Have Microbubbles Burst Through the Barriers of Genetic Medicine Delivery?

After more than 20 years working on viral and nonviral delivery modalities, Kenneth Greenberg, PhD, thought he had seen it all in genetic medicine delivery—until he met Steve Feinstein, MD, and Michael Davidson, MD, in 2021. Feinstein, a clinical cardiologist, had been working with ultrasound and contrast ultrasound for decades.

“Steve was scratching his head in the 90s trying to better diagnose heart disease patients, wondering why there’s a contrast agent for every other imaging modality except ultrasound,” Greenberg told Inside Precision Medicine.

Feinstein’s solution was microbubbles. These tiny gas-filled spheres (1-10 μm) with lipid, protein, or polymer shells can safely circulate through capillaries and resonate in response to ultrasound waves when injected intravenously, improving blood flow and tissue perfusion visualization before being cleared by the lungs and liver.

It was Feinstein that got the FDA to approve the first two ultrasound contrast imaging agents. Beyond diagnostics, he found new uses for microbubbles. Certain acoustic conditions could allow them to deliver therapeutic payloads directly into tissues.

Together with Davidson, a lipidologist and preventive cardiology specialist, Feinstein formed a long-term research partnership in Chicago’s academic medical community that resulted in the founding of SonoGene in 2000 to translate and commercialize ultrasound-mediated gene delivery.

kenneth greenberg sonothera
Kenneth Greenberg, PhD, co-founder and CEO of SonoThera [SonoThera]

Though SonoGene never made a splash, Feinstein and Davidson were able to generate preclinical data, which Greenberg found “mindblowing.”

“It showed me that you could use ultrasound and nonviral DNA payloads to achieve delivery and gene expression,” said Greenberg. “This is in rodents, but it was enough to persuade me that if it worked in humans anywhere near as well as it does in rodents, it could completely change the landscape of gene delivery. I thought it was just such an elegant idea. These components have been available for years, and we can repurpose them in a creative way to accomplish things that you could never do with existing modalities.”

In 2022, Greenberg, Feinstein, and Davidson joined forces to launch SonoThera, backed by a $60.75 million Series A financing with the goal of developing a nonviral, ultrasound-mediated gene delivery platform capable of producing safe, targeted, redosable, and cost-effective genetic medicines.

Four years later, investors are reaffirming that vision. SonoThera closed an oversubscribed $125 million Series B financing to advance its lead programs to the clinic and develop its ultrasound-enabled delivery platform. The funding comes at a crucial time for genetic medicine, where delivery challenges continue to temper therapeutic innovation.

RIPPLE effect

The genetic medicine revolution has produced transformative therapies across rare diseases, oncology, and metabolic disorders. Yet despite the success of viral vectors such as adeno-associated virus (AAV) and nonviral systems such as lipid nanoparticles (LNPs), researchers continue to grapple with payload-size constraints, limited tissue targeting, inability to redose, manufacturing complexity, and immune-related toxicities.

For Kenneth Greenberg, PhD, those challenges create an opening for a fundamentally different delivery strategy. “The field and investors recognize that this is a big problem, and no one has yet been able to solve it,” he said. “Coming up from a very different angle, I think it is getting people excited that this could ever come.”

Rather than engineering new viral capsids or nanoparticle chemistries, SonoThera has built its platform around two technologies already widely used in medicine: ultrasound systems and microbubble contrast agents. The company’s innovation lies in combining them with naked DNA payloads and proprietary ultrasound waveforms, called RIPPLE, to drive gene transfer into tissues.

“Our strategy has been to use the existing infrastructure as much as possible and not to develop bespoke hardware or novel microbubbles,” Greenberg said. “We want this to be widely utilized and have great patient access and clinicians to be familiar with the systems and the components.”

Unlike AAVs or LNPs, SonoThera does not package DNA inside a carrier. Instead, naked DNA and microbubbles circulate independently in the bloodstream until ultrasound is applied to a target organ. “There are some common misconceptions about the mechanism,” Greenberg said. “The mechanism basically involves taking the genetic payload, which is naked DNA. It’s not encapsulated in anything.”

The ultrasound activates circulating microbubbles in a multi-step process. First, acoustic energy creates temporary gaps in the endothelial lining of blood vessels, allowing DNA to access target tissues. The microbubbles are then collapsed, creating transient pores in cell membranes that permit intracellular entry of the payload. Finally, ultrasound-driven modulation of the nuclear pore complex facilitates transport of DNA into the nucleus for transcription and protein production. “The ultrasound can basically do everything in one single profile,” Greenberg said. “We can modulate the waveform in ways to drive this mechanism of delivery. We don’t need receptors, endosomes, or anything like that, which gives the platform a huge advantage in versatility to target different organs.”

That receptor-independent mechanism may offer one of the platform’s biggest advantages. Existing delivery systems typically depend on receptor-mediated cellular uptake, which can activate innate immune pathways and restrict tissue tropism. According to Greenberg, microbubbles largely avoid those limitations. “It’s also key to how we avoid the immune system, the innate immune system’s response that typically gets triggered by viruses and LNPs,” Greenberg said.

Because microbubbles are micron-sized rather than nanosized, they never enter the cell and are destroyed extracellularly after ultrasound activation. The DNA itself enters cells independently. While naked DNA degrades relatively quickly in circulation, Greenberg said its half-life of roughly 30 to 60 minutes is sufficient because infusion and ultrasound delivery occur simultaneously.

In contrast, LNPs enter cells through endocytosis, carrying lipids and genetic cargo that can activate innate immune sensors such as cGAS-STING and TLR9. AAVs similarly rely on receptor-mediated uptake pathways that can provoke immune responses and limit redosing.

