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Earlier this week, the US surgeon general, also known as the “nation’s doctor,” authored an article making the case that health warnings should accompany social media. The goal: to protect teenagers from its harmful effects. “Adolescents who spend more than three hours a day on social media face double the risk of anxiety and depression symptoms,” Vivek Murthy wrote in a piece published in the New York Times. “Additionally, nearly half of adolescents say social media makes them feel worse about their bodies.”
His concern instinctively resonates with me. I’m in my late 30s, and even I can end up feeling a lot worse about myself after a brief stint on Instagram. I have two young daughters, and I worry about how I’ll respond when they reach adolescence and start asking for access to whatever social media site their peers are using. My children already have a fascination with cell phones; the eldest, who is almost six, will often come into my bedroom at the crack of dawn, find my husband’s phone, and somehow figure out how to blast “Happy Xmas (War Is Over)” at full volume.
But I also know that the relationship between this technology and health isn’t black and white. Social media can affect users in different ways—often positively. So let’s take a closer look at the concerns, the evidence behind them, and how best to tackle them.
Murthy’s concerns aren’t new, of course. In fact, almost any time we are introduced to a new technology, some will warn of its potential dangers. Innovations like the printing press, radio, and television all had their critics back in the day. In 2009, the Daily Maillinked Facebook use to cancer.
More recently, concerns about social media have centered on young people. There’s a lot going on in our teenage years as our brains undergo maturation, our hormones shift, and we explore new ways to form relationships with others. We’re thought to be more vulnerable to mental-health disorders during this period too. Around half of such disorders are thought to develop by the age of 14, and suicide is the fourth-leading cause of death in people aged between 15 and 19, according to the World Health Organization. Many have claimed that social media only makes things worse.
Reports have variously cited cyberbullying, exposure to violent or harmful content, and the promotion of unrealistic body standards, for example, as potential key triggers of low mood and disorders like anxiety and depression. There have also been several high-profile cases of self-harm and suicide with links to social media use, often involving online bullying and abuse. Just this week, the suicide of an 18-year-old in Kerala, India, was linked to cyberbullying. And children have died after taking part in dangerous online challenges made viral on social media, whether from inhaling toxic substances, consuming ultra-spicy tortilla chips, or choking themselves.
Murthy’s new article follows an advisory on social media and youth mental health published by his office in 2023. The 25-page document, which lays out some of known benefits and harms of social media use as well as the “unknowns,” was intended to raise awareness of social media as a health issue. The problem is that things are not entirely clear cut.
“The evidence is currently quite limited,” says Ruth Plackett, a researcher at University College London who studies the impact of social media on mental health in young people. A lot of the research on social media and mental health is correlational. It doesn’t show that social media use causes mental health disorders, Plackett says.
The surgeon general’s advisory cites some of these correlational studies. It also points to survey-based studies, including one looking at mental well-being among college students after the rollout of Facebook in the mid-2000s. But even if you accept the authors’ conclusion that Facebook had a negative impact on the students’ mental health, it doesn’t mean that other social media platforms will have the same effect on other young people. Even Facebook, and the way we use it, has changed a lot in the last 20 years.
Other studies have found that social media has no effect on mental health. In a study published last year, Plackett and her colleagues surveyed 3,228 children in the UK to see how their social media use and mental well-being changed over time. The children were first surveyed when they were aged between 12 and 13, and again when they were 14 to 15 years old.
Plackett expected to find that social media use would harm the young participants. But when she conducted the second round of questionnaires, she found that was not the case. “Time spent on social media was not related to mental-health outcomes two years later,” she tells me.
Other research has found that social media use can be beneficial to young people, especially those from minority groups. It can help some avoid loneliness, strengthen relationships with their peers, and find a safe space to express their identities, says Plackett. Social media isn’t only for socializing, either. Today, young people use these platforms for news, entertainment, school, and even (in the case of influencers) business.
“It’s such a mixed bag of evidence,” says Plackett. “I’d say it’s hard to draw much of a conclusion at the minute.”
In his article, Murthy calls for a warning label to be applied to social media platforms, stating that “social media is associated with significant mental-health harms for adolescents.”
But while Murthy draws comparisons to the effectiveness of warning labels on tobacco products, bingeing on social media doesn’t have the same health risks as chain-smoking cigarettes. We have plenty of strong evidence linking smoking to a range of diseases, including gum disease, emphysema, and lung cancer, among others. We know that smoking can shorten a person’s life expectancy. We can’t make any such claims about social media, no matter what was written in that Daily Mail article.
Health warnings aren’t the only way to prevent any potential harms associated with social media use, as Murthy himself acknowledges. Tech companies could go further in reducing or eliminating violent and harmful content, for a start. And digital literacy education could help inform children and their caregivers how to alter the settings on various social media platforms to better control the content children see, and teach them how to assess the content that does make it to their screens.
I like the sound of these measures. They might even help me put an end to the early-morning Christmas songs.
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Bills designed to make the internet safer for children have been popping up across the US. But individual states take different approaches, leaving the resulting picture a mess, as Tate Ryan-Mosley explored.
Dozens of US states sued Meta, the parent company of Facebook, last October. As Tate wrote at the time, the states claimed that the company knowingly harmed young users, misled them about safety features and harmful content, and violated laws on children’s privacy.
China has been implementing increasingly tight controls over how children use the internet. In August last year, the country’s cyberspace administrator issued detailed guidelines that include, for example, a rule to limit use of smart devices to 40 minutes a day for children under the age of eight. And even that use should be limited to content about “elementary education, hobbies and interests, and liberal arts education.” My colleague Zeyi Yang had the story in a previous edition of his weekly newsletter, China Report.
Last year, TikTok set a 60-minute-per-day limit for users under the age of 18. But the Chinese domestic version of the app, Douyin, has even tighter controls, as Zeyi wrote last March.
One way that social media can benefit young people is by allowing them to express their identities in a safe space. Filters that superficially alter a person’s appearance to make it more feminine or masculine can help trans people play with gender expression, as Elizabeth Anne Brown wrote in 2022. She quoted Josie, a trans woman in her early 30s. “The Snapchat girl filter was the final straw in dropping a decade’s worth of repression,” Josie said. “[I] saw something that looked more ‘me’ than anything in a mirror, and I couldn’t go back.”
From around the web
Could gentle shock waves help regenerate heart tissue? A trial of what’s being dubbed a “space hairdryer” suggests the treatment could help people recover from bypass surgery. (BBC)
“We don’t know what’s going on with this virus coming out of China right now.” Anthony Fauci gives his insider account of the first three months of the covid-19 pandemic. (The Atlantic)
Microplastics are everywhere. It was only a matter of time before scientists found them in men’s penises. (The Guardian)
Is the singularity nearer? Ray Kurzweil believes so. He also thinks medical nanobots will allow us to live beyond 120. (Wired)
In a clean room in his lab, Sean Moore peers through a microscope at a bit of intestine, its dark squiggles and rounded structures standing out against a light gray background. This sample is not part of an actual intestine; rather, it’s human intestinal cells on a tiny plastic rectangle, one of 24 so-called “organs on chips” his lab bought three years ago.
Moore, a pediatric gastroenterologist at the University of Virginia School of Medicine, hopes the chips will offer answers to a particularly thorny research problem. He studies rotavirus, a common infection that causes severe diarrhea, vomiting, dehydration, and even death in young children. In the US and other rich nations, up to 98% of the children who are vaccinated against rotavirus develop lifelong immunity. But in low-income countries, only about a third of vaccinated children become immune. Moore wants to know why.
His lab uses mice for some protocols, but animal studies are notoriously bad at identifying human treatments. Around 95% of the drugs developed through animal research fail in people. Researchers have documented this translation gap since at least 1962. “All these pharmaceutical companies know the animal models stink,” says Don Ingber, founder of the Wyss Institute for Biologically Inspired Engineering at Harvard and a leading advocate for organs on chips. “The FDA knows they stink.”
But until recently there was no other option. Research questions like Moore’s can’t ethically or practically be addressed with a randomized, double-blinded study in humans. Now these organs on chips, also known as microphysiological systems, may offer a truly viable alternative. They look remarkably prosaic: flexible polymer rectangles about the size of a thumb drive. In reality they’re triumphs of bioengineering, intricate constructions furrowed with tiny channels that are lined with living human tissues. These tissues expand and contract with the flow of fluid and air, mimicking key organ functions like breathing, blood flow, and peristalsis, the muscular contractions of the digestive system.
More than 60 companies now produce organs on chips commercially, focusing on five major organs: liver, kidney, lung, intestines, and brain. They’re already being used to understand diseases, discover and test new drugs, and explore personalized approaches to treatment.
As they continue to be refined, they could solve one of the biggest problems in medicine today. “You need to do three things when you’re making a drug,” says Lorna Ewart, a pharmacologist and chief scientific officer of Emulate, a biotech company based in Boston. “You need to show it’s safe. You need to show it works. You need to be able to make it.”
All new compounds have to pass through a preclinical phase, where they’re tested for safety and effectiveness before moving to clinical trials in humans. Until recently, those tests had to run in at least two animal species—usually rats and dogs—before the drugs were tried on people.
But in December 2022, President Biden signed the FDA Modernization Act, which amended the original FDA Act of 1938. With a few small word changes, the act opened the door for non-animal-based testing in preclinical trials. Anything that makes it faster and easier for pharmaceutical companies to identify safe and effective drugs means better, potentially cheaper treatments for all of us.
Moore, for one, is banking on it, hoping the chips help him and his colleagues shed light on the rotavirus vaccine responses that confound them. “If you could figure out the answer,” he says, “you could save a lot of kids’ lives.”
While many teams have worked on organ chips over the last 30 years, the OG in the field is generally acknowledged to be Michael Shuler, a professor emeritus of chemical engineering at Cornell. In the 1980s, Shuler was a math and engineering guy who imagined an “animal on a chip,” a cell culture base seeded with a variety of human cells that could be used for testing drugs. He wanted to position a handful of different organ cells on the same chip, linked to one another, which could mimic the chemical communication between organs and the way drugs move through the body. “This was science fiction,” says Gordana Vunjak-Novakovic, a professor of biomedical engineering at Columbia University whose lab works with cardiac tissue on chips. “There was no body on a chip. There is still no body on a chip. God knows if there will ever be a body on a chip.”
Shuler had hoped to develop a computer model of a multi-organ system, but there were too many unknowns. The living cell culture system he dreamed up was his bid to fill in the blanks. For a while he played with the concept, but the materials simply weren’t good enough to build what he imagined.
“You can force mice to menstruate, but it’s not really menstruation. You need the human being.”
Linda Griffith, founding professor of biological engineering at MIT and a 2006 recipient of a MacArthur “genius grant”
He wasn’t the only one working on the problem. Linda Griffith, a founding professor of biological engineering at MIT and a 2006 recipient of a MacArthur “genius grant,” designed a crude early version of a liver chip in the late 1990s: a flat silicon chip, just a few hundred micrometers tall, with endothelial cells, oxygen and liquid flowing in and out via pumps, silicone tubing, and a polymer membrane with microscopic holes. She put liver cells from rats on the chip, and those cells organized themselves into three-dimensional tissue. It wasn’t a liver, but it modeled a few of the things a functioning human liver could do. It was a start.
Griffith, who rides a motorcycle for fun and speaks with a soft Southern accent, suffers from endometriosis, an inflammatory condition where cells from the lining of the uterus grow throughout the abdomen. She’s endured decades of nausea, pain, blood loss, and repeated surgeries. She never took medical leaves, instead loading up on Percocet, Advil, and margaritas, keeping a heating pad and couch in her office—a strategy of necessity, as she saw no other choice for a working scientist. Especially a woman.
And as a scientist, Griffith understood that the chronic diseases affecting women tend to be under-researched, underfunded, and poorly treated. She realized that decades of work with animals hadn’t done a damn thing to make life better for women like her. “We’ve got all this data, but most of that data does not lead to treatments for human diseases,” she says. “You can force mice to menstruate, but it’s not really menstruation. You need the human being.”
Or, at least, the human cells. Shuler and Griffith, and other scientists in Europe, worked on some of those early chips, but things really kicked off around 2009, when Don Ingber’s lab in Cambridge, Massachusetts, created the first fully functioning organ on a chip. That “lung on a chip” was made from flexible silicone rubber, lined with human lung cells and capillary blood vessel cells that “breathed” like the alveoli—tiny air sacs—in a human lung. A few years later Ingber, an MD-PhD with the tidy good looks of a younger Michael Douglas, founded Emulate, one of the earliest biotech companies making microphysiological systems. Since then he’s become a kind of unofficial ambassador for in vitro technologies in general and organs on chips in particular, giving hundreds of talks, scoring millions in grant money, repping the field with scientists and laypeople. Stephen Colbert once ragged on him after the New York Times quoted him as describing a chip that “walks, talks, and quacks like a human vagina,” a quote Ingber says was taken out of context.
Ingber began his career working on cancer. But he struggled with the required animal research. “I really didn’t want to work with them anymore, because I love animals,” he says. “It was a conscious decision to focus on in vitro models.” He’s not alone; a growing number of young scientists are speaking up about the distress they feel when research protocols cause pain, trauma, injury, and death to lab animals. “I’m a master’s degree student in neuroscience and I think about this constantly. I’ve done such unspeakable, horrible things to mice all in the name of scientific progress, and I feel guilty about this every day,” wrote one anonymous student on Reddit. (Full disclosure: I switched out of a psychology major in college because I didn’t want to cause harm to animals.)
Emulate is one of the companies building organ-on-a-chip technology. The devices combine live human cells with a microenvironment designed to emulate specific tissues.
EMULATE
Taking an undergraduate art class led Ingber to an epiphany: mechanical forces are just as important as chemicals and genes in determining the way living creatures work. On a shelf in his office he still displays a model he built in that art class, a simple construction of sticks and fishing line, which helped him realize that cells pull and twist against each other. That realization foreshadowed his current work and helped him design dynamic microfluidic devices that incorporated shear and flow.
Ingber coauthored a 2022 paper that’s sometimes cited as a watershed in the world of organs on chips. Researchers used Emulate’s liver chips to reevaluate 27 drugs that had previously made it through animal testing and had then gone on to kill 242 people and necessitate more than 60 liver transplants. The liver chips correctly flagged problems with 22 of the 27 drugs, an 87% success rate compared with a 0% success rate for animal testing. It was the first time organs on chips had been directly pitted against animal models, and the results got a lot of attention from the pharmaceutical industry. Dan Tagle, director of the Office of Special Initiatives for the National Center for Advancing Translational Sciences (NCATS), estimates that drug failures cost around $2.6 billion globally each year. The earlier in the process failing compounds can be weeded out, the more room there is for other drugs to succeed.
“The capacity we have to test drugs is more or less fixed in this country,” says Shuler, whose company, Hesperos, also manufactures organs on chips. “There are only so many clinical trials you can do. So if you put a loser into the system, that means something that could have won didn’t get into the system. We want to change the success rate from clinical trials to a much higher number.”
In 2011, the National Institutes of Health established NCATS and started investing in organs on chips and other in vitro technologies. Other government funders, like the Defense Advanced Research Projects Agency and the Food and Drug Administration, have followed suit. For instance, NIH recently funded NASA scientists to send heart tissue on chips into space. Six months in low gravity ages the cardiovascular system 10 years, so this experiment lets researchers study some of the effects of aging without harming animals or humans.
Scientists have made liver chips, brain chips, heart chips, kidney chips, intestine chips, and even a female reproductive system on a chip (with cells from ovaries, fallopian tubes, and uteruses that release hormones and mimic an actual 28-day menstrual cycle). Each of these chips exhibits some of the specific functions of the organs in question. Cardiac chips, for instance, contain heart cells that beat just like heart muscle, making it possible for researchers to model disorders like cardiomyopathy.
Shuler thinks organs on chips will revolutionize the world of research for rare diseases. “It is a very good model when you don’t have enough patients for normal clinical trials and you don’t have a good animal model,” he says. “So it’s a way to get drugs to people that couldn’t be developed in our current pharmaceutical model.” Shuler’s own biotech company used organs on chips to test a potential drug for myasthenia gravis, a rare neurological disorder. In 2022,the FDA approved the drug for clinical trials based on that data—one of six Hesperos drugs that have so far made it to that stage.
Each chip starts with a physiologically based pharmacokinetic model, known as a PBPK model—a mathematical expression of how a chemical compound behaves in a human body. “We try and build a physical replica of the mathematical model of what really occurs in the body,” explains Shuler. That model guides the way the chip is designed, re-creating the amount of time a fluid or chemical stays in that particular organ—what’s known as the residence time. “As long as you have the same residence time, you should get the same response in terms of chemical conversion,” he says.
Tiny channels on each chip, each between 10 and 100 microns in diameter, help bring fluids and oxygen to the cells. “When you get down to less than one micron, you can’t use normal fluid dynamics,” says Shuler. And fluid dynamics matters, because if the fluid moves through the device too quickly, the cells might die; too slowly, and the cells won’t react normally.
Chip technology, while sophisticated, has some downsides. One of them is user friendliness. “We need to get rid of all this tubing and pumps and make something that’s as simple as a well plate for culturing cells,” says Vunjak-Novakovic. Her lab and others are working on simplifying the design and function of such chips so they’re easier to operate and are compatible with robots, which do repetitive tasks like pipetting in many labs.
Cost and sourcing can also be challenging. Emulate’s base model, which looks like a simple rectangular box from the outside,starts at around $100,000 and rises steeply from there. Most human cells come from commercial suppliers that arrange for donations from hospital patients. During the pandemic, when people had fewer elective surgeries, many of those sources dried up. As microphysiological systems become more mainstream, finding reliable sources of human cells will be critical.
“As your confidence in using the chips grows, you might say, Okay, we don’t need two animals anymore— we could go with chip plus one animal.”
Lorna Ewart, Chief Scientific Officer, Emulate
Another challenge is that every company producing organs on chips uses its own proprietary methods and technologies. Ingber compares the landscape to the early days of personal computing, when every company developed its own hardware and software, and none of them meshed well. For instance, the microfluidic systems in Emulate’s intestine chips are fueled by micropumps, while those made by Mimetas, another biotech company, use an electronic rocker and gravity to circulate fluids and air. “This is not an academic lab type of challenge,” emphasizes Ingber. “It’s a commercial challenge. There’s no way you can get the same results anywhere in the world with individual academics making [organs on chips], so you have to have commercialization.”
Namandje Bumpus, the FDA’s chief scientist, agrees. “You can find differences [in outcomes] depending even on what types of reagents you’re using,” she says. Those differences mean research can’t be easily reproduced, which diminishes its validity and usefulness. “It would be great to have some standardization,” she adds.
On the plus side, the chip technology could help researchers address some of the most deeply entrenched health inequities in science. Clinical trials have historically recruited white men, underrepresenting people of color, women (especially pregnant and lactating women), the elderly, and other groups. And treatments derived from those trials all too often fail in members of those underrepresented groups, as in Moore’s rotavirus vaccine mystery. “With organs on a chip, you may be able to create systems by which you are very, very thoughtful—where you spread the net wider than has ever been done before,” says Moore.
This microfluidic platform, designed by MIT engineers, connects engineered tissue from up to 10 organs.
FELICE FRANKEL
Another advantage is that chips will eventually reduce the need for animals in the lab even as they lead to better human outcomes. “There are aspects of animal research that make all of us uncomfortable, even people that do it,” acknowledges Moore. “The same values that make us uncomfortable about animal research are also the same values that make us uncomfortable with seeing human beings suffer with diseases that we don’t have cures for yet. So we always sort of balance that desire to reduce suffering in all the forms that we see it.”
Lorna Ewart, who spent 20 years at the pharma giant AstraZeneca before joining Emulate, thinks we’re entering a kind of transition time in research, in which scientists use in vitro technologies like organs on chips alongside traditional cell culture methods and animals. “As your confidence in using the chips grows, you might say, Okay, we don’t need two animals anymore—we could go with chip plus one animal,” she says.
In the meantime, Sean Moore is excited about incorporating intestine chips more and more deeply into his research. His lab has been funded by the Gates Foundation to do what he laughingly describes as a bake-off between intestine chips made by Emulate and Mimetas. They’re infecting the chips with different strains of rotavirus to try to identify the pros and cons of each company’s design. It’s too early for any substantive results, but Moore says he does have data showing that organ chips are a viable model for studying rotavirus infection. That could ultimately be a real game-changer in his lab and in labs around the world.
