Tag: Academic research

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Smart MRI Agents Combine Cancer Imaging and Therapy in Single Platform

Researchers at NYU Abu Dhabi have developed manganese-based molecules that combine cancer detection and treatment within a single system, allowing for simultaneous imaging and therapy using magnetic resonance imaging (MRI). The research, published in the Journal of the American Chemical Society, details the development of metal–organic structures that remain stable in healthy tissue but become active within the tumor microenvironment, where they both enhance MRI contrast and induce cancer cell death.

“Our goal was to create materials that allow doctors to see cancer clearly and treat it at the same time,” said lead author Farah Benyettou, PhD, a research scientist at NYU Abu Dhabi. “The ability to image and target brain tumors with high precision is particularly exciting.”

The molecules the researchers developed are composed of manganese ions coordinated with organic frameworks arranged into interlocked topologies. Unlike conventional drugs, which are small and relatively simple, these molecules have interlocked structures that resemble knots and rings. This design allows them to behave differently inside the body, improving both imaging and therapeutic performance.

“Manganese (Mn)-based metal–organic architectures offer a unique avenue for integrating magnetic resonance imaging (MRI) and cancer therapy within a single molecular platform,” the researchers wrote. The geometrical complexity and electropositive, pH-labile coordination framework allow the molecules to remain intact in normal tissue but disassemble when exposed to the acidic tumor microenvironment.

This pH-responsive behavior is the key to their dual function. In healthy tissue, the molecules maintain stability and limit off-target effects. Once inside tumors, where acidity is elevated, they release Mn2+ ions. These ions enhance T1-weighted MRI signals, making tumors more visible, while also triggering biological pathways that lead to cancer cell death. The researchers wrote that this process culminates in “lysosomal acidification, pH-triggered disassembly, Mn2+ release, ROS accumulation, and caspase-dependent apoptosis,” marrying their imaging capability directly to therapeutic action.

The novel molecule design builds on prior prior research of manganese-based imaging agents and topological chemistry. The researchers noted that conventional gadolinium-based contrast agents have safety limitations, including toxicity and accumulation in tissues, while earlier manganese agents lacked stability and tumor targeting. “These drawbacks underscore the need for next-generation Mn platforms with enhanced stability and tumor specificity,” the researchers wrote. In previous studies, the NYU Abu Dhabi researchers had demonstrated that metal-templated trefoil knots could induce apoptosis in drug-resistant cancer cells, a finding that spurred their efforts to integrate therapeutic activity with an imaging agent.

To evaluate the new molecules, the team conducted both in vitro and in vivo experiments, focused on glioblastoma. In cell studies, Mn-TK and Mn-BR showed selective toxicity toward cancer cells while sparing normal cells. In animal models, the molecules accumulated in tumors, produced strong MRI contrast, and inhibited tumor growth.

An important finding of the study was data that showed both Mn-TK and Mn-BR were able to cross the blood–brain barrier and accumulate in glioblastoma tumors. This has traditionally been a major limitation of MRI contrast agents, which often fail to image tumors in the brain.

The implications for clinical care include the potential to replace separate diagnostic and therapeutic steps with a single intervention. By combining imaging and treatment, the molecules could provide earlier detection, more accurate tumor delineation, and targeted therapy with reduced side effects. The manganese-based design may also offer a safer alternative to gadolinium, which could produce long-term retention and toxicity.

“This work introduces a generalizable strategy for designing manganese-based theranostic agents by integrating topological coordination chemistry with tunable lipophilicity and electrostatics,” the researchers noted, adding that this method could be used to develop additional agents tailored to different cancers or imaging needs.

Next steps for the team include further evaluation of safety, optimization of molecular design, and studies to support clinical translation. The researchers identify Mn-TK and Mn-BR as leading candidates due to their combination of tumor targeting, imaging performance, and therapeutic activity. Continued work will likely focus on refining these properties and assessing their performance in additional disease models.

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Smart Contact Lens Offers Glaucoma Treatment Potential

A “smart contact lens” can monitor eye pressure and manage and release glaucoma drugs to counteract any rises in this, preclinical research suggests.

The all-polymer, microfluidic lens, described in Science Translational Medicine, represents further progress towards personalized eye technologies in a “theranostic” approach that combines diagnostics and therapy.

The battery-free device was able to monitor intraocular pressure—the most prominent, modifiable risk factor for glaucoma—and could release glaucoma drugs timolol and brimonidine at pressure thresholds in animal studies.

The device could one day provide frequent, real-time pressure monitoring with responsive drug release for patients at home, offering an alternative to the infrequent gold-standard measurements in the office, which only occur every six to 12 months.

“This electronic- and power-free device combines softness, optical transparency, biocompatibility, and cost-effectiveness, offering a noninvasive approach to continuously monitor IOP and deliver individualized therapy,” reported Yuting Cai, PhD, from Hong Kong University of Science and Technology, and co-workers.

