The burgeoning field of brain mapping

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 to map 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. 

Read more from Tech Review’s archive

In 2013, Courtney Humphries reported on the development of BigBrain, a human brain atlas based on MRI images of more than 7,000 brain slices. 

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)

Cancer vaccines are having a renaissance

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)

My biotech plants are dead

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.

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).

Brain-cell transplants are the newest experimental epilepsy treatment

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.

Justin Graves was managing a scuba dive shop in Louisville, Kentucky, when he first had a seizure. He was talking to someone and suddenly the words coming out of his mouth weren’t his. Then he passed out. Half a year later he was diagnosed with temporal-lobe epilepsy.

JUSTIN GRAVES

Graves’s passion was swimming. He’d been on the high school team and had just gotten certified in open-water diving. But he lost all that after his epilepsy diagnosis 17 years ago. “If you have ever had seizures, you are not even supposed to scuba-dive,” Graves says. “It definitely took away the dream job I had.”

You can’t drive a car, either. Graves moved to California and took odd jobs, at hotels and dog kennels. Anywhere on a bus line. For a while, he drank heavily. That made the seizures worse. 

Epilepsy, it’s often said, is a disease that takes people hostage.

So Graves, who is now 39 and two and half years sober, was ready when his doctors suggested he volunteer for an experimental treatment in which he got thousands of lab-made neurons injected into his brain. 

“I said yes, but I don’t think I understood the magnitude of it,” he says. 

The treatment, developed by Neurona Therapeutics, is shaping up as a breakthrough for stem-cell technology. That’s the idea of using embryonic human cells, or cells converted to an embryonic-like state, to manufacture young, healthy tissue.

And stem cells could badly use a win. There are plenty of shady health clinics that say stem cells will cure anything, and many people who believe it. In reality, though, turning these cells into cures has been a slow-moving research project that, so far, hasn’t resulted in any approved medicines.

But that could change, given the remarkable early results of Neurona’s tests on the first five volunteers. Of those, four, including Graves, are reporting that their seizures have decreased by 80% and more. There are also improvements in cognitive tests. People with epilepsy have a hard time remembering things, but some of the volunteers can now recall an entire series of pictures.

“It’s early, but it could be restorative,” says Cory Nicholas, a former laboratory scientist who is the CEO of Neurona. “I call it activity balancing and repair.”

Starting with a supply of stem cells originally taken from a human embryo created via IVF, Neurona grows “inhibitory interneurons.” The job of these neurons is to quell brain activity—they tell other cells to reduce their electrical activity by secreting a chemical called GABA.

Graves got his transplant in July. He was wheeled into an MRI machine at the University of California, San Diego. There, surgeon Sharona Ben-Haim watched on a screen as she guided a ceramic needle into his hippocampus, dropping off the thousands of the inhibitory cells. The bet was that these would start forming connections and dampen the tsunami of misfires that cause epileptic seizures.

Ben-Haim says it’s a big change from the surgeries she performs most often. Usually, for bad cases of epilepsy, she is trying to find and destroy the “focus” of misbehaving cells causing seizures. She will cut out part of the temporal lobe or use a laser to destroy smaller spots. While this kind of surgery can stop seizures permanently, it comes with the risk of “major cognitive consequences.” People can lose memories, or even their vision. 

That’s why Ben-Haim thinks cell therapy could be a fundamental advance. “The concept that we can offer a definitive treatment for a patient without destroying underlying tissue would be potentially a huge paradigm shift in how we treat epilepsy,” she says. 

Nicholas, Neurona’s CEO, is blunter. “The current standard of care is medieval,” he says. “You are chopping out part of the brain.”

For Graves, the cell transplant seems to be working. He hasn’t had any of the scary “grand mal” attacks, that kind can knock you out, since he stopped drinking. But before the procedure in San Diego, he was still having one or two smaller seizures a day. These episodes, which feel like euphoria or déjà vu, or an absent blank stare, would last as long as half a minute. 

Now, in a diary he keeps as part of the study to count his seizures, most days Graves circles “none.”

LUIS FUENTEALBA AND DANIEL CHERKOWSKY

Other patients in the study are also telling stories of dramatic changes. A woman in Oregon, Annette Adkins, was having seizures every week; but now hasn’t had one for eight consecutive months, according to Neurona. Heather Longo, the mother of another subject, has also said her son has gone for periods without any seizures. She’s hopeful his spirits are picking up and said that his memory, balance, and cognition, are improving.