“There’s more players in the space right now,” says Moore. “And that competition is going to be a healthy thing.”
Harriet Brown writes about health, medicine, and science. Her most recent book is Shadow Daughter: A Memoir of Estrangement. She’s a professor of magazine, news, and digital journalism at Syracuse University’s Newhouse School.
This article first appeared in The Checkup, MIT Technology Review’s weekly biotech newsletter. To receive it in your inbox every Thursday, and read articles like this first, sign up here.
The outbreak of avian influenza on US dairy farms has started to make milk seem a lot less wholesome. Milk that’s raw, or unpasteurized, can actually infect mice that drink it, and a few dairy workers have already caught the bug.
The FDA says that commercial milk is safe because it is pasteurized, killing the germs. Even so, it’s enough to make a person ponder a life beyond milk—say, taking your coffee black or maybe drinking oat milk.
But for those of us who can’t do without the real thing, it turns out some genetic engineers are working on ways to keep the milk and get rid of the cows instead. They’re doing it by engineering yeasts and plants with bovine genes so they make the key proteins responsible for milk’s color, satisfying taste, and nutritional punch.
The proteins they’re copying are casein, a floppy polymer that’s the most abundant protein in milk and is what makes pizza cheese stretch, and whey, a nutritious combo of essential amino acids that’s often used in energy powders.
It’s part of a larger trend of replacing animals with ingredients grown in labs, steel vessels, or plant crops. Think of the Impossible burger, the veggie patty made mouthwatering with the addition of heme, a component of blood that’s produced in the roots of genetically modified soybeans.
One of the milk innovators is Remilk, an Israeli startup founded in 2019, which has engineered yeast so it will produce beta-lactoglobulin (the main component of whey). Company cofounder Ori Cohavi says a single biotech factory of bubbling yeast vats feeding on sugar could in theory “replace 50,000 to 100,000 cows.”
Remilk has been making trial batches and is testing ways to formulate the protein with plant oils and sugar to make spreadable cheese, ice cream, and milk drinks. So yes, we’re talking “processed” food—one partner is a local Coca-Cola bottler, and advising the company are former executives of Nestlé, Danone, and PepsiCo.
But regular milk isn’t exactly so natural either. At milking time, animals stand inside elaborate robots, and it looks for all the world as if they’re being abducted by aliens. “The notion of a cow standing in some nice green scenery is very far from how we get our milk,” says Cohavi. And there are environmental effects: cattle burp methane, a potent greenhouse gas, and a lactating cow needs to drink around 40 gallons of water a day.
“There are hundreds of millions of dairy cows on the planet producing greenhouse waste, using a lot of water and land,” says Cohavi. “It can’t be the best way to produce food.”
For biotech ventures trying to displace milk, the big challenge will be keeping their own costs of production low enough to compete with cows. Dairies get government protections and subsidies, and they don’t only make milk. Dairy cows are eventually turned into gelatin, McDonald’s burgers, and the leather seats of your Range Rover. Not much goes to waste.
At Alpine Bio, a biotech company in San Francisco (also known as Nobell Foods), researchers have engineered soybeans to produce casein. While not yet cleared for sale, the beans are already being grown on USDA-sanctioned test plots in the Midwest, says Alpine’s CEO, Magi Richani.
Richani chose soybeans because they’re already a major commodity and the cheapest source of protein around. “We are working with farmers who are already growing soybeans for animal feed,” she says. “And we are saying, ‘Hey, you can grow this to feed humans.’ If you want to compete with a commodity system, you have to have a commodity crop.”
Alpine intends to crush the beans, extract the protein, and—much like Remilk—sell the ingredient to larger food companies.
Everyone agrees that cow’s milk will be difficult to displace. It holds a special place in the human psyche, and we owe civilization itself, in part, to domesticated animals. In fact, they’ve left their mark in our genes, with many of us carrying DNA mutations that make cow’s milk easier to digest.
But that’s why it might be time for the next technological step, says Richani. “We raise 60 billion animals for food every year, and that is insane. We took it too far, and we need options,” she says. “We need options that are better for the environment, that overcome the use of antibiotics, and that overcome the disease risk.”
It’s not clear yet whether the bird flu outbreak on dairy farms is a big danger to humans. But making milk without cows would definitely cut the risk that an animal virus will cause a new pandemic. As Richani says: “Soybeans don’t transmit diseases to humans.”
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Hungry for more from the frontiers of fromage? In the Build issue of our print magazine, Andrew Rosenblum tasted a yummy brie made only from plants. Harder to swallow was the claim by developer Climax Foods that its cheese was designed using artificial intelligence.
The idea of using yeast to create food ingredients, chemicals, and even fuel via fermentation is one of the dreams of synthetic biology. But it’s not easy. In 2021, we raised questions about high-flying startup Ginkgo Bioworks. This week its stock hit an all-time low of $0.49 per share as the company struggles to make … well, anything.
This spring, I traveled to Florida to watch attempts to create life in a totally new way: using a synthetic embryo made in a lab. The action involved cattle at the animal science department of the University of Florida, Gainesville.
From around the web
How many human bird flu cases are there? No one knows, because there’s barely any testing. Scientists warn we’re flying blind as US dairy farms struggle with an outbreak. (NBC)
Moderna, one of the companies behind the covid-19 shots, is seeing early success with a cancer vaccine. It uses the same basic technology: gene messages packed into nanoparticles. (Nature)
It’s the covid-19 theory that won’t go away. This week the New York Times published an op-ed arguing that the virus was the result of a lab accident. We previously profiled the author, Alina Chan, who is a scientist with the Broad Institute. (NYTimes)
Sales of potent weight loss drugs, like Ozempic, are booming. But it’s not just humans who are overweight. Now the pet care industry is dreaming of treating chubby cats and dogs, too. (Bloomberg)
On Tuesday, the FDA asked a panel of experts to weigh in on whether the evidence shows that MDMA, also known as ecstasy, is a safe and efficacious treatment for PTSD. The answer was a resounding no. Just two out of 11 panel members agreed that MDMA-assisted therapy is effective. And only one panel member thought the benefits of the therapy outweighed the risks.
The outcome came as a surprise to many, given that trial results have been positive. And it is also a blow for advocates who have been working to bring psychedelic therapy into mainstream medicine for more than two decades. This isn’t the final decision on MDMA. The FDA has until August 11 to make that ruling. But while the agency is under no obligation to follow the recommendations of its advisory committees, it rarely breaks with their decisions.
Today on The Checkup, let’s unpack the advisory committee’s vote and talk about what it means for the approval of other recreational drugs as therapies.
One of the main stumbling blocks for the committee was the design of the two efficacy studies that have been completed. Trial participants weren’t supposed to know whether they were in the treatment group, but the effects of MDMA make it pretty easy to tell whether you’ve been given a hefty dose, and most correctly guessed which group they had landed in.
In 2021, MIT Technology Review’s Charlotte Jee interviewed an MDMA trial participant named Nathan McGee. “Almost as soon as I said I didn’t think I’d taken it, it kicked in. I mean, I knew,” he told her. “I remember going to the bathroom and looking in the mirror, and seeing my pupils looking like saucers. I was like, ‘Wow, okay.’”
The Multidisciplinary Association for Psychedelic Studies, better known as MAPS, has been working with the FDA to develop MDMA as a treatment since 2001. When the organization met with the FDA in 2016 to hash out the details of its phase III trials, studies to test whether a treatment works, agency officials suggested that MAPS use an active compound for the control group to help mask whether participants had received the drug. But MAPS pushed back, and the trial forged ahead with a placebo.
No surprise, then, that about 90% of those assigned to the MDMA group and 75% of those assigned to the placebo group accurately identified which arm of the study they had landed in. And it wasn’t just participants. Therapists treating the participants also likely knew whether those under their supervision had been given the drug. It’s called “functional unblinding,” and the issue came up at the committee meeting again and again. Here’s why it’s a problem: If a participant strongly believes that MDMA will help their PTSD and they know they’ve received MDMA, this expectation bias could amplify the treatment effect. This is especially a problem when the outcome is based on subjective measures like how a person feels rather than, say, laboratory data.
Another sticking point was the therapy component of the treatment. Lykos Therapeutics (the for-profit spinoff of MAPS) asked the FDA to approve MDMA-assisted therapy: that’s MDMA administered in concert with psychotherapy. Therapists oversaw participants during the three MDMA sessions. But participants also received three therapy sessions before getting the drug, and three therapy sessions afterwards to help them process their experience.
Because the two treatments were administered together, there was no good way to tell how much of the effect was due to MDMA and how much was due to the therapy. What’s more, “the content or approach of these integrated sessions was not standardized in the treatment manuals and was mainly left up to the individual therapist,” said David Millis, a clinical reviewer for the FDA, at the committee meeting.
Several committee members also raised safety concerns. They worried that MDMA’s effects might make people more suggestible and vulnerable to abuse, and they brought up allegations of ethics violations outlined in a recent report from the Institute for Clinical and Economic Review.
Because of these issues and others, most committee members felt compelled to vote against MDMA-assisted therapy. “I felt that the large positive effect was denuded by the significant confounders,” said committee member Maryann Amirshahi, a professor of emergency medicine at Georgetown University School of Medicine, after the vote. “Although I do believe that there was a signal, it just needs to be better studied.”
Whether this decision will be a setback for the entire field remains to be seen. “To make it crystal clear: It isn’t MDMA itself that was rejected per se, but the specific, poor data set provided by Lykos Therapeutics; in my opinion, there is still a strong chance that MDMA, with a properly conducted clinical Phase 3 trial program that addresses those concerns of the FDA advisory committee, will get approved.” wrote Christian Angermayer, founder of ATAI Therapeutics, a company that is also working to develop MDMA as a therapy.
If the FDA denies approval of MDMA therapy, Lykos or another company could conduct additional studies and reapply. Many of the committee members said they believed MDMA does hold promise, but that the studies conducted thus far were inadequate to demonstrate the drug’s safety and efficacy.
Psilocybin is likely to be the next psychedelic therapy considered by the FDA, and in some ways, it might have an easier path to approval. The idea behind MDMA is that it alleviates PTSD by helping facilitate psychotherapy. The therapy is a crucial component of the treatment, which is problematic because the FDA regulates drugs, not psychotherapy. With psilocybin, a therapist is present, but the drug appears to do the heavy lifting. “We are not offering therapy; we are offering psychological support that’s designed for the patient’s safety and well-being,” says Kabir Nath, CEO of Compass Pathways, the company working to bring psilocybin to market. “What we actually find during a six- to eight-hour session is most of it is silent. There’s actually no interaction.”
That could make the approval process more straightforward. “The difficult thing … is that we don’t regulate psychotherapy, and also we don’t really have any say in the design or the implementation of the particular therapy that is going to be used,” said Tiffany Farchione, director of the FDA’s division of psychiatry, at the committee meeting. “This is something unprecedented, so we certainly want to get as many opinions and as much input as we can.”
Sally Adee dives deep into the messy history of electric medicine and what the future might hold for research into electric therapies. “Instead of focusing only on the nervous system—the highway that carries electrical messages between the brain and the body—a growing number of researchers are finding clever ways to electrically manipulate cells elsewhere in the body, such as skin and kidney cells, more directly than ever before,” she writes.
MDMA does seem to have helped some individuals. Nathan McGee, who took the drug as part of a clinical trial, told Charlotte Jee that he “understands what joy is now.”
Researchers are working to design virtual-reality programs that recreate the trippy experience of taking psychedelics. Hana Kiros has the story.
– Finland is poised to become the first country to start administering bird flu vaccine—albeit to a very limited subset of people, including poultry and mink farmers, vets, and scientists who study the virus (Stat)
– What are the most pressing questions about bird flu? They revolve around what’s happening in cows, what’s happening in farm workers, and what’s happening to the virus. (Stat)
– A man in Mexico has died of H5N2, a strain of bird flu that has never before been reported in humans. (CNN)
Biodegradable, squishy sensors injected into the brain hold promise for detecting changes following a head injury or cancer treatment. (Nature)
A synthetic version of a hallucinogenic toad toxin could be a promising treatment for mental-health disorders. (Undark)
MIT Technology Review’s What’s Next series looks across industries, trends, and technologies to give you a first look at the future. You can read the rest of them here.
MDMA, sometimes called Molly or ecstasy, has been banned in the United States for more than three decades. Now this potent mind-altering drug is poised to become a badly needed therapy for PTSD.
On June 4, the Food and Drug Administration’s advisory committee will meet to discuss the risks and benefits of MDMA therapy. If the committee votes in favor of the drug, it could be approved to treat PTSD this summer. The approval would represent a momentous achievement for proponents of mind-altering drugs, who have been working toward this goal for decades. And it could help pave the way for FDA approval of other illicit drugs like psilocybin. But the details surrounding how these compounds will make the transition from illicit substances to legitimate therapies are still foggy.
Here’s what to know ahead of the upcoming hearing.
What’s the argument for legitimizing MDMA?
Studies suggest the compound can help treat mental-health disorders like PTSD and depression. Lykos, the company that has been developing MDMA as a therapy, looked at efficacy in two clinical trials that included about 200 people with PTSD. Researchers randomly assigned participants to receive psychotherapy with or without MDMA. The group that received MDMA-assisted therapy had a greater reduction in PTSD symptoms. They were also more likely to respond to treatment, to meet the criteria for PTSD remission, and to lose their diagnosis of PTSD.
But some experts question the validity of the results. With substances like MDMA, study participants almost always know whether they’ve received the drug or a placebo. That can skew the results, especially when the participants and therapists strongly believe a drug is going to help. The Institute for Clinical and Economic Review (ICER), a nonprofit research organization that evaluates the clinical and economic value of drugs, recently rated the evidence for MDMA-assisted therapy as “insufficient.”
In briefing documents published ahead of the June 4 meeting, FDA officials write that the question of approving MDMA “presents a number of complex review issues.”
The ICER report also referenced allegations of misconduct and ethical violations. Lykos (formerly the Multidisciplinary Association for Psychedelic Studies Public Benefit Corporation) acknowledges that ethical violations occurred in one particularly high-profile case. But in a rebuttal to the ICER report, more than 70 researchers involved in the trials wrote that “a number of assertions in the ICER report represent hearsay, and should be weighted accordingly.” Lykos did not respond to an interview request.
At the meeting on the 4th, the FDA has asked experts to discuss whether Lykos has demonstrated that MDMA is effective, whether the drug’s effect lasts, and what role psychotherapy plays. The committee will also discuss safety, including the drug’s potential for abuse and the risk posed by the impairment MDMA causes.
What’s stopping people from using this therapy?
MDMA is illegal. In 1985, the Drug Enforcement Agency grew concerned about growing street use of the drug and added it to its list of Schedule 1 substances—those with a high abuse potential and no accepted medical use.
MDMA boosts the brain’s production of feel-good neurotransmitters, causing a burst of euphoria and good will toward others. But the drug can also cause high blood pressure, memory problems, anxiety, irritability, and confusion. And repeated use can cause lasting changes in the brain.
If the FDA approves MDMA therapy, when will people be able to access it?
That has yet to be determined. It could take months for the DEA to reclassify the drug. After that, it’s up to individual states.
Lykos applied for approval of MDMA-assisted therapy, not just the compound itself. In the clinical trials, MDMA administration happened in the presence of licensed therapists, who then helped patients process their emotions during therapy sessions that lasted for hours.
But regulating therapy isn’t part of the FDA’s purview. The FDA approves drugs; it doesn’t oversee how they’re administered. “The agency has been clear with us,” says Kabir Nath, CEO of Compass Pathways, the company working to bring psilocybin to market. “They don’t want to regulate psychotherapy, because they see that as the practice of medicine, and that’s not their job.”
However, for drugs that carry a risk of serious side effects, the FDA can add a risk evaluation and mitigation strategy to its approval. For MDMA that might include mandating that the health-care professionals who administer the medication have certain certifications or specialized training, or requiring that the drug be dispensed only in licensed facilities.
For example, Spravato, a nasal spray approved in 2019 for depression that works much like ketamine, is available only at a limited number of health-care facilities and must be taken under the observation of a health-care provider. Having safeguards in place for MDMA makes sense, at least at the outset, says Matt Lamkin, an associate professor at the University of Tulsa College of Law who has been following the field closely.: “Given the history, I think it would only take a couple of high-profile bad incidents to potentially set things back.”
What mind-altering drug is next in line for FDA approval?
Psilocybin, a.k.a. the active ingredient in magic mushrooms. This summer Compass Pathways will release the first results from one of its phase 3 trials of psilocybin to treat depression. Results from the other trial will come in the middle of 2025, which—if all goes well—puts the company on track to file for approval in the fall or winter of next year. With the FDA review and the DEA rescheduling, “it’s still kind of two to three years out,” Nath says.
Some states are moving ahead without formal approval. Oregon voters made psilocybin legal in 2020, and the drug is now accessible there at about 20 licensed centers for supervised use. “It’s an adult use program that has a therapeutic element,” says Ismail Ali, director of policy and advocacy at the Multidisciplinary Association for Psychedelic Studies (MAPS).
Colorado voted to legalize psilocybin and some other plant-based psychedelics in 2022, and the state is now working to develop a framework to guide the licensing of facilitators to administer these drugs for therapeutic purposes. More states could follow.
So would FDA approval of these compounds open the door to legal recreational use of psychedelics?
Maybe. The DEA can still prosecute physicians if they’re prescribing drugs outside of their medically accepted uses. But Lamkin does see the lines between recreational use and medical use getting blurry. “What we’re seeing is that the therapeutic uses have recreational side effects and the recreation has therapeutic side effects,” he says. “I’m interested to see how long they can keep the genie in the bottle.”
What’s the status of MDMA therapies elsewhere in the world?
Last summer, Australia became the first country to approve MDMA and psilocybin as medicines to treat psychiatric disorders, but the therapies are not yet widely available. The first clinic opened just a few months ago. The US is poised to become the second country if the FDA greenlights Lykos’s application. Health Canada told the CBC it is watching the FDA’s review of MDMA “with interest.” Europe is lagging a bit behind, but there are some signs of movement. In April, the European Medicines Agency convened a workshop to bring together a variety of stakeholders to discuss a regulatory framework for psychedelics.
This article first appeared in The Checkup, MIT Technology Review’s weekly biotech newsletter. To receive it in your inbox every Thursday, and read articles like this first, sign up here.
Here in the US, bird flu has now infected cows in nine states, millions of chickens, and—as of last week—a second dairy worker. There’s no indication that the virus has acquired the mutations it would need to jump between humans, but the possibility of another pandemic has health officials on high alert. Last week, they said they are working to get 4.8 million doses of H5N1 bird flu vaccine packaged into vials as a precautionary measure.
The good news is that we’re far more prepared for a bird flu outbreak than we were for covid. We know so much more about influenza than we did about coronaviruses. And we already have hundreds of thousands of doses of a bird flu vaccine sitting in the nation’s stockpile.
The bad news is we would need more than 600 million doses to cover everyone in the US, at two shots per person. And the process we typically use to produce flu vaccines takes months and relies on massive quantities of chicken eggs. Yes, chickens. One of the birds that’s susceptible to avian flu. (Talk about putting all our eggs in one basket. #sorrynotsorry)
This week in The Checkup, let’s look at why we still use a cumbersome, 80-year-old vaccine production process to make flu vaccines—and how we can speed it up.
The idea to grow flu virus in fertilized chicken eggs originated with Frank Macfarlane Burnet, an Australian virologist. In 1936, he discovered that if he bored a tiny hole in the shell of a chicken egg and injected flu virus between the shell and the inner membrane, he could get the virus to replicate.
Even now, we still grow flu virus in much the same way. “I think a lot of it has to do with the infrastructure that’s already there,” says Scott Hensley, an immunologist at the University of Pennsylvania’s Perelman School of Medicine. It’s difficult for companies to pivot.
The process works like this:Health officials provide vaccine manufacturers with a candidate vaccine virus that matches circulating flu strains. That virus is injected into fertilized chicken eggs, where it replicates for several days. The virus is then harvested, killed (for most use cases), purified, and packaged.