They added: “Beyond glaucoma, the platform is compatible with commercial soft contact lenses and can be reconfigured to monitor additional tear biomarkers, enabling a wider range of ocular care applications.”

Biosafety assessment of AP-TSCL-Timo and AP-TSCL-Pro after two weeks of wear [Yangzhi Zhu, Terasaki Institute for Biomedical Innovation]

Glaucoma is often referred to as the “silent thief of sight” and is the leading cause of irreversible blindness worldwide.

Its prevalence is predicted to increase sharply due to aging populations, rising from 80 million people in 2020 to around 134 million in 2040.

Although it is progressive and incurable, early diagnosis and treatment can preserve vision and maintain quality of life, although this requires reliable tools to identify those at risk and deliver therapies.

While smart contact lenses represent a promising platform to deliver this, the need to embed electronics, power sources, and manufacturing costs represent potential barriers in terms of patient comfort and accessibility.

To address this, the team developed an all-polymer theranostic smart contact lens (AP-TSCL) capable of continuously measuring intraocular pressure with autonomous programmable drug delivery without the need for bulky electronic components or manual operation.

The lens integrates a noninvasive, real-time microfluidic sensor that measures intraocular pressure together with a multidose, feedback-responsive drug release unit.

A biomimetic silk sponge enhances both its sensing sensitivity and the consistency of drug delivery, providing high mechanical robustness and operates well over a physiological pressure range of 16 to 32 mmHg.

By coupling the intraocular pressure readout with pressure-gated drug release, the platform is designed to enhance therapeutic efficacy while reducing unnecessary exposure under normotensive conditions. This may help mitigate ocular irritation and systemic side effects associated with conventional topical β-blockers in susceptible patients, the authors explain.

Comprehensive in vitro, ex vivo studies in cow eyes, and in vivo studies in rabbits validated its biocompatibility, accuracy, and therapeutic efficacy, demonstrating its potential as a low-cost, patient-compliant platform for personalized glaucoma therapy in real-world settings.

“This power- and electronic-free SCL represents a remarkable advancement toward multifunctional ocular medical devices that integrate diagnostics and therapeutics for intelligent ocular health care delivery,” the research team maintained.

“It lays the groundwork for developing a family of pharmacy-on-a-contact-lens tools capable of delivering clinically relevant information about human health and establishes the foundation for next-generation, self-powered, electronic-free SCLs capable of accessible diagnosis and therapeutics.”

 

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Predicting Momentary Suicidal Ideation From Smartphone Screenshots Using Vision-Language Models: Prospective Machine Learning Study

Background: Passive smartphone sensing shows promise for suicide prevention, but behavioral metadata (GPS, screen time, and accelerometry) often lacks the contextual information needed to detect acute psychological distress. Analyzing what people actually see, read, and type on their phones—rather than just usage patterns—may provide more proximal signals of risk. Objective: This study aimed to test whether vision-language models (VLMs) applied to passively captured smartphone screenshots can predict momentary suicidal ideation (SI). Methods: Seventy-nine adults with past month suicidal thoughts or behaviors completed ecological momentary assessments (EMA) over 28 days while screenshots were captured every 5 seconds during active phone use. We fine-tuned open-source VLMs (Qwen2.5-VL [Alibaba Cloud], LFM2-VL [Liquid AI]), and text-only models (Qwen3 [Alibaba Cloud]) to predict SI from screenshots captured in the 2 hours preceding each EMA. We evaluated performance with temporal and subject holdouts. Results: The analytic sample comprised 2.5 million screenshots from 70 participants. Temporal holdout models achieved strong discrimination at the EMA level (AUC=0.83; AUPRC=0.77), with image-based models outperforming text-only models (AUC=0.83 vs 0.79; 95% CI 0.003-0.07). Subject holdout generalization was near chance (AUC≈0.50), though a simple lexical screening method retained modest discrimination (AUC=0.62). Smaller models performed comparably to larger models, supporting feasible on-device deployment. Conclusions: Screen content predicts short-term SI with clinically meaningful accuracy when models are personalized but does not generalize across individuals. These findings support a 2-stage clinical architecture, coarse lexical screening for new patients, with personalized VLM-based monitoring after a calibration period. On-device inference may enable privacy-preserving deployment.
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Bladder Cancer: Urine Test Improves Relapse Predictions

Stanford researchers have developed a urine test that can accurately predict which patients with bladder cancer will respond to standard surgery and immunotherapy treatments. In a study published in Cell, they report that this DNA test takes into account background mutations caused by aging that existing tests may otherwise mistake for cancer. 

“Our test can detect minimal residual disease non-invasively after bladder cancer treatment, while accounting for mutations present in normal urothelium that have complicated prior studies,” said Joseph C. Liao, MD, professor of urology and senior author of the study. “For the first time, we were able to distinguish patients likely cured by [immunotherapy] from those cured by surgery.”