Getting consistent results from a treatment made of living cells is not going to be easy, however. One volunteer in the study saw no benefit, at least initially, while Graves’s seizures tapered away so soon after the procedure that it’s unclear whether the new cells could have caused the change, since it can takes weeks for them to grow out synapses and connect to other cells.

“I don’t think we really understand all the biology,” says Ben-Haim.

Neurona plans a larger study to help sift through cause and effect. Nicholas says the next stage of the trial will enroll 30 volunteers, half of whom will undergo “sham” surgeries. That is, they’ll all don surgical gowns, and doctors will drill holes into their skulls. But only some will get the cells; for the rest it will be play-acting. That is to rule out a placebo effect or the possibility that, somehow, simply passing a needle into the brain has some benefit.

JUSTIN GRAVES

Graves tells MIT Technology Review he is sure the cells helped him. “What else could it be? I haven’t changed anything else,” he says.

Now he is ready to believe he can get parts of his life back. He hopes to swim again. And if he can drive, he plans to move home to Louisville to be near his parents. “Road trips were always something I liked,” he says. “One of the plans I had was to go across the country. To not have any rush to it and see what I want.”

Now read the rest of The Checkup 

Read more from MIT Technology Review’s archive

This summer, I checked into what 25 years of research using embryonic stem cells had delivered. The answer: lots of hype and no cures…yet.

Earlier this month, Cassandra Willyard wrote about the many scientific uses of “organoids.” These blobs of tissue (often grown from stem cells) mimic human organs in miniature and are proving useful for testing drugs and studying viral infections. 

Our 2023 list of young innovators to watch included Julia Joung, who is discovering the protein factors that tell stem cells what to develop into.

There’s a different kind of stem cell in your bone marrow—the kind that makes blood. Gene-editing these cells can cure sickle-cell disease. The process is grueling, though. In December, one patient, Jimi Olaghere, told us his story.

From around the web

The share of abortions that are being carried out with pills in the US continues to rise, reaching 63%. The trend predates the 2022 Supreme Court decision allowing states to bar doctors from providing abortions. Since then, more women may have started getting the pills outside the formal health-care system. (New York Times)

Excitement over pricey new weight-loss drugs is causing “pharmaco-amnesia,” Daniel Engber says. People are forgetting there were already some decent weight-loss pills that he says were “half as good … for one-30th the price.” (The Atlantic)

There’s a bird flu outbreak among US dairy cattle. It’s troubling to see a virus jump species, but so far, it’s not that bad for cows. “It was kind of like they had a cold,” one source told the AP. (Associated Press)

How scientists traced a mysterious covid case back to six toilets

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.

This week I have a mystery for you. It’s the story of how a team of researchers traced a covid variant in Wisconsin from a wastewater plant to six toilets at a single company. But it’s also a story about privacy concerns that arise when you use sewers to track rare viruses back to their source. 

That virus likely came from a single employee who happened to be shedding an enormous quantity of a very weird variant. The researchers would desperately like to find that person. But what if that person doesn’t want to be found?

A few years ago, Marc Johnson, a virologist at the University of Missouri, became obsessed with weird covid variants he was seeing in wastewater samples. The ones that caught his eye were odd in a couple of different ways: they didn’t match any of the common variants, and they didn’t circulate. They would pop up in a single location, persist for some length of time, and then often disappear—a blip. Johnson found his first blip in Missouri. “It drove me nuts,” he says. “I was like, ‘What the hell was going on here?’” 

Then he teamed up with colleagues in New York, and they found a few more.

Hoping to pin down even more lineages, Johnson put a call out on Twitter (now X) for wastewater. In January 2022, he got another hit in a wastewater sample shipped from a Wisconsin treatment plant. He and David O’Connor, a virologist at the University of Wisconsin, started working with state health officials to track the signal—from the treatment plant to a pumping station and then to the outskirts of the city, “one manhole at a time,” Johnson says. “Every time there was a branch in the road, we would check which branch [the signal] was coming from.”

They chased some questionable leads. The researchers were suspicious the virus might be coming from an animal. At one point O’Connor took people from his lab to a dog park to ask dog owners for poop samples. “There were so many red herrings,” Johnson says.