From sonoporation to clinical translation

The platform’s flexibility has become increasingly apparent as SonoThera expanded beyond its initial liver studies. The company subsequently evaluated delivery to kidney, skeletal muscle, heart, brain, and adipose tissue. “What we’ve found is that the delivery technology works in all organs in the body, as far as we can tell,” Greenberg said. The notable exception is the lung, where air attenuates ultrasound energy.

Perhaps most striking is the company’s work in the brain. The SonoThera platform can temporarily open the blood-brain barrier and deliver payloads using the same mechanism as other tissues. “A common misconception is that the bone can attenuate the ultrasound energy. But that’s not the case,” Greenberg said. “The frequencies are such that they can penetrate easily through the skull and get into the brain.”

If that capability translates clinically, it could represent a significant advantage over delivery technologies that remain largely confined to the liver or a limited set of tissues.

SonoThera’s initial pipeline targets diseases where current delivery systems struggle. In Duchenne muscular dystrophy (DMD), the full-length dystrophin gene is too large for AAV vectors. The company’s ADPKD program has a larger payload.

“The overarching strategy when we’ve approached indications is that it’s challenging to get access to large payloads that are prohibitively large for AAVs,” Greenberg said. “With our ADPKD program, the payloads are even larger. That’s about a 22 KB payload, while the DMD payload is about 13 kb.”

Redosing is also important. Many genetic diseases require long-term treatment, especially in children whose tissues grow. AAV therapies are rarely administered again due to immune responses, making therapeutic expression difficult. “There are indications where the disease really requires redosing over time,” Greenberg said. “DMD is a good example because we’re treating really young boys as their bodies grow.”

SonoThera delivers mutation-agnostic full-length dystrophin with redoseability. The company also targets skeletal muscle, heart, and diaphragm simultaneously to address cardiopulmonary complications that kill many DMD patients.

The platform uses episomal DNA rather than genome editing. Greenberg believes the DNA behaves like AAV-delivered episomes, becoming chromatinized in the nucleus and maintaining expression. “We’ve got durability data out to a year so far with a single treatment,” he said.

Target tissue will determine redosing frequency: rapidly dividing cells may dilute episomal DNA, but quiescent tissues may maintain expression longer. Despite its focus on gene replacement, SonoThera has shown compatibility with gene editing and targeted integration methods. “For us, it’s really about using the right tool for the right job,” Greenberg said. “We don’t want to do gene editing just because it’s sexy.”

The scientific foundation for SonoThera’s platform is rooted in sonoporation, a concept that has been explored academically for decades but has never successfully reached the clinic. Greenberg believes the field historically struggled with two major hurdles: achieving sufficient transfection efficiency and broad biodistribution. “In the first two years of the company, we basically focused on solving those problems and really innovating to achieve extremely high delivery efficiency and broad organ biodistribution,” he said.

Those advances have now positioned the company to enter clinical development. SonoThera is conducting IND-enabling studies, manufacturing activities, and GLP toxicology work while refining clinical trial designs with physician and disease-area experts. The initial studies will focus primarily on safety while also evaluating biomarkers and early signs of efficacy. In DMD, the company has already generated preclinical biopsies showing expression of full-length dystrophin protein in muscle tissue.

Although SonoThera’s internal pipeline currently focuses on rare diseases, Greenberg sees broader opportunities ahead. Pharmaceutical companies have increasingly shifted attention toward common diseases with larger commercial potential, and many are searching for delivery platforms that can overcome the limitations of AAV-based therapies.

Investor confidence—but can it scale?

Greenberg says industry interest in nonviral, redosable systems may be better for common diseases, especially when manufacturing costs and reimbursement issues make one-time treatments unsustainable. SonoThera will advance its pipeline and partner with larger companies seeking platform access to capitalize on those opportunities. “Our strategy as a small biotech company has been to have our internal pipeline but, in parallel, be able to have licensing deals and partnerships that allow us to expand the reach of the technology and the much larger patient populations.”

The oversubscribed $125 million Series B financing suggests investors increasingly view delivery as the next major frontier in genetic medicine. As SonoThera approaches the clinic, it faces many of the same questions every new gene-delivery platform has faced for creating a paradigm-shifting delivery modality: safety, durability, and scale.

Because SonoThera’s platform relies on ultrasound-driven physical mechanisms rather than biological targeting, factors such as organ size, anatomy, blood flow, and patient variability could provide challenges to translatability.

Delivering DNA to a mouse liver or muscle is very different from delivering therapeutic amounts of genetic cargo throughout the muscles, heart, and diaphragm of a growing child with Duchenne muscular dystrophy. While microbubbles have a decades-long track record as imaging agents, repeated therapeutic delivery tools are a different proposition.

While the company argues that naked DNA and ultrasound avoid many of AAV’s payload limitations, questions remain about the doses required for large organs and whether manufacturing and administration can scale efficiently. Relatedly, SonoThera has reported preclinical expression lasting up to a year after a single treatment, but long-term persistence remains unknown. If repeat dosing is required, the company will need to demonstrate that repeated ultrasound exposure and cycles of vascular permeabilization can be performed safely over time.

SonoThera’s appeal reflects a broader reality: despite decades of innovation, delivery remains genetic medicine’s biggest unsolved problem. The company’s platform is scientifically elegant and potentially transformative, but only clinical data will determine whether ultrasound-mediated gene transfer represents a true breakthrough—or simply the latest attempt to solve one of biotechnology’s most stubborn challenges.

The post Have Microbubbles Burst Through the Barriers of Genetic Medicine Delivery? appeared first on Inside Precision Medicine.

