Radically different
Seeking an expert to support the development of a study on deinstitutionalisation (DI) and psychosocial disabilities in Europe, exploring how mental health systems and disability-inclusive policies can be better aligned at the EU level.
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For four days in February 2019, some 30 synthetic biologists and ethicists hunkered down at a conference center in Northern Virginia to brainstorm high-risk, cutting-edge, irresistibly exciting ideas that the National Science Foundation should fund. By the end of the meeting, they’d landed on a compelling contender: making “mirror” bacteria. Should they come to be, the lab-created microbes would be structured and organized like ordinary bacteria, with one important exception: Key biological molecules like proteins, sugars, and lipids would be the mirror images of those found in nature. DNA, RNA, and many other components of living cells are chiral, which means they have a built-in rotational structure. Their mirrors would twist in the opposite direction.
Researchers thrilled at the prospect. “Everybody—everybody—thought this was cool,” says John Glass, a synthetic biologist at the J. Craig Venter Institute in La Jolla, California, who attended the 2019 workshop and is a pioneer in developing synthetic cells. It was “an incredibly difficult project that would tell us potentially new things about how to design and build cells, or about the origin of life on Earth.” The group saw enormous potential for medicine, too. Mirror microbes might be engineered as biological factories, producing mirror molecules that could form the basis for new kinds of drugs. In theory, such therapeutics could perform the same functions as their natural counterparts, but without triggering unwelcome immune responses.
After the meeting, the biologists recommended NSF funding for a handful of research groups to develop tools and carry out preliminary experiments, the beginnings of a path through the looking glass. The excitement was global. The National Natural Science Foundation of China funded major projects in mirror biology, as did the German Federal Ministry of Research, Technology, and Space.
By five years later, in 2024, many researchers involved in that NSF meeting had reversed course. They’d become convinced that in the worst of all possible futures, mirror organisms could trigger a catastrophic event threatening every form of life on Earth; they’d proliferate without predators and evade the immune defenses of people, plants, and animals.
“I wish that one sunny afternoon we were having coffee and we realized the world’s about to end, but that’s not what happened.”
Kate Adamala, synthetic biologist, University of Minnesota
Over the past two years, they’ve been ringing alarm bells. They published an article in Science in December 2024, accompanied by a 299-page technical report addressing feasibility and risks. They’ve written essays and convened panels and cofounded the Mirror Biology Dialogues Fund (MBDF), a broadly funded nonprofit charged with supporting work on understanding and addressing the risk. The issue has received a blaze of media attention and ignited dialogues among not only chemists and synthetic biologists but also bioethicists and policymakers.
What’s received less attention, however, is how we got here and what uncertainties still remain about any potential threat. Creating a mirror-life organism would be tremendously complicated and expensive. And although the scientific community is taking the alarm seriously, some scientists doubt whether it’s even possible to create a mirror organism anytime soon. “The hypothetical creation of mirror-image organisms lies far beyond the reach of present-day science,” says Ting Zhu, a molecular biologist at Westlake University, in China, whose lab focuses on synthesizing mirror-image peptides and other molecules. He and others have urged colleagues not to let speculation and anxiety guide decision-making and argued that it’s premature to call for a broad moratorium on early-stage research, which they say could have medical benefits.
But the researchers who are raising flags describe a pathway, even multiple pathways, to bringing mirror life into existence—and they say we urgently need guardrails to figure out what kinds of mirror-biology research might still be safe. That means they’re facing a question that others have encountered before, multiple times over the last several decades and with mixed results—one that doesn’t have a neat home in the scientific method. What should scientists do when they see the shadow of the end of the world in their own research?
The French chemist and microbiologist Louis Pasteur was the first to recognize that biological molecules had built-in handedness. In the late 19th century, he described all living species as “functions of cosmic asymmetry.” What would happen, he mused, if one could replace these chiral components with their mirror opposites?
Scientists now recognize that chirality is central to life itself, though no one knows why. In humans, 19 of the 20 so-called “standard” amino acids that make up proteins are chiral, and all in the same way. (The outlier, glycine, is symmetrical.) The functions of proteins are intricately tied to their shapes, and they mostly interact with other molecules through chiral structures. Almost all receptors on the surface of a cell are chiral. During an infection, the immune system’s sentinels use chirality to detect and bind to antigens—substances that trigger an immune response—and to start the process of building antibodies.
By the late 20th century, researchers had begun to explore the idea of reversing chirality. In 1992, one team reported having synthesized the first mirror-image protein. That, in turn, set off the first clarion call about the risk: In response to the discovery, chemists at Purdue University pointed out, briefly, that mirror-life organisms, if they escaped from a lab, would be immune to any attack by “normal” life. A 2010 story in Wired highlighting early findings in the area noted that if a such a microbe developed the ability to photosynthesize, it could obliterate life as we know it.
The synthetic biology community didn’t seriously weigh those threats then, says David Relman, a specialist who bridges infectious disease and microbiology at Stanford University and a trailblazer in studying the gut and oral microbiomes. The idea of a mirror microbe seemed too far beyond the actual progress on proteins. “This was almost a solely theoretical argument 20 years ago,” he says.
Now the research landscape has changed.
Scientists are quickly making progress on mirror images of the machinery cells use to make proteins and to self-replicate. Those components include DNA, which encodes the recipes for proteins; DNA polymerases, which help copy genetic material; and RNA, which carries recipes to ribosomes, the cell’s protein factories. If researchers could make self-replicating mirror ribosomes, then they would have an efficient way to produce mirror proteins. That could be used as a biological manufacturing method for therapeutics. But embedded in a self-replicating, metabolizing synthetic cell, all these pieces could give rise to a mirror microbe.
When synthetic biologists convened in Northern Virginia in 2019, they didn’t recognize how quickly the technology was advancing, and if they saw a threat at all, it may have been obscured by the blinding appeal of pushing the science forward. What’s become apparent now, says Glass, is that scientists in different disciplines, all related to mirror life, were largely unaware of what other scientists had been doing. Chemists didn’t know that synthetic biologists had made so much progress on creating mirror cells with natural chirality from scratch. Biologists didn’t appreciate that chemists were building ever-larger mirror macromolecules. “We tend to be siloed,” Glass says. And nobody, he says, had thought to seriously examine the immune system concerns that had already been raised in response to earlier work. “There was not an immunologist or an infectious disease person in the room,” Glass says, reflecting on the 2019 meeting. “I may have come closest, given that I work with pathogenic bacteria and viruses,” he adds, but his work doesn’t address how they cause infections in their hosts.
These scientists also didn’t know that around the same time as their meeting, another conversation about mirror life was happening—a darker dialogue that was as focused on danger as it was on discovery. Starting around 2016, researchers with a nonprofit called Open Philanthropy had begun compiling research files on catastrophic biological risks. The organization, which rebranded as Coefficient Giving in 2025, funds projects across a range of focus areas; it adheres to a divisive philanthropic philosophy called effective altruism, which advocates giving money to projects with the highest potential benefit to the most people. While that might not sound objectionable, critics point out that the metrics devotees use to gauge “effectiveness” can prioritize long-term solutions while neglecting social injustices or systemic problems.
Someone in Open Philanthropy’s