Finally, after sampling about 50 manholes, the researchers found the manhole, the last one on the branch that had the variant. They got lucky. “The only source was this company,” Johnson says. Their results came out in March in Lancet Microbe. 

Wastewater surveillance might seem like a relatively new phenomenon, born of the pandemic, but it goes back decades. A team of Canadian researchers outlines several historical examples in this story. In one example, a public health official traced a 1946 typhoid outbreak to the wife of a man who sold ice cream at the beach. Even then, the researcher expressed some hesitation. The study didn’t name the wife or the town, and he cautioned that infections probably shouldn’t be traced back to an individual “except in the presence of an outbreak.”

In a similar study published in 1959, scientists traced another typhoid epidemic to one woman, who was then banned from food service and eventually talked into having her gallbladder removed to eliminate the infection. Such publicity can have a “devastating effect on the carrier,” they remarked in their write-up of the case. “From being a quiet and respected citizen, she becomes a social pariah.”

When Johnson and O’Connor traced the virus to that last manhole, things got sticky. Until that point, the researchers had suspected these cryptic lineages were coming from animals. Johnson had even developed a theory involving organic fertilizer from a source further upstream. Now they were down to a single building housing a company with about 30 employees. They didn’t want to stigmatize anyone or invade their privacy. But someone at the company was shedding an awful lot of virus. “Is it ethical to not tell them at that point?” Johnson wondered.

O’Connor and Johnson had been working with state health officials from the very beginning. They decided the best path forward would be to approach the company, explain the situation, and ask if they could offer voluntary testing. The decision wasn’t easy. “We didn’t want to cause panic and say there’s a dangerous new variant lurking in our community,” Ryan Westergaard, the state epidemiologist for communicable diseases at the Wisconsin Department of Health Services, told Nature. But they also wanted to try to help the person who was infected. 

The company agreed to testing, and 19 of its 30 employees turned up for nasal swabs. They were all negative.

That may mean one of the people who didn’t test was carrying the infection. Or could it mean that the massive covid infection in the gut didn’t show up on a nasal swab? “This is where I would use the shrug emoji if we were doing this over email,” O’Connor says.

At the time, the researchers had the ability to test stool samples for the virus, but they didn’t have approval. Now they do, and they’re hoping stool will lead them to an individual infected with one of these strange viruses who can help answer some of their questions. Johnson has identified about 50 of these cryptic covid variants in wastewater. “The more I study these lineages, the more I am convinced that they are replicating in the GI tract,” Johnson says. “It wouldn’t surprise me at all if that’s the only place they were replicating.” 

But how far should they go to find these people? That’s still an open question. O’Connor can imagine a dizzying array of problems that might arise if they did identify an individual shedding one of these rare variants. The most plausible hypothesis is that the lineages arise in individuals who have immune disorders that make it difficult for them to eliminate the infection. That raises a whole host of other thorny questions: what if that person had a compromised immune system due to HIV in addition to the strange covid variant? What if that person didn’t know they were HIV positive, or didn’t want to divulge their HIV status? What if the researchers told them about the infection, but the person couldn’t access treatment? “If you imagine what the worst-case scenarios are, they’re pretty bad,” O’Connor says.

On the other hand, O’Connor says, they think there are a lot of these people around the country and the world. “Isn’t there also an ethical obligation to try to learn what we can so that we can try to help people who are harboring these viruses?” he asks.

Now read the rest of The Checkup

More from MIT Technology Review

Longevity specialists aim to help people live longer and healthier lives. But they have yet to establish themselves as a credible medical field. Expensive longevity clinics that cater to the wealthy worried well aren’t helping. Jessica Hamzelou takes us inside the quest to legitimize longevity medicine.

Drug developers bet big on AI to help speed drug development. But when will we see our first generative drug? Antonio Regalado has the story. 

Read more from MIT Technology Review’s archive

The covid pandemic brought the tension between privacy and public health into sharp relief, wrote Karen Hao in 2020. 

That same year Genevieve Bell argued that we can reimagine contact tracing in a way that protects privacy.

In 2021, Antonio Regalado covered some of the first efforts to track the spread of covid variants using wastewater.  

Earlier this year I wrote about using wastewater to track measles. 

