2026-01-14 05:44:52
“Generative biology is moving drug discovery from a process of chance to one of design.”
Antibodies touch nearly every corner of healthcare. These carefully crafted proteins can target cancer cells, control autoimmune diseases, fight infections, and destroy the toxic proteins that drive neurological disorders. They’re also notoriously difficult to make.
Over 160 antibody therapies have been approved globally. Their market value is expected to reach $445 billion in the next five years. But the traditional design process takes years of trial and error and is often constrained to structures similar to existing proteins.
With AI, however, we can now generate completely new antibody designs—never before seen in nature—from scratch. Last year, labs and commercial companies raced to build increasingly sophisticated algorithms to predict and generate these therapeutics. While some tools are proprietary, many are open source, allowing researchers to tailor them to a specific project.
Some AI-optimized antibodies are already in early clinical trials. In late September, Generate:Biomedicines in Somerville, Massachusetts presented promising data from patients with asthma treated with an antibody designed with AI’s help. A shot every six months lowered asthma-triggering protein levels without notable side effects.
“Generative biology is moving drug discovery from a process of chance to one of design,” said Mike Nally, CEO of Generate, in a press release.
Nobel Prize winner David Baker at the University of Washington would likely agree. Known for his work on protein structure prediction and design, his team upgraded an AI last year to dream up antibodies for any target at the atomic level.
Pills containing small-molecule drugs like Tylenol still dominate healthcare. But antibody therapies are catching up. These therapies work by grabbing onto a given protein, like a key fitting into a lock. The interaction then either activates or inhibits the target.
Antibodies come in different shapes and sizes. Monoclonal antibodies, for example, are lab-made proteins that precisely dock to a single biological target, such as one involved in the growth or spread of cancer. Nanobodies, true to their name, are smaller but pack a similar punch. The FDA has approved one treatment based on the technology for a blood clotting disorder.
Regardless of type, however, antibody treatments traditionally start from similar sources. Researchers usually engineer them by vaccinating animals, screening antibody libraries, or isolating them from people. Laborious optimization procedures follow, such as mapping the exact structure of the binding pocket on the target—the lock—and tweaking the antibody key.
The process is tedious and unpredictable. Many attempts fail to find antibodies that reliably scout out their intended docking site. It’s also largely based on variations of existing proteins that may not have the best therapeutic response or safety profile. Candidates are then painstakingly optimized using iterations of computational design and lab validation.
The rise of AI that can model protein structures—and their interactions with other molecules—as well as AI that generates proteins from scratch has sparked new vigor in the field. These models are similar to those powering the AI chatbots that have taken the world by storm for their uncanny ability to dream up (sometimes bizarre) text, images, and video.
In a way, antibody structures can be represented as 3D images, and their molecular building blocks as text. Training a generative AI on this data can yield an algorithm that produces completely new designs. Rather than depending on chance, it may be possible to rationally design the molecules for any given protein lock—including those once deemed “undruggable.”
But biology is complex. Even the most thoughtful designs could fail in the body, unable to grasp their target or latching onto unintended targets, leading to side effects. Antibodies rely on a flexible protein loop to recognize their specific targets, but early AI models, such as DeepMind’s AlphaFold, struggled to map the structure and behavior of these loops.
The latest AI is faring better. An upgraded version of Baker lab’s RFdiffusion model, introduced last year, specifically tackles these intricate loops based on information about the structure of the target and location of the binding pocket. Improved prediction quickly led to better designs.
Initially, the AI could only make nanobodies. These are short but functional chunks of antibodies for a range of viruses, such as the flu, and antidotes against deadly snake venoms. After further tweaking, the AI suggested longer, more traditional antibodies against a toxin produced by a type of life-threatening bacteria that often thwarts antibacterial drugs.
Lab tests confirmed that the designer proteins reliably latched onto their targets at commonly used doses without notable off-site interactions.
“Building useful antibodies on a computer has been a holy grail in science. This goal is now shifting from impossible to routine,” said study author Rob Ragotte.
There have been more successes. One lab introduced a generative model that can be fine-tuned using the language of proteins—for example, adding structural constraints of the final product. In a test, the team selected 15 promising AI-made nanobody designs for cancer, infections, and other diseases, and each successfully found its target in living cells. Another lab publicly released an AI called Germinal that’s also focused on making nanobodies from scratch.
