If They Become Conscious?
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."
MILESTONE: Doctors have transplanted a pig organ into a human for the first time in history
Surgeons at Massachusetts General Hospital made history last week when they successfully transplanted a pig kidney into a human patient for the first time ever.
The recipient was a 62-year-old man named Richard Slayman who had been living with end-stage kidney disease caused by diabetes. While Slayman had received a kidney transplant in 2018 from a human donor, his diabetes ultimately caused the kidney to fail less than five years after the transplant. Slayman had undergone dialysis ever since—a procedure that uses an artificial kidney to remove waste products from a person’s blood when the kidneys are unable to—but the dialysis frequently caused blood clots and other complications that landed him in the hospital multiple times.
As a last resort, Slayman’s kidney specialist suggested a transplant using a pig kidney provided by eGenesis, a pharmaceutical company based in Cambridge, Mass. The highly experimental surgery was made possible with the Food and Drug Administration’s “compassionate use” initiative, which allows patients with life-threatening medical conditions access to experimental treatments.
The new frontier of organ donation
Like Slayman, more than 100,000 people are currently on the national organ transplant waiting list, and roughly 17 people die every day waiting for an available organ. To make up for the shortage of human organs, scientists have been experimenting for the past several decades with using organs from animals such as pigs—a new field of medicine known as xenotransplantation. But putting an animal organ into a human body is much more complicated than it might appear, experts say.
“The human immune system reacts incredibly violently to a pig organ, much more so than a human organ,” said Dr. Joren Madsen, director of the Mass General Transplant Center. Even with immunosuppressant drugs that suppress the body’s ability to reject the transplant organ, Madsen said, a human body would reject an animal organ “within minutes.”
So scientists have had to use gene-editing technology to change the animal organs so that they would work inside a human body. The pig kidney in Slayman’s surgery, for instance, had been genetically altered using CRISPR-Cas9 technology to remove harmful pig genes and add human ones. The kidney was also edited to remove pig viruses that could potentially infect a human after transplant.
With CRISPR technology, scientists have been able to prove that interspecies organ transplants are not only possible, but may be able to successfully work long term, too. In the past several years, scientists were able to transplant a pig kidney into a monkey and have the monkey survive for more than two years. More recently, doctors have transplanted pig hearts into human beings—though each recipient of a pig heart only managed to live a couple of months after the transplant. In one of the patients, researchers noted evidence of a pig virus in the man’s heart that had not been identified before the surgery and could be a possible explanation for his heart failure.
So far, so good
Slayman and his medical team ultimately decided to pursue the surgery—and the risk paid off. When the pig organ started producing urine at the end of the four-hour surgery, the entire operating room erupted in applause.
Slayman is currently receiving an infusion of immunosuppressant drugs to prevent the kidney from being rejected, while his doctors monitor the kidney’s function with frequent ultrasounds. Slayman is reported to be “recovering well” at Massachusetts General Hospital and is expected to be discharged within the next several days.Niklas Anzinger is the founder of Infinita VC based in the charter city of Prospera in Honduras. Infinita focuses on a new trend of charter cities and other forms of alternative jurisdictions. Healso hosts a podcast about how to accelerate the future by unblocking “stranded technologies”.This spring he was a part of the network city experiment Zuzalu spearheaded by Ethereum founder Vitalik Buterin where a few hundred invited guests from the spheres of longevity, biotechnology, crypto, artificial intelligence and investment came together to form a two-monthlong community. It has been described as the world’s first pop-up city. Every morning Vitalians would descend on a long breakfast—the menu had been carefully designed by famed radical longevity self-experimenter Bryan Johnson—and there is where I first met Anzinger who told me about Prospera. Intrigued to say the least, I caught up with him later the same week and the following is a record of our conversation.
Q. We are sitting here in the so-called pop-up network state Zuzalu temporarily realized in the village of Lusticia Bay by the beautiful Mediterranean Sea. To me this is an entirely new concept: What is a network state?
A. A network state is a highly aligned online community that has a level of in-person civility; it crowd-funds territory, and it eventually seeks diplomatic recognition. In a way it's about starting a new country. The term was coined by the crypto influencer and former CTO of Coinbase Balaji Srinivasan in a book by the same title last year [2022]. What many people don't know is that it is a more recent addition or innovation in a space called competitive governance. The idea is that you have multiple jurisdictions competing to provide you services as a customer. When you have competition among governments or government service providers, these entities are forced to provide you with a better service instead of the often worse service at higher prices or higher taxes that we're currently getting. The idea went from seasteading, which was hardly feasible because of costs, to charter cities getting public/private partnerships with existing governments and a level of legal autonomy, to special economic zones, to now network states.