From network hub to therapeutic target: the role of mediodorsal thalamic nucleus in epilepsy

Mediodorsal thalamic nucleus (MD) is a pivotal hub for cortical functions, characterized by significant heterogeneity in its anatomical connectivity, cytoarchitecture, and function, constituting a complex nucleus composed of multiple functionally specialized subregions. We elaborates on the heterogeneous anatomical connectivity of MD and its crucial role in supporting higher cognitive functions such as working memory, cognitive control, and emotional integration. It then focuses on the multifaceted role of MD within epileptic pathological networks. Substantial evidence indicates that MD in patients with epilepsy exhibits structural atrophy and abnormalities in functional connectivity, with its activity being recruited early during seizures and likely involved in seizure propagation and generalization. However, the therapeutic efficacy of neuromodulation targeting MD, such as deep brain stimulation (DBS), remains contentious, highlighting the current insufficient understanding of its distinct functional subregions and specific pathway mechanisms. Finally, the review discusses the challenges and future directions in translating MD into an effective therapeutic target. It emphasizes that future research must endeavor to elucidate its causal mechanisms within epileptic networks at the subregional level, account for the heterogeneity of seizure onset frequencies, and develop precise intervention strategies targeting specific epileptogenic pathways, thereby advancing novel therapies focused on thalamocortical circuits toward clinical application.

A connectome-based neural correlate of pediatric ADHD hyperactivity–impulsivity symptoms

BackgroundThis study examined the brain networks related to hyperactivity and impulsivity in children with Attention-Deficit/Hyperactivity Disorder (ADHD) and aimed to develop a resting-state functional connectivity marker that can predict symptom severity.MethodsA total of 44 children with ADHD (31 boys and 13 girls; mean age = 8.45 ± 1.52 years; range = 6–12 years) who met DSM-5 criteria were included. Resting-state fMRI data and clinical symptom scores were collected. Connectome-based predictive modeling (CPM) was used to predict hyperactivity–impulsivity symptoms based on whole-brain functional connectivity matrices. Symptoms were assessed using the SNAP-IV Parent and Teacher Rating Scales and the Conners Comprehensive Behavior Rating Scale. Model performance was tested with leave-one-out cross-validation and permutation testing.ResultsThe CPM model based on interregional functional connectivity successfully predicted hyperactivity–impulsivity symptoms (SNAP-IV parent and teacher ratings: r = 0.48, p = 0.001). The model also generalized well within the same dataset, as the selected functional connections significantly predicted hyperactivity–impulsivity scores on the Conners Parent Rating Scale (r = 0.49, p = 0.0009). Further analysis showed that stronger connectivity between the frontoparietal control network (FPN) and the dorsal attention network (DAN), and weaker connectivity between the FPN and the ventral attention network (VAN) and between the FPN and the somatomotor network (SMN), were related to symptom severity.ConclusionsWhole-brain functional connectivity is associated with hyperactivity–impulsivity symptoms in children with ADHD. The findings highlight the key role of FPN-related networks in these symptoms and provide a neural correlate that, pending further validation, represents a preliminary candidate for a neuroimaging marker.

Hacking the atmosphere: Geoengineering gets a reality check

Jim Franke pulls away the cover page of a presentation on the wraparound desk in his office, revealing an illustration of an odd-­looking aircraft with massive wings stretching out from a stubby fuselage.

The uncrewed plane is soaring thousands of meters higher than commercial jets fly—so high you can see the curvature of the Earth. It’s precisely the type of aircraft one would need to begin artificially cooling the planet. Those outsize wings would keep the plane and its payload aloft in the stratosphere, about a dozen miles (or 20 kilometers) above the surface, where the air is much thinner—as little as 5% the density near the ground. Once at altitude, the plane would release materials that could, after a few steps of chemistry, reflect sunlight back into space.

“If you want to get to 20 kilometers in the near term, this is probably the best bet,” says Franke, a research assistant professor at the University of Chicago.

Franke is one of a small but growing cohort of scientists focused on the engineering challenges associated with solar geoengineering, the controversial idea that we could deliberately intervene in the climate system to counteract global warming.

The concept came from volcanoes. Massive eruptions in the past have reduced temperatures worldwide by blasting sulfur dioxide and other compounds into the stratosphere, where they convert into sunlight-scattering particles. Hundreds of studies in recent decades have suggested that a human attempt to mimic this mechanism would work quickly and efficiently—at least within the confines of climate models.

But these computer simulations are approximations of how the real world works. They gloss over numerous challenges. Like the fact that aircraft capable of carrying the necessary loads to the necessary altitudes don’t exist. Or that we don’t know for sure how to release material so that most of it turns into tiny reflective aerosols instead of, say, clumping together and falling out of the sky. Or even what specific substance we would want to load onto an aircraft, given open questions about safety, cost, and effectiveness. 

Amid these compounding unknowns, more and more research on solar geoengineering is moving beyond computer simulations, delving into the detailed design and practical engineering work that would be needed before we could carry out a campaign to dial down temperatures. The tasks required range from inventing high-altitude aircraft to mastering the precise chemistry and delivery mechanisms for dispersing materials to building out the monitoring infrastructure that we’ll need in order to know if any of it actually works.

The question of whether we should geoengineer the planet has no clear-cut answer. It might save millions of lives by reducing the dangers of catastrophic heat waves, floods, droughts, and famines. But many fear it’s too dangerous to even consider, much less seriously study, arguing that we can’t possibly predict the spiraling consequences of manipulating such large, complex, interconnected planetary systems. 

Critics argue that the building momentum in this phase of research will make it ever more likely that someone, somewhere in the world, will eventually pull the trigger on geoengineering, no matter the remaining unknowns or the dangers for certain parts of the world.  

“I do think it’s very dangerous because of what we know about science and technology,” says Jennie Stephens, a professor of climate justice at Maynooth University in Ireland. “The more investment that’s made, the further the advances, the more likely it is that it will be deployed.”

But proponents of this practical research argue that playing out how we’d mount a solar geoengineering program will improve our understanding of the potential benefits and risks, helping to ensure that if anyone does try to tweak the climate, they might at least do so in an informed and potentially safer way.