Commercial companies are hot on academia’s heels.
Nabla Bio, based in Cambridge, Massachusetts, announced a generative AI-based platform called JAM that can tackle targets previously unreachable by antibodies. One example is a highly complex protein class called G-protein-coupled receptors. These seven-arm molecules form the “largest and most diverse group” of protein receptors embedded in cell membranes. Depending on chemical signals, the receptors trigger myriad cell responses—tweaking gene activation, brain signaling, hormones—but their elaborate structure makes designing antibodies a headache.
With JAM, the company designed antibodies to target these difficult proteins, showcasing the AI’s potential to unlock previously unreachable targets. They’re releasing parts of the data involved in characterized antibodies from the study, but most of the platform is proprietary.
Momentum for clinical trials is also building.
After promising initial results, Generate:Biomedicines launched a large Phase 3 study late last year. The trial involves roughly 1,600 people with severe asthma across the globe and is testing an antibody optimized—not engineered from scratch—with the help of AI.
The hope is AI could eventually take over the entire antibody-design process: predicting target pockets, generating potential candidates, and ranking them for further optimization. Rational design could also lead to antibodies that better navigate the body’s crooks and crannies, including those that can penetrate into the brain.
It’ll be a long journey, and safety is key. Because the dreamed-up proteins are unfamiliar to the body, they could trigger immune attacks.
But ultimately, “AI antibody design will transform the biotechnology and pharmaceutical industries, enabling precise targeting and simpler drug development,” says Baker.
The post AI-Designed Antibodies Are Racing Toward Clinical Trials appeared first on SingularityHub.
2026-01-13 06:36:16
The skin could allow machines to dynamically blend into their surroundings or be used to create adaptive displays and artwork.
An octopus’s adaptive camouflage has long inspired materials scientists looking to come up with new cloaking technologies. Now researchers have created a synthetic “skin” that independently shifts its surface patterns and colors like these intelligent invertebrates.
The ability to alter an object’s appearance on demand has a host of applications, from allowing machines to dynamically blend into their surroundings to creating adaptive displays and artwork. Octopuses are an obvious source of inspiration thanks to their unique ability to change the color and physical structure of their skin in just seconds.
So far, however, materials scientists have struggled to replicate this dual control. Materials that change color typically use nanostructures to reflect light in specific ways. But changing a surface’s shape interferes with these interactions, making it challenging to tune both properties simultaneously.
Now, in a paper published in Nature, Stanford University researchers cracked the problem by creating a synthetic skin made of two independently controlled polymer layers: One changes color and the other shape.
“For the first time, we can mimic key aspects of octopus, cuttlefish, and squid camouflage in different environments: namely, controlling complex, natural-looking textures and at the same time, changing independent patterns of color,” Siddharth Doshi, first author of the paper, told The Financial Times.
The new camouflage system took direct inspiration from cephalopods, which use tiny muscle-controlled structures called papillae to reshape their skin’s surface while separate pigment cells alter color.
To recreate these abilities, the researchers turned to a polymer called PEDOT:PSS, which swells when it absorbs water. The team used electron-beam lithography—a technology typically used to etch patterns into computer chips—to control how much different areas of the polymer swell when exposed to liquid.
The team covered one layer of the polymer in a single layer of gold to create textures that switch between a shiny and matte appearance. They then sandwiched another layer of the polymer between two layers of gold, creating an optical cavity that could be used to generate a wide variety of colors as the distance between the gold sheets changes.
The researchers can create four distinct visual states—texture combined with a color pattern, texture only, color only, and no texture or color pattern—by exposing each side of the skin to either water or isopropyl alcohol. The system switches between states in about 20 seconds, and the process is fully reversible.
“By dynamically controlling the thickness and topography of a polymer film, you can realize a very large variety of beautiful colors and textures,” Mark Brongersma, a senior author on the paper, said in a press release. “The introduction of soft materials that can expand, contract, and alter their shape opens up an entirely new toolbox in the world of optics to manipulate how things look.”
Applications could extend beyond camouflage the researchers say—for instance using texture changes to control whether small robots cling to or slide across surfaces or creating advanced displays for wearable devices or art projects.