Making flu vaccine in eggs has a couple of major drawbacks. For a start, the virus doesn’t always grow well in eggs. So the first step in vaccine development is creating a virus that does. That happens through an adaptation process that can take weeks or even months. This process is particularly tricky for bird flu: Viruses like H5N1 are deadly to birds, so the virus might end up killing the embryo before the egg can produce much virus. To avoid this, scientists have to develop a weakened version of the virus by combining genes from the bird flu virus with genes typically used to produce seasonal flu virus vaccines.
And then there’s the problem of securing enough chickens and eggs. Right now, many egg-based production lines are focused on producing vaccines for seasonal flu. They could switch over to bird flu, but “we don’t have the capacity to do both,” Amesh Adalja, an infectious disease specialist at Johns Hopkins University, told KFF Health News. The US government is so worried about its egg supply that it keeps secret, heavily guarded flocks of chickens peppered throughout the country.
Most of the flu virus used in vaccines is grown in eggs, but there are alternatives. The seasonal flu vaccine Flucelvax, produced by CSL Seqirus, is grown in a cell line derived in the 1950s from the kidney of a cocker spaniel. The virus used in the seasonal flu vaccine FluBlok, made by Protein Sciences, isn’t grown; it’s synthesized. Scientists engineer an insect virus to carry the gene for hemagglutinin, a key component of the flu virus that triggers the human immune system to create antibodies against it. That engineered virus turns insect cells into tiny hemagglutinin production plants.
And then we have mRNA vaccines, which wouldn’t require vaccine manufacturers to grow any virus at all. There aren’t yet any approved mRNA vaccines for influenza, but many companies are fervently working on them, including Pfizer, Moderna, Sanofi, and GSK. “With the covid vaccines and the infrastructure that’s been built for covid, we now have the capacity to ramp up production of mRNA vaccines very quickly,” says Hensley. This week, the Financial Timesreported that the US government will soon close a deal with Moderna to provide tens of millions of dollars to fund a large clinical trial of a bird flu vaccine the company is developing.
There are hints that egg-free vaccines might work better than egg-based vaccines.A CDC study published in January showed that people who received Flucelvax or FluBlok had more robust antibody responses than those who received egg-based flu vaccines. That may be because viruses grown in eggs sometimes acquire mutations that help them grow better in eggs. Those mutations can change the virus so much that the immune response generated by the vaccine doesn’t work as well against the actual flu virus that’s circulating in the population.
Hensley and his colleagues are developing an mRNA vaccine against bird flu. So far they’ve only tested it in animals, but the shot performed well, he claims. “All of our preclinical studies in animals show that these vaccines elicit a much stronger antibody response compared with conventional flu vaccines.”
No one can predict when we might need a pandemic flu vaccine. But just because bird flu hasn’t made the jump to a pandemic doesn’t mean it won’t. “The cattle situation makes me worried,” Hensley says. Humans are in constant contact with cows, he explains. While there have only been a couple of human cases so far, “the fear is that some of those exposures will spark a fire.” Let’s make sure we can extinguish it quickly.
I don’t have to tell you that mRNA vaccines are a big deal. In 2021, MIT Technology Review highlighted them as one of the year’s 10 breakthrough technologies. Antonio Regalado explored their massive potential to transform medicine. Jessica Hamzelou wrote about the other diseases researchers are hoping to tackle.I followed up with a story after two mRNA researchers won a Nobel Prize. And earlier this year I wrote about a new kind of mRNA vaccine that’s self-amplifying, meaning it not only works at lower doses, but also sticks around for longer in the body.
From around the web
Researchers installed a literal window into the brain, allowing for ultrasound imaging that they hope will be a step toward less invasive brain-computer interfaces. (Stat)
People who carry antibodies against the common viruses used to deliver gene therapies can mount a dangerous immune response if they’re re-exposed. That means many people are ineligible for these therapies and others can’t get a second dose. Now researchers are hunting for a solution. (Nature)
More good news about Ozempic. A new study shows that the drug can cut the risk of kidney complications, including death in people with diabetes and chronic kidney disease. (NYT)
Must read: This story, the second in series on the denial of reproductive autonomy for people with sickle-cell disease, examines how the US medical system undermines a woman’s right to choose. (Stat)
In the early 2010s, electricity seemed poised for a hostile takeover of your doctor’s office. Research into how the nervous system controls the immune response was gaining traction. And that had opened the door to the possibility of hacking into the body’s circuitry and thereby controlling a host of chronic diseases, including rheumatoid arthritis, asthma, and diabetes, as if the immune system were as reprogrammable as a computer.
To do that you’d need a new class of implant: an “electroceutical,” formally introduced in an article in Naturein 2013. “What we are doing is developing devices to replace drugs,” coauthor and neurosurgeon Kevin Tracey told Wired UK. These would become a “mainstay of medical treatment.” No more messy side effects. And no more guessing whether a drug would work differently for you and someone else.
There was money behind this vision: the British pharmaceutical giant GlaxoSmithKline announced a $1 million research prize, a $50 million venture fund, and an ambitious program to fund 40 researchers who would identify neural pathways that could control specific diseases. And the company had an aggressive timeline in mind. As one GlaxoSmithKline executive put it, the goal was to have “the first medicine that speaks the electrical language of our body ready for approval by the end of this decade.”
In the 10 years or so since, around a billion dollars has accreted around the effort by way of direct and indirect funding. Some implants developed in that electroceutical push have trickled into clinical trials, and two companies affiliated with GlaxoSmithKline and Tracey are ramping up for splashy announcements later this year. We don’t know much yet about how successful the trials now underway have been. But widespread regulatory approval of the sorts of devices envisioned in 2013—devices that could be applied to a broad range of chronic diseases—is not imminent. Electroceuticals are a long way from fomenting a revolution in medical care.
At the same time, a new area of science has begun to cohere around another way of using electricity to intervene in the body. Instead of focusing only on the nervous system—the highway that carries electrical messages between the brain and the body—a growing number of researchers are finding clever ways to electrically manipulate cells elsewhere in the body, such as skin and kidney cells, more directly than ever before. Their work suggests that this approach could match the early promise of electroceuticals, yielding fast-healing bioelectric bandages, novel approaches to treating autoimmune disorders, new ways of repairing nerve damage, and even better treatments for cancer. However, such ventures have not benefited from investment largesse. Investors tend to understand the relationship between biology and electricity only in the context of the nervous system. “These assumptions come from biases and blind spots that were baked in during 100 years of neuroscience,” says Michael Levin, a bioelectricity researcher at Tufts University.
Electrical implants have already had success in targeting specific problems like epilepsy, sleep apnea, and catastrophic bowel dysfunction. But the broader vision of replacing drugs with nerve-zapping devices, especially ones that alter the immune system, has been slower to materialize. In some cases, perhaps the nervous system is not the best way in. Looking beyond this singular locus of control might open the way for a wider suite of electromedical interventions—especially if the nervous system proves less amenable to hacking than originally advertised.
How it started
GSK’s ambitious electroceutical venture was a response to an increasingly onerous problem: 90% of drugs fall down during the obstacle race through clinical trials. A new drug that does squeak by can cost $2 billion or $3 billion and take 10 to 15 years to bring to market, a galling return on investment. The flaw is in the delivery system. The way we administer healing chemicals hasn’t had much of a conceptual overhaul since the Renaissance physician Paracelsus: ingest or inject. Both approaches have built-in inefficiencies: it takes a long time for the drugs to build up in your system, and they can disperse widely before arriving in diluted form at their target, which may make them useless where they are needed and toxic elsewhere. Tracey and Kristoffer Famm, a coauthor on the Nature article who was then a VP at GlaxoSmithKline, explained on the publicity circuit that electroceuticals would solve these problems—acting more quickly and working only in the precise spot where the intervention was needed. After 500 years, finally, here was a new idea.
Well … new-ish.Electrically stimulating the nervous system had racked up promising successes since the mid-20th century. For example, the symptoms of Parkinson’s disease had been treated via deep brain stimulation, and intractable pain via spinal stimulation. However, these interventions could not be undertaken lightly; the implants needed to be placed in the spine or the brain, a daunting prospect to entertain. In other words, this idea would never be a money spinner.
The vagus nerve runs from the brain through the body
WELLCOME COLLECTION
What got GSK excited was recent evidence that health could be more broadly controlled, and by nerves that were easier to access. By the dawn of the 21st century it had become clear you could tap the nervous system in a way that carried fewer risks and more rewards. That was because of findings suggesting that the peripheral nervous system—essentially, everything but the brain and spine—had much wider influence than previously believed.
The prevailing wisdom had long been that the peripheral nervous system had only one job: sensory awareness of the outside world. This information is ferried to the brain along many little neural tributaries that emerge from the extremities and organs, most of which converge into a single main avenue at the torso: the vagus nerve.
Starting in the 1990s, research by Linda Watkins, a neuroscientist leading a team at the University of Colorado, Boulder, suggested that this main superhighway of the peripheral nervous system was not a one-way street after all. Instead it seemed to carry message traffic in both directions, not just into the brain but from the brain back into all those organs. Furthermore, it appeared that this comms link allows the brain to exert some control over the immune system—for example, stoking a fever in response to an infection.
And unlike the brain or spinal cord, the vagus nerve is comparatively easy to access: its path to and from the brain stem runs close to the surface of the neck, along a big cable on either side. You could just pop an electrode on it—typically on the left branch—and get zapping.
Meddling with the flow of traffic up the vagus nerve in this wayhad successfully treated issues in the brain, specifically epilepsy and treatment-resistant depression (and electrical implants for those applications were approved by the FDA around the turn of the millennium). But the insights from Watkins’s team put the down direction in play.
It was Kevin Tracey who joined all these dots, after which it did not take long for him to become the public face of research on vagus nerve stimulation. During the 2000s, he showed that electrically stimulating the nerve calmed inflammation in animals. This “inflammatory reflex,” as he came to call it, implied that the vagus nerve could act as a switch capable of turning off a wide range of diseases, essentially hacking the immune system. In 2007, while based at what is now called the Feinstein Institutes for Medical Research, in New York, he spun his insights off into a Boston startup called SetPoint Medical. Its aim was to develop devices to flip this switch and bring relief, starting with inflammatory bowel disease and rheumatoid arthritis.
By 2012, a coordinated relationship had developed between GSK, Tracey, and US government agencies. Tracey says that Famm and others contacted him “to help them on that Nature article.” A year later the electroceuticals road map was ready to be presented to the public.
The story the researchers told about the future was elegant and simple. It was illustrated by a tale Tracey recounted frequently on the publicity circuit, of a first-in-human case study SetPoint had coordinated at the University of Amsterdam’s Academic Medical Center. That team had implanted a vagus nerve stimulator in a man suffering from rheumatoid arthritis. The stimulation triggered his spleen to release a chemical called acetylcholine. This in turn told the cells in the spleen to switch off production of inflammatory molecules called cytokines. For this man, the approach worked well enough to let him resume his job, play with his kids, and even take up his old hobbies. In fact, his overenthusiastic resumption of his former activities resulted in a sports injury, as Tracey delighted in recounting for reporters and conferences.
Such case studies opened the money spigot. The combination of a wider range of disease targets and less risky surgical targets was an investor’s love language. Where deep brain stimulation and other invasive implants had been limited to rare, obscure, and catastrophic problems, this new interface with the body promised many more customers: the chronic diseases now on the table are much more prevalent, including not only rheumatoid arthritis but diabetes, asthma, irritable bowel syndrome, lupus, and many other autoimmune disorders. GSK launched an investment arm it dubbed Action Potential Venture Capital Limited, with $50 million in the coffers to invest in the technologies and companies that would turn the futuristic vision of electroceuticals into reality. Its inaugural investment was a $5 million stake in SetPoint.
If you were superstitious, what happened next might have looked like an omen. The word “electroceutical” already belonged to someone else—a company called Ivivi Technologies had trademarked it in 2008. “I am fairly certain we sent them a letter soon after they started that campaign, to alert them of our trademark,” says Sean Hagberg, a cofounder and then chief science officer at the company. Today neither GSK nor SetPoint can officially call its tech “electroceuticals,” and both refer to the implants they are developing as “bioelectronic medicine.” However, this umbrella term encompasses a wide range of other interventions, some quite well established, including brain implants, spine implants, hypoglossal nerve stimulation for sleep apnea (which targets a motor nerve running through the vagus), and other peripheral-nervous-system implants, including those for people with severe gastric disorders.
Kevin Tracey has been one of the leading proponents of using electrical stimulation to target inflammation in the body.
MIKE DENORA VIA WIKIPEDIA
The next problem appeared in short order: how to target the correct nerve. The vagus nerve has roughly 100,000 fibers packed tightly within it, says Kip Ludwig, who was then with the US National Institutes of Health and now co-directs the Wisconsin Institute for Translational Neuroengineering at the University of Wisconsin, Madison. These myriad fibers connect to many different organs, including the larynx and lower airways, and electrical fields are not precise enough to hit a single one without hitting many of its neighbors (as Ludwig puts it, “electric fields [are] really promiscuous”).
This explains why a wholesale zap of the entire bundle had long been associated with unpredictable “on-target effects” and unpleasant “off-target effects,” which is another way of saying it didn’t always work and could carry side effects that ranged from the irritating, like a chronic cough, to the life-altering, including headaches and a shortness of breath that is better described as air hunger. Singling out the fibers that led to the particular organ you were after was hard for another reason, too: the existing maps of the human peripheral nervous system were old and quite limited. Such a low-resolution road map wouldn’t be sufficient to get a signal from the highway all the way to a destination.
In 2014, to remedy this and generally advance the field of peripheral nerve stimulation, the NIH announced a research initiative known as SPARC—Stimulating Peripheral Activity to Relieve Conditions—with the aim of pouring $248 million into research on new ways to exploit the nervous system’s electrical pathways for medicine. “My job,” says Gene Civillico, who managed the program until 2021, “was to do a program related to electroceuticals that used the NIH policy options that were available to us to try to make something catalytic happen.” The idea was to make neural anatomical maps and sort out the consequences of following various paths. After the organs were mapped, Civillico says, the next step was to figure out which nerve circuit would stimulate them, and settle on an access point—“And the access point should be the vagus nerve, because that’s where the most interest is.”
Two years later, as SPARC began to distribute its funds, companies moved forward with plans for the first generation of implants. GSK teamed up with Verily (formerly Google Life Sciences) on a $715 million research initiative they called Galvani Bioelectronics, with Famm at its helm as president. SetPoint, which had relocated to Valencia, California, moved to an expanded location, a campus that had once housed a secret Lockheed R&D facility.
How it’s going
Ten years after electroceuticals entered (and then quickly departed) the lexicon, the SPARC program has yielded important information about the electrical particulars of the peripheral nervous system. Its maps have illuminated nodes that are both surgically attractive and medically relevant. It has funded a global constellation of academic researchers. But its insights will be useful for the next generation of implants, not those in trials today.
Today’s implants, from SetPoint and Galvani, will be in the news later this year. Though SetPoint estimates that an extended study of its phase III clinical trial will conclude in 2027, the primary outcomes will be released this summer, says Ankit Shah, a marketing VP at SetPoint. And while Galvani’s trial will conclude in 2029, Famm says, the company is “coming to an exciting point” and will publish patient data later in 2024.
The results could be interpreted as a referendum on the two companies’ different approaches. Both devices treat rheumatoid arthritis, and both target the immune system via the peripheral nervous system, but that’s where the similarities end. SetPoint’s device uses a clamshell design that cuffs around the vagus nerve at the neck. It stimulates for just one minute, once per day. SetPoint representatives say they have never seen the sorts of side effects that have resulted from using such stimulators to treat epilepsy. But if anyone did experience those described by other researchers—even vomiting and headaches—they might be tolerable if they only lasted a minute.
But why not avoid the vagus nerve entirely? Galvani is using a more precise implant that targets the “end organ” of the spleen. If the vagus nerve can be considered the main highway of the peripheral nervous system, an end organ is essentially a particular organ’s “driveway.” Galvani’s target is the point where the splenic nerve (having split off from a system connected to the vagus highway) meets the spleen.
To zero in on such a specific target, the company has sacrificed ease of access. Its implant, which is about the size of a house key, is laparoscopically injected into the body through the belly button. Famm says if this approach works for rheumatoid arthritis, then it will likely translate for all autoimmune disorders. Highlighting this clinical trial in 2022, he told Nature Reviews: “This is what makes the next 10 years exciting.”
The Galvani device and system targets the splenic nerve.
GALVANI VIA BUSINESSWIRE
Perhaps more so for researchers than for patients, however. Even as Galvani and SetPoint prepare talking points, other SPARC-funded groups are still pondering the sorts of research questions suggesting that the best technological interface with the immune system is still up for debate. At the moment, electroceuticals are in the spotlight, but they have a long way to go, says Vaughan Macefield, a neurophysiologist at Monash University in Australia, whose work is funded by a more recent $21 million SPARC grant: “It’s an elegant idea, [but] there are conflicting views.”
Macefield doesn’t think zapping the entire bundle is a good idea. Many researchers are working on ways to get more selective about which particular fibers of the vagus nerve they stimulate. Some are designing novel electrodes that will penetrate specific fibers rather than clamping around all of them. Others are trying to hit the vagus at deeper points in the abdomen. Indeed, some aren’t sure either electricity or an implant is a necessary ingredient of the “electroceutical.” Instead, they are pivoting from electrical stimulation to ultrasound.
The sheer range of these approaches makes it pretty clear that the electroceutical’s final form is still an open research question. Macefield says we still don’t know the nitty-gritty of how vagus nerve stimulation works.
However, Tracey thinks the variety of approaches being developed doesn’t contravene the merits of the basic idea. How tech companies will make this work in the clinic, he says, is a separate business and IP question: “Can you do it with focused ultrasound? Can you do it with a device implanted with abdominal surgery? Can you do it with a device implanted in the neck? Can you do it with a device implanted in the brain, even? All of these strategies are enabled by the idea of the inflammatory reflex.” Until clinical trial data is in, he says, there’s no point arguing about the best way to manipulate the mechanism—and if one approach fails to work, that is not a referendum on the validity of the inflammatory reflex.
After stepping down from SetPoint’s board to resume a purely consulting role in 2011, Tracey focused on his lab work at the Feinstein Institutes, which he directs, to deepen understanding of this pathway. The research there is wide-ranging. Several researchers under his remit are exploring a type of noninvasive, indirect manipulation called transcutaneous auricular vagus nerve stimulation, which stimulates the skin of the ear with a wearable device. Tracey says it’s a “malapropism” to call this approach vagus nerve stimulation. “It’s just an ear buzzer,” he says. It may stimulate a sensory branch of the vagus nerve, which may engage the inflammatory reflex. “But nobody knows,” he says. Nonetheless, several clinical trials are underway.
SetPoint’s device is cuffed around the vagus nerve within the neck of a patient.
SETPOINT MEDICAL
“These things take time,” Tracey says. “It is extremely difficult to invent and develop a completely revolutionary new thing in medicine. In the history of medicine, anything that was truly new and revolutionary takes between 20 and 40 years from the time it’s invented to the time it’s widely adopted.”
“As the discoverer of this pathway,” he says, “what I want to see is multiple therapies, helping millions of people.” This vision will hinge on bigger trials conducted over many more years. These tend to be about as hard for devices as they are for drugs. Many results that look compelling in early trials disappoint in later rounds—just as for drugs. It will be possible, says Ludwig, “for them to pass a short-duration FDA trial yet still really not be a major improvement over the drug solutions.” Even after FDA approval, should it come, yet more studies will be needed to determine whether the implants are subject to the same issues that plague drugs, including habituation.
This vision of electroceuticals seems to have placed about a billion eggs into the single basket of the peripheral nervous system. In some ways, this makes sense. After all, the received wisdom has it that these nervous signals are the only way to exert electrical control of the other cells in the body. Those other trillions—the skin cells, the immune cells, the stem cells—are beyond the reach of direct electrical intervention.
Except in the past 20 years it’s become abundantly clear thatthey are not.
Other cells speak electricity
At the end of the 19th century, the German physiologist Max Verworn watched as a single-celled marine creature was drawn across the surface of his slide as if captured by a tractor beam. It had been, in a way: under the influence of an electric field, it squidged over to the cathode (the pole that attracts positive charge). Many other types of cells could be coaxed to obey the directional wiles of an electric field, a phenomenon known as galvanotaxis.