Even when detected in early stages, bladder cancer has a high relapse rate. Patients with non-muscle invasive bladder cancer (NMIBC), whose tumors are still confined to the inner layers of the bladder, are typically treated with surgery. Those with higher risk profiles are then given a bacillus Calmette Guerin (BCG) immunotherapy, which can significantly reduce recurrence risk after surgery. 

However, while some patients respond well to surgery without immunotherapy, others may end up relapsing even after receiving BCG immunotherapy. Until now, there was no reliable way to predict which patients will respond to each of these treatments, making it difficult for physicians and patients alike to make informed clinical decisions. 

The molecular test developed by Liao and colleagues analyzes urine tumor DNA in urine samples to detect the presence of tumor DNA and predict whether a patient will respond to standard surgery or BCG treatment. Importantly, the test was designed to account for the “field effect,” a phenomenon where even healthy people can carry cancer-associated mutations in the bladder’s lining, with these mutations becoming increasingly common as the person ages. 

“By correcting for the field effect, a known confounder of mutation-based bladder cancer detection, we improved the specificity of urine tumor DNA liquid biopsies,” said William Y. Shi, MD/PhD student at Stanford School of Medicine and lead author of the study. “This allowed us to molecularly distinguish the relative contributions of surgery and BCG to disease control.”

The researchers evaluated the urine test in a cohort of 261 NMIBC patients who underwent surgery and BCG treatment. Results revealed three distinct molecular patterns of treatment response. These included surgery responders, for whom tumor DNA disappeared after surgery; BCG responders, who showed tumor DNA after surgery that was eliminated with the immunotherapy; and non-responders who saw tumor DNA levels remain stable or even increase after both treatments. 

“The ability to distinguish responders from non-responders to the two treatments also allowed us to study which molecular properties make tumors more likely to benefit from each therapy,” said Max Diehn, MD, PhD, professor of radiation oncology and senior author of the study. 

The study also revealed distinct molecular patterns driving response to surgery and response to BCG immunotherapy. On the one hand, patients who relapsed after surgery had tumors with genetic activity linked to cell growth and invasion. On the other hand, tumors who responded to BCG had a higher mutation burden and tended to have features that made them more visible to the immune system. 

Following validation in a larger patient cohort, this urine test could help spare patients who respond well to surgery from receiving an unnecessary course of immunotherapy. In particular, BCG supply has suffered from shortages for the past decade, leaving many patients waiting for longer than necessary. In the face of shortages, a predictive test could help prioritize those who are most likely to benefit from it. 

For patients who are unlikely to respond to both surgery and BCG, the urine test could also prove valuable in escalating treatment early on. In the study, the test was able to identify recurrence risk in patients for whom routine cystoscopy exams appeared normal, meaning it could be able to detect relapse earlier than the current standard. 

“These kinds of predictive biomarkers are critical,” said Eila C. Skinner, MD, professor of urology and chair of Stanford’s Department of Urology. “We have new treatments that are costly and carry risk of side effects. We would love to personalize therapy to ensure each patient receives the best treatment for their individual cancer.”

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Scalable Embryonic Stem Cell Platform Enables Mitochondrial DNA Research in Mice

Salk Institute scientists have developed a biological platform for studying mitochondrial DNA in physiology, adaptation, disease mechanisms, and therapeutic development. Headed by Ronald Evans, PhD, professor and director of the Gene Expression Laboratory and holder of the March of Dimes Chair in Molecular and Developmental Biology at Salk, the team has already used the platform to generate a library of 155 mitochondrial DNA mutant cell lines and reveal correlations between mouse development and mitochondrial function. They suggest that the platform, library, and findings will accelerate therapeutic development for mitochondrial disorders, as well as help scientists treat mitochondrial dysfunction in other diseases and conditions like cancer or aging.

“Mitochondrial DNA accumulates mutations at a high rate, and more than 260 inherited disease-causing mtDNA mutations have been identified in humans,” said Evans. “Until now, a lack of models representing this diversity has limited mechanistic insight and therapeutic development. Our new platform will allow scientists to investigate mitochondrial DNA variation in health, disease, and evolution, which will enable therapeutic innovation for mitochondrial disorders.”

Evans is co-corresponding author of the team’s published paper in PNAS, titled “A scalable embryonic stem cell–based platform for efficient generation of mitochondrial DNA mutant mice,” in which they concluded that their new platform, “… opens the door to mechanistic dissection of how mtDNA variation influences metabolism, adaptation, and disease, and provides a strategically valuable foundation for accel­erating therapeutic development through genetically precise mito­chondrial disease models.”