From around the web

Surgeons have transplanted a kidney from a genetically engineered pig into a 62-year-old man in Boston. (New York Times)
→ Surgeons transplanted a similar kidney into a brain-dead patient in 2021. (MIT Technology Review) 
→ Researchers are also looking into how to transplant other organs. Just a few months ago, surgeons connected a genetically engineered pig liver to another brain-dead patient. (MIT Technology Review)

The FDA has approved a new gene therapy for a rare but fatal genetic disorder in children. Its $4.25 million price tag will make it the world’s most expensive medicine, but it promises to give children with the disease a shot at a normal life. (CNN)
→ Read Antonio Regalado’s take on the curse of the costliest drug. (MIT Technology Review)

People who practice intermittent fasting have an increased risk of dying of heart disease, according to new research presented at the American Heart Association meeting in Chicago. There are, of course, caveats. (Washington Post and Stat)

Some parents aren’t waiting to give their young kids the new miracle drug to treat cystic fibrosis. They’re starting the treatment in utero. (The Atlantic) 

Brazil is fighting dengue with bacteria-infected mosquitos

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.

As dengue cases continue to rise in Brazil, the country is facing a massive public health crisis. The viral disease, spread by mosquitoes, has sickened more than a million Brazilians in 2024 alone, overwhelming hospitals.

The dengue crisis is the result of the collision of two key factors. This year has brought an abundance of wet, warm weather, boosting populations of Aedes aegypti, the mosquitoes that spread dengue. It also happens to be a year when all four types of dengue virus are circulating. Few people have built up immunity against them all.   

Brazil is busy fighting back.  One of the country’s anti-dengue strategies aims to hamper the mosquitoes’ ability to spread disease by infecting the insects with a common bacteria—Wolbachia. The bacteria seems to boost the mosquitoes’ immune response, making it more difficult for dengue and other viruses to grow inside the insects. It also directly competes with viruses for crucial molecules they need to replicate. 

The World Mosquito Program breeds mosquitoes infected with Wolbachia in insectaries and releases them into communities. There they breed with wild mosquitoes. Wild females that mate with Wolbachia-infected males produce eggs that don’t hatch. Wolbachia-infected females produce offspring that are also infected. Over time, the bacteria spread throughout the population. Last year I visited the program’s largest insectary—a building in Medellín, Colombia, buzzing with thousands of mosquitoes in netted enclosures— with a group of journalists. “We’re essentially vaccinating mosquitoes against giving humans disease,” said Bryan Callahan, who was director of public affairs at the time.

The World Mosquito Program first began releasing Wolbachia mosquitoes in Brazil in 2014. The insects now cover an area with a population of more than 3 million across five municipalities: Rio de Janeiro, Niterói, Belo Horizonte, Campo Grande, and Petrolina.

In Niterói, a community of about 500,000 that lies on the coast just across a large bay from Rio de Janeiro, the first small pilot releases began in 2015, and in 2017 the World Mosquito Program began larger deployments. By 2020, Wolbachia had infiltrated the population. Prevalence of the bacteria ranged from 80% in some parts of the city to 40% in others. Researchers compared the prevalence of viral illnesses in areas where mosquitoes had been released with a small control zone where they hadn’t released any mosquitoes. Dengue cases declined by 69%. Areas with Wolbachia mosquitoes also experienced a 56% drop in chikungunya and a 37% reduction in Zika.

How is Niterói faring during the current surge? It’s early days. But the data we have so far are encouraging. The incidence of dengue is one of the lowest in the state, with 69 confirmed cases per 100,000 people. Rio de Janeiro, a city of nearly 7 million, has had more than 42,000 cases, an incidence of 700 per 100,000.

“Niterói is the first Brazilian city we have fully protected with our Wolbachia method,” says Alex Jackson, global editorial and media relations manager for the World Mosquito Program. “The whole city is covered by Wolbachia mosquitoes, which is why the dengue cases are dropping significantly.”

The program hopes to release Wolbachia mosquitoes in six more cities this summer. But Brazil has more than 5,000 municipalities. To make a dent in the overall incidence in Brazil, the program will have to release millions more mosquitoes. And that’s the plan.

The World Mosquito Program is about to start construction on a mass rearing facility—the biggest in the world—in Curitiba. “And we believe that will allow us to essentially cover most of urban Brazil within the next 10 years,” Callahan says.

There are also other mosquito-based approaches in the works. The UK company Oxitec has been providing genetically modified “friendly” mosquito eggs to Indaiatuba, Brazil, since 2018. The insects that hatch—all males—don’t bite. And when they mate, their female offspring don’t survive, reducing populations. 