Q. How do network states compare to charter cities and similar jurisdictions?
A. Charter cities and special economic zones were legal forks from other existing states. Dubai, Shenzhen in China, to some degree Hong Kong, to some degree Singapore are some examples. There's a host of other charter cities, one of which I'm based in myself, which is Prospera located in Honduras on the island Roatán. Charter cities provide the full stack of governance; they provide new laws and regulations, business registration, tax codes and governance services, Estonia style: you log on to the government platform and you get services as a citizen.
When conceptualizing network states, Balagi Srinivasan turns the idea of a charter city a bit on its head: he doesn't want to start with this full stack because it's still very hard to get these kinds of partnerships with government. It's very expensive and requires lots of experience and lots of social capital. He is saying that network states could instead start as an online community. They could have a level of alignment where they trade with each other; they have their own economy; they meet in person in regular gatherings like we're doing here in Zuzulu for two months, and then they negotiate with existing governments or host cities to get a certain degree of legal autonomy that is centered around a moral innovation. So, his idea is: don't focus on building a completely new country or city; focus on a moral innovation.
Q. What would be an example of such a moral innovation?
A. An example would be longevity—life is good; death is bad—let's see what we can do to foster progress around that moral innovation and see how we can get legal forks from the existing system that allow us to accelerate progress in that area. There is an increasing realization in the science that there are hallmarks of aging and that aging is a cause of other diseases like cancer, ALS or Alzheimer's. But aging is not recognized as a disease by the FDA in the United States and in most countries around the world, so it's very hard to get scientific funding for biotechnology that would attack the hallmarks of aging and allow us potentially to reverse aging and extend life. This is a significant shortcoming of existing government systems that groups such as the ones that have come together here in Montenegro are now seeking alternatives too. Charter cities and now network states are such alternatives.
Q.Would it not be better to work within the current systems, and try to improve them, rather than abandon them for new experimental jurisdictions?
A. There are numerous failures of public policies. These failures are hard, if not impossible, to reverse, because as soon as you have these policies, you have entrenched interests who benefit from the regulations. The only way to disrupt incumbent industries is with start-ups, but the way the system is set up makes it excessively hard for such start-ups to become big companies. In fact, larger companies are weaponizing the legal system against small companies, because they can afford the lawyers and the fixed cost of compliance.
I don't believe that our institutions in many developed countries are beyond hope. I just think it's easier to change them if you could point at successful examples. ‘Hey, this country or this zone is already doing it very successfully’; if they can extend people’s lifespan by 10 years, if they can reduce maternal mortality, and if they have a massive medical tourism where people come back healthier, then that is just very embarrassing for the FDA.
Q. Perhaps a comparison here would be the relationship between Hong Kong and China?
A. Correct, so having Hong Kong right in front of your door … ‘Hey, this capitalism thing seems to work, why don't we try it here?’ It was due to the very bold leadership by Deng Xiaoping that they experimented with it in the development zone of Shenzhen. It worked really well and then they expanded with more special economic zones that also worked.
Próspera is a private city and special economic zone on the island of Roatán in the Central American state of Honduras.
Q. Tell us about Prospera, the charter city in Honduras, that you are intimately connected with.
A. Honduras is a very poor country. It has a lot of crime, never had a single VC investment, and has a GDP per capita of 2,000 per year. Honduras has suffered tremendously. The goal of these special economic zones is to bring in economic development. That's their sole purpose. It's a homegrown innovation from Honduras that started in 2009 with a very forward-thinking statesman, Octavio Sanchez, who was the chief of staff to the president of Honduras, and then president. He had his own ideas about making Honduras a more decentralized system, where more of the power lies in the municipalities.
Inspired by the ideas of Nobel laureate economist Paul Romer, who gave a famous Ted Talk in 2009 about charter cities, Sanchez initiated a process that lasted for years and eventually led to the creation of a special economic zone legal regime that’s anchored in the Hunduran constitution that provides the highest legal autonomy in the world to these zones. There are today three special economic zones approved by the Honduran government: Prospera, Ciudad Morazan and Orchidea.
Q. How did you become interested and then involved in Prospera?
A. I read about it first in an article by Scott Alexander, a famous rationalist blogger, who wrote a very long article about Prospera, and I thought, this is amazing! Then I came to Prospera and I found it to be one of the most if not the most exciting project in the world going on right now and that it also opened my heart to the country and its people. Most of my friends there are Honduran, they have been working on this for 10 or more years. They want to remake Honduras and put it on the map as the place in the world where this legal and governance innovation started.