Some of your most important life partners are the mitochondria that power all your cells. You and these little cellular powerhouses are in a 1.5-billion-year-old evolutionary relationship—but mitochondria brought some baggage. Mitochondria brought their own DNA with them when they joined with the bigger, more complex cells so long ago, and today that mitochondrial DNA influences human health. Mitochondrial DNA does the extremely important job of creating the proteins needed for energy production—but it also has an especially high rate of mutation, and those mutations can accumulate thanks to inefficient repair mechanisms. Because mitochondria are essential parts of every cell, their dysfunction can lead to body-wide dysfunction, with especially devastating impact on high-energy organs like the brain and heart. Without enough power in your cells, symptoms like migraines, muscle weakness, and loss of hearing or sight can begin to manifest.

“Mitochondria are central to energy metabolism and cellular signaling, and mutations in mitochondrial DNA (mtDNA) can disrupt these processes and contribute to human disease,” the authors wrote. “Mitochondrial DNA (mtDNA) accumulates mutations at a high rate, and more than 260 pathogenic germline mtDNA mutations have been identified in humans, producing diverse and often tissue-specific disorders.”

The chronic and broad impact of mitochondrial dysfunction makes it especially important to study. However, trying to pinpoint the outcome of specific mitochondrial DNA mutations has for many years been a slow, arduous process for many years. “… progress in defining how mtDNA variation influences adaptation, pathophysiology, and disease susceptibility has been limited by the lack of suitable animal models,” the team continued. “Researchers would create mouse models one-by-one with different mitochondrial DNA mutations, with just one model sometimes taking years,” said Salk staff scientist Weiwei Fan, PhD. This was a problem that Fan had noted early in his scientific career and set his mind to as a PhD student.

The new Salk model is a scalable, embryonic stem-cell (ES)-based platform creating mice with mutations to their mitochondrial DNA. “This new work is all building off an original platform I generated during my PhD,” says Fan, first and co-corresponding author of the study. “That platform was inefficient—it took a long time to generate just one mitochondrial DNA mutant. With some technological improvements and modifications, this new platform is much more efficient and can create dozens of mutants with far greater ease.”

A playful representation of a mitochondrion moving into a larger cell, bringing with it the "baggage" of mutated mitochondrial DNA. Researchers at the Salk Institute developed a new platform for studying that mutated mitochondrial DNA, helping explain the ways it influences human health. [Salk Institute]
A playful representation of a mitochondrion moving into a larger cell, bringing with it the “baggage” of mutated mitochondrial DNA. Researchers at the Salk Institute developed a new platform for studying that mutated mitochondrial DNA, helping explain the ways it influences human health. [Salk Institute]

The authors explained, “… we developed a scalable ES cell–based platform that integrates mtDNA mutagenesis, cybrid technology, high-sensitivity mutation detection, and optimized mouse transgenesis.” The platform starts with a protein, called mitochondrial DNA polymerase, generating randomly mutated mitochondrial DNA. That mutated mitochondrial DNA is then transferred into stem cells, which can be integrated with mouse embryos to create mice for study. Once one of these mice is established, researchers can investigate the specific symptoms of their specific mitochondrial DNA mutation and the mechanisms by which those symptoms arise—insight that can be used to design targeted therapies down the line. “Optimized ES cell–embryo aggregation enables robust contribution of mtDNA mutant ES cells to host embryos, producing chimeric mice with germline transmission,” the investigators noted.

Using this platform, the Salk team generated a library of 155 mitochondrial DNA mutation cell lines, each with its own distinct impact on mitochondrial performance. “Using this platform, we generate a library of 155 donor fibroblast lines carrying distinct homoplasmic single-nucleotide mtDNA mutations that produce diverse mitochondrial phenotypes, including impaired oxidative phosphorylation, increased reactive oxygen species, and altered mitochondrial membrane potential,” they stated. They then used that library to validate that the cells could be used to generate mice with single mitochondrial DNA mutations. These mice allowed them to find a strong correlation between mitochondrial function and early embryonic development, suggesting a baseline energy level is required for normal development.

“Our library is a huge milestone and is very diverse, with a scale of diversity similar to the known human disease-causing mutation diversity of around 260,” said Fan. “And with this collection of mutant cells, we can not only look at inherited mutations but also at ones that occur based on other stresses like environmental cues or aging.” The authors added, “Together, the advances outlined in this study establish a powerful and generalizable platform for systematically modeling the functional diversity of human mtDNA mutations and polymorphisms in vivo.”

The new platform and library are cracking open the world of mitochondrial DNA. With the ability to generate mitochondrial DNA mutants more rapidly, therapeutic development for mitochondrial disease and dysfunction will come more rapidly, too. The mouse models are already a huge step forward for the field, but the researchers are also eager to move into human models in a more human-relevant context.

“The majority of human diseases come with or cause mitochondrial dysfunction,” said Evans. “Progress in this field has been limited, but this new platform is going to fuel so much important research that points to therapeutic approaches to combat mitochondrial diseases, as well as diseases or conditions associated with mitochondrial dysfunction like cancer or aging.”