Another company, Forrest Brasil Tecnologia, has been releasing sterile male mosquitoes in parts of Ortigueira. When these males mate with wild females, they produce eggs that don’t hatch.  From November 2020 to July 2022, the company recorded a 98.7% decline in the Ades aegypti  population in Ortigueira. 

Brazil is also working on efforts to provide its citizens with greater immunity, vaccinating the most vulnerable with a new shot from Japan and working on its own home-grown dengue vaccine. 

None of these solutions are a quick fix. But they all provide some hope that the world can find ways to fight back even as climate change drives dengue and other infections to new peaks and into new territories. ““Cases of dengue fever are rising at an alarming rate,” Gabriela Paz-Bailey, who specializes in dengue at the US Centers for Disease Control and Prevention, told the Washington Post. “It’s becoming a public health crisis and coming to places that have never had it before.”

Now read the rest of The Checkup

Read more from MIT Technology Review’s archive

We’ve written about the World Mosquito Program before. Here’s a 2016 story from Antonio Regalado that looked at early excitement and Bill Gates’ backing of the project. 

That same year we reported on Oxitec’s early work in Brazil using genetically modified mosquitoes. Flavio Devienne Ferreira has the story. 

And this story from Emily Mullin looks at Google’s sister company, Verily. It built a robot to create Wolbachia-infected mosquitoes and began releasing them in California in 2017. (The project is now called Debug). 

From around the web

The FDA-approved ALS drug Relyvrio has failed to benefit patients in a large clinical trial. It was approved early amidst questions about its efficacy, and now the medicine’s manufacturer has to decide whether to pull it off the  market. (NYT)

Wegovy: it’s not just for weight loss anymore. The FDA has approved a label expansion that will allow Novo Nordisk to market the drug for its heart benefits, which might prompt more insurers to cover it. (CNN)

Covid killed off one strain of the flu and experts suggest dropping it from the next flu vaccine. (Live Science) 

Scientists have published the first study linking microplastic pollution to human disease. The research shows that people with plastic in their artery tissues were twice as likely to have a heart attack, stroke, or die than people without plastic. (CNN)

The many uses of mini-organs

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.

This week I wrote about a team of researchers who managed to grow lung, kidney, and intestinal organoids from fetal cells floating around in the amniotic fluid. Because these tiny 3D cell clusters come from the fetus and mimic some of the features of a real, full-size organ, they can provide a sneak peek at how the fetus is developing. That’s something nearly impossible to do with existing tools.

An ultrasound, for example, might reveal that a fetus’s kidneys are smaller than they should be, but absent a glaring genetic defect, doctors can’t say why they’re small or figure out a fix. But if they can take a small sample of amniotic fluid and grow a kidney organoid, the problem might become evident, and so might a potential solution.  

Exciting, right? But organoids can do so much more!

Let’s do a roundup of some of the weird, wild, wonderful, and downright unsettling uses that researchers have come up with for organoids.

Organoids could help speed drug development. By some estimates, 90% of drug candidates fail during human trials. That’s because the preclinical testing happens largely in cells and rodents. Neither is a perfect model. Cells lack complexity. And mice, as we all know, are not humans.

Organoids aren’t humans either, but they come from humans. And they have the advantage of having more complexity than a layer of cells in a dish. That makes them a good model for screening drug candidates. When I wrote about organoids in 2015, one cancer researcher told me that studying cells to understand how an organ functions is like studying a pile of bricks to understand the function of a house. Why not just study the house?

Big Pharma appears to agree. In 2022, Roche hired organoid pioneer Hans Clevers to head its Pharma Research and Early Development division. “My belief is that human organoids will eventually complement everything we are currently doing. I’m convinced, now that I’ve seen how the whole drug development process runs, that one can implement human organoids at every step of the way,” Clevers told Nature.

Organoids are trickier to grow than cell lines, but some companies are working to make the process automated. The Philadelphia-based biotech Vivodyne has developed a robotic system that combines organoids with organ-on-a-chip technology. The system grows 20 kinds of human tissue, each containing 200,000 to 500,000 cells, and then doses them with drugs. These “lab-grown human test subjects” provide “huge amounts of complex human data—larger than you could get from any clinical trial,” said Andrei Georgescu, CEO and cofounder of Vivodyne, in a press release.