David Keith
The Climate Systems Engineering Initiative (CSEi) at the University of Chicago formally launched in 2024 under the leadership of the prominent geoengineering researcher David Keith.
MIT TECHNOLOGY REVIEW | JUSTIN SAGLIO

It’s still very much a niche field. Much of the work now underway is happening at the Climate Systems Engineering Initiative (CSEi) at the University of Chicago, which formally launched in 2024 under the leadership of the prominent geoengineering researcher David Keith. 

Franke, a professional engineer before earning his doctorate in geosciences, is overseeing a series of overlapping research projects and collaborations aimed at resolving many of the engineering uncertainties. That includes working out the designs now on his desk—renderings of the type of aircraft that could be used in the initial phase of a geoengineering program. 

Franke argues that more computer simulations are simply not going to answer the big remaining questions in the field, including the most compelling one: the “boogeyman” of what could go wrong. 

“I’m kind of personally skeptical that additional model development or more simulations are going to satisfactorily resolve those things,” he says. “And so I’m not really that interested in turning the crank on more models.”

For Franke, it’s time for the next step: “We’re interested in seeing how you’d actually do this thing if you wanted to do it.”

What we don’t know

Solar geoengineering is often portrayed as a relatively cheap and easy fix for climate change. But as researchers take a harder look at the nuts and bolts, they’re finding considerable uncertainties, missing tools, and unbuilt infrastructure.

None of that may be a showstopper, but we’ll need time and money to develop the components necessary to implement even the early stages of a solar geoengineering program. What this research is about, at its core, is not actually launching something, but figuring out what it would take to do so. 

A young San Francisco nonprofit, Reflective, recently worked with scientists in the field to figure out just how much we still don’t know.

The process began by outlining what the organization, which pools money from donors to fund geoengineering studies, describes as a “well-managed, moderate” scenario: In 2035, some nation or group of nations begins a small-scale geoengineering deployment, spraying an equal amount of sulfur dioxide or hydrogen sulfide—gases that should convert into reflective aerosols in the stratosphere—near both the North and South Poles. The initial program would release enough material to reduce temperatures by about 0.1 °C, shaving off a fraction of the roughly 1.4 °C of worldwide warming that’s occurred since the start of the industrial era.

The poles figure prominently in this and other early-stage geoengineering scenarios, for a simple reason: The stratosphere starts as low as seven kilometers there—as opposed to around 18 to 20 kilometers at the equator. That makes it easier to reach, enabling existing aircraft, with some modifications, to carry sizable payloads up there. 

The wrinkle is that the cooling effect would be more pronounced in the northernmost and southernmost latitudes. That’s because, among other complicated mechanisms, higher temperatures in the tropical stratosphere would mostly prevent aerosols released around the poles from drifting toward the equator. So deploying geoengineering in those areas would likely have milder effects on the hotter and poorer nations around the tropics, which are also some of the areas most vulnerable to climate change.

To cool the world evenly—and fairly—you’d eventually want to add flights closer to the equator. Over the following decade or so, under Reflective’s scenario, the program would scale up, shift to novel aircraft flying above the subtropics, and release enough material to achieve global cooling of 0.5 °C. 

The question the researchers then examined was: If we wanted to carry out such a scenario, what would we still need to do to pull it off? 

Quite a bit, it turns out. Earlier this year, Reflective published its SAI Uncertainty Database (SAI stands for “stratospheric aerosol injection”), highlighting a variety of scientific unknowns and six engineering obstacles.

Among them: sorting out how hard or expensive it would be to retrofit existing aircraft to carry out the early stages of the project. Deploying at the poles could also require constructing new airports, establishing new shipping lanes or railways to transport supplies, and building facilities that could process raw materials—by, for example, combusting elemental sulfur to produce sulfur dioxide.

We would also need to build more instruments and send them up to the stratosphere aboard balloons, drones, or other aircraft to observe the baseline chemistry, reflectivity, and distribution of compounds there—and to track what changed once new materials were released.

Finally, the main satellites that observe the stratosphere from space are set to go out of commission in the coming years, creating the risk of an “imminent data desert,” as a 2025 paper in the Bulletin of the American Meteorological Society warned. Several new instruments are in development or available for launch, but there could be a gap in observations at a point where we’d want to have a clear picture of the baseline conditions, Reflective notes.

Dakota Gruener, the chief executive officer of the nonprofit, stresses that the organization isn’t advocating the use of solar geoengineering. But she says it’s important for the field to begin addressing engineering uncertainties now because it stress-tests the assumptions in climate models. It helps us determine whether the scenarios explored in silico are feasible in the real world.

It’s also important to do this, she says, because it may take a long time to resolve all these unknowns while the climate grows steadily warmer. “If we aren’t putting adequate attention to them now, we might be caught flat-footed,” Gruener told MIT Technology Review.

A 2024 analysis in the journal Earth’s Future highlighted just how expensive and time-consuming it might be to develop the aircraft and infrastructure required for an initial deployment. The study explored what it would take for a geoengineering program around the poles, capable of reducing temperatures by 2 °C in the northernmost and southernmost parts of the planet, to be up and running by 2040. The conclusion: It could require at least a decade of work and a $35 billion investment. 

Wake Smith, a research fellow at Harvard and lead author of the study, also says that researchers need to move forward with engineering studies now, because the urge to use the technology will likely grow stronger as climate change becomes increasingly catastrophic.

“The risk I worry about is needing it before we understand it and therefore doing it badly,” he says, later adding: “The sooner we get going with it, the better decisions we’ll be able to make a few decades hence in terms of whether to do it, how to do it, when to do it.”

A novel aircraft

The aircraft pictured on Franke’s desk, which is still just a concept, could reach just beyond the threshold of the stratosphere above the tropics when fully loaded. A fleet of 270 of them could disperse about a million metric tons of material per year, enough to ease global surface temperatures by about 0.26 °C. 