In their paper the team concluded, “The library provides a unique and comprehensive resource for modeling the diversity of human mtDNA variation in vitro and can also be used to generate in vivo models through ES-cybrid technology … By enabling the generation of both pathogenic and physiologically relevant mtDNA variants—including those resembling somatic mutations associated with aging and cancer—this platform substantially expands the toolkit available to mitochondrial researchers.”

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Gene Therapy Improves Outcomes of Nerve Graft Surgery in Mice

Researchers from Ohio State University have developed a gene therapy that promotes blood vessel growth following nerve graft surgery. A study published today in Science Advances reports a significant improvement in both nerve growth and muscle strength in treated mice. 

Peripheral nerve injury can cause long-term disability, weakness, numbness, or loss of function. While nerve grafts can help repair some of these injuries by regrowing damaged nerves and reconnecting any gaps left by the original injury, many patients still can’t fully recover mobility or feeling. 

The new approach developed at Ohio State combines traditional nerve graft surgery with a gene therapy delivered using quick electrical pulses to the nerve drafts. This technique, known as tissue nanotransfection (TNT) is used to introduce three genes (Etv2, Fli1 and Foxc2) into graft cells that promote the formation of new blood vessels. 

“This study is the first to combine TNT with nerve graft surgery,” said Daniel Gallego-Perez, PhD, professor of biomedical engineering at Ohio State and senior author of the study. “While healing nerves do need oxygen and nutrients, blood vessels do much more than just deliver supplies—they help guide and support the repair process. By helping the body quickly grow new blood vessels, our approach creates a healthier environment that allows nerves to heal more effectively.”

In a mouse model of peripheral nerve injury, mice treated with the gene therapy grew more blood vessels than those only receiving a conventional nerve graft surgery. The treatment did not just help nerves regrow and reconnect, but also improved function and general health outcomes in mice. 

“We saw improvements not just under the microscope, but in real function like stronger muscle contractions and better grip strength,” said Amy Moore, MD, chair of Ohio State’s Department of Plastic and Reconstructive Surgery and interim dean of the university’s College of Medicine. “The findings from this study advance our ability to reconstruct long nerve gaps and restore function to limbs with devastating nerve injuries.” 

Moore noted that this approach could make a significant difference when treating severe, complex nerve injuries common among military services injured in training or combat. The treatment is being developed as part of the Military Medicine Program at Ohio State, which focuses on offering surgical reconstruction and pain management care for wounded service members.  

Development of the gene therapy will continue with studies in larger animals before human trials can begin. Next, the research team plans to investigate how long the benefits of the treatment last.

This novel approach could one day become part of routine nerve graft surgery, adding a simple short step to significantly improve the outcomes of a well-established procedure. Salazar-Puerta added: “This is designed to fit into the operating room and is a single treatment that could have lasting benefits.” 

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23andMe Reports Genetic Predictors of Response to GLP-1 Drugs for Obesity

On any given morning, skyrocketing numbers of people reach for a small injection pen (and soon a pill) that, just a few years ago, was barely available outside of diabetes clinics. Drugs like semaglutide and tirzepatide have become cultural phenomena, reshaping not only medicine but also public discourse and the advertising industry around weight, metabolism, and obesity. Today, it is impossible to open a magazine, turn on the TV or radio, or walk down the grocery aisle without encountering some form of advertisement for these GLP-1 receptor agonists (GLP-1RAs). 

Almost any individual in the United States can obtain a subscription to a GLP-1RA without having to visit a doctor’s office. Just visit Hims/Hers, Ro, or Noom and answer a few questions about weight, height, goals, and concerns to get a prescription. (One such site claims it is taking weight and height data and “combining with clinical data,” whatever that means, before presenting a plan and steps for ordering a prescription.) 

But there are some major problems, one being that these drugs don’t work uniformly. Some patients respond to GLP-1RAs almost immediately, reporting diminished cravings within days. Others see little change. Side effects, too, can vary dramatically, from mild discomfort to debilitating nausea and vomiting. The spread of outcomes is wide and not fully understood. 

Before blindly beginning to take a drug that, on the one hand, has seemingly miraculous effects and, on the other hand, might cause serious side effects like pancreatitis, gallbladder disease, and kidney failure, wouldn’t prescribers and prescription seekers want to know this information? 

A study published in Nature by the 23andMe Research Institute—the new nonprofit entity founded by the company’s co-founder, Anne Wojcicki, for $305 million to replace the bankrupt biotechnology company—suggests the answer may be found, at least in part, in something far more fundamental than diet or willpower: our genes. 

In speaking with Inside Precision Medicine for the first time since the company filed for bankruptcy and was resold to the nonprofit public benefit corporation, Adam Auton, PhD, vice president of Human Genetics at the 23andMe Research Institute, said, “The ‘GLP-1s’ have completely transformed weight loss management. A huge fraction of the population is benefiting. It’s a very natural question: Are people’s experiences on GLP-1s modulated by genetics?”  