But this was too weird for biology, and charlatans already occupied too much of the space in the Venn diagram where electricity met medicine. (The association was formalized in 1910 in the Flexner Report, commissioned to improve the dismal state of American medical schools, which sent electrical medicine into exile along with the likes of homeopathy.) Everyone politely forgot about galvanotaxis until the 1970s and ’80s, when the peculiar behavior resurfaced. Yeast, fungi, bacteria, you name it—they all liked a cathode. “We were pulling every kind of cell along on petri dishes with an electric field,” says Ann Rajnicek of the University of Aberdeen in Scotland, who was among the first group of researchers who tried to discover the mechanism when scientific interest reawakened.
Galvanotaxis would have raised few eyebrows if the behavior had been confined to neurons. Those cells have evolved receptors that sense electric fields; they are a fundamental aspect of the mechanism the nervous system uses to send its information. Indeed, the reason neurons are so amenable to electrical manipulation in the first place is that electric implants hijack a relatively predictable mechanism. Zap a nerve or a muscle and you are forcing it to “speak” a language in which it is already fluent.
Non-excitable cells such as those found in skin and bone don’t share these receptors, but it keeps getting more obvious that they somehow still sense and respond to electric fields.
Why? We keep finding more reasons. Galvanotaxis, for example, is increasingly understood to play a crucial role in wound healing. In every species studied, injury to the skin produces an instant, internally generated electric field, and there’s overwhelming evidence that it guides patch-up cells to the center of the wound to start the rebuilding process. But galvanotaxis is not the only way these cells are led by electricity. During development, immature cells seem to sense the electric properties of their neighbors, which plays a role in their future identity—whether they become neurons, skin cells, fat cells, or bone cells.
Early experiments showed that paramecia on a wet plate will orient themselves in the direction of a cathode.
PUBLIC DOMAIN
Intriguing as this all was, no one had much luck turning such insights into medicine. Even attempts to go after the lowest-hanging fruit—by exploiting galvanotaxis for novel bandages—were for many years at best hit or miss. “When we’ve come upon wounds that are intractable, resistant, and will not heal, and we apply an electric field, only 50% or so of the cases actually show any effect,” says Anthony Guiseppi-Elie, a senior fellow with the American International Institute for Medical Sciences, Engineering, and Innovation.
However, in the past few years, researchers have found ways to make electrical stimulation outside the nervous system less of a coin toss.
That’s down to steady progress in our understanding of how exactly non-neural cells pick up on electric fields, which has helped calm anxieties around the mysticism and the Frankenstein associations that have attended biological responses to electricity.
The first big win came in 2006, with the identification of specific genes in skin cells that get turned on and off by electric fields. When skin is injured, the body’s native electric field orients cells toward the center of the wound, and the physiologist Min Zhao and his colleagues found important signaling pathways that are turned on by this field and mobilized to move cells toward this natural cathode. He also found associated receptors, and other scientists added to the catalogue of changes to genes and gene regulatory networks that get switched on and off under an electric field.
What has become clear since then is that there is no simple mechanism waiting at the end of the rainbow. “There isn’t one single master protein, as far as anybody knows, that regulates responses [to an electric field],” says Daniel Cohen, a bioengineer at Princeton University. “Every cell type has a different cocktail of stuff sticking out of it.”
But recent years have brought good news, in both experimental and applied science. First, the experimental platforms to investigate gene expression are in the middle of a transformation. One advance was unveiled last year by Sara Abasi, Guiseppi-Elie, and their colleagues at Texas A&M and the Houston Methodist Research Institute: their carefully designed research platform kept track of pertinent cellular gene expression profiles and how they change under electric fields—specifically, ones tuned to closely mimic what you find in biology. They found evidence for the activation of two proteins involved in tissue growth along with increased expression of a protein called CD-144, a specific version of what’s known as a cadherin. Cadherins are important physical structures that enable cells to stick to each other, acting like little handshakes between cells. They are crucial to the cells’ ability to act en masse instead of individually.
The other big improvement is in tools that can reveal just how cells work together in the presence of electric fields.
A different kind of electroceutical
A major limit on past experiments was that they tended to test the effects of electrical fields either on single cells or on whole animals. Neither is quite the right scale to offer useful insights, explains Cohen: measuring these dynamics in animals is too “messy,” but in single cells, the dynamics are too artificial to tell you much about how cells behave collectively as they heal a wound. That behavior emerges only at relevant scales, like bird flocks, schools of fish, or road traffic. “The math is identical to describe these types of collective dynamics,” he says.
In 2020, Cohen and his team came up with a solution: an experimental setup that strikes the balance between single cell (tells you next to nothing) and animal (tells you too many things at once). The device, called SCHEEPDOG, can reveal what is going on at the tissue level, which is the relevant scale for investigating wound healing.
It uses two sets of electrodes—a bit the way you might twiddle the dials on an Etch A Sketch—placed in a closed bioreactor, which better approximates how electric fields operate in biology. With this setup, Cohen and his colleagues can precisely tune the electrical environment of tens of thousands of cells at a time to influence their behavior.
In this time-lapse, SCHEEPDOG maneuvers epithelial cells with electric fields.
COHEN ET AL
Their subsequent “healing-on-a-chip” platform yielded an interesting discovery: skin cells’ response to an electric field depends on their maturity. The less mature, the easier they were to control.
The culprit? Those cadherins that Abasi and Guiseppi-Elie had also observed changing under electric fields. In mature cells, these little handshakes had become so strong that a competing electric field, instead of gently guiding the cells, caused them to rip apart. The immature skin cells followed the electric field’s directions without complaint.
After they found a way to dial down the cadherins with an antibody drug, all the cells synchronized. For Cohen, the lesson was that it’s more important to look at the system, and the collective dynamics that govern a behavior like wound healing, than at what is happening in any single cell. “This is really important because many clinical attempts at using electrical stimulation to accelerate wound healing have failed,” says Guiseppi-Elie, and it had never become clear why some worked and others some didn’t.
Cohen’s team is now working to translate these findings into next-generation bioelectric plasters. They are far from alone, and the payoff is more than skin deep. A lot of work is going on, some of it open and some behind closed doors with patents being closely guarded, says Cohen.
At Stanford, the University of Arizona, and Northwestern, researchers are creating smart electric bandages that can be implanted under the skin. They can also monitor the state of the wound in real time, increasing the stimulation if healing is too slow. More challenging, says Rajnicek, are ways to interface with less accessible areas of the body. However, here too new tools are revealing intriguing creative solutions.
Electric fields don’t have to directly changecells’ gene expression to be useful. There is another way their application can be turned to medical benefit. Electric fields evoke reactive oxygen species (ROS) in biological cells. Normally, these charged molecules are a by-product of a cell’s everyday metabolic activities. If you induce them purposefully using an external DC current, however, they can be hijacked to do your bidding.
Starting in 2020, theSwiss bioengineer Martin Fussenegger and an international team of collaborators began to publish investigations into this mechanism to power gene expression. He and his team engineered human kidney cells to be hypersensitive to the induced ROSs in quantities that normal cells couldn’t sense. But when these were generated by DC electrodes, the kidney cells could sense the minute quantities just fine.
Using this instrument, in 2023 they were able to create a tiny, wearable insulin factory. The designer kidney cells were created with a synthetic promoter—an engineered sequence of DNA that can drive expression of a target gene—that reacted to those faint inducedROSs by activating a cascade of genetic changes that opened a tap for insulin production on demand.
Then they packaged this electrogenetic contraption into a wearable device that worked for a month in a living mouse, which had been engineered to be diabetic (Fussenegger says that “others have shown that implanted designer cells can generally be active for over a year”). The designer cells in the wearable are kept alive by algae gelatine but are fed by the mouse’s own vascular system, permitting the exchange of nutrients and protein. The cells can’t get out, but the insulin they secrete can, seeping straight into the mouse’s bloodstream. Ten seconds a day of electrical stimulation delivered via needles connected to three AAA batteries was enough to make the implant perform like a pancreas, returning the mouse’s blood sugar to nondiabetic levels. Given how easy it would be to generalize the mechanism, Fussenegger says, there’s no reason insulin should be the only drug such a device can generate. He is quick to stress that this wearable device is very much in the proof-of-concept stage, but others outside the team are excited about its potential. It could provide a more direct electrical alternative to the solution electroceuticals promised for diabetes.
Escaping neurochauvinism
Before the concerted push around branding electroceuticals, efforts to tap the peripheral nervous system were fragmented and did not share much data. Today, thanks to SPARC, which is winding down, data-sharing resources have been centralized. And money, both direct and indirect, for the electroceuticals project has been lavish. Therapies—especially vagus nerve stimulation—have been the subject of “a steady increase in funding and interest,” says Imran Eba, a partner at GSK’s bioelectronics investment arm Action Potential Venture Capital. Eba estimates that the initial GSK seed of $50 million at Action Potential has grown to about $200 million in assets under management.
Whether you call it bioelectronic medicine or electroceuticals, some researchers would like to see the definition take on a broader remit. “It’s been an extremely neurocentric approach,” says Daniel Cohen.
Neurostimulation has not yet shown success against cancer. Other forms of electrical stimulation, however, have proved surprisingly effective. In one study on glioblastoma, tumor-treating fields offered an electrical version of chemotherapy: an electric field blasts a brain tumor, preferentially killing only cells whose electrical identity marks them as dividing (which cancer cells do, pathologically—but neurons, being fully differentiated, do not). A study recently published in The Lancet Oncology suggests that these fields could also work in lung cancer to boost existing drugs and extend survival.
All of this points to more sophisticated interventions than a zap to a nerve. “The complex things that we need to do in medicine will be about communicating with the collective decision-making and problem-solving of the cells,” says Michael Levin. He has been working to repurpose already-approved drugs so they can be used to target the electrical communication between cells. In a funny twist, he has taken to calling these drugs electroceuticals, which has ruffled some feathers. But he would certainly find support from researchers like Cohen. “I would describe electroceuticals much more broadly as anything that manipulates cellular electrophysiology,” Cohen says.
Even interventions with the nervous system could be helped by expanding our understanding of the ways nerve cells react to electricity beyond action potentials. Kim Gokoffski, a professor of clinical ophthalmology at the University of Southern California, is working with galvanotaxis as a possible means of repairing damage to the optic nerve. In prior experiments that involve regrowing axons—the cables that carry messages out of neurons—these new nerve fibers tend to miss the target they’re meant to rejoin. Existing approaches “are all pushing the gas pedal,” she says, “but no one is controlling the steering wheel.” So her group uses electric fields to guide the regenerating axons into position. In rodent trials, this has worked well enough to partially restore sight.
And yet, Cohen says, “there’s massive social stigma around this that is significantly hampering the entire field.” That stigma has dramatically shaped research direction and funding. For Gokoffski, it has led to difficulties with publishing. She also recounts hearing a senior NIH official refer to her lab’s work on reconnecting optic nerves as “New Age–y.” It was a nasty surprise: “New Age–y has a very bad connotation.”
However, there are signs of more support for work outside the neurocentric model of bioelectric medicine. The US Defense Department funds projects in electrical wound healing (including Gokoffski’s). Action Potential’s original remit—confined to targeting peripheral nerves with electrical stimulation—has expanded. “We have a broader approach now, where energy (in any form, be it electric, electromagnetic, or acoustic) can be directed to regulate neuronal or other cellular activities in the body,” Eba wrote in an email. Three of the companies now in their portfolio focus on areas outside neurostimulation. “While we don’t have any investments targeting wound healing or regenerative medicine specifically, there is no explicit exclusion here for us,” he says.
This suggests that the “social stigma” Cohen described around electrical medicine outside the nervous system is slowly beginning to abate. But if such projects are to really flourish, the field needs to be supported, not just tolerated—perhaps with its own road map and dedicated NIH program. Whether or not bioelectric medicine ends up following anything like the original electroceuticals road map, SPARC ensured a flourishing research community, one that is in hot pursuit of promising alternatives.
The use of electricity outside the nervous system needs a SPARC program of its own. But if history is any guide, first it needs a catchy name. It can’t be “electroceuticals.” And the researchers should definitely check the trademark listings before rolling it out.
This article first appeared in The Checkup, MIT Technology Review’s weekly biotech newsletter. To receive it in your inbox every Thursday, and read articles like this first, sign up here.
The study didn’t garner as much media attention as previous, much smaller studies that focused on helping people with paralysis walk. Tech that allows people to type slightly faster or put their hair in a ponytail unaided just doesn’t have the same allure. “The image of a paralyzed person getting up and walking is almost biblical,” Charles Liu, director of the Neurorestoration Center at the University of Southern California, once told a reporter.
For the people who have spinal cord injuries, however, incremental gains can have a huge impact on quality of life.
So today in The Checkup, let’s talk about this tech and who it serves.
In 2004, Kim Anderson-Erisman, a researcher at Case Western Reserve University, who also happens to be paralyzed, surveyed more than 600 people with spinal cord injuries. Wanting to better understand their priorities, she asked them to consider seven different functions—everything from hand and arm mobility to bowel and bladder function to sexual function. She asked respondents to rank these functions according to how big an impact recovery would have on their quality of life.
Walking was one of the functions, but it wasn’t the top priority for most people. Most quadriplegics put hand and arm function at the top of the list. For paraplegics, meanwhile, the top priority was sexual function. I interviewed Anderson-Erisman for a story I wrote in 2019 about research on implantable stimulators as a way to help people with spinal cord injuries walk. For many people, “not being able to walk is the easy part of spinal cord injury,” she told me. “[If] you don’t have enough upper-extremity strength or ability to take care of yourself independently, that’s a bigger problem than not being able to walk.”
One of the research groups I focused on was at the University of Louisville. When I visited in 2019, the team had recently made the news because two people with spinal cord injuries in one of their studies had regained the ability to walk, thanks to an implanted stimulator. “Experimental device helps paralyzed man walk the length of four football fields,” one headline had trumpeted.
But when I visited one of those participants, Jeff Marquis, in his condo in Louisville, I learned that walking was something he could only do in the lab. To walk he needed to hold onto parallel bars supported by other people and wear a harness to catch him if he fell. Even if he had extra help at home, there wasn’t enough room for the apparatus. Instead, he gets around his condo the same way he gets around outside his condo: in a wheelchair. Marquis does stand at home, but even that requires a bulky frame. And the standing he does is only for therapy. “I mostly just watch TV while I’m doing that,” he said.
That’s not to say the tech has been useless. The implant helped Marquis gain some balance, stamina, and trunk stability. “Trunk stability is kind of underrated in how much easier that makes every other activity I do,” he told me. “That’s the biggest thing that stays with me when I have [the stimulator] turned off.”
What’s exciting to me about this latest study is that the tech gave the participants skills they could use beyond the lab. And because the stimulator is external, it is likely to be more accessible and vastly cheaper. Yes, the newly enabled movements are small, but if you listen to the palpable excitement of one study participant as he demonstrates how he can move a small ball into a cup, you’ll appreciate that incremental gains are far from insignificant. That’s according to Melanie Reid, one of the participants in the latest trial, who spoke at a press conference last week. “There [are] no miracles in spinal injury, but tiny gains can be life-changing.”
Now read the rest of The Checkup
Read more from MIT Technology Review’s archive
In 2017, we hailed as a breakthrough technology electronic interfaces designed to reverse paralysis by reconnecting the brain and body. Antonio Regalado has the story.
An implanted stimulator changed John Mumford’s life, allowing him to once again grasp objects after a spinal cord injury left him paralyzed. But when the company that made the device folded, Mumford was left with few options for keeping the device running. “Limp limbs can be reanimated by technology, but they can be quieted again by basic market economics,” wrote Brian Bergstein in 2015.
In 2014, Courtney Humphries covered some of the rat research that laid the foundation for the technological developments that have allowed paralyzed people to walk.
From around the web
Lots of bird flu news this week. A second person in the US has tested positive for the illness after working with infected livestock. (NBC)
The livestock industry, which depends on shipping tens of millions of live animals, provides some ideal conditions for the spread of pathogens, including bird flu. (NYT)
Long read: How the death of a nine-year-old boy in Cambodia triggered a global H5N1 alert. (NYT)
You’ve heard about tracking viruses via wastewater. H5N1 is the first one we’re tracking via store-bought milk. (STAT)
The first organ transplants from pigs to humans have not ended well, but scientists are learning valuable lessons about what they need to do better. (Nature)
Another long read that’s worth your time: an inside look at just how long 3M knew about the pervasiveness of “forever chemicals.” (New Yorker)
An animated video posted this week has a voice-over that sounds like a late-night TV ad, but the pitch is straight out of the far future. The arms of an octopus-like robotic surgeon swirl, swiftly removing the head of a dying man and placing it onto a young, healthy body.
This is BrainBridge, the animated video claims—“the world’s first revolutionary concept for a head transplant machine, which uses state-of-the-art robotics and artificial intelligence to conduct complete head and face transplantation.”
First posted on Tuesday, the video has millions of views, more than 24,000 comments on Facebook, and a content warning on TikTok for its grisly depictions of severed heads. A slick BrainBridge website has several job postings, including one for a “neuroscience team leader” and another for a “government relations adviser.” It is all convincing enough for the New York Post to announce that BrainBridge is “a biomedical engineering startup” and that “the company” plans a surgery within eight years.
We can report that BrainBridge is not a real company—it’s not incorporated anywhere. The video was made by Hashem Al-Ghaili, a Yemeni science communicator and film director who in 2022 made a viral video called “EctoLife,” about artificial wombs, that also left journalists scrambling to determine if it was real or not.
Yet BrainBridge is not merely a provocative work of art. This video is better understood as a public billboard for a hugely controversial scheme to defeat death that’s recently been gaining attention among some life-extension proponents and entrepreneurs.
“It’s about recruiting newcomers to join the project,” says Al-Ghaili.
This morning, Al-Ghaili, who lives in Dubai, was up at 5 a.m., tracking the video as its viewership ballooned around social media. “I am monitoring its progress,” he says, but he insists he didn’t make the film for clicks: “Being viral is not the goal. I can be viral anytime. It’s pushing boundaries and testing feasibility.”
The video project was bankrolled in part by Alex Zhavoronkov, the founder of Insilico Medicine, a large AI drug discovery company, who is also a prominent figure in anti-aging research. After Zhavoronkov posted the video on his LinkedIn account, commenters noticed that it is his face on the two bodies shown in the video.
“I can confirm I helped design and fund a few things,” Zhavoronkov told MIT Technology Review in a WhatsApp message, in which he also claimed that “some important and famous people are supporting [it] financially.”
Zhavoronkov declined to name these individuals. He also didn’t respond when asked if the job ads—whose cookie-cutter descriptions of qualifications and responsibilities appear to have been written by an AI—are real roles or make-believe positions.
Aging bypass
What is certain is that head transplantation—or body transplant, as some prefer to call it—is a subject of growing, if speculative, interest in longevity circles, the kind inhabited by biohackers, techno-anarchists, and others on the fringes of biotechnology and the startup scene and who form the most dedicated cadre of extreme life-extensionists.
Many proponents of longer life spans will admit things don’t look good. Anti-aging medicine so far hasn’t achieved any breakthroughs. In fact, as research advances into the molecular details, the problem of death only looks more and more complicated. As we age, our billions of cells gradually succumb to the irreversible effects of entropy. Fixing that may never be possible.
By comparison, putting your head on a young body looks comparatively easy—a way to bypass aging in a single stroke, at least as long as your brain holds out. The idea was strongly endorsed in a technical road map put forward this year by the Longevity Biotech Fellowship, a group espousing radical life extension, which rated “body replacement” as the cheapest, fastest pathway to “solve aging.”
Will head transplants work? In a crude way, they already have. In the early 1970s, the American neurosurgeon Robert White performed a “cephalic exchange,” cutting off the head of a monkey, placing it on the body of another, and sewing together their circulatory systems. Reports suggest the head remained conscious, and able to see, for a few days before it died.
Most likely, a human head transplant would also be fatal. But even if you lived, you’d be a mind atop a paralyzed body, since exchanging heads means severing the spinal cord.
Yet head-swapping proponents can point to plausible solutions for that, too—a number of which appear in the BrainBridge video. In Europe, for instance, some paralyzed people have walked again after doctors bridged their spinal injuries with electronics. Other scientists in China are studying growth factors to regrow nerves.
Joined at the neck
As shocking as the video is, BrainBridge is in some ways overly conventional in its thinking. If you want to keep your brain going, why must it be on a human body? You might instead keep the head alive on a heart-lung machine—with an Elon Musk neural implant to let it surf the internet, for as long as it lives. Or consider how doctors hoping to solve the organ shortage have started putting hearts and kidneys from genetically engineered pigs into patients. If you don’t mind having a tail and four legs, maybe your head could be placed onto a pig’s body.