The CSEi outsourced the work of designing it to John Langford, a well-known aeronautical engineer and entrepreneur. Langford’s company, Electra.aero, had previously collaborated with the MIT Department of Aeronautics and Astronautics to develop autonomous, solar-powered aircraft that could carry out extended scientific missions in the stratosphere. He is now spinning out a new business, Iris Aero, to produce those planes, which are assembled from a single, continuous wing covered in solar panels and suspended above a tiny fuselage.

Langford expects the solar plane to find its main initial commercial applications in wildfire monitoring and forecasting. But by swapping in a different set of instruments, it could be used to monitor how materials dispersed in the stratosphere might alter conditions there, he says.

The novel aircraft is a variation on the observational plane, with the added space and thrust necessary to carry these materials to the stratosphere and release them. It has a wider wingspan and swaps out those solar panels for a pair of Rolls-Royce AE 3007 engines.

The aircraft would also include a detachable tank that would function something like a trailer on a semi. This would make it possible to load materials between flights and prevent any damage to the plane itself from those materials, some of which are corrosive, Langford says. 

He says he and his team have completed the initial designs and are now doing more detailed engineering and cost analyses. They intend to publish the findings when the effort is complete. 

“We’d love to build a prototype of such an airplane and feel we could do so relatively quickly,” Langford says. “But that all depends on what David’s group wants to do.”

The program

David Keith’s group, CSEi, is still coming together.

The University of Chicago unveiled the research initiative in 2024 and has committed to hiring 10 additional faculty members to advance scientific understanding of various forms of geoengineering and explore the thorny questions related to policy, ethics, and governance. It had hired two of them as of press time.

The university saw an opportunity to step up as a leader in a field that wasn’t getting adequate academic attention despite its potential to address the dangers of climate change, says Michael Greenstone, a climate economist and the founding director of the university’s Institute for Climate and Sustainable Growth.

“Universities, as a whole, were committing academic malpractice by not investigating the technical, the social, the political, and the even kind of humanist elements of geoengineering,” Greenstone says.

He helped recruit Keith to lead the initiative. 

Keith, 62, previously spent nearly 13 years as a professor of applied physics and public policy at Harvard, where he led the establishment of the university’s Solar Geoengineering Research Program. More famously, he strove to carry out what could have been the first solar geoengineering experiment to release material in the stratosphere, known as SCoPEx. But after years of work and multiple delays, the research team finally scrapped the project in early 2024, following mounting criticism from environmental and Indigenous groups and the eventual intervention of the Swedish government.

Keith has long argued that researchers should seriously study geoengineering because it might substantially reduce the dangers of climate change, alleviating death, destruction, and suffering on massive scales.

He says that the overarching goal of the Chicago initiative is to expand the field by bringing together “enough independent professors and other research professionals” to “build a community around climate engineering as a broad field of inquiry.”

“Solar geoengineering certainly has complex and potentially dangerous political consequences, but so do a host of other emerging ideas and technologies.”

David Keith, geoengineering researcher

“The University of Chicago was the first big university to try and build this as a field in a serious way, to make it not about one person,” he tells me. “It’s a giant commitment.”

Keith himself has become a divisive figure, the face of geoengineering to some. He says he now wants to help build a larger, sustainable research program that will outlive his involvement. He told the administrators that he shouldn’t run the program for more than five years.

“It’s important to have a generational handover,” he says, adding: “I think it’s really important that this not be ‘the David Keith Show.’”

The CSEi researchers are now exploring nearly every engineering challenge that Reflective highlighted in its analysis. In addition to the work on novel aircraft and in situ observations, the group is designing small “cube” satellites with optical sensors optimized for observing the stratosphere. It is also studying which materials might prove most practical to ship to the stratosphere and how best to release them.

The goal is “producing public information which can be independently assessed, critically assessed, so policymakers can understand more about what’s possible and not,” Keith says.

Normalizing a dangerous idea

The debate around solar geoengineering is quickly moving beyond the academic and theoretical realm. A handful of startups, some more serious than others, have begun testing technologies that could one day be used to cool the planet. 

Yet to critics, solar geoengineering is the peak of techno-solutionism, affixing a high-tech Band-Aid to a global crisis caused by earlier technologies instead of addressing the root cause. Further, they argue that there’s no way to deploy or govern it in a globally equitable way, because any use of it will prove more advantageous to some regions than others. 

Even if solar geoengineering succeeded in reducing the average global temperature by 1 °C or so, that would mean very different things in different regions.

It could keep farmers prosperous and cities safe across, say, much of the US and the world’s temperate zones. But the lower temperature might be too cool for Russia to boost its agricultural productivity, while it might still be too hot for subsistence farming in northern Africa. 

Some studies also suggest that high levels of solar geoengineering could create new dangers in some regions, potentially altering monsoon rains, decreasing agricultural output, shifting the range of infectious diseases, and more. 

These complications raise a long list of thorny and divisive ethical questions. Even if solar geoengineering produced better conditions across most of the planet relative to a world with unchecked climate change, would it still be acceptable if it unleashed deadly famines or floods in a few regions? What kind of global consensus should be required to decide it’s okay to deploy it? And how should we determine where to set the planet’s temperature—and when, if ever, to shut the technology off?

Stephens argues that the answers, like so much else in the world, will come down to wealth and power. Countries, corporations, or even wealthy individuals with the resources to deploy such a system would have every incentive to tune it for their optimal benefit, no matter what it might mean for others. 

“It will be certain people who have a lot of wealth and power deciding when and how, and who should benefit and who will get screwed,” she says. “That’s the fundamental reason I think any advance in this technology is so dangerous.”