According to Viodyne’s website, the proprietary machines can test 10,000 independent human tissues at a time, “yielding vivarium-scale output.” Vivarium-scale output. I had to roll this phrase around my brain quite a few times before I understood what they meant: the robot provides the same amount of data as a building full of lab mice.

Organoids could help doctors make medical decisions for individual patients. These mini organs can be grown from stem cells, but they can also be grown from adult cells that have been nudged into a stem-like state. That makes it possible to grow organoids from anyone for any number of uses. In cancer patients, for instance, these patient-derived organoids could be used to help figure out the best therapy.

Cystic fibrosis is another example. Many cystic fibrosis therapies are approved to treat people with specific mutations. But for people who have rarer mutations, it’s not clear which therapies will work. Enter organoids.

Doctors take rectal biopsies from people with the disease, use the cells to create personalized intestinal organoids, and then apply different drugs. If a given treatment works, the ion channels open, water rushes in, and the organoids visibly swell. The results of this test have been used to guide the off-label use of these medications. In one recent case, the test allowed a woman with cystic fibrosis to access one of these drugs through a compassionate use program. 

Organoids are also poised to help researchers better understand how our bodies interact with the microbes that surround (and sometimes infect) us. During the Zika health emergency in 2015, researchers used brain organoids to figure out how the virus causes microcephaly and brain malformations. Researchers have also managed to use organoids to grow norovirus, the pathogen responsible for most stomach flus. Human norovirus doesn’t infect mice, and it has proved especially tricky to culture in cells. That’s probably part of the reason we have no therapies for the illness.  

I’ve saved the weirdest and arguably creepiest applications for last. Some researchers are working to leverage the brain’s unparalleled ability to learn by developing brain organoid biocomputers. The current iterations of these biocomputers aren’t doing any high-level thinking. One clump of brain cells in a dish learned to play the video game Pong. Another hybrid biocomputer maybe managed to decode some audio signals from people pronouncing Japanese vowels. The field is still in extremely early stages, and researchers are wary of overhyping the technology. But given where the field wants to go—full-fledged organoid intelligence—it’s not too early to talk about ethical concerns. Could a biocomputer become conscious? Organoids arise from cells taken from an individual. What rights would that person have? Would the biocomputer have rights of its own? And what about rodents that have had brain organoids implanted in them? (Yes, that’s happening too). 

Last year, researchers reported that human organoids implanted in rat brains expanded into millions of neurons and managed to wire themselves into the animal’s brain. When they blew a puff of air over the rat’s whiskers, they could record an electrical signal zipping through the human neurons.

In a 2017 Stat story on efforts to implant human brain organoids into rodents, the late Sharon Begley talked to legal scholar and bioethicist Hank Greely of Stanford University. During their conversation, he invoked the literary classic Frankenstein as a cautionary and relevant tale: “it could be that what you’ve built is entitled to some kind of respect,” he told her.

Now read the rest of The Checkup

Read more from MIT Technology Review’s archive

In 2023, scientists reported that brain organoids  hitched to an electronic chip could perform  some very basic speech recognition tasks. Abdullahi Tsanni has the story.

Saima Sidik tells us how organoids created from the uterine lining might reveal the mysteries of menstruation. Here’s her report. 

When will we be able to transplant mini lungs, livers, or thyroids into people? Ten years …  maybe, said my colleague Jess Hamzelou in this past issue of The Checkup. 

From around the web

An Alabama bill passed on Wednesday creates a “legal moat” around embryos. Under the new law, providers and recipients of IVF could not be prosecuted or sued for damaging or destroying embryos. But the law doesn’t answer the central question raised by Alabama courts last week: Are embryos people? (NYT)

More legal news. The Senate homeland security committee passed a bill this week that would block certain Chinese biotechs from conducting business in the US. The aim is to keep them from accessing Americans personal health data and genetic information. But some critics have raised supply chain concerns. (Reuters)

Some scientists have expressed concern that too many covid shots could fatigue the immune system and make vaccination less effective. But a man who got a whopping 217 covid vaccines showed no signs of a flagging immune response. (Washington Post)

Buckle up. Norovirus is coming for you. (USA Today).Small studies showing that ibogaine, a psychedelic derived from tree bark, can treat opioid addiction have renewed interest in this illegal drug. But some researchers question whether it could ever be a feasible therapy (NYT)