The short answer is, yes. Auton and 23andMe Research Institute scientists have provided genetic evidence that variation in drug target genes contributes to variability in response among individuals, laying the groundwork for consumer-based precision medicine approaches to obesity treatment and beyond. 

Crowd-sourcing GLP-1 genetics 

To better understand why responses to GLP-1 receptor agonists vary so widely, the 23andMe Research Institute team leveraged its uniquely large and engaged research cohort. Over the past decade, the company has assembled genetic data from more than 15 million participants who consented to research, enabling analyses that would be difficult in traditional clinical trials. Immediately following the company’s filing for bankruptcy in March 2025, 23andMe reported that over 1.9 million users requested for their data to be deleted. Auton told Inside Precision Medicine that the current number of consented customers is around 11 million. 

Building on this resource, Auton and colleagues launched a targeted survey asking participants detailed questions about their GLP-1 drug use, including medication type, duration, dosage, weight loss, and side effects. More than 27,885 customers responded, providing a rich, real-world dataset. “That’s the power of having a large, engaged cohort,” said Auton. “You can ask a question and very rapidly get meaningful data back.”

Using these data, Auton and colleagues conducted a genome-wide association study (GWAS), scanning millions of genetic variants to identify those associated with treatment outcomes. “You’re starting with the entire genome,” Auton explained. “You’re testing every variant for correlation with the trait of interest. And when you see a signal, it tends to be overwhelming.”  

The team focused on two primary traits: weight loss and the presence of side effects. The strongest association emerged in GLP1R, the gene encoding the GLP-1 receptor—the direct target of these drugs. A missense variant, rs10305420, was linked to significantly greater weight loss, with each copy associated with an additional 0.76 kilograms lost.  

“It made very clear biological sense,” Auton said. “This is the receptor that the drug is acting on.” The missense variant may affect how much receptor is expressed on the cell surface, meaning individuals with more receptors could experience a stronger response to the same dose. 

A second key finding involved a substitution in GIPR (rs1800437; p.Glu354Gln), which encodes the receptor for glucose-dependent insulinotropic polypeptide and is targeted by dual agonists such as tirzepatide. Unlike the GLP1R result, this association was not related to weight loss but to drug tolerability. Carriers of the variant were more likely to report nausea and vomiting—but only when taking medications that act on the GIP receptor. No such effect was observed among users of semaglutide, which does not target GIPR.  

“It was very, very clean,” Auton said. “We saw this effect specifically in people taking the medications that actually target that receptor.”  

Together, these findings underscore a central principle of pharmacogenetics: genetic variation can shape not only whether a drug works, but also how it is experienced, often in highly drug-specific ways. 

Who is represented 

One of the study’s more unconventional aspects is its reliance on self-reported data, a method sometimes viewed with skepticism in clinical research given the limits of memory and potential inaccuracies in reporting weight loss or medication use. Anticipating this concern, scientists at the 23andMe Research Institute validated their findings using a subset of participants who also shared electronic health records (EHRs), enabling direct comparison between self-reported and clinically recorded data.

The results were reassuring: survey-reported weight loss closely tracked with medical records, and medication histories aligned well across both sources. Although participants tended to slightly overestimate weight loss, they also reported longer treatment durations, effects that largely offset each other. Importantly, the genetic associations remained robust under independent scrutiny, with replication in the All of Us Research Program, a large, federally funded dataset based on clinical records rather than self-report. 

While weight loss is the headline feature of GLP-1RAs, side effects often determine whether patients persist with treatment. Nausea, vomiting, and gastrointestinal discomfort are among the most common reasons for discontinuation, yet they are frequently underreported in traditional clinical datasets. EHRs may document when a medication is stopped but rarely capture why. Self-reported data addresses this gap by directly capturing patient experience. 

“We were able to ask people directly about their experiences,” Auton said. “That’s something that’s often missing from clinical datasets.” By linking these experiences to genetic variation, the study enables a more refined understanding of drug tolerability, moving beyond population averages to individualized risk profiles. 

As with many large-scale genetic studies, statistical power was greatest among individuals of European ancestry, reflecting broader imbalances in genomic datasets. However, the key findings were consistent across multiple ancestral groups, supporting their generalizability.

“We’re not seeing fundamentally different genetic effects across populations,” Auton said. Still, increasing diversity in genetic research remains essential to ensure equitable advances in precision medicine. As digital tools continue to integrate genetic, clinical, and self-reported data, this participant-driven model may play an increasingly central role in biomedical discovery. 

Putting pharmacogenomics in patients’ hands 

Identifying genetic variants is only the first step, of course. The larger goal is to translate those discoveries into tools that can guide real-world decisions. To that end, the 23andMe Research Institute scientists developed predictive models that combine genetic information with clinical factors to estimate treatment outcomes. 