Duncan McLaren, an environmental researcher and political scientist, argues that the shift into practical engineering studies demands more oversight of the research field.  

For many critics of outdoor experiments like SCoPEx, he explains, the major concern wasn’t the environmental or safety risks, which were minimal; the issue was the normalization of a concept that could reduce pressures to cut greenhouse-­gas emissions. 

He says that any advance in research—whether it’s on paper, in the lab, or in the stratosphere—raises a similar risk: undermining progress on climate action by allowing the fossil-fuel sector and other business interests to say there’s an easier solution in development that doesn’t require overhauling our energy systems. A policy paper that the Texas Conservative Coalition Research Institute released in March advanced this very argument, citing the far lower costs of solar geoengineering relative to the “staggering costs” of a “forced transition.” 

Given this so-called moral hazard risk, design and engineering work should demand the same level of scientific supervision that outdoor experiments do, including ethical review, risk assessments, and public engagement, McLaren says.

“It ought to be more onerous,” he says. “There ought to be more barriers to researchers saying they want to do this.”

“The next ethical step”

Keith pushes back forcefully on that assertion, condemning as “profoundly illiberal” the idea that we should regulate open academic research posing no physical risks. 

“Solar geoengineering certainly has complex and potentially dangerous political consequences, but so do a host of other emerging ideas and technologies,” he said in an email. “The best chance to manage these challenges is to debate them openly and freely.”

Keith is all for keeping solar geoengineering technology in the public domain, and he agrees that the first line of climate defense must be rapid and deep reduction of greenhouse-gas emissions. But the world has made little progress in cutting climate pollution, carbon dioxide can persist for thousands of years in the atmosphere, and the planet is heating up fast. So, he argues, we may need to pursue other measures to temper the growing threats.

The bar for restricting research in this field should be “very high,” he says, given the potential promise of the technology. 

After visiting flood-devastated villages in Bangladesh, Keith underscored this point in an interview with the director of Plan C for Civilization, a recent documentary that profiles his work. “I think people have to take the next ethical step,” he said. “Because if you are really going to withhold access to and knowledge of a technology that could potentially save enormous numbers of lives—real lives, people we’ve met in the last few days—you’ve got to be very confident that that technology is going to be misused.”

The particles

Mingyi Wang, an assistant professor at the University of Chicago, leads me down the hall to a square, white lab room in the Henry Hinds Laboratory for Geophysical Sciences.

He pulls open the doors to a gray Haier biomedical freezer just inside the entrance, revealing a transparent flow tube hanging vertically and tapering at the bottom.

It’s a miniature stratosphere, chilled below −50 °C and filled with the same mix  of oxygen, nitrogen, and other air molecules you’d find 20 or so kilometers above us. A series of Teflon and stainless-­steel tubes run into the vessel, allowing Wang and his team to add various gases or particles and observe how they react.

Wang is an atmospheric scientist who studies how aerosols form, and he is now exploring what materials might be the most effective for reducing temperatures. 

an aircraft shown from above flying over the clouds
This rendering illustrates the type of high-altitude aircraft that could one day be used to deliver Earth-cooling material into the stratosphere.
COURTESY OF IRIS AERO CORP.

Most modeling experiments focusing on solar geoengineering explore the impact of adding sulfuric acid to the stratosphere, because that’s what ultimately ends up there after a volcanic blast. 

But it would be costly and complicated to simply haul sulfuric acid up there and release it, because it’s heavy and sticky. So Wang and his team are conducting experiments in that chilly flow tube to determine what substances, including precursors to the acid, might do the best job of producing aerosols of the ideal size for reflecting away sunlight—and how best to prevent the materials from simply clumping together with existing particles and falling out of the stratosphere.

Wang, whom Keith refers to as a “young star,” has arrived at a novel solution to this problem, though he’s not ready to share the full details yet. He and his team are feeding the findings from their experiments into computer simulations of stratospheric plumes that they’ve developed. These, in turn, can be plugged into large-scale climate models to improve their simulation of smaller-scale effects—and thus enhance our understanding of stratospheric chemistry.

Wang says that it’s important to do this detailed research because until now, climate models simply assumed you’d wind up with the right aerosols of the right size. 

“Scientifically, we may understand it reasonably well, but on the engineering perspective—do we really know how to do it right?” he asks. “That’s a big question.” 

What’s next

As I began reporting on CSEi, I assumed that some of the engineering and design work would lead to new proposals for stratospheric experiments, picking up from where SCoPEx left off. 

Keith, though, insists he has no interest in reliving that experience, given the weight the experiment took on as the focal point for a broader societal debate over solar geoengineering. He doesn’t see any of the other “practical engineering” work at the initiative leading toward field experiments either, at least at this stage.

Much of the work, in fact, is focused on a step beyond that: exploring what it would take to start a geoengineering campaign, if a nation or group of them eventually decides to. Franke notes that we already have balloons and other aircraft that could get to the lower bounds of the stratosphere to release an experimental amount of, say, sulfur dioxide. 

“We’re thinking of it right now as: We’re trying to develop, we think, the tools should someone want to start doing SAI,” he says. 

He and Keith are quick to stress that the research group does not intend to actually build the physical hardware that would be needed to deploy solar geoengineering—not even the aircraft that Langford’s company is designing. 

Indeed, most of the researchers at the University of Chicago stress that they are not advocating for use of geoengineering; they’re doing the research to inform the public and policymakers about its benefits and risks.

But after decades closely studying the topic, Keith, at least, has evolved in his thinking on this point, and his public comments reflect that. 

“As a scientist, I think the evidence [indicates] that early deployment—careful, hemispherically balanced, slow, monitored early deployment—would have benefits that are higher than the risks,” he says. “I think that evidence is very strong.”

Keith adds that if there were somehow a global referendum on whether to start, he would vote yes. 