The current need to apply water to control the appearance of the skin is “a huge limitation,” Debashis Chanda, a physicist at the University of Central Florida, told Nature. But the researchers told the Financial Times they plan to introduce digital control systems to future versions of the skin.
They also hope to add computer vision algorithms to provide information about the surrounding environment the skin needs to blend in with. “We want to be able to control this with neural networks—basically an AI-based system—that could compare the skin and its background, then automatically modulate it to match in real time, without human intervention,” Doshi said in the press release.
While the research faces a long road from the lab bench to commercial reality, sci-fi style cloaking technology has taken a tiny step closer to reality.
The post Sci-Fi Cloaking Technology Takes a Step Closer to Reality With Synthetic Skin Like an Octopus appeared first on SingularityHub.
2026-01-11 03:10:13
Google Gemini Is Taking Control of Humanoid Robots on Auto Factory FloorsWill Knight | Wired ($)
“Google DeepMind is teaming up with Boston Dynamics to give its humanoid robots the intelligence required to navigate unfamiliar environments and identify and manipulate objects—precisely the kinds of capabilities needed to perform manual labor.”
Distinct AI Models Seem to Converge on How They Encode RealityBen Brubaker | Quanta Magazine
“Is the inside of a vision model at all like a language model? Researchers argue that as the models grow more powerful, they may be converging toward a singular ‘Platonic’ way to represent the world.”
Flu Is Relentless. CRISPR Might Be Able to Shut It Down.
David Cox | Wired ($)
“They believe CRISPR could be tailored to create a next-generation treatment for influenza, whether that’s the seasonal strains which plague both the northern and southern hemispheres on an annual basis or the worrisome new variants in birds and other wildlife that might trigger the next pandemic.”
Next-Level Quantum Computers Will Almost Be UsefulDina Genkina | IEEE Spectrum
“The machine that Microsoft and Atom Computing will be delivering, called Magne, will have 50 logical qubits, built from some 1,200 physical qubits, and should be operational by the start of 2027. QuEra’s machine at AIST has around 37 logical qubits (depending on implementation) and 260 physical qubits, Boger says.”
AI Coding Assistants Are Getting Worse
Jamie Twiss | IEEE Spectrum
“In recent months, I’ve noticed a troubling trend with AI coding assistants. After two years of steady improvements, over the course of 2025, most of the core models reached a quality plateau, and more recently, seem to be in decline. A task that might have taken five hours assisted by AI, and perhaps ten hours without it, is now more commonly taking seven or eight hours, or even longer.”
Meta Unveils Sweeping Nuclear-Power Plan to Fuel Its AI Ambitions
Jennifer Hiller | The Wall Street Journal ($)
“Meta Platforms on Friday unveiled a series of agreements that would make it an anchor customer for new and existing nuclear power in the US, where it needs city-size amounts of electricity for its artificial-intelligence data centers. …Financial details weren’t disclosed, but the arrangements are among the most sweeping and ambitious so far between tech companies and nuclear-power providers.”
Even the Companies Making Humanoid Robots Think They’re OverhypedSean McLain | The Wall Street Journal ($)
“Billions of dollars are flowing into humanoid robot startups, as investors bet that the industry will soon put humanlike machines in warehouses, factories and our living rooms. For all the recent advances in the field, humanoid robots, they say, have been overhyped and face daunting technical challenges before they move from science experiments to a replacement for human workers.”
Former Google CEO Plans to Singlehandedly Fund a Hubble Telescope Replacement
Eric Berger | Ars Technica
“On Wednesday evening, former Google CEO Eric Schmidt and his wife, Wendy, announced a major investment in not just one telescope project, but four. Each of these new telescopes brings a novel capability online; however, the most intriguing new instrument is a space-based telescope named Lazuli. This spacecraft, if successfully launched and deployed, would offer astronomers a more capable and modern version of the Hubble Space Telescope, which is now three decades old.”
Uber’s Not Done With Self-Driving Cars Just Yet. It’s Designing a New Robotaxi With Lucid and NuroSasha Lekach | Gizmodo
“The companies said that on-road testing [in San Francisco] started at the end of last year, which isn’t surprising as Nuro already holds driverless testing permits through the California DMV. Eventually, the trio plan to offer the Level 4 robotaxi prototype everywhere Uber has a presence—if all goes well, that is.”