Let’s take it a step further. Why does the body “donor” have to be dead at all? Anatomically, it’s possible to have two heads. There are conjoined twins who share one body. If your spouse were diagnosed with a fatal cancer, you would surely welcome his or her head next to yours, if it allowed their mind to live on. After all, the concept of a “living donor” is widely accepted in transplant medicine already, and married couples are often said to be joined at the hip. Why not at the neck, too?
If the video is an attempt to take the public’s temperature and gauge reactions, it’s been successful. Since it was posted, thousands of commenters have explored the moral dilemmas posed by the procedure. For instance, if someone is left brain dead—say, in a motorcycle accident—surgeons can use their heart, liver, and kidneys to save multiple other people. Would it be ethical to use a body to help only one person?
“The most common question is ‘Where do you get the bodies from?’” says Al-Ghaili. The BrainBridge website answers this question by stating it will source “ethically grown” unconscious bodies from EctoLife, the artificial womb company that is Al-Ghaili’s previous fiction. He also suggests that people undergoing euthanasia because of chronic pain, or even psychiatric problems, could provide an additional supply.
For the most part, the public seems to hate the idea. On Facebook, a pastor, Matthew. W. Tucker, called the concept “disgusting, immoral, unnecessary, pagan, demonic and outright idiotic,” adding that “they have no idea what they are doing.” A poster from the Middle East apologized for the video, joking that its creator “is one of our psychiatric patients who escaped last night.” “We urge the public to go about [their] business as everything is under control,” this person said.
Al-Ghaili is monitoring the feedback with interest and some concern. “The negativity is huge, to be honest,” he says. “But behind that are the ones who are sending emails. These are people who want to invest, or who are expressing their personal health challenges. These are the ones who matter.”
He says if suitable job applicants appear, the backers of BrainBridge are prepared to fund a small technical feasibility study to see if their idea has legs.
Fourteen years ago, a journalist named Melanie Reid attempted a jump on horseback and fell. The accident left her mostly paralyzed from the chest down. Eventually she regained control of her right hand, but her left remained “useless,” she told reporters at a press conference last week.
Now, thanks to a new noninvasive device that delivers electrical stimulation to the spinal cord, she has regained some control of her left hand. She can use it to sweep her hair into a ponytail, scroll on a tablet, and even squeeze hard enough to release a seatbelt latch. These may seem like small wins, but they’re crucial, Reid says.
“Everyone thinks that [after] spinal injury, all you want to do is be able to walk again. But if you’re a tetraplegic or a quadriplegic, what matters most is working hands,” she said.
Reid received the device, called ARCex, as part of a 60-person clinical trial. She and the other participants completed two months of physical therapy, followed by two months of physical therapy combined with stimulation. The results, published today in Nature Medicine, show that the vast majority of participants benefited. By the end of the four-month trial, 72% experienced some improvement in both strength and function of their hands or arms when the stimulator was turned off. Ninety percent had improvement in at least one of those measures. And 87% reported an improvement in their quality of life.
This isn’t the first study to test whether noninvasive stimulation of the spine can help people who are paralyzed regain function in their upper body, but it’s important because a trial has never been done before in this number of rehabilitation centers or in this number of subjects, says Igor Lavrov, a neuroscientist at the Mayo Clinic in Minnesota, who was not involved in the study. He points out, however, that the therapy seems to work best in people who have some ability to move below the site of their injury.
The trial was the last hurdle before the researchers behind the device could request regulatory approval, and they hope it might be approved in the US by the end of the year.
ARCex consists of a small stimulator connected by wires to electrodes placed on the spine—in this case, in the area responsible for hand and arm control, just below the neck. It was developed by Onward Medical, a company cofounded by Grégoire Courtine, a neuroscientist at the Swiss Federal Institute of Technology in Lausanne and now chief scientific officer at the company.
The stimulation won’t work in the small percentage of people who have no remaining connection between the brain and spine below their injury. But for people who still have a connection, the stimulation appears to make voluntary movements easier by making the nerves more likely to transmit a signal. Studies over the past couple of decades in animals suggest that the stimulation activates remaining nerve fibers and, over time, helps new nerves grow. That’s why the benefits persist even when the stimulator is turned off.
The big advantage of an external stimulation system over an implant is that it doesn’t require surgery, which makes using the device less of a commitment. “There are many, many people who are not interested in invasive technologies,” said Edelle Field-Fote, director of research on spinal cord injury at the Shepherd Center, at the press conference. An external device is also likely to be cheaper than any surgical options, although the company hasn’t yet set a price on ARCex.
“What we’re looking at here is a device that integrates really seamlessly with the physical therapy and occupational therapy that’s already offered in the clinic,” said Chet Moritz, an engineer and neuroscientist at the University of Washington in Seattle, at the press conference. The rehab that happens soon after the injury is crucial, because that’s when the opportunity for recovery is greatest. “Being able to bring that function back without requiring a surgery could be life-changing for the majority of people with spinal cord injury,” he adds.
Reid wishes she could have used the device soon after her injury, but she is astonished by the amount of function she was able to regain after all this time. “After 14 years, you think, well, I am where I am and nothing’s going change,” she says. So to suddenly find she had strength and power in her left hand—“It was extraordinary,” she says.
Onward is also developing implantable devices, which can deliver stronger, more targeted stimulation and thus could be effective even in people with complete paralysis. The company hopes to launch a trial of those next year.
This article first appeared in The Checkup, MIT Technology Review’s weekly biotech newsletter. To receive it in your inbox every Thursday, and read articles like this first, sign up here.
Last week, I scoured the internet in search of a robotic dog. I wanted a belated birthday present for my aunt, who was recently diagnosed with Alzheimer’s disease. Studies suggest that having a companion animal can stave off some of the loneliness, anxiety, and agitation that come with Alzheimer’s. My aunt would love a real dog, but she can’t have one.
That’s how I discovered the Golden Pup from Joy for All. It cocks its head. It sports a jaunty red bandana. It barks when you talk. It wags when you touch it. It has a realistic heartbeat. And it’s just one of the many, many robots designed for people with Alzheimer’s and dementia.
This week on The Checkup, join me as I go down a rabbit hole. Let’s look at the prospect of using robots to change dementia care.
As robots go, Golden Pup is decidedly low tech. It retails for $140. For around $6,000 you can opt for Paro, a fluffy robotic baby seal developed in Japan, which can sense touch, light, sound, temperature, and posture. Its manufacturer says it develops its own character, remembering behaviors that led its owner to give it attention.
Golden Pup and Paro are available now. But researchers are working on much more sophisticated robots for people with cognitive disorders—devices that leverage AI to converse and play games. Researchers from Indiana University Bloomington are tweaking a commercially available robot system called QT to serve people with dementia and Alzheimer’s. The researchers’ two-foot-tall robot looks a little like a toddler in an astronaut suit. Its round white head holds a screen that displays two eyebrows, two eyes, and a mouth that together form a variety of expressions. The robot engages people in conversation, asking AI-generated questions to keep them talking.
The AI model they’re using isn’t perfect, and neither are the robot’s responses. In one awkward conversation, a study participant told the robot that she has a sister. “I’m sorry to hear that,” the robot responded. “How are you doing?”
But as large language models improve—which is happening already—so will the quality of the conversations. When the QT robot made that awkward comment, it was running Open AI’s GPT-3, which was released in 2020. The latest version of that model, GPT-4o, which was released this week, is faster and provides for more seamless conversations. You can interrupt the conversation, and the model will adjust.
The idea of using robots to keep dementia patients engaged and connected isn’t always an easy sell. Some people see it as an abdication of our social responsibilities. And then there are privacy concerns. The best robotic companions are personalized. They collect information about people’s lives, learn their likes and dislikes, and figure out when to approach them. That kind of data collection can be unnerving, not just for patients but also for medical staff. Lillian Hung, creator of the Innovation in Dementia care and Aging (IDEA) lab at the University of British Columbia in Vancouver, Canada, told one reporter about an incident that happened during a focus group at a care facility. She and her colleagues popped out for lunch. When they returned, they found that staff had unplugged the robot and placed a bag over its head. “They were worried it was secretly recording them,” she said.
On the other hand, robots have some advantages over humans in talking to people with dementia. Their attention doesn’t flag. They don’t get annoyed or angry when they have to repeat themselves. They can’t get stressed.
What’s more, there are increasing numbers of people with dementia, and too few people to care for them. According to the latest report from the Alzheimer’s Association, we’re going to need more than a million additional care workers to meet the needs of people living with dementia between 2021 and 2031. That is the largest gap between labor supply and demand for any single occupation in the United States.
Have you been in an understaffed or poorly staffed memory care facility? I have. Patients are often sedated to make them easier to deal with. They get strapped into wheelchairs and parked in hallways. We barely have enough care workers to take care of the physical needs of people with dementia, let alone provide them with social connection and an enriching environment.
“Caregiving is not just about tending to someone’s bodily concerns; it also means caring for the spirit,” writes Kat McGowan in this beautiful Wiredstory about her parents’ dementia and the promise of social robots. “The needs of adults with and without dementia are not so different: We all search for a sense of belonging, for meaning, for self-actualization.”
If robots can enrich the lives of people with dementia even in the smallest way, and if they can provide companionship where none exists, that’s a win.
“We are currently at an inflection point, where it is becoming relatively easy and inexpensive to develop and deploy [cognitively assistive robots] to deliver personalized interventions to people with dementia, and many companies are vying to capitalize on this trend,” write a team of researchers from the University of California, San Diego, in a 2021 article in Proceedings of We Robot. “However, it is important to carefully consider the ramifications.”
Many of the more advanced social robots may not be ready for prime time, but the low-tech Golden Pup is readily available. My aunt’s illness has been progressing rapidly, and she occasionally gets frustrated and agitated. I’m hoping that Golden Pup might provide a welcome (and calming) distraction. Maybe it will spark joy during a time that has been incredibly confusing and painful for my aunt and uncle. Or maybe not. Certainly a robotic pup isn’t for everyone. Golden Pup may not be a dog. But I’m hoping it can be a friendly companion.
Now read the rest of The Checkup
Read more from MIT Technology Review’s archive
Robots are cool, and with new advances in AI they might also finally be useful around the house, writes Melissa Heikkilä.
Social robots could help make personalized therapy more affordable and accessible to kids with autism. Karen Hao has the story.
Japan is already using robots to help with elder care, but in many cases they require as much work as they save. And reactions among the older people they’re meant to serve are mixed. James Wright wonders whether the robots are “a shiny, expensive distraction from tough choices about how we value people and allocate resources in our societies.”
From around the web
A tiny probe can work its way through arteries in the brain to help doctors spot clots and other problems. The new tool could help surgeons make diagnoses, decide on treatment strategies, and provide assurance that clots have been removed. (Stat)
Richard Slayman, the first recipient of a pig kidney transplant, has died, although the hospital that performed the transplant says the death doesn’t seem to be linked to the kidney. (Washington Post)
EcoHealth, the virus-hunting nonprofit at the center of covid lab-eak theories, has been banned from receiving federal funding. (NYT)
In a first, scientists report that they can translate brain signals into speech without any vocalization or mouth movements, at least for a handful of words. (Nature)
No matter who he called—his mother, his father, his brother, his cousins—the phone would just go to voicemail. Cell service was out around Maui as devastating wildfires swept through the Hawaiian island. But while Raven Imperial kept hoping for someone to answer, he couldn’t keep a terrifying thought from sneaking into his mind: What if his family members had perished in the blaze? What if all of them were gone?
Hours passed; then days. All Raven knew at that point was this: there had been a wildfire on August 8, 2023, in Lahaina, where his multigenerational, tight-knit family lived. But from where he was currently based in Northern California, Raven was in the dark. Had his family evacuated? Were they hurt? He watched from afar as horrifying video clips of Front Street burning circulated online.
Much of the area around Lahaina’s Pioneer Mill Smokestack was totally destroyed by wildfire.
ALAMY
The list of missing residents meanwhile climbed into the hundreds.
Raven remembers how frightened he felt: “I thought I had lost them.”
Raven had spent his youth in a four-bedroom, two-bathroom, cream-colored home on Kopili Street that had long housed not just his immediate family but also around 10 to 12 renters, since home prices were so high on Maui. When he and his brother, Raphael Jr., were kids, their dad put up a basketball hoop outside where they’d shoot hoops with neighbors. Raphael Jr.’s high school sweetheart, Christine Mariano, later moved in, and when the couple had a son in 2021, they raised him there too.
From the initial news reports and posts, it seemed as if the fire had destroyed the Imperials’ entire neighborhood near the Pioneer Mill Smokestack—a 225-foot-high structure left over from the days of Maui’s sugar plantations, which Raven’s grandfather had worked on as an immigrant from the Philippines in the mid-1900s.
Then, finally, on August 11, a call to Raven’s brother went through. He’d managed to get a cell signal while standing on the beach.
“Is everyone okay?” Raven asked.
“We’re just trying to find Dad,” Raphael Jr. told his brother.
From his current home in Northern California, Raven Imperial spent days not knowing what had happened to his family in Maui.
WINNI WINTERMEYER
In the three days following the fire, the rest of the family members had slowly found their way back to each other. Raven would learn that most of his immediate family had been separated for 72 hours: Raphael Jr. had been marooned in Kaanapali, four miles north of Lahaina; Christine had been stuck in Wailuku, more than 20 miles away; both young parents had been separated from their son, who escaped with Christine’s parents. Raven’s mother, Evelyn, had also been in Kaanapali, though not where Raphael Jr. had been.
But no one was in contact with Rafael Sr. Evelyn had left their home around noon on the day of the fire and headed to work. That was the last time she had seen him. The last time they had spoken was when she called him just after 3 p.m. and asked: “Are you working?” He replied “No,” before the phone abruptly cut off.
“Everybody was found,” Raven says. “Except for my father.”
Within the week, Raven boarded a plane and flew back to Maui. He would keep looking for him, he told himself, for as long as it took.
That same week, Kim Gin was also on a plane to Maui. It would take half a day to get there from Alabama, where she had moved after retiring from the Sacramento County Coroner’s Office in California a year earlier. But Gin, now an independent consultant on death investigations, knew she had something to offer the response teams in Lahaina. Of all the forensic investigators in the country, she was one of the few who had experience in the immediate aftermath of a wildfire on the vast scale of Maui’s. She was also one of the rare investigators well versed in employing rapid DNA analysis—an emerging but increasingly vital scientific tool used to identify victims in unfolding mass-casualty events.
Gin started her career in Sacramento in 2001 and was working as the coroner 17 years later when Butte County, California, close to 90 miles north, erupted in flames. She had worked fire investigations before, but nothing like the Camp Fire, which burned more than 150,000 acres—an area larger than the city of Chicago. The tiny town of Paradise, the epicenter of the blaze, didn’t have the capacity to handle the rising death toll. Gin’s office had a refrigerated box truck and a 52-foot semitrailer, as well as a morgue that could handle a couple of hundred bodies.
Kim Gin, the former Sacramento County coroner, had worked fire investigations in her career, but nothing prepared her for the 2018 Camp Fire.
BRYAN TARNOWSKI
“Even though I knew it was a fire, I expected more identifications by fingerprints or dental [records]. But that was just me being naïve,” she says. She quickly realized that putting names to the dead, many burned beyond recognition, would rely heavily on DNA.
“The problem then became how long it takes to do the traditional DNA [analysis],” Gin explains, speaking to a significant and long-standing challenge in the field—and the reason DNA identification has long been something of a last resort following large-scale disasters.
While more conventional identification methods—think fingerprints, dental information, or matching something like a knee replacement to medical records—can be a long, tedious process, they don’t take nearly as long as traditional DNA testing.
Historically, the process of making genetic identifications would often stretch on for months, even years. In fires and other situations that result in badly degraded bone or tissue, it can become even more challenging and time consuming to process DNA, which traditionally involves reading the 3 billion base pairs of the human genome and comparing samples found in the field against samples from a family member. Meanwhile, investigators frequently need equipment from the US Department of Justice or the county crime lab to test the samples, so backlogs often pile up.
A supply kit with swabs, gloves, and other items needed to take a DNA sample in the field.
A demo chip for ANDE’s rapid DNA box.
This creates a wait that can be horrendous for family members. Death certificates, federal assistance, insurance money—“all that hinges on that ID,” Gin says. Not to mention the emotional toll of not knowing if their loved ones are alive or dead.
But over the past several years, as fires and other climate-change-fueled disasters have become more common and more cataclysmic, the way their aftermath is processed and their victims identified has been transformed. The grim work following a disaster remains—surveying rubble and ash, distinguishing a piece of plastic from a tiny fragment of bone—but landing a positive identification can now take just a fraction of the time it once did, which may in turn bring families some semblance of peace more swiftly than ever before.
The key innovation driving this progress has been rapid DNA analysis, a methodology that focuses on just over two dozen regions of the genome. The 2018 Camp Fire was the first time the technology was used in a large, live disaster setting, and the first time it was used as the primary way to identify victims. The technology—deployed in small high-tech field devices developed by companies like industry leader ANDE, or in a lab with other rapid DNA techniques developed by Thermo Fisher—is increasingly being used by the US military on the battlefield, and by the FBI and local police departments after sexual assaults and in instances where confirming an ID is challenging, like cases of missing or murdered Indigenous people or migrants. Yet arguably the most effective way to use rapid DNA is in incidents of mass death. In the Camp Fire, 22 victims were identified using traditional methods, while rapid DNA analysis helped with 62 of the remaining 63 victims; it has also been used in recent years following hurricanes and floods, and in the war in Ukraine.
“These families are going to have to wait a long period of time to get identification. How do we make this go faster?”
Tiffany Roy, a forensic DNA expert with consulting company ForensicAid, says she’d be concerned about deploying the technology in a crime scene, where quality evidence is limited and can be quickly “exhausted” by well-meaning investigators who are “not trained DNA analysts.” But, on the whole, Roy and other experts see rapid DNA as a major net positive for the field. “It is definitely a game-changer,” adds Sarah Kerrigan, a professor of forensic science at Sam Houston State University and the director of its Institute for Forensic Research, Training, and Innovation.
But back in those early days after the Camp Fire, all Gin knew was that nearly 1,000 people had been listed as missing, and she was tasked with helping to identify the dead. “Oh my goodness,” she remembers thinking. “These families are going to have to wait a long period of time to get identification. How do we make this go faster?”
Ten days
One flier pleading for information about “Uncle Raffy,” as people in the community knew Rafael Sr., was posted on a brick-red stairwell outside Paradise Supermart, a Filipino store and restaurant in Kahului, 25 miles away from the destruction. In it, just below the words “MISSING Lahaina Victim,” the 63-year-old grandfather smiled with closed lips, wearing a blue Hawaiian shirt, his right hand curled in the shaka sign, thumb and pinky pointing out.
Raven remembers how hard his dad, Rafael, worked. His three jobs took him all over town and earned him the nickname “Mr. Aloha.”
COURTESY OF RAVEN IMPERIAL
“Everybody knew him from restaurant businesses,” Raven says. “He was all over Lahaina, very friendly to everybody.” Raven remembers how hard his dad worked, juggling three jobs: as a draft tech for Anheuser-Busch, setting up services and delivering beer all across town; as a security officer at Allied Universal security services; and as a parking booth attendant at the Sheraton Maui. He connected with so many people that coworkers, friends, and other locals gave him another nickname: “Mr. Aloha.”
Raven also remembers how his dad had always loved karaoke, where he would sing “My Way,” by Frank Sinatra. “That’s the only song that he would sing,” Raven says. “Like, on repeat.”
Since their home had burned down, the Imperials ran their search out of a rental unit in Kihei, which was owned by a local woman one of them knew through her job. The woman had opened her rental to three families in all. It quickly grew crowded with side-by-side beds and piles of donations.
Each day, Evelyn waited for her husband to call.
She managed to catch up with one of their former tenants, who recalled asking Rafael Sr. to leave the house on the day of the fires. But she did not know if he actually did. Evelyn spoke to other neighbors who also remembered seeing Rafael Sr. that day; they told her that they had seen him go back into the house. But they too did not know what happened to him after.