“I think that this field needs to stop being so ashamed of using the ‘deployment’ word,” he says. 

Smartphone-based Intervention for Young Adults With ADHD

Conditions: Attention Deficit/Hyperactivity Disorder(ADHD); Alcohol Use

Interventions: Device: Ecological Momentary Assessment for ADHD and Substance Use – Intervention Group; Device: Ecological Momentary Assessment for ADHD & Substance Use – Control Group

Sponsors: Traci Kennedy; National Institute on Alcohol Abuse and Alcoholism (NIAAA)

Recruiting

Digital Technologies for Children With Hearing Impairments to Support Language Learning: Scoping Review

Background: Children with hearing impairments (HIs) have traditionally faced difficulties with language acquisition due to various factors, such as difficulties in accessing early intervention and therapy, among others. There is an opportunity for digital technology to address this problem; however, how different technologies can facilitate language acquisition, as well as the level of evidence, is not well understood. Objective: This study aimed to explore the types, roles, and outcomes of different digital technologies in supporting language development in children with HIs. Methods: Following Arksey and O’Malley’s framework for conducting a scoping review and the PRISMA-ScR (Preferred Reporting Items for Systematic Reviews and Meta-Analyses Extension for Scoping Reviews), we systematically searched 6 online databases from 2014 to September 2024 for relevant studies on the role of digital technologies in supporting language learning among children with HIs (aged <18 years). Results: A total of 45 studies met the inclusion criteria. Mobile apps were the most frequently reported technologies, followed by digital books, extended reality, computer-based programs, and tangible or robotic tools. The most commonly used signed-language apps focus on vocabulary development and visual communication. Spoken language tools were less common but included augmentative and alternative communication (AAC) systems and auditory training apps. The efficacy outcomes of 12 studies included in this review showed that AAC-based apps had stronger effects on expressive language, pragmatic communication skills, and vocabulary development. These outcomes occurred when AAC-based apps were used in structured contexts with a therapist or parent. In contrast, signed language apps often reported narrower, word-level outcomes. Notably, relatively few interventions targeted early spoken language development, despite early childhood being a critical period for language acquisition. In addition, limited attention was given to visual design considerations related to user comfort, cultural relevance, and contextual adaptation. Conclusions: The evidence base reveals 3 structural patterns: the dominance of accessibility-driven mobile technologies; an imbalance between signed and spoken-language interventions, characterized by a greater number of signed-language tools but stronger and more consistent evidence for spoken-language outcomes, particularly in AAC-based interventions; and limited integration of digital technologies across home, school, and clinical contexts. Future research should prioritize the co-design and evaluation of culturally responsive, integrated, developmentally appropriate digital systems that support early spoken-language development and sustained, family-mediated language learning across contexts.

Using a Virtual Reality CAVE–Based Mindfulness Intervention to Promote Mental Well-Being in Adolescents With Anxiety Symptoms: Pre-Post Mixed Methods Pilot Study

Background: Adolescent anxiety is a growing public health concern associated with significant social and emotional impairment. Mindfulness-based interventions (MBIs) have shown promise in reducing anxiety and improving well-being; however, engagement remains challenging. Virtual reality (VR)–based delivery may enhance immersion and attention, potentially addressing barriers of traditional mindfulness formats. Evidence on VR-based mindfulness interventions for adolescents, particularly in Hong Kong, remains limited. Objective: This study aimed to evaluate the feasibility and acceptability of a VR-MBI delivered via a CAVE, an enclosed VR environment with three projected walls displaying immersive natural scenes and ambient sounds, for adolescents with mild-to-moderate anxiety symptoms in Hong Kong. Secondary aims were to explore preliminary effects on psychological outcomes and physiological stress regulation and to identify facilitators and barriers to engagement. Methods: A mixed methods, single-group pre-post study was conducted with adolescents experiencing mild-to-moderate anxiety symptoms, recruited from secondary schools and youth service organizations in Hong Kong. Participants completed an 8-week group-based VR-MBI. Feasibility and acceptability were assessed using recruitment, attendance, retention, homework practice frequency, dropouts, and adverse events. Psychological outcomes were measured using the Depression Anxiety Stress Scale–21 and the Mindful Attention Awareness Scale. Heart rate variability indices, including the standard deviation of normal-to-normal intervals and root-mean-square of successive differences, were collected at baseline and postintervention using a wearable device. Focus group interviews explored participants’ experiences. Paired-sample tests and Wilcoxon signed rank tests examined pre-post changes, and qualitative data were analyzed using thematic analysis, with findings integrated through triangulation. Results: A total of 42 participants (mean age 14.88, SD 1.90 years; 20/42, 47.6% female; 22/42, 52.4% male) enrolled and completed both assessments. Attendance was high, with 73.8% (31/42) of participants attending at least 80% (8/10) sessions, and participants engaged in regular homework practice. No dropouts or adverse events were reported. No significant pre-post changes were observed in self-reported distress, anxiety, depression, stress, or trait mindfulness (all >.05). However, significant improvements were observed in both heart rate variability indices, standard deviation of normal-to-normal intervals (mean difference 17.6 ms, 95% CI −33.88 to −1.32; =.04; Cohen =0.38) and root-mean-square of successive differences (mean difference 20.20 ms, 95% CI −38.76 to −1.65; =.03; Cohen =0.39), which may suggest preliminary enhancements in physiological stress regulation. Qualitative findings suggested perceived benefits in emotional regulation, stress reduction, focus, and sleep, with the immersive environment and group-based format identified as key facilitators. Conclusions: The CAVE-based VR-MBI was feasible and acceptable for adolescents with mild-to-moderate anxiety symptoms in Hong Kong. Despite no significant changes in self-reported outcomes, physiological improvements and positive qualitative feedback suggest early benefits not captured by self-report measures. These findings support further investigation of using controlled designs and longer follow-up periods.