Kawasaki’s Four-Legged Robot-Horse Vehicle Is Going Into ProductionBronwyn Thompson | New Atlas
“What was announced as a 2050 pipe dream by Kawasaki, the company’s hydrogen-powered, four-hooved, all-terrain robot horse vehicle Corleo is actually going into production and is now expected to be commercially available decades earlier—with the first model to debut in just four years.”
NASA’s Science Budget Won’t Be a Train Wreck After AllEric Berger | Ars Technica
“On Monday, Congress made good on…promises [to fund most of NASA’s science portfolio], releasing a $24.4 billion budget plan for NASA as part of the conferencing process, when House and Senate lawmakers convene to hammer out a final budget. The result is a budget that calls for just a 1 percent cut in NASA’s science funding, to $7.25 billion, for fiscal year 2026.”
AI Is Being Used to Find Valuable Commodities in Our TrashRyan Dezember | The Wall Street Journal ($)
“Murphy Road executives say the technology allows them to sort up to 60 tons an hour of curbside recycling from around Connecticut and western Massachusetts into precisely sorted bales of paper, plastic, aluminum cans, and other materials. The material is sold to mills, manufacturers, and remelt facilities, which pay more for cleaner bales.”
The post This Week’s Awesome Tech Stories From Around the Web (Through January 10) appeared first on SingularityHub.
2026-01-09 23:00:00
There’s a case to be made that Earth’s life arrived on meteorites from Mars. Here’s the evidence for and against.
How did life begin on Earth? While scientists have theories, they don’t yet fully understand the precise chemical steps that led to biology or when the first primitive life forms appeared.
But what if Earth’s life did not originate here, instead arriving on meteorites from Mars? It’s not the most favored theory for life’s origins, but it remains an intriguing hypothesis. Here, we’ll examine the evidence for and against.
Timing is a key factor. Mars formed around 4.6 billion years ago, while Earth is slightly younger at 4.54 billion years old. The surfaces of both planets were initially molten, before gradually cooling and hardening.
Life could, in theory, have arisen independently on both Earth and Mars shortly after formation. While the surface of Mars today is probably uninhabitable for life as we know it, early Mars probably had similar conditions to the early Earth.
Early Mars seems to have had a protective atmosphere and liquid water in the form of oceans, rivers, and lakes. It may also have been geothermally active, with plenty of hydrothermal vents and hot springs to provide the necessary conditions for the emergence of life.
However, about 4.51 billion years ago, a Mars-sized, rocky planet called Theia crashed into the proto-Earth. This impact caused both bodies to melt together and then separate into our Earth and its moon. If life had begun before this event, it certainly would not have survived it.
Mars, on the other hand, probably didn’t experience a global remelting event. The red planet had its fair share of impacts in the violent early solar system, but evidence suggests that none of these would have been large enough to completely destroy the planet—and some areas could have remained relatively stable.
So if life arose on Mars shortly after formation of the planet 4.6 billion years ago, it could have continued evolving without major interruptions for at least half a billion years. After this time, Mars’ magnetic field collapsed, marking the beginning of the end for Martian habitability. The protective atmosphere disappeared, leaving the planet’s surface exposed to freezing temperatures and ionizing radiation from space.
But what of Earth: How soon did life appear after the impact that formed the moon? Tracing the tree of life back to its root leads to a microorganism called Luca—the last universal common ancestor. This is the microbial species from which all life today is descended. A recent study reconstructed Luca’s characteristics using genetics and the fossil record of early life on Earth. It inferred that Luca lived 4.2 billion years ago—earlier than some previous estimates.
Luca was not the earliest organism on Earth, but one of multiple species of microbe existing in tandem on our planet at this time. They were competing, cooperating, and surviving the elements, as well as fending off attacks from viruses.
If small but fairly complex ecosystems were present on Earth around 4.2 billion years ago, life must have originated earlier. But how much earlier? The new estimate for the age of Luca is 360 million years after the formation of the Earth and 290 million years after the moon-forming impact. All we know is that in these 290 million years, chemistry somehow became biology. Was this enough time for life to originate on Earth and then diversify into the ecosystems present when Luca was alive?