Q. To what extent is Prospera autonomous relative to the Honduran government?
A. What's interesting about the Honduran model is that it's anchored within the Honduran constitution, and it has a very clear framework for what's possible and what's not possible, and what's possible ensures the highest degree of legal autonomy anywhere seen in the world. Prospera has really pushed the model furthest in creating a common law-based polycentric legal system. The idea is that you don't have a legislature, instead you have common law and it's based on the best practice common law principles that a legal scholar named Tom W. Bell created.
One of the core ideas is that as a business you're not obligated to follow one regulatory monopoly like the FDA. You have regulatory flexibility so you can choose what you're regulated under. So, you can say: ‘if I do a medical clinic, I do it under Norwegian law here’. And you even have the possibility to amend it a bit. You're still required to have liability insurance, and have to agree to binding arbitration in case there's a legal dispute. And your insurance has to approve you. So, under that model the insurance becomes the regulator and they regulate through prices. The limiting factor is criminal law; Honduran criminal law fully applies. So does immigration law. And we pay taxes.
Q. Is there also an idea of creating a kind of healthy living there, and encourage medical tourism?
A. Yes, we specifically look for legal advantages in autonomy around creating new drugs, doing clinical trials, doing self-medication and experimentation. There is a stem cell clinic here and they're doing clinical trials. The island of Roatán is very easily accessible for American tourists. It's a beautiful island, and it's for regulatory reasons hard to do stem cell therapies in the United States, so they're flying in patients from the United States. Most of them are very savvy and often have PhDs in biotech and are able to assess the risk for themselves of taking drugs and doing clinical trials. We're also going to get a wellness center, and there have been ideas around establishing a peptide clinic and a compound pharmacy and things like that. We are developing a healthcare ecosystem.
Q. This kind of experimental tourism raises some ethical issues. What happens if patients are harmed? And what are the moral implications for society of these new treatments?
A. As a moral principle we believe in medical freedom: people have rights over their bodies, even at the (informed) risk of harm to themselves if no unconsenting third-parties are harmed; this is a fundamental right currently not protected effectively.
What we do differently is not changing ethical norms around safety and efficacy, we’re just changing the institutional setup. Instead of one centralized bureaucracy, like the FDA, we have regulatory pluralism that allows different providers of safety and efficacy to compete under market rules. Like under any legal system, common law in Prospera punishes malpractice, fraud, murder etc. This system will still produce safe and effective drugs, and it will still work with common sense legal notions like informed consent and liability for harm. There are regulations for medical practice, there is liability insurance and things like that. It will just do so more efficiently than the current way of doing things (unless it won’t, in which case it will change and evolve – or fail).
A direct moral benefit ´to what we do is that we increase accessibility. Typical gene therapies on the market cost $1 million dollars in the US. The gene therapy developed in Prospera costs $25,000. As to concern about whether such treatments are problematic, we do not share this perspective. We are for advancing science responsibly and we believe that both individuals and society stand to gain from improving the resiliency of the human body through advanced biotechnology.
Q. How does Prospera relate to the local Honduran population?
A. I think it's very important that our projects deliver local benefits and that they're well anchored in local communities. Because when you go to a new place, you're seen as a foreigner, and you're seen as potentially a danger or a threat. The most important thing for Prospera and Ciudad Morazan is to show we're creating jobs; we're creating employment; we're improving people's lives on the ground. Prospera is directly and indirectly employing 1,100 people. More than 2/3 of the people who are working for Prospera are Honduran. It has a lot of local service workers from the island, and it has educated Hondurans from the mainland for whom it's an alternative to going to the United States.
Q. What makes a good Prosperian citizen?
A. People in Prospera are very entrepreneurial. They're opening companies on a small scale. For example, Vehinia, who is the cook in the kitchen at Prospera, she's from the neighboring village and she started an NGO that is now funding a school where children from the local village can go to instead of a school that's 45 minutes away. There's very much a spirit of ‘let's exchange and trade with each other’. Some people might see that as a bit too commercial, but that's something about the culture that people accept and that people see as a good thing.
Q. Five years from now, if everything goes well, what do we see in Prospera?
A. I think Prospera will have at least 10,000 residents and I think Honduras hopefully will have more zones. There could be zones with a thriving industrial sector and sort of a labor-intensive economy and some that are very strong in pharmaceuticals, there could also be other zones for synthetic biology, and other zones focused on agriculture. The zones of Prospera, Ciudad Morazan and Orchidea are already showing the results we want to see, the results that we will eventually be measured by, and I'm tremendously excited about Honduras.