A friend of Raven’s who got into the largely restricted burn zone told him he’d spotted Rafael Sr.’s Toyota Tacoma on the street, not far from their house. He sent a photo. The pickup was burned out, but a passenger-side door was open. The family wondered: Could he have escaped?
Evelyn called the Red Cross. She called the police. Nothing. They waited and hoped.
Back in Paradise in 2018, as Gin worried about the scores of waiting families, she learned there might in fact be a better way to get a positive ID—and a much quicker one. A company called ANDE Rapid DNA had already volunteered its services to the Butte County sheriff and promised that its technology could process DNA and get a match in less than two hours.
“I’ll try anything at this point,” Gin remembers telling the sheriff. “Let’s see this magic box and what it’s going to do.”
In truth, Gin did not think it would work, and certainly not in two hours. When the device arrived, it was “not something huge and fantastical,” she recalls thinking. A little bigger than a microwave, it looked “like an ordinary box that beeps, and you put stuff in, and out comes a result.”
The “stuff,” more specifically, was a cheek or bloodstain swab, or a piece of muscle, or a fragment of bone that had been crushed and demineralized. Instead of reading 3 billion base pairs in this sample, Selden’s machine examined just 27 genome regions characterized by particular repeating sequences. It would be nearly impossible for two unrelated people to have the same repeating sequence in those regions. But a parent and child, or siblings, would match, meaning you could compare DNA found in human remains with DNA samples taken from potential victims’ family members. Making it even more efficient for a coroner like Gin, the machine could run up to five tests at a time and could be operated by anyone with just a little basic training.
ANDE’s chief scientific officer, Richard Selden, a pediatrician who has a PhD in genetics from Harvard, didn’t come up with the idea to focus on a smaller, more manageable number of base pairs to speed up DNA analysis. But it did become something of an obsession for him after he watched the O.J. Simpson trial in the mid-1990s and began to grasp just how long it took for DNA samples to get processed in crime cases. By this point, the FBI had already set up a system for identifying DNA by looking at just 13 regions of the genome; it would later add seven more. Researchers in other countries had also identified other sets of regions to analyze. Drawing on these various methodologies, Selden homed in on the 27 specific areas of DNA he thought would be most effective to examine, and he launched ANDE in 2004.
But he had to build a device to do the analysis. Selden wanted it to be small, portable, and easily used by anyone in the field. In a conventional lab, he says, “from the moment you take that cheek swab to the moment that you have the answer, there are hundreds of laboratory steps.” Traditionally, a human is holding test tubes and iPads and sorting through or processing paperwork. Selden compares it all to using a “conventional typewriter.” He effectively created the more efficient laptop version of DNA analysis by figuring out how to speed up that same process.
No longer would a human have to “open up this bottle and put [the sample] in a pipette and figure out how much, then move it into a tube here.” It is all automated, and the process is confined to a single device.
The rapid DNA analysis boxes from ANDE can be used in the field by anyone with just a bit of training.
ANDE
Once a sample is placed in the box, the DNA binds to a filter in water and the rest of the sample is washed away. Air pressure propels the purified DNA to a reconstitution chamber and then flattens it into a sheet less than a millimeter thick, which is subjected to about 6,000 volts of electricity. It’s “kind of an obstacle course for the DNA,” he explains.
The machine then interprets the donor’s genome and and provides an allele table with a graph showing the peaks for each region and its size. This data is then compared with samples from potential relatives, and the machine reports when it has a match.
Rapid DNA analysis as a technology first received approval for use by the US military in 2014, and in the FBI two years later. Then the Rapid DNA Act of 2017 enabled all US law enforcement agencies to use the technology on site and in real time as an alternative to sending samples off to labs and waiting for results.
But by the time of the Camp Fire the following year, most coroners and local police officers still had no familiarity or experience with it. Neither did Gin. So she decided to put the “magic box” through a test: she gave Selden, who had arrived at the scene to help with the technology, a DNA sample from a victim whose identity she’d already confirmed via fingerprint. The box took about 90 minutes to come back with a result. And to Gin’s surprise, it was the same identification she had already made. Just to make sure, she ran several more samples through the box, also from victims she had already identified. Again, results were returned swiftly, and they confirmed hers.
“I was a believer,” she says.
The next year, Gin helped investigators use rapid DNA technology in the 2019 Conception disaster, when a dive boat caught fire off the Channel Islands in Santa Barbara. “We ID’d 34 victims in 10 days,” Gin says. “Completely done.” Gin now works independently to assist other investigators in mass-fatality events and helps them learn to use the ANDE system.
Its speed made the box a groundbreaking innovation. Death investigations, Gin learned long ago, are not as much about the dead as about giving peace of mind, justice, and closure to the living.
Fourteen days
Many of the people who were initially on the Lahaina missing persons list turned up in the days following the fire. Tearful reunions ensued.
Two weeks after the fire, the Imperials hoped they’d have the same outcome as they loaded into a truck to check out some exciting news: someone had reported seeing Rafael Sr. at a local church. He’d been eating and had burns on his hands and looked disoriented. The caller said the sighting had occurred three days after the fire. Could he still be in the vicinity?
When the family arrived, they couldn’t confirm the lead.
“We were getting a lot of calls,” Raven says. “There were a lot of rumors saying that they found him.”
None of them panned out. They kept looking.
The scenes following large-scale destructive events like the fires in Paradise and Lahaina can be sprawling and dangerous, with victims sometimes dispersed across a large swath of land if many people died trying to escape. Teams need to meticulously and tediously search mountains of mixed, melted, or burned debris just to find bits of human remains that might otherwise be mistaken for a piece of plastic or drywall. Compounding the challenge is the comingling of remains—from people who died huddled together, or in the same location, or alongside pets or other animals.
This is when the work of forensic anthropologists is essential: they have the skills to differentiate between human and animal bones and to find the critical samples that are needed by DNA specialists, fire and arson investigators, forensic pathologists and dentists, and other experts. Rapid DNA analysis “works best in tandem with forensic anthropologists, particularly in wildfires,” Gin explains.
“The first step is determining, is it a bone?” says Robert Mann, a forensic anthropologist at the University of Hawaii John A. Burns School of Medicine on Oahu. Then, is it a human bone? And if so, which one?
Forensic anthropologist Robert Mann has spent his career identifying human remains.
AP PHOTO/LUCY PEMONI
Mann has served on teams that have helped identify the remains of victims after the terrorist attacks of September 11, 2001, and the 2004 Indian Ocean tsunami, among other mass-casualty events. He remembers how in one investigation he received an object believed to be a human bone; it turned out to be a plastic replica. In another case, he was looking through the wreckage of a car accident and spotted what appeared to be a human rib fragment. Upon closer examination, he identified it as a piece of rubber weather stripping from the rear window. “We examine every bone and tooth, no matter how small, fragmented, or burned it might be,” he says. “It’s a time-consuming but critical process because we can’t afford to make a mistake or overlook anything that might help us establish the identity of a person.”
For Mann, the Maui disaster felt particularly immediate. It was right near his home. He was deployed to Lahaina about a week after the fire, as one of more than a dozen forensic anthropologists on scene from universities in places including Oregon, California, and Hawaii.
While some anthropologists searched the recovery zone—looking through what was left of homes, cars, buildings, and streets, and preserving fragmented and burned bone, body parts, and teeth—Mann was stationed in the morgue, where samples were sent for processing.
It used to be much harder to find samples that scientists believed could provide DNA for analysis, but that’s also changed recently as researchers have learned more about what kind of DNA can survive disasters. Two kinds are used in forensic identity testing: nuclear DNA (found within the nuclei of eukaryotic cells) and mitochondrial DNA (found in the mitochondria, organelles located outside the nucleus). Both, it turns out, have survived plane crashes, wars, floods, volcanic eruptions, and fires.
Theories have also been evolving over the past few decades about how to preserve and recover DNA specifically after intense heat exposure. One 2018 study found that a majority of the samples actually survived high heat. Researchers are also learning more about how bone characteristics change depending on the degree. “Different temperatures and how long a body or bone has been exposed to high temperatures affect the likelihood that it will or will not yield usable DNA,” Mann says.
Typically, forensic anthropologists help select which bone or tooth to use for DNA testing, says Mann. Until recently, he explains, scientists believed “you cannot get usable DNA out of burned bone.” But thanks to these new developments, researchers are realizing that with some bone that has been charred, “they’re able to get usable, good DNA out of it,” Mann says. “And that’s new.” Indeed, Selden explains that “in a typical bad fire, what I would expect is 80% to 90% of the samples are going to have enough intact DNA” to get a result from rapid analysis. The rest, he says, may require deeper sequencing.
The aftermath of large-scale destructive events like the fire in Lahaina can be sprawling and dangerous. Teams need to meticulously search through mountains of mixed, melted, or burned debris to find bits of human remains.
GLENN FAWCETT VIA ALAMY
Anthropologists can often tell “simply by looking” if a sample will be good enough to help create an ID. If it’s been burned and blackened, “it might be a good candidate for DNA testing,” Mann says. But if it’s calcined (white and “china-like”), he says, the DNA has probably been destroyed.
On Maui, Mann adds, rapid DNA analysis made the entire process more efficient, with tests coming back in just two hours. “That means while you’re doing the examination of this individual right here on the table, you may be able to get results back on who this person is,” he says. From inside the lab, he watched the science unfold as the number of missing on Maui quickly began to go down.
Within three days, 42 people’s remains were recovered inside Maui homes or buildings and another 39 outside, along with 15 inside vehicles and one in the water. The first confirmed identification of a victim on the island occurred four days after the fire—this one via fingerprint. The ANDE rapid DNA team arrived two days after the fire and deployed four boxes to analyze multiple samples of DNA simultaneously. The first rapid DNA identification happened within that first week.
Sixteen days
More than two weeks after the fire, the list of missing and unaccounted-for individuals was dwindling, but it still had 388 people on it. Rafael Sr. was one of them.
Raven and Raphael Jr. raced to another location: Cupies café in Kahului, more than 20 miles from Lahaina. Someone had reported seeing him there.
Rafael’s family hung posters around the island, desperately hoping for reliable information. (Phone number redacted by MIT Technology Review.)
ERIKA HAYASAKI
The tip was another false lead.
As family and friends continued to search, they stopped by support hubs that had sprouted up around the island, receiving information about Red Cross and FEMA assistance or donation programs as volunteers distributed meals and clothes. These hubs also sometimes offered DNA testing.
Raven still had a “50-50” feeling that his dad might be out there somewhere. But he was beginning to lose some of that hope.
Gin was stationed at one of the support hubs, which offered food, shelter, clothes, and support. “You could also go in and give biological samples,” she says. “We actually moved one of the rapid DNA instruments into the family assistance center, and we were running the family samples there.” Eliminating the need to transport samples from a site to a testing center further cut down any lag time.
Selden had once believed that the biggest hurdle for his technology would be building the actual device, which took about eight years to design and another four years to perfect. But at least in Lahaina, it was something else: persuading distraught and traumatized family members to offer samples for the test.
Nationally, there are serious privacy concerns when it comes to rapid DNA technology. Organizations like the ACLU warn that as police departments and governments begin deploying it more often, there must be more oversight, monitoring, and training in place to ensure that it is always used responsibly, even if that adds some time and expense. But the space is still largely unregulated, and the ACLU fears it could give rise to rogue DNA databases “with far fewer quality, privacy, and security controls than federal databases.”
Family support centers popped up around Maui to offer clothing, food, and other assistance, and sometimes to take DNA samples to help find missing family members.
In a place like Hawaii, these fears are even more palpable. The islands have a long history of US colonialism, military dominance, and exploitation of the Native population and of the large immigrant working-class population employed in the tourism industry.
Native Hawaiians in particular have a fraught relationship with DNA testing. Under a US law signed in 1921, thousands have a right to live on 200,000 designated acres of land trust, almost for free. It was a kind of reparations measure put in place to assist Native Hawaiians whose land had been stolen. Back in 1893, a small group of American sugar plantation owners and descendants of Christian missionaries, backed by US Marines, held Hawaii’s Queen Lili‘uokalani in her palace at gunpoint and forced her to sign over 1.8 million acres to the US, which ultimately seized the islands in 1898.
Hawaii’s Queen Lili‘uokalani was forced to sign over 1.8 million acres to the US.
PUBLIC DOMAIN VIA WIKIMEDIA COMMONS
To lay their claim to the designated land and property, individuals first must prove via DNA tests how much Hawaiian blood they have. But many residents who have submitted their DNA and qualified for the land have died on waiting lists before ever receiving it. Today, Native Hawaiians are struggling to stay on the islands amid skyrocketing housing prices, while others have been forced to move away.
Meanwhile, after the fires, Filipino families faced particularly stark barriers to getting information about financial support, government assistance, housing, and DNA testing. Filipinos make up about 25% of Hawaii’s population and 40% of its workers in the tourism industry. They also make up 46% of undocumented residents in Hawaii—more than any other group. Some encountered language barriers, since they primarily spoke Tagalog or Ilocano. Some worried that people would try to take over their burned land and develop it for themselves. For many, being asked for DNA samples only added to the confusion and suspicion.
Selden says he hears the overall concerns about DNA testing: “If you ask people about DNA in general, they think of Brave New World and [fear] the information is going to be used to somehow harm or control people.” But just like regular DNA analysis, he explains, rapid DNA analysis “has no information on the person’s appearance, their ethnicity, their health, their behavior either in the past, present, or future.” He describes it as a more accurate fingerprint.
Gin tried to help the Lahaina family members understand that their DNA “isn’t going to go anywhere else.” She told them their sample would ultimately be destroyed, something programmed to occur inside ANDE’s machine. (Selden says the boxes were designed to do this for privacy purposes.) But sometimes, Gin realizes, these promises are not enough.
“You still have a large population of people that, in my experience, don’t want to give up their DNA to a government entity,” she says. “They just don’t.”
Gin understands that family members are often nervous to give their DNA samples. She promises the process of rapid DNA analysis respects their privacy, but she knows sometimes promises aren’t enough.
BRYAN TARNOWSKI
The immediate aftermath of a disaster, when people are suffering from shock, PTSD, and displacement, is the worst possible moment to try to educate them about DNA tests and explain the technology and privacy policies. “A lot of them don’t have anything,” Gin says. “They’re just wondering where they’re going to lay their heads down, and how they’re going to get food and shelter and transportation.”
Unfortunately, Lahaina’s survivors won’t be the last people in this position. Particularly given the world’s current climate trajectory, the risk of deadly events in just about every neighborhood and community will rise. And figuring out who survived and who didn’t will be increasingly difficult. Mann recalls his work on the Indian Ocean tsunami, when over 227,000 people died. “The bodies would float off, and they ended up 100 miles away,” he says. Investigators were at times left with remains that had been consumed by sea creatures or degraded by water and weather. He remembers how they struggled to determine: “Who is the person?”
Mann has spent his own career identifying people including “missing soldiers, sailors, airmen, Marines, from all past wars,” as well as people who have died recently. That closure is meaningful for family members, some of them decades, or even lifetimes, removed.
In the end, distrust and conspiracy theories did in fact hinder DNA-identification efforts on Maui, according to a police department report.
33 days
By the time Raven went to a family resource center to submit a swab, some four weeks had gone by. He remembers the quick rub inside his cheek.
Some of his family had already offered their own samples before Raven provided his. For them, waiting wasn’t an issue of mistrusting the testing as much as experiencing confusion and chaos in the weeks after the fire. They believed Uncle Raffy was still alive, and they still held hope of finding him. Offering DNA was a final step in their search.
“I did it for my mom,” Raven says. She still wanted to believe he was alive, but Raven says: “I just had this feeling.” His father, he told himself, must be gone.
Just a day after he gave his sample—on September 11, more than a month after the fire—he was at the temporary house in Kihei when he got the call: “It was,” Raven says, “an automatic match.”
Raven gave a cheek swab about a month after the disappearance of his father. It didn’t take long for him to get a phone call: “It was an automatic match.”
WINNI WINTERMEYER
The investigators let the family know the address where the remains of Rafael Sr. had been found, several blocks away from their home. They put it into Google Maps and realized it was where some family friends lived. The mother and son of that family had been listed as missing too. Rafael Sr., it seemed, had been with or near them in the end.
By October, investigators in Lahaina had obtained and analyzed 215 DNA samples from family members of the missing. By December, DNA analysis had confirmed the identities of 63 of the most recent count of 101 victims. Seventeen more had been identified by fingerprint, 14 via dental records, and two through medical devices, along with three who died in the hospital. While some of the most damaged remains would still be undergoing DNA testing months after the fires, it’s a drastic improvement over the identification processes for 9/11 victims, for instance—today, over 20 years later, some are still being identified by DNA.
Raven remembers how much his father loved karaoke. His favorite song was “My Way,” by Frank Sinatra.
COURTESY OF RAVEN IMPERIAL
Rafael Sr. was born on October 22, 1959, in Naga City, the Philippines. The family held his funeral on his birthday last year. His relatives flew in from Michigan, the Philippines, and California.
Raven says in those weeks of waiting—after all the false tips, the searches, the prayers, the glimmers of hope—deep down the family had already known he was gone. But for Evelyn, Raphael Jr., and the rest of their family, DNA tests were necessary—and, ultimately, a relief, Raven says. “They just needed that closure.”
Erika Hayasaki is an independent journalist based in Southern California.
This article first appeared in The Checkup, MIT Technology Review’s weekly biotech newsletter. To receive it in your inbox every Thursday, and read articles like this first, sign up here.
The human brain is an engineering marvel: 86 billion neurons form some 100 trillion connections to create a network so complex that it is, ironically, mind boggling.
This week scientists published the highest-resolution map yet of one small piece of the brain, a tissue sample one cubic millimeter in size. The resulting data set comprised 1,400 terabytes. (If they were to reconstruct the entire human brain, the data set would be a full zettabyte. That’s a billion terabytes. That’s roughly a year’s worth of all the digital content in the world.)
This map is just one of many that have been in the news in recent years. (I wrote about another brain map last year.) So this week I thought we could walk through some of the ways researchers make these maps and how they hope to use them.
Scientists have been trying to map the brain for as long as they’ve been studying it. One of the most well-known brain maps came from German anatomist Korbinian Brodmann. In the early 1900s, he took sections of the brain that had been stained to highlight their structure and drew maps by hand, with 52 different areas divided according to how the neurons were organized. “He conjectured that they must do different things because the structure of their staining patterns are different,” says Michael Hawrylycz, a computational neuroscientist at the Allen Institute for Brain Science. Updated versions of his maps are still used today.
“With modern technology, we’ve been able to bring a lot more power to the construction,” he says. And over the past couple of decades we’ve seen an explosion of large, richly funded mapping efforts.
BigBrain, which was released in 2013, is a 3D rendering of the brain of a single donor, a 65-year-old woman. To create the atlas, researchers sliced the brain into more than 7,000 sections, took detailed images of each one, and stitched the sections into a three-dimensional reconstruction.
In the Human Connectome Project, researchers scanned 1,200 volunteers in MRI machines to map structural and functional connections in the brain. “They were able to map out what regions were activated in the brain at different times under different activities,” Hawrylycz says.
This kind of noninvasive imaging can provide valuable data, but “Its resolution is extremely coarse,” he adds. “Voxels [think: a 3D pixel] are of the size of a millimeter to three millimeters.”
And there are other projects too. The Synchrotron for Neuroscience—an Asia Pacific Strategic Enterprise, a.k.a. “SYNAPSE,” aims tomap the connections of an entire human brain at a very fine-grain resolution using synchrotron x-ray microscopy. The EBRAINS human brain atlas contains information on anatomy, connectivity, and function.
The work I wrote about last year is part of the $3 billion federally funded Brain Research Through Advancing Innovative Neurotechnologies (BRAIN) Initiative, which launched in 2013. In this project, led by the Allen Institute for Brain Science, which has developed a number of brain atlases, researchers are working to develop a parts list detailing the vast array of cells in the human brain by sequencing single cells to look at gene expression. So far they’ve identified more than 3,000 types of brain cells, and they expect to find many more as they map more of the brain.
The draft map was based on brain tissue from just two donors. In the coming years, the team will add samples from hundreds more.