A Martian origin for terrestrial life circumvents this question. According to the hypothesis, species of Martian microorganism could have traveled to Earth on meteorites just in time to take advantage of the clement conditions following the moon’s formation.
The timing may be convenient for this idea. However, as someone who works in the field, my hunch would be that 290 million years is plenty of time for chemical reactions to produce the first living organisms on Earth and for biology to subsequently diversify and become more complex.
Luca’s reconstructed genome suggests that it could live off molecular hydrogen or simple organic molecules as food sources. Along with other evidence, this suggests that Luca’s habitat was either a shallow marine hydrothermal vent system or a geothermal hot spring. Current thought in the origin of life field is that these kinds of environments on the early Earth had the necessary conditions for life to emerge from non-living chemistry.
Luca also contained biochemical machinery that could protect it from high temperatures and UV radiation—real dangers in these early Earth environments.
However, it’s far from certain that early life forms could have survived the journey from Mars to Earth. And there’s nothing in Luca’s genome to suggest that it was particularly well adapted to space flight.
In order to have made it to Earth, microorganisms would need to have survived the initial impact on Mars’ surface, a high-speed ejection from the Martian atmosphere, and travel through the vacuum of space while being bombarded by cosmic rays for at least the best part of a year.
They would then have needed to survive the high-temperature entry through Earth’s atmosphere and another impact onto the surface. This last event may or may not have deposited it in an environment to which it was even remotely adapted.
The chances of all of this seem pretty slim to me. However difficult the transition from chemistry to biology may appear, it seems far easier to me than the idea that this transition would occur on Mars, with life forms surviving the journey to Earth, and then adapting to a completely new planet. However, I could be wrong.
It’s useful to look at studies of whether microorganisms could survive the journey between planets. So far, it looks like only the hardiest microorganisms could survive the journey between Mars and Earth. These are species adapted to preventing damage from radiation and capable of surviving desiccation through the formation of spores.
But maybe, just maybe, if a population of microorganisms were trapped in the interior of a sufficiently large meteorite, they could be protected from most of the harsh conditions of space. Some computer simulations even support this idea. Further simulations and laboratory experiments to test this are ongoing.
This raises another question—if life made it from Mars to Earth within the first 500 million years of our solar system’s existence, why hasn’t it spread from Earth to the rest of the solar system in the following four billion years? Maybe we’re not the Martians after all.
This article is republished from The Conversation under a Creative Commons license. Read the original article.
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2026-01-08 23:00:00
The treatment converted the liver into an immune cell “nursery” that pumped out greater numbers of healthy T cells.
Our immune system is a fierce brigade. Roaming immune cells scan for bacteria, viruses, and other invaders. They also communicate with tissues to catch early signs of cancer. After detecting a threat, the immune system kickstarts formidable defenses to snuff it out.
But our immunity loses power as we age. Immune cells dwindle, and those that remain struggle to perform their usual roles. As a result, immune defenses weaken, increasing the chances of infection and cancer. This also makes vaccines less effective in older adults.
Now, a new treatment using mRNA technology similar to that in Covid vaccines rejuvenated the immune systems of old mice with twice-weekly shots. The injections transformed the liver into a temporary nursery to boost the numbers and health of key immune cells.
Treated mice, aged the human-equivalent of their early 60s, saw a rapid rise in multiple T cell types after vaccination. They also rallied against tumors with a popular cancer immunotherapy.
Resetting immunity isn’t just about defense. The immune system is intricately tied to the health of other organs. Chronic inflammation steadily rises as we age, wreaking havoc on memory, cognition, and metabolism. It also stiffens tissues in multiple organs, increasing the chances of heart attacks and kidney failure.
“If we can restore something essential like the immune system, hopefully we can help people stay free of disease for a longer span of their life,” study author Feng Zhang at MIT said in a press release.
Multiple immune cell types protect our bodies, but T cells are one of the most prominent.
Some T cells seek and destroy virus-infected cells and cancer. Others coordinate immune responses and balance the attack to prevent autoimmune problems or runaway inflammation. Still more “remember” prior threats to trigger a faster immune response when re-exposed.