The vision is straightforward: before starting a GLP-1 drug, a patient could receive a personalized profile indicating likely weight loss and risk of side effects. “People are making decisions about whether these medications are right for them,” Auton said. “Can we give them information to help with that decision?” 

Such tools could have immediate clinical applications. A patient with a high predicted risk of nausea, for example, might start at a lower dose or follow a slower titration schedule. Another with a favorable genetic profile might be reassured about expected benefits. 

For now, these findings are unlikely to immediately change prescribing practices, as clinical guidelines will require further validation through prospective studies. However, the trajectory is clear. In the near future, patients considering GLP-1 therapies may undergo genetic testing as part of routine care, with treatment decisions—such as drug choice, dosing, and expectations—guided in part by their DNA. For a class of drugs already transforming millions of lives, this approach could further enhance both efficacy and tolerability, underscoring that responses to GLP-1 therapies are shaped not only by pharmacology but also by the subtle variations of the human genome. 

The broader significance of the study lies in its contribution to precision medicine: the idea that treatments should be tailored to individual biology rather than applied uniformly. In fields like oncology, this approach is already standard. But precision obesity treatment is in far earlier stages.  

Auton is quick to re-emphasize that genetics is only one piece of the puzzle. Lifestyle, environment, treatment adherence, and underlying health conditions all shape outcomes. Still, even a partial predictive signal could be transformative in a field where trial-and-error prescribing is common. 

As researchers continue to study GLP-1RAs, their potential appears to extend far beyond weight and blood sugar. Early evidence suggests benefits in cardiovascular health, inflammation, and even neurological conditions. Some studies are exploring their role in addiction and compulsive behaviors. “There’s an increasing literature that they’re beneficial in multiple areas,” Auton said. 

This expanding scope makes understanding variability even more important. If GLP-1 drugs are to be used to treat a wide range of conditions, predicting who will benefit and who may be at risk becomes one of the most important, if not the most important, challenges.

What about sequencing? 

Throughout our conversation, there was at least one elephant in the room. One is that this is not the first study to identify genetic variants influencing responses to GLP-1 drugs, as prior research has also implicated rs10305420. Slovenian researchers showed that genetic variability in GLP1R is associated with inter-individual differences in the weight-lowering-lowering potential of GLP-1 drugs in obese women with polycystic ovary syndrome (PCOS) in 2015, at a time when the main GLP-1 drug was liraglutide, which required daily injection.

More provocative is that the directionality of the variants’ effect reported in the Nature paper is the opposite of these previous studies. Auton’s team writes that such discrepancies may stem from differences in disease context, smaller sample sizes, limited statistical power, and variations in drug type, cohorts, and analytical methods.

Additionally, the GIPR variant rs1800437 (p.Glu354Gln) is already a known partial loss-of-function mutation, previously identified in a study of Chinese type 2 diabetes patients in 2019. 

Perhaps the more significant issue is the question of sequencing. It’s not a space that 23andMe has completely avoided, as their premier consumer kit employs exome sequencing. But the cost of whole genome sequencing (WGS) direct-to-consumer products is now often priced lower than 23andMe’s premier kit, which goes for $499. 

When asked about employing WGS, Auton revealed little of the calculus behind why 23andMe hasn’t added WGS to its arsenal of tools for interrogating genomes. “We’re very excited about that space,” Auton said. “Our focus has always been on what we can do in a direct consumer framework. There’s always been a price question there for WGS. It’s great. But when it was $1,000, it wasn’t obvious that that was going to be a compelling consumer offering. The pricing has reached its current level. It’s an area we’re very excited about and we’ll continue to look at.”

With studies like this, 23andMe 2.0 is making a case, perhaps its strongest yet, that its true value lies in something far more consequential: the ability to predict how individuals will respond to medicine before they ever take it. If that vision holds, the implications extend well beyond GLP-1 drugs. It suggests a future where prescribing a medication without first consulting a patient’s genetic profile feels incomplete, even irresponsible. 

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A Social Justice Approach to Assistive Technology and Well-Being of People With Visual Disabilities in Low- and Middle-Income Countries: Qualitative Narrative Study