Age-Related Mutations in Brain Immune Cells Linked to Alzheimer’s Inflammation

Researchers have uncovered evidence that age-related genetic mutations commonly associated with cancer and blood disorders may also contribute to the chronic brain inflammation characteristic of Alzheimer’s disease.

In a study published in Cell, investigators from the Icahn School of Medicine at Mount Sinai and Boston Children’s Hospital identified somatic mutations in brain immune cells from patients with Alzheimer’s disease. The findings suggest that genetic alterations acquired during aging may reshape the behavior of these cells, driving inflammatory processes linked to neurodegeneration.

The work introduces a potential new biological mechanism connecting aging, immune dysfunction, and Alzheimer’s disease, a condition that affects millions of people worldwide and remains one of the leading causes of dementia.

Linking aging, immunity, and neurodegeneration

Inflammation has long been recognized as a central feature of Alzheimer’s disease. Activated immune cells are commonly observed surrounding amyloid plaques and other pathological hallmarks of the disease. However, the factors that initiate and sustain these harmful immune responses have remained incompletely understood.

The new study focused on microglia, the brain’s resident immune cells. These specialized cells play critical roles in maintaining neural health by clearing cellular debris, regulating synaptic connections, responding to injury, and coordinating immune activity within the central nervous system.

Previous research has shown that microglia can adopt disease-associated states during Alzheimer’s progression, but the molecular triggers responsible for these changes have been unclear.

“Our data suggest that some immune cells in Alzheimer’s disease undergo genetic changes over time that alter their behavior and potentially contribute to chronic inflammation in the brain,” said senior author Samuele Marro, PhD, associate professor in the Nash Family Department of Neuroscience and The Friedman Brain Institute at Mount Sinai.

“These findings provide a new framework for understanding how aging, immune dysfunction, and neurodegeneration may intersect in Alzheimer’s disease.”

Large-scale analysis of Alzheimer’s brains

To investigate whether acquired mutations might contribute to disease pathology, researchers analyzed 311 postmortem brain samples from individuals with Alzheimer’s disease and age-matched controls.

Using ultra-deep sequencing, the team screened 149 genes frequently associated with cancer and clonal hematopoiesis, an age-related condition in which blood stem cells acquire mutations that allow certain cell populations to expand disproportionately over time.

The analysis revealed significantly higher numbers of somatic mutations in Alzheimer’s disease brains compared with controls.

Several of the most frequently mutated genes, including TET2, DNMT3A, and ASXL1, are well-known drivers of clonal hematopoiesis and have previously been implicated in age-related blood disorders and cancer development.

Many of these mutations were highly enriched in microglia-like immune cells while being largely absent from neurons, suggesting that immune cells may be a primary target of these age-related genetic alterations.

Evidence for blood-derived immune cell involvement

The researchers also examined matched blood samples from some patients and found that many of the same mutations detected in the brain were present in circulating blood cells.

This observation suggests a possible route by which mutated immune cells originating from the blood may enter the brain and adopt microglia-like functions.

Growing evidence has indicated that peripheral immune cells can contribute to neuroinflammation under certain conditions. The new findings raise the possibility that age-related expansion of mutated blood cell clones could influence inflammatory processes within the brain.

Such a mechanism would provide a direct biological link between clonal hematopoiesis—an increasingly recognized consequence of aging—and neurodegenerative disease.

Functional effects of Alzheimer’s-associated mutations

To determine whether these mutations actively alter immune cell behavior, the researchers combined single-cell analyses with stem cell-based experimental models.

Using CRISPR gene editing, they engineered induced pluripotent stem cell-derived microglia-like cells carrying mutations identified in Alzheimer’s disease samples.

The resulting cells displayed profound changes in gene expression, adopting inflammatory programs and disease-associated microglial states that have previously been linked to neurodegeneration.

“Our study provides functional evidence that mutations commonly associated with aging blood cells and cancer biology can directly alter the behavior of brain immune cells,” said co-corresponding author Eirini Papapetrou, MD, PhD, professor of oncological sciences at Mount Sinai and director of the Center for Advancement of Blood Cancer Therapies.

“These mutated cells showed inflammatory signatures strongly associated with neurodegeneration.”

The findings suggest that these mutations are not merely bystanders but may actively influence cellular pathways involved in disease progression.

A potential new contributor to Alzheimer’s pathology

The study expands the growing view of Alzheimer’s disease as a disorder involving complex interactions between the immune system and the nervous system.

Historically, Alzheimer’s research has focused heavily on amyloid-beta plaques and tau tangles. More recently, attention has shifted toward the role of neuroinflammation and immune dysfunction as key drivers of disease progression.

The identification of somatic mutations in microglia-like cells adds another layer to this emerging picture. Rather than being solely inherited or environmentally driven, some aspects of Alzheimer’s pathology may arise from genetic alterations that accumulate naturally with age.

Because clonal hematopoiesis becomes increasingly common in older adults, the findings may have implications beyond Alzheimer’s disease and could influence understanding of other neurodegenerative disorders characterized by chronic inflammation.

Implications for future therapies

Although the study does not establish that these mutations directly cause Alzheimer’s disease, it identifies a plausible mechanism through which age-related genetic changes could exacerbate neurodegeneration.

Future studies will be needed to determine how early these mutations emerge, whether they predict disease risk, and whether interventions targeting mutated immune cell populations could slow disease progression.

“This work highlights a potentially important connection between aging blood biology and neurodegenerative disease,” said Marro.

“If confirmed in future studies, these findings could open new avenues for therapies that target harmful inflammatory immune cell populations in the brain.”

The researchers are now planning follow-up studies in animal models to further investigate the role of mutated immune cells in Alzheimer’s disease and evaluate whether reducing their inflammatory activity can modify the course of neurodegeneration.

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