Despite their wide range, all T cells are born in the bone marrow. Baby T cells then journey to the thymus, a small organ sitting at the top of the heart, where they mature and diversify. In this nursery, the cells learn friend from foe, ensuring they’ll only attack legitimate threats while leaving healthy cells alone. The process is mostly coordinated by cocktails of proteins and other signaling molecules, which direct the fate of immature cells and help them survive.
The aging process gradually degrades the nursery. The thymus shrinks, and much of its working tissue is replaced by fat, leading to a drop in newly minted T cells.
“As we get older, the immune system begins to decline. We wanted to think about how can we maintain this kind of immune protection for a longer period of time, and that’s what led us to think about what we can do to boost immunity,” said study author Mirco Friedrich.
For years scientists have tried to revive the organ. Hormones and immune-related proteins have struggled to bring it back to health. More exotic approaches, such as infusing the blood of young animals, transplanting stem cells, or directly tinkering with blood stem cells have shown some promise but are hard to turn into clinical treatments.
“Much has already been attempted to halt or reverse the age-related involution of the thymus,” said Friedrich. “Unfortunately, without much success so far.”
Rather than reviving the struggling organ, the team built a new T cell nursery in another part of the body.
They began by comprehensively mapping genetic changes in infant and elderly mice and deciphering how shifts in gene expression influenced T cell production.
The screen surfaced three genes that play a critical role in T cell maturation. The proteins those genes produce fall with age, correlating with lower T cell numbers. Refreshing the proteins could, in theory, reboot immune cell production.
This “is more of a synthetic approach,” said Zhang. “We’re engineering the body to mimic thymic factor secretion.”
They decided on the liver as a temporary nursery for several reasons. The organ faithfully synthesizes proteins even into old age, and it’s a relatively easy target for mRNA treatments.
The team packaged mRNA encoding the three nurturing proteins into fatty nanoparticles and injected them into mice’s blood twice weekly for a month, beginning when the mice were aged the rough equivalent of people in their 60s. While far from elderly, T cell defects are noticeable around this age, and the cells could benefit from early intervention.
Compared to untreated peers, those given the shots produced more, healthier T cells. The treatment also boosted the critters’ immunity. In one test, mice vaccinated against ovalbumin, a major protein in egg whites, had a far stronger immune response against the protein compared to peers without the mRNA treatment.
The shots also helped the mice’s laggy immune systems better coordinate with checkpoint inhibitors, a common cancer medication. Mice with cancer given both treatments survived longer and at higher rates than those given only the inhibitors. More tests found all three protein-encoding mRNA sequences were needed to rejuvenate the immune system.
To be clear, this isn’t a one-and-done shot. The effects wane after treatment ends. While it seems like an inconvenience, the flexibility allows scientists to further tinker with dosage and treatment schedule and minimize side effects. More broadly, the study shows restoring the thymus isn’t necessary for turning back the clock on the immune system. Mimicking its signals in other parts of the body could also help T cells thrive, even in old age.
These are early results, and more tests are needed before bringing the therapy to people. The team plans to study the mRNA trio in other animals and hunt down more proteins that nurture T cells. They’re also looking to expand the strategy to other immune cell types, like the B cells that pump out antibodies.
“The immune system ages, but it does not irreversibly lose its abilities. If we provide it with the missing signals again, it can once more perform amazing feats,” said Friedrich.
The post Aging Weakens Immunity. An mRNA Shot Turned Back the Clock in Mice. appeared first on SingularityHub.
2026-01-06 23:00:00
This year saw the meteoric rise of a promising new therapy for brain health.
Microglia are the silent guardians of the brain. They hunt down pathogens, clean up toxic protein clumps, and even shape the brain’s wiring. They’re also robust. Neurons can’t divide to generate new copies of themselves. But microglia can renew, especially during inflammation, stroke, or diseases that erode cognition.
And yet this regenerative ability has a limit, especially when the cells harbor genetic mutations. One solution? Replace diseased or injured cells with a fresh supply.
This year saw a meteoric rise in microglia replacement therapy, with clinical trials highlighting its brain-protecting potential. Refreshing microglia could, in theory, boost their beneficial effects.
Tinkering with the brain’s complex immune system isn’t straightforward, but “microglia replacement has emerged as a groundbreaking paradigm,” wrote Bo Peng and colleagues at Fudan University. The therapy could tackle a range of conditions from rare genetic diseases to more familiar foes such as Alzheimer’s.