Mapping the cell types present in the brain seems like a straightforward task, but it’s not. The first stumbling block is deciding how to define a cell type. Seth Ament, a neuroscientist at the University of Maryland, likes to give his neuroscience graduate students a rundown of all the different ways brain cells can be defined: by their morphology, or by the way the cells fire, or by their activity during certain behaviors. But gene expression may be the Rosetta stone brain researchers have been looking for, he says: “If you look at cells from the perspective of just what genes are turned on in them, it corresponds almost one to one to all of those other kinds of properties of cells.” That’s the most remarkable discovery from all the cell atlases, he adds.
I have always assumed the point of all these atlases is to gain a better understanding of the brain. But Jeff Lichtman, a neuroscientist at Harvard University, doesn’t think “understanding” is the right word. He likens trying to understand the human brain to trying to understand New York City. It’s impossible. “There’s millions of things going on simultaneously, and everything is working, interacting, in different ways,” he says. “It’s too complicated.”
But as this latest paper shows, it is possible to describe the human brain in excruciating detail. “Having a satisfactory description means simply that if I look at a brain, I’m no longer surprised,” Lichtman says. That day is a long way off, though. The data Lichtman and his colleagues published this week was full of surprises—and many more are waiting to be uncovered.
Now read the rest of The Checkup
Another thing
The revolutionary AI tool AlphaFold, which predicts proteins’ structures on the basis of their genetic sequence, just got an upgrade, James O’Donnell reports. Now the tool can predict interactions between molecules.
And in 2017, we flagged the Human Cell Atlas project, which aims to categorize all the cells of the human body, as a breakthrough technology. That project is still underway.
All these big, costly efforts to map the brain haven’t exactly led to a breakthrough in our understanding of its function, writes Emily Mullin in this story from 2021.
From around the web
The Apple Watch’s atrial fibrillation (AFib) feature received FDA approval to track heart arrhythmias in clinical trials, making it the first digital health product to be qualified under the agency’s Medical Device Development Tools program. (Stat)
A CRISPR gene therapy improved vision in several people with an inherited form of blindness, according to an interim analysis of a small clinical trial to test the therapy. (CNN)
Long read: The covid vaccine, like all vaccines, can cause side effects. But many people who say they have been harmed by the vaccine feel that their injuries are being ignored. (NYT)
A team led by scientists from Harvard and Google has created a 3D, nanoscale-resolution map of a single cubic millimeter of the human brain. Although the map covers just a fraction of the organ—a whole brain is a million times larger—that piece contains roughly 57,000 cells, about 230 millimeters of blood vessels, and nearly 150 million synapses. It is currently the highest-resolution picture of the human brain ever created.
To make a map this finely detailed, the team had to cut the tissue sample into 5,000 slices and scan them with a high-speed electron microscope. Then they used a machine-learning model to help electronically stitch the slices back together and label the features. The raw data set alone took up 1.4 petabytes. “It’s probably the most computer-intensive work in all of neuroscience,” says Michael Hawrylycz, a computational neuroscientist at the Allen Institute for Brain Science, who was not involved in the research. “There is a Herculean amount of work involved.”
Many other brain atlases exist, but most provide much lower-resolution data. At the nanoscale, researchers can trace the brain’s wiring one neuron at a time to the synapses, the places where they connect. “To really understand how the human brain works, how it processes information, how it stores memories, we will ultimately need a map that’s at that resolution,” says Viren Jain, a senior research scientist at Google and coauthor on the paper, published in Science on May 9. The data set itself and a preprint version of this paper were released in 2021.
Brain atlases come in many forms. Some reveal how the cells are organized. Others cover gene expression. This one focuses on connections between cells, a field called “connectomics.” The outermost layer of the brain contains roughly 16 billion neurons that link up with each other to form trillions of connections. A single neuron might receive information from hundreds or even thousands of other neurons and send information to a similar number. That makes tracing these connections an exceedingly complex task, even in just a small piece of the brain..
To create this map, the team faced a number of hurdles. The first problem was finding a sample of brain tissue. The brain deteriorates quickly after death, so cadaver tissue doesn’t work. Instead, the team used a piece of tissue removed from a woman with epilepsy during brain surgery that was meant to help control her seizures.
Once the researchers had the sample, they had to carefully preserve it in resin so that it could be cut into slices, each about a thousandth the thickness of a human hair. Then they imaged the sections using a high-speed electron microscope designed specifically for this project.
Next came the computational challenge. “You have all of these wires traversing everywhere in three dimensions, making all kinds of different connections,” Jain says. The team at Google used a machine-learning model to stitch the slices back together, align each one with the next, color-code the wiring, and find the connections. This is harder than it might seem. “If you make a single mistake, then all of the connections attached to that wire are now incorrect,” Jain says.
“The ability to get this deep a reconstruction of any human brain sample is an important advance,” says Seth Ament, a neuroscientist at the University of Maryland. The map is “the closest to the ground truth that we can get right now.” But he also cautions that it’s a single brain specimen taken from a single individual.
The map, which is freely available at a web platform called Neuroglancer, is meant to be a resource other researchers can use to make their own discoveries. “Now anybody who’s interested in studying the human cortex in this level of detail can go into the data themselves. They can proofread certain structures to make sure everything is correct, and then publish their own findings,” Jain says. (The preprint has already been cited at least 136 times.)
The team has already identified some surprises. For example, some of the long tendrils that carry signals from one neuron to the next formed “whorls,” spots where they twirled around themselves. Axons typically form a single synapse to transmit information to the next cell. The team identified single axons that formed repeated connections—in some cases, 50 separate synapses. Why that might be isn’t yet clear, but the strong bonds could help facilitate very quick or strong reactions to certain stimuli, Jain says. “It’s a very simple finding about the organization of the human cortex,” he says. But “we didn’t know this before because we didn’t have maps at this resolution.”
The data set was full of surprises, says Jeff Lichtman, a neuroscientist at Harvard University who helped lead the research. “There were just so many things in it that were incompatible with what you would read in a textbook.” The researchers may not have explanations for what they’re seeing, but they have plenty of new questions: “That’s the way science moves forward.”
Correction: Due to a transcription error, a quote from Viren Jain referred to how the brain ‘exports’ memories. It has been updated to reflect that he was speaking of how the brain ‘stores’ memories.
It was a cool morning at the beef teaching unit in Gainesville, Florida, and cow number #307 was bucking in her metal cradle as the arm of a student perched on a stool disappeared into her cervix. The arm held a squirt bottle of water.
Seven other animals stood nearby behind a railing; it would be their turn next to get their uterus flushed out. As soon as the contents of #307’s womb spilled into a bucket, a worker rushed it to a small laboratory set up under the barn’s corrugated gables.
“It’s something!” said a postdoc named Hao Ming, dressed in blue overalls and muck boots, corralling a pink wisp of tissue under the lens of a microscope. But then he stepped back, not as sure. “It’s hard to tell.”
The experiment, at the University of Florida, is an attempt to create a large animal starting only from stem cells—no egg, no sperm, and no conception. A week earlier, “synthetic embryos,” artificial structures created in a lab, had been transferred to the uteruses of all eight cows. Now it was time to see what had grown.
About a decade ago, biologists started to observe that stem cells, left alone in a walled plastic container, will spontaneously self-assemble and try to make an embryo. These structures, sometimes called “embryo models” or embryoids, have gradually become increasingly realistic. In 2022, a lab in Israel grew the mouse version in a jar until cranial folds and a beating heart appeared.
At the Florida center, researchers are now attempting to go all the way. They want to make a live animal. If they do, it wouldn’t just be a totally new way to breed cattle. It could shake our notion of what life even is. “There has never been a birth without an egg,” says Zongliang “Carl” Jiang, the reproductive biologist heading the project. “Everyone says it is so cool, so important, but show me more data—show me it can go into a pregnancy. So that is our goal.”
For now, success isn’t certain, mostly because lab-made embryos generated from stem cells still aren’t exactly like the real thing. They’re more like an embryo seen through a fun-house mirror; the right parts, but in the wrong proportions. That’s why these are being flushed out after just a week—so the researchers can check how far they’ve grown and to learn how to make better ones.
“The stem cells are so smart they know what their fate is,” says Jiang. “But they also need help.”
So far, most research on synthetic embryos has involved mouse or human cells, and it’s stayed in the lab. But last year Jiang, along with researchers in Texas, published a recipe for making a bovine version, which they called “cattle blastoids” for their resemblance to blastocysts, the stage of the embryo suitable for IVF procedures.
Some researchers think that stem-cell animals could be as big a deal as Dolly the sheep, whose birth in 1996 brought cloning technology to barnyards. Cloning, in which an adult cell is placed in an egg, has allowed scientists to copy mice, cattle, pet dogs, and even polo ponies. The players on one Argentine team all ride clones of the same champion mare, named Dolfina.
Synthetic embryos are clones, too—of the starting cells you grow them from. But they’re made without the need for eggs and can be created in far larger numbers—in theory, by the tens of thousands. And that’s what could revolutionize cattle breeding. Imagine that each year’s calves were all copies of the most muscled steer in the world, perfectly designed to turn grass into steak.
“I would love to see this become cloning 2.0,” says Carlos Pinzón-Arteaga, the veterinarian who spearheaded the laboratory work in Texas. “It’s like Star Wars with cows.”
Endangered species
Industry has started to circle around. A company called Genus PLC, which specializes in assisted reproduction of “genetically superior” pigs and cattle, has begun buying patents on synthetic embryos. This year it started funding Jiang’s lab to support his effort, locking up a commercial option to any discoveries he might make.
Zoos are interested too. With many endangered animals, assisted reproduction is difficult. And with recently extinct ones, it’s impossible. All that remains is some tissue in a freezer. But this technology could, theoretically, blow life back into these specimens—turning them into embryos, which could be brought to term in a surrogate of a sister species.
But there’s an even bigger—and stranger—reason to pay attention to Jiang’s effort to make a calf: several labs are creating super-realistic synthetic human embryos as well. It’s an ethically charged arena, particularly given recent changes in US abortion laws. Although these human embryoids are considered nonviable—mere “models” that are fair-game for research—all that could all change quickly if the Florida project succeeds.
“If it can work in an animal, it can work in a human,” says Pinzón-Arteaga, who is now working at Harvard Medical School. “And that’s the Black Mirror episode.”
Industrial embryos
Three weeks before cow #307 stood in the dock, she and seven other heifers had been given stimulating hormones, to trick their bodies into thinking they were pregnant. After that, Jiang’s students had loaded blastoids into a straw they used like a popgun to shoot them towards each animal’s oviducts.
Many researchers think that if a stem-cell animal is born, the first one is likely to be a mouse. Mice are cheap to work with and reproduce fast. And one team has already grown a synthetic mouse embryo for eight days in an artificial womb—a big step, since a mouse pregnancy lasts only three weeks.
But bovines may not be far behind. There’s a large assisted-reproduction industry in cattle, with more than a million IVF attempts a year, half of them in North America. Many other beef and dairy cattle are artificially inseminated with semen from top-rated bulls. “Cattle is harder,” says Jiang. “But we have all the technology.”
Inspecting a “synthetic” embryo that gestated in a cow for a week at the University of Florida, Gainesville.
ANTONIO REGALADO
The thing that came out of cow #307 turned out to be damaged, just a fragment. But later that day, in Jiang’s main laboratory, students were speed-walking across the linoleum holding something in a petri dish. They’d retrieved intact embryonic structures from some of the other cows. These looked long and stringy, like worms, or the skin shed by a miniature snake.
That’s precisely what a two-week-old cattle embryo should look like. But the outer appearance is deceiving, Jiang says. After staining chemicals are added, the specimens are put under a microscope. Then the disorder inside them is apparent. These “elongated structures,” as Jiang calls them, have the right parts—cells of the embryonic disc and placenta—but nothing is in quite the right place.
“I wouldn’t call them embryos yet, because we still can’t say if they are healthy or not,” he says. “Those lineages are there, but they are disorganized.”
Cloning 2.0
Jiang demonstrated how the blastoids are grown in a plastic plate in his lab. First, his students deposit stem cells into narrow tubes. In confinement, the cells begin communicating and very quickly start trying to form a blastoid. “We can generate hundreds of thousands of blastoids. So it’s an industrial process,” he says. “It’s really simple.”
That scalability is what could make blastoids a powerful replacement for cloning technology. Cattle cloning is still a tricky process, which only skilled technicians can manage, and it requires eggs, too, which come from slaughterhouses. But unlike blastoids, cloning is well established and actually works, says Cody Kime, R&D director at Trans Ova Genetics, in Sioux Center, Iowa. Each year, his company clones thousands of pigs as well as hundreds of prize-winning cattle.
“A lot of people would like to see a way to amplify the very best animals as easily as you can,” Kime says. “But blastoids aren’t functional yet. The gene expression is aberrant to the point of total failure. The embryos look blurry, like someone sculpted them out of oatmeal or Play-Doh. It’s not the beautiful thing that you expect. The finer details are missing.”
This spring, Jiang learned that the US Department of Agriculture shared that skepticism, when they rejected his application for $650,000 in funding. “I got criticism: ‘Oh, this is not going to work.’ That this is high risk and low efficiency,” he says. “But to me, this would change the entire breeding program.”
One problem may be the starting cells. Jiang uses bovine embryonic stem cells—taken from cattle embryos. But these stem cells aren’t as quite as versatile as they need to be. For instance, to make the first cattle blastoids, the team in Texas had to add a second type of cell, one that can make a placenta.
What’s needed instead are specially prepared “naïve” cells that are better poised to form the entire conceptus—both the embryo and placenta. Jiang showed me a PowerPoint with a large grid of different growth factors and lab conditions he is testing. Growing stem cells in different chemicals can shift the pattern of genes that are turned on. The latest batch of blastoids, he says, were made using a newer recipe and only needed to start with one type of cell.
Slaughterhouse
Jiang can’t say how long it will be before he makes a calf. His immediate goal is a pregnancy that lasts 30 days. If a synthetic embryo can grow that long, he thinks, it could go all the way, since “most pregnancy loss in cattle is in the first month.”
For a project to reinvent reproduction, Jiang’s budget isn’t particularly large, and he frets about the $2-a-day bill to feed each of his cows. During a tour of UFL’s animal science department, he opened the door to a slaughter room, a vaulted space with tracks and chains overhead, where a man in a slicker was running a hose. It smelled like freshly cleaned blood.
Reproductive biologist Carl Jiang leads an effort to make animals from stem cells. The cow stands in a “hydraulic squeeze chute” while its uterus is checked.
ANTONIO REGALADO
This is where cow #307 ended up. After a about 20 embryo transfers over three years, her cervix was worn out, and she came here. She was butchered, her meat wrapped and labeled, and sold to the public at market prices from a small shop at the front of the building. It’s important to everyone at the university that the research subjects aren’t wasted. “They are food,” says Jiang.
But there’s still a limit to how many cows he can use. He had 18 fresh heifers ready to join the experiment, but what if only 1% of embryos ever develop correctly? That would mean he’d need 100 surrogate mothers to see anything. It reminds Jiang of the first attempts at cloning: Dolly the sheep was one of 277 tries, and the others went nowhere. “How soon it happens may depend on industry. They have a lot of animals. It might take 30 years without them,” he says.
“It’s going to be hard,” agrees Peter Hansen, a distinguished professor in Jiang’s department. “But whoever does it first …” He lets the thought hang. “In vitrobreeding is the next big thing.”
Human question
Cattle aren’t the only species in which researchers are checking the potential of synthetic embryos to keep developing into fetuses. Researchers in China have transplanted synthetic embryos into the wombs of monkeys several times. A report in 2023 found that the transplants caused hormonal signals of pregnancy, although no monkey fetus emerged.
Because monkeys are primates, like us, such experiments raise an obvious question. Will a lab somewhere try to transfer a synthetic embryo to a person? In many countries that would be illegal, and scientific groups say such an experiment should be strictly forbidden.
This summer, research leaders were alarmed by a media frenzy around reports of super-realistic models of human embryos that had been created in labs in the UK and Israel—some of which seemed to be nearly perfect mimics. To quell speculation, in June the International Society for Stem Cell Research, a powerful science and lobbying group, put out a statement declaring that the models “are not embryos” and “cannot and will not develop to the equivalent of postnatal stage humans.”
Some researchers worry that was a reckless thing to say. That’s because the statement would be disproved, biologically, as soon as any kind of stem-cell animal is born. And many top scientists expect that to happen. “I do think there is a pathway. Especially in mice, I think we will get there,” says Jun Wu, who leads the research group at UT Southwestern Medical Center, in Dallas, that collaborated with Jiang. “The question is, if that happens, how will we handle a similar technology in humans?”
Jiang says he doesn’t think anyone is going to make a person from stem cells. And he’s certainly not interested in doing so. He’s just a cattle researcher at an animal science department. “Scientists belong to society, and we need to follow ethical guidelines. So we can’t do it. It’s not allowed,” he says. “But in large animals, we are allowed. We’re encouraged. And so we can make it happen.”
This article first appeared in The Checkup, MIT Technology Review’s weekly biotech newsletter. To receive it in your inbox every Thursday, and read articles like this first, sign up here.
Last week, Moderna and Merck launched a large clinical trial in the UK of a promising new cancer therapy: a personalized vaccine that targets a specific set of mutations found in each individual’s tumor. This study is enrolling patients with melanoma. But the companies have also launched a phase III trial for lung cancer. And earlier this month BioNTech and Genentech announced that a personalized vaccine they developed in collaboration shows promise in pancreatic cancer, which has a notoriously poor survival rate.
Drug developers have been working for decades on vaccines to help the body’s immune system fight cancer, without much success. But promising results in the past year suggest that the strategy may be reaching a turning point. Will these therapies finally live up to their promise?
This week in The Checkup, let’s talk cancer vaccines. (And, you guessed it, mRNA.)
Long before companies leveraged mRNA to fight covid, they were developing mRNA vaccines to combat cancer. BioNTech delivered its first mRNA vaccines to people with treatment-resistant melanoma nearly a decade ago. But when the pandemic hit, development of mRNA vaccines jumped into warp drive. Now dozens of trials are underway to test whether these shots can transform cancer the way they did covid.
Recent news has some experts cautiously optimistic. In December, Merck and Moderna announced results from an earlier trial that included 150 people with melanoma who had undergone surgery to have their cancer removed. Doctors administered nine doses of the vaccine over about six months, as well as what’s known as an immune checkpoint inhibitor. After three years of follow-up, the combination had cut the risk of recurrence or death by almost half compared with the checkpoint inhibitor alone.
The new results reported by BioNTech and Genentech, from a small trial of 16 patients with pancreatic cancer, are equally exciting. After surgery to remove the cancer, the participants received immunotherapy, followed by the cancer vaccine and a standard chemotherapy regimen. Half of them responded to the vaccine, and three years after treatment, six of those people still had not had a recurrence of their cancer. The other two had relapsed. Of the eight participants who did not respond to the vaccine, seven had relapsed. Some of these patients might not have responded because they lacked a spleen, which plays an important role in the immune system. The organ was removed as part of their cancer treatment.
The hope is that the strategy will work in many different kinds of cancer. In addition to pancreatic cancer, BioNTech’s personalized vaccine is being tested in colorectal cancer, melanoma, and metastatic cancers.
The purpose of a cancer vaccine is to train the immune system to better recognize malignant cells, so it can destroy them. The immune system has the capacity to clear cancer cells if it can find them. But tumors are slippery. They can hide in plain sight and employ all sorts of tricks to evade our immune defenses. And cancer cells often look like the body’s own cells because, well, they are the body’s own cells.
There are differences between cancer cells and healthy cells, however. Cancer cells acquire mutations that help them grow and survive, and some of those mutations give rise to proteins that stud the surface of the cell—so-called neoantigens.
Personalized cancer vaccines like the ones Moderna and BioNTech are developing are tailored to each patient’s particular cancer. The researchers collect a piece of the patient’s tumor and a sample of healthy cells. They sequence these two samples and compare them in order to identify mutations that are specific to the tumor. Those mutations are then fed into an AI algorithm that selects those most likely to elicit an immune response. Together these neoantigens form a kind of police sketch of the tumor, a rough picture that helps the immune system recognize cancerous cells.
“A lot of immunotherapies stimulate the immune response in a nonspecific way—that is, not directly against the cancer,” said Patrick Ott, director of the Center for Personal Cancer Vaccines at the Dana-Farber Cancer Institute, in a 2022 interview. “Personalized cancer vaccines can direct the immune response to exactly where it needs to be.”