Background: The United Nations’ third Sustainable Development Goal emphasizes ensuring healthy lives and promoting well-being (WB) for all, which requires effective assistive technology (AT) for persons with disabilities. In low- and middle-income countries (LMICs), however, AT remains largely inaccessible, and high abandonment rates indicate that many existing solutions fail to meet users’ needs. To improve AT design and effectiveness, a deeper understanding of users’ lived experiences and the ways AT influences WB is essential. Objective: This study aimed to explore how technology creates opportunities or barriers in the daily lives of persons with visual disabilities in LMICs and how it affects their WB. Methods: We conducted a qualitative narrative study guided by deductive qualitative analysis, using the capability approach (CA) and disadvantage theory (DT) as theoretical frameworks. Nineteen adults with visual disabilities from Cali, Colombia, participated in in-depth, semistructured interviews. A focus group (n=5) deepened the exploration of shared experiences. Data analysis followed three stages: (1) deductive coding using Nussbaum list of central capabilities and key CA constructs (functionings, conversion factors, and agency); (2) recoding through DT concepts (insecure functioning, corrosive disadvantages, and fertile functionings); and (3) inductive analysis to capture emergent sociocultural themes. Results: AT shaped both opportunities and constraints in participants’ lives. While functionings such as employment, mobility, and affiliation were highly valued, they often remained insecure due to systemic barriers. Corrosive disadvantages—such as unemployment, exclusion, and limited spatial autonomy—undermined multiple capabilities simultaneously. Conversely, fertile functionings such as equitable employment, adaptive sports, and access to well-designed AT supported agency and resilience. The inductive analysis revealed 3 interconnected themes: the aspiration to explore and expand movement, the desire to appear attractive, and the adoption of nonconfrontational strategies to maintain social harmony. These findings highlight how emotional, aesthetic, and cultural dimensions shape the experience and meaning of AT. Conclusions: While AT research in LMICs often emphasizes availability, it rarely addresses how social norms, structural violence, and fear affect meaningful use. The combined CA and DT lens reveals that AT can either enable or constrain WB depending on how it aligns with users’ lived contexts. Designing for fertile functionings—those that support agency, safety, and resilience—is essential. Participatory, context-sensitive design must prioritize not only functionality, but also aesthetic dignity, cultural relevance, and emotional security. Including the voices—and silences—of persons with disabilities in the Global South is crucial for transforming AT from a mere tool into a catalyst for real freedom and WB.
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Provider-Engaged Development of a Sexual Dysfunction Screening Approach for Adolescents and Young Adult Childhood Cancer Survivors: Iterative Co-Design Study

Background: Sexual dysfunction (SD) is common among childhood cancer survivors, affecting approximately 20% to 50% of patients. National guidelines recommend discussions about sexuality throughout cancer care, and prior work demonstrates patient interest in SD conversations. Despite its prevalence and importance, SD is widely underrecognized and undertreated, creating gaps in comprehensive whole-person care. Objective: Our research aims to collaborate with provider partners to co-design an SD screening intervention prototype for implementation in a clinical oncology setting. This study outlines the co-design process to serve as a case study, highlighting challenges and strategies to achieve a consensus-driven intervention and implementation plan. Methods: We engaged pediatric cancer providers in a series of co-design sessions at a National Cancer Institute–designated cancer center within an academic children’s hospital. For each co-design session, the research team created a template outlining considerations from formative work (eg, patient privacy) and key decisions to be made (eg, screening modality). Co-design session moderators facilitated discussion, guiding participants toward a consensus decision for each intervention component. A final process mapping session reviewed and outlined the entire SD prototype. We conducted a rapid qualitative analysis, compiling a templated summary synthesizing and organizing findings by discussion topic and decision point. Based on co-design discussions, the research team compiled a menu of options outlining key thematic findings, core screening intervention functions, and intervention form options to allow for future expansion and tailoring of the SD prototype. Results: Six provider participants, including attending physicians, advanced practice providers, and registered nurses representing multiple oncology subspecialty groups, engaged in a series of 5 co-design sessions. Participants assessed specific intervention component options, reached consensus on component decisions, and determined an intervention and implementation workflow for each. Throughout, providers needed to ensure workflows aligned with patient and provider priorities from foundational work and to ensure design feasibility, acceptability, and appropriateness. Key intervention and implementation decisions included target population, screening frequency, screening modality and workflow, management of screening results, clinic reminders and cues, and provider education and training. With several decisions being interconnected, there was often a cascade effect in which one decision influenced or limited future decisions and, in some cases, required revisiting prior decisions to ensure cohesive alignment into a single prototype. Co-design session moderators used several strategies (eg, reminders, redirection, providing information on feasibility, etc) to facilitate decision-making and implementation strategy selection. Conclusions: Engaging provider partners in co-design sessions allowed for the collaborative development of a preliminary SD screening approach for adolescents and young adults with and surviving cancer. The dynamic co-design process and moderator strategies ensured that intervention and implementation decisions reflected the patient and provider priorities identified in prior work. Future work will test, adapt, and refine the prototype SD screening approach prior to effectiveness testing and eventual dissemination.
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Smart contact lens monitors eye pressure and delivers glaucoma drugs in early tests

Glaucoma is the second-leading cause of blindness, and a silent one at that. It’s estimated that half of the patients who develop it are unaware of their condition, as they lose peripheral vision only when the disease is more advanced, and the damage is irreversible. 

There isn’t a cure, and while medication can control hypertension in the eye to slow or stop further damage to the optical nerve, it has shortcomings. 

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