Microglia are odd ducks. Like other immune cells that patrol the body, they usually start out as blood stem cells in bone marrow before migrating to the brain. Once settled, they stay at their post, exclusively protecting the brain.
The cells are usually shaped like shrubs in need of a haircut. But once activated, they shrink into puff balls and recruit other brain cells to fight off invaders and prevent brain damage.
Microglia also reconfigure the brain’s wiring. They prune extra synapses—connection points that allow neurons to talk to each other—and pump out nutritious molecules to support established neural networks and encourage baby neurons to grow.
It’s no wonder that when microglia go awry so does the brain. This happens in Alzheimer’s, other neurodegenerative diseases, and even just as we age. But more commonly, it’s because of genetic mutations in the cells.
Gene therapy is seemingly the best way to fix these problems. But microglia are notoriously terrible candidates. A gene therapy is usually shuttled into cells within safe viral carriers or tiny bubbles of fat. Few of these can enter the brain’s immune cells. Microglia-specific carriers exist, but they need to be injected directly into the brain. Complications from surgery aside, injected cells only reach a small area—hardly enough to make a notable difference.
Microglia replacement gets around this roadblock. Replacing mutated or aged cells with a healthy supply could correct genetic problems and “replenish populations lost to degeneration, inflammation, or developmental failure,” wrote Peng and colleagues.
Transplanting healthy donor microglia directly into the brain is nearly impossible because existing microglia often turn against the new arrivals. But because microglia start life as blood stem cells, a bone marrow transplant from a healthy, matching donor is a viable alternative. Once mature, the cells journey to the brain, where they divide and thrive.
The first and most taxing step of a bone marrow transplant is making space for the new cells. This requires extensive radiation or chemotherapy, but often without direct treatment to the head. The step also destroys the recipient’s immune system, leaving them vulnerable to infections and at higher risk for cancer.
Unfortunately, the standard treatment doesn’t work for microglia replacement, largely because diseased microglia still living in the brain leave little room for healthy new cells to settle.
But in 2020, Peng’s team developed a drug that depleted microglia in the brains of mice, making room for healthy cells. Then this July, Peng and colleagues successfully used a bone marrow transplant to treat a fatal brain disease called CAMP (CSF1R-associated microgliopathy). Here, mutations in a gene critical to microglia survival destroys the cells’ health, causing the brain’s wiring to physically disintegrate over time. Within a few years, people with the condition struggle with everyday reasoning, motor skills, and often fall into depression.
In mice and eight people in a small clinical trial with the disease, the treatment halted their decline for at least two years without notable side effects.
Researchers have also seen early success in other conditions.
Sandhoff disease is one that stands out. People with this inherited condition can’t break down certain fats, which leads to neuron death. The disease is partly caused by miscommunication between microglia and neurons. Normally, microglia shuttle an enzyme to neurons that helps recycle the fatty molecules. Mutated microglia can’t do this. In mice, bone marrow transplants of cells without the mutation improved the mice’s mobility, survival, and brain health.
Another study tackling Sandhoff disease used a different, more daring method. The team isolated the young cells that eventually become microglia and grew them in petri dishes.
After radiation therapy in mice, targeted to their heads, the team infused the healthy lab-grown microglia into the mice’s brains. The cells made themselves at home and worked as normal. The treatment avoided full-body radiation and damage to other organs but the approach could also kill off stem cells that generate new neurons in the brain and so may be limited in its efficacy.
Immune rejection also poses a major stumbling block. But induced pluripotent stem cells (iPSCs), where a person’s skin cells are reprogrammed into other cell types, may reduce the risk. In a proof of concept also in mice, microglia made from iPSCs replaced damaged microglia and slowed neurodegeneration by gobbling up toxic proteins related to Alzheimer’s.
Physicians will need to study the long-term consequences of head-only radiation, and test microglia replacement in a wider range of diseases. If all goes well though, the versatile cells could be used to even ferry medications into the brain like Trojan horses.
In just five years, microglia replacement has gone from animal studies to the first clinical treatment. Once a niche moonshot, it’s now “a topic of great interest in neuroscience and cell therapy,” wrote the team. While there’s plenty more work to do, the therapy could “mature from early breakthroughs into a generalizable platform across neurological diseases.”
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