How many neoantigens do you need to create that sketch? “We don’t really know what the magical number is,” says Michelle Brown, vice president of individualized neoantigen therapy at Moderna. Moderna’s vaccine has 34. “It comes down to what we could fit on the mRNA strand, and it gives us multiple shots to ensure that the immune system is stimulated in the right way,” she says. BioNTech is using 20.
The neoantigens are put on an mRNA strand and injected into the patient. From there, they are taken up by cells and translated into proteins, and those proteins are expressed on the cell’s surface, raising an immune response
mRNA isn’t the only way to teach the immune system to recognize neoantigens. Researchers are also delivering neoantigens as DNA, as peptides, or via immune cells or viral vectors. And many companies are working on “off the shelf” cancer vaccines that aren’t personalized, which would save time and expense. Out of about 400 ongoing clinical trials assessing cancer vaccines last fall, roughly 50 included personalized vaccines.
There’s no guarantee any of these strategies will pan out. Even if they do, success in one type of cancer doesn’t automatically mean success against all. Plenty of cancer therapies have shown enormous promise initially, only to fail when they’re moved into large clinical trials.
But the burst of renewed interest and activity around cancer vaccines is encouraging. And personalized vaccines might have a shot at succeeding where others have failed. The strategy makes sense for “a lot of different tumor types and a lot of different settings,” Brown says. “With this technology, we really have a lot of aspirations.”
Now read the rest of The Checkup
Read more from MIT Technology Review’s archive
mRNA vaccines transformed the pandemic. But they can do so much more. In this feature from 2023, Jessica Hamzelou covered the myriad other uses of these shots, including fighting cancer.
This article from 2020 covers some of the background on BioNTech’s efforts to develop personalized cancer vaccines. Adam Piore had the story.
Years before the pandemic, Emily Mullin wrote about early efforts to develop personalized cancer vaccines—the promise and the pitfalls.
From around the web
Yes, there’s bird flu in the nation’s milk supply. About one in five samples had evidence of the H5N1 virus. But new testing by the FDA suggests that the virus is unable to replicate. Pasteurization works! (NYT)
Studies in which volunteers are deliberately infected with covid—so-called challenge trials—have been floated as a way to test drugs and vaccines, and even to learn more about the virus. But it turns out it’s tougher to infect people than you might think. (Nature)
When should women get their first mammogram to screen for breast cancer? It’s a matter of hot debate. In 2009, an expert panel raised the age from 40 to 50. This week they lowered it to 40 again in response to rising cancer rates among younger women. Women with an average risk of breast cancer should get screened every two years, the panel says. (NYT)
Wastewater surveillance helped us track covid. Why not H5N1? A team of researchers from New York argues it might be our best tool for monitoring the spread of this virus. (Stat)
Long read: This story looks at how AI could help us better understand how babies learn language, and focuses on the lab I covered in this story about an AI model trained on the sights and sounds experienced by a single baby. (NYT)
This article first appeared in The Checkup, MIT Technology Review’s weekly biotech newsletter. To receive it in your inbox every Thursday, and read articles like this first, sign up here.
Six weeks ago, I pre-ordered the “Firefly Petunia,” a houseplant engineered with genes from bioluminescent fungi so that it glows in the dark.
After years of writing about anti-GMO sentiment in the US and elsewhere, I felt it was time to have some fun with biotech. These plants are among the first direct-to-consumer GM organisms you can buy, and they certainly seem like the coolest.
But when I unboxed my two petunias this week, they were in bad shape, with rotted leaves. And in a day, they were dead crisps. My first attempt to do biotech at home is a total bust, and it cost me $84, shipping included.
My plants did arrive in a handsome black box with neon lettering that alerted me to the living creature within. The petunias, about five inches tall, were each encased in a see-through plastic pod to keep them upright. Government warnings on the back of the box assured me they were free of Japanese beetles, sweet potato weevils, the snail Helix aspera, and gypsy moths.
The problem was when I opened the box. As it turns out, I left for a week’s vacation in Florida the same day that Light Bio, the startup selling the petunia, sent me an email saying “Glowing plants headed your way,” with a UPS tracking number. I didn’t see the email, and even if I had, I wasn’t there to receive them.
That meant my petunias sat in darkness for seven days. The box became their final sarcophagus.
My fault? Perhaps. But I had no idea when Light Bio would ship my order. And others have had similar experiences. Mat Honan, the editor in chief of MIT Technology Review, told me his petunia arrived the day his family flew to Japan. Luckily, a house sitter feeding his lizard eventually opened the box, and Mat reports the plant is still clinging to life in his yard.
One of the ill-fated petunia plants and its sarcophagus. Credit: Antonio Regalado
ANTONIO REGALADO
But what about the glow? How strong is it?
Mat says so far, he doesn’t notice any light coming from the plant, even after carrying it into a pitch-dark bathroom. But buyers may have to wait a bit to see anything. It’s the flowers that glow most brightly, and you may need to tend your petunia for a couple of weeks before you get blooms and see the mysterious effect.
“I had two flowers when I opened mine, but sadly they dropped and I haven’t got to see the brightness yet. Hoping they will bloom again soon,” says Kelsey Wood, a postdoctoral researcher at the University of California, Davis.
She would like to use the plants in classes she teaches at the university. “It’s been a dream of synthetic biologists for so many years to make a bioluminescent plant,” she says. “But they couldn’t get it bright enough to see with the naked eye.”
Others are having success right out of the box. That’s the case with Tharin White, publisher of EYNTK.info, a website about theme parks. “It had a lot of protection around it and a booklet to explain what you needed to do to help it,” says White. “The glow is strong, if you are [in] total darkness. Just being in a dark room, you can’t really see it. That being said, I didn’t expect a crazy glow, so [it] meets my expectations.”
That’s no small recommendation coming from White, who has been a “cast member” at Disney parks and an operator of the park’s Avatar ride, named after the movie whose action takes place on a planet where the flora glows. “I feel we are leaps closer to Pandora—The World of Avatar being reality,” White posted to his X account.
Chronobiologist Brian Hodge also found success by resettling his petunia immediately into a larger eight-inch pot, giving it flower food and a good soaking, and putting it in the sunlight. “After a week or so it really started growing fast, and the buds started to show up around day 10. Their glow is about what I expected. It is nothing like a neon light but more of a soft gentle glow,” says Hodge, a staff scientist at the University of California, San Francisco.
In his daily work, Hodge has handled bioluminescent beings before—bacteria mostly—and says he always needed photomultiplier tubes to see anything. “My experience with bioluminescent cells is that the light they would produce was pretty hard to see with the naked eye,” he says. “So I was happy with the amount of light I was seeing from the plants. You really need to turn off all the lights for them to really pop out at you.”
Hodge posted a nifty snapshot of his petunia, but only after setting his iPhone for a two-second exposure.
Light Bio’s CEO Keith Wood didn’t respond to an email about how my plants died, but in an interview last month he told me sales of the biotech plant had been “viral” and that the company would probably run out of its initial supply. To generate new ones, it hires commercial greenhouses to place clippings in water, where they’ll sprout new roots after a couple of weeks. According to Wood, the plant is “a rare example where the benefits of GM technology are easily recognized and experienced by the public.”
Hodge says he got interested in the plants after reading an article about combating light pollution by using bioluminescent flora instead of streetlamps. As a biologist who studies how day and night affect life, he’s worried that city lights and computer screens are messing with natural cycles.
“I just couldn’t pass up being one of the first to own one,” says Hodge. “Once you flip the lights off, the glow is really beautiful … and it sorta feels like you are witnessing something out of a futuristic sci-fi movie!”
It makes me tempted to try again.
Now read the rest of The Checkup
From the archives
We’re not sure if rows of glowing plants can ever replace streetlights, but there’s no doubt light pollution is growing. Artificial light emissions on Earth grew by about 50% between 1992 and 2017—and as much as 400% in some regions. That’s according to Shel Evergreen,in his story on the switch to bright LED streetlights.
It’s taken a while for scientists to figure out how to make plants glow brightly enough to interest consumers. In 2016, I looked at a failed Kickstarter that promised glow-in-the-dark roses but couldn’t deliver.
Another thing
Cassandra Willyard is updating us on the case of Lisa Pisano, a 54-year-old woman who is feeling “fantastic” two weeks after surgeons gave her a kidney from a genetically modified pig. It’s the latest in a series of extraordinary animal-to-human organ transplants—a technology, known as xenotransplantation, that may end the organ shortage.
From around the web
Taiwan’s government is considering steps to ease restrictions on the use of IVF. The country has an ultra-low birth rate, but it bans surrogacy, limiting options for male couples. One Taiwanese pair spent $160,000 to have a child in the United States. (CNN)
Communities in Appalachia are starting to get settlement payments from synthetic-opioid makers like Johnson & Johnson, which along with other drug vendors will pay out $50 billion over several years. But the money, spread over thousands of jurisdictions, is “a feeble match for the scale of the problem.” (Wall Street Journal)
A startup called Climax Foods claims it has used artificial intelligence to formulate vegan cheese that tastes “smooth, rich, and velvety,” according to writer Andrew Rosenblum. He relates the results of his taste test in the new “Build” issue of MIT Technology Review. But one expert Rosenblum spoke to warns that computer-generated cheese is “significantly” overhyped.
AI hype continued this week in medicine when a startup claimed it has used “generative AI” to quickly discover new versions of CRISPR, the powerful gene-editing tool. But new gene-editing tricks won’t conquer the main obstacle, which is how to deliver these molecules where they’re needed in the bodies of patients. (New York Times).
A month ago, Richard Slayman became the first living person to receive a kidney transplant from a gene-edited pig. Now, a team of researchers from NYU Langone Health reports that Lisa Pisano, a 54-year-old woman from New Jersey, has become the second. Her new kidney has just a single genetic modification—an approach that researchers hope could make scaling up the production of pig organs simpler.
Pisano, who had heart failure and end-stage kidney disease, underwent two operations, one to fit her with a heart pump to improve her circulation and the second to perform the kidney transplant. She is still in the hospital, but doing well. “Her kidney function 12 days out from the transplant is perfect, and she has no signs of rejection,” said Robert Montgomery, director of the NYU Langone Transplant Institute, who led the transplant surgery, at a press conference on Wednesday.
“I feel fantastic,” said Pisano, who joined the press conference by video from her hospital bed.
Pisano is the fourth living person to receive a pig organ. Two men who received heart transplants at the University of Maryland Medical Center in 2022 and 2023 both died within a couple of months after receiving the organ. Slayman, the first pig kidney recipient, is still doing well, says Leonardo Riella, medical director for kidney transplantation at Massachusetts General Hospital, where Slayman received the transplant.
“It’s an awfully exciting time,” says Andrew Cameron, a transplant surgeon at Johns Hopkins Medicine in Baltimore. “There is a bright future in which all 100,000 patients on the kidney transplant wait list, and maybe even the 500,000 Americans on dialysis, are more routinely offered a pig kidney as one of their options,” Cameron adds.
All the living patients who have received pig hearts and kidneys have accessed the organs under the FDA’s expanded access program, which allows patients with life-threatening conditions to receive investigational therapies outside of clinical trials. But patients may soon have another option. Both Johns Hopkins and NYU are aiming to start clinical trials in 2025.
In the coming weeks, doctors will be monitoring Pisano closely for signs of organ rejection, which occurs when the recipient’s immune system identifies the new tissue as foreign and begins to attack it. That’s a concern even with human kidney transplants, but it’s an even greater risk when the tissue comes from another species, a procedure known as xenotransplantation.
To prevent rejection, the companies that produce these pigs have introduced genetic modifications to make their tissue appear less foreign and reduce the chance that it will spark an immune attack. But it’s not yet clear just how many genetic alterations are necessary to prevent rejection. Slayman’s kidney came from a pig developed by eGenesis, a company based in Cambridge, Massachusetts; it has 69 modifications. The vast majority of those modifications focus on inactivating viral DNA in the pig’s genome to make sure those viruses can’t be transmitted to the patient. But 10 were employed to help prevent the immune system from rejecting the organ.
Pisano’s kidney came from pigs that carry just a single genetic alteration—to eliminate a specific sugar called alpha-gal, which can trigger immediate organ rejection, from the surface of its cells. “We believe that less is more, and that the main gene edit that has been introduced into the pigs and the organs that we’ve been using is the fundamental problem,” Montgomery says. “Most of those other edits can be replaced by medications that are available to humans.”
JOE CARROTTA/NYU LANGONE HEALTH
The kidney is implanted along with a piece of the pig’s thymus gland, which plays a key role in educating white blood cells to distinguish between friend and foe. The idea is that the thymus will help Pisano’s immune system learn to accept the foreign tissue. The so-called UThymoKidney is being developed by United Therapeutics Corporation, but the company has also created pigs with 10 genetic alterations. The company “wanted to take multiple shots on goal,” says Leigh Peterson,executive vice president of product development and xenotransplantation at United Therapeutics.
There’s one major advantage to using a pig with a single genetic modification. “The simpler it is, in theory, the easier it’s going to be to breed and raise these animals,” says Jayme Locke, a transplant surgeon at the University of Alabama at Birmingham. Pigs with a single genetic change can be bred, but pigs with many alterations require cloning, Montgomery says. “These pigs could be rapidly expanded, and more quickly and completely solve the organ supply crisis.”
But Cameron isn’t sure that a single alteration will be enough to prevent rejection. “I think most people are worried that one knockout might not be enough, but we’re hopeful,” he says.
So is Pisano, who is working to get strong enough to leave the hospital. “I just want to spend time with my grandkids and play with them and be able to go shopping,” she says.
This article first appeared in The Checkup, MIT Technology Review’s weekly biotech newsletter. To receive it in your inbox every Thursday, and read articles like this first, sign up here.
In the world of brain-computer interfaces, it can seem as if one company sucks up all the oxygen in the room. Last month, Neuralink posted a video to X showing the first human subject to receive its brain implant, which will be named Telepathy. The recipient, a 29-year-old man who is paralyzed from the shoulders down, played computer chess, moving the cursor around with his mind. Learning to control it was “like using the force,” he says in the video.
Neuralink’s announcement of a first-in-human trial made a big splash not because of what the man was able to accomplish—scientists demonstrated using a brain implant to move a cursor in 2006—but because the technology is so advanced. The device is unobtrusive and wireless, and it contains electrodes so thin and fragile they must be stitched into the brain by a specialized robot. It also commanded attention because of the wild promises Neuralink founder Elon Musk has made. It’s no secret that Musk is interested in using his chip to enhance the mind, not just restore function lost to injury or illness.
But Neuralink isn’t the only company developing brain-computer interfaces to help people who have lost the ability to move or speak. In fact, Synchron, a New York–based company backed by funding from Bill Gates and Jeff Bezos, has already implanted its device in 10 people. Last week, it launched a patient registry to gear up for a larger clinical trial.
Today in The Checkup, let’s take a look at some of the companies developing brain chips, their progress, and their different approaches to the technology.
Most of the companies working in this space have the same goal: capturing enough information from the brain to decipher the user’s intention. The idea is to aid communication for people who can’t easily move or speak, either by helping them navigate a computer cursor or by actually translating their brain activity into speech or text.
There are a variety of ways to classify these devices, but Jacob Robinson, a bioengineer at Rice University, likes to group them by their invasiveness. There’s an inherent trade-off. The deeper the electrodes go, the more invasive the surgery required to implant them, and the greater the risks. But going deeper also puts the electrodes closer to the brain activity these companies hope to record, which means the device can capture higher-resolution information that might, say, allow the device to decode speech. That’s the goal of companies like Neuralink and Paradromics.
Robinson is CEO and cofounder of a company called Motif Neurotech, which is developing a brain-computer interface that only penetrates the skull (more on this later). In contrast, Neuralink’s device has electrodes that go into the cortex, “right in the first couple of millimeters,” Robinson says. Two other companies—the Austin-based startup Paradromics and Blackrock Neurotech—have also developed chips designed to penetrate the cortex.
“That allows you to get really close to the neurons and get information about what each brain cell is doing,” Robinson says. Proximity to the neurons and a greater number of electrodes that can “listen” to their activity increases the speed of data transfer, or the “bandwidth.” And the greater the bandwidth, the more likely it is that the device will be able to translate brain activity into speech or text.
When it comes to the sheer amount of human experience, Blackrock Neurotech is far ahead of the pack. Its Utah array has been implanted in dozens of people since 2004. It’s the array used by academic labs all over the country. And it’s the array that forms the basis of Blackrock’s MoveAgain device, which received an FDA Breakthrough Designation in 2021. But its bandwidth is likely lower than that of Neuralink’s device, says Robinson.
“Paradromics actually has the highest-bandwidth interface, but they haven’t demonstrated it in humans yet,” Robinson says. The electrodes sit on a chip about the size of a watch battery, but the device requires a separate wireless transmitter that is implanted in the chest and connected to the brain implant by a wire.
There’s a drawback to all these high-bandwidth devices, though. They all require open brain surgery, and “the brain doesn’t really like having needles put into it,” said Synchron founder Tom Oxley in a 2022 TED talk. Synchron has developed an electrode array mounted on a stent, the very same device doctors use to prop open clogged arteries. The “Stentrode” is delivered via an incision in the neck to a blood vessel just above the motor cortex. This unique delivery method avoids brain surgery. But having the device placed above the brain rather than in it limits the amount of data it can capture, Robinson says. He is skeptical the device will be able to capture enough data to move a mouse. But it is sufficient to generate mouse clicks. “They can click yes or no; they can click up and down,” he says.
Newcomer Precision Neuroscience, founded by a former Neuralink executive, has developed a flexible electrode array thinner than a human hair that resembles a piece of Scotch tape. It slides on top of the cortex through a small incision. The company launched its first human trials last year. In these initial studies, the array was implanted temporarily in people who were having brain surgery for other reasons.
Last week, Robinson and his colleagues reported in Science Advances the first human test of Motif Neurotech’s device, which only penetrates the skull. They temporarily placed the small, battery-free device, known as the Digitally Programmable Over-brain Therapeutic (DOT), above the motor cortex of an individual who was already scheduled to undergo brain surgery. When they switched the device on, they saw movement in the patient’s hand.
The ultimate goal of Motif’s device isn’t to produce movement. They’ve set their sights on a completely different application: alleviating mood disorders. “For every person with a spinal cord injury, there are 10 people suffering major depressive disorder and not responding to drugs,” Robinson says. “They’re just as desperate. It’s just not visible.”But the study shows that the device is powerful enough to stimulate the brain, a first step toward the company’s goals.
The device sits above the brain, so it won’t be able to capture high-bandwidth data. But because Motif isn’t actually trying to decode speech or help people move things with their mind, they don’t need it to. “Your emotions don’t change nearly as quickly as the sounds coming out of your mouth,” Robinson says.
Which of these companies will succeed remains to be seen, but with the momentum the field has already gained, controlling technology with your mind no longer seems like the stuff of science fiction. Still, these devices are primarily intended for people who have serious physical impairments. Don’t expect brain implants to achieve Neuralink’s goals of “redefining the boundaries of human capability” or “expanding how we experience the world” anytime soon.
Now read the rest of The Checkup
Read more from Tech Review’s archive
Elon Musk claimed he wants to use brain implants to increase “bandwidth” between people. But the idea of extra-fast communication is “largely hogwash,” said Antonio Regalado in a previous issue of The Checkup. In some instances, however, bandwidth really does matter.
Phil Kennedy, one of the inventors of brain-computer interfaces, ended up getting one himself in pursuit of data. This fascinating and bizarre story from Adam Piore really delivers.
Long read: This 2021 profile of one brain implant user, by Antonio Regalado, covers almost everything you might want to know about brain implants and dives deeper into some of the technologies I mention above.
From around the web
People with HIV have to remember to take a once-daily pill, but in the coming years new, long-acting therapies may be available that would require a weekly pill or a monthly shot. These treatments could prove especially useful for reaching the more than 9 million people who are not receiving treatment. (NYT)
Tests that search for signs of cancer in the blood—sometimes called liquid biopsies—could represent a breakthrough in cancer detection. As many as 20 tests are in various stages of development, and some are already in use. But the evidence that these tests improve survival or reduce the number of deaths is lacking. (Washington Post)
As neurotech expands, there’s a lingering question of who owns your neural data. A new report finds that in many cases, privacy policies don’t protect this information. Some people are trying to change that, including legislators in Colorado, where a bill expanding neurorights protections was just signed into law on Wednesday. (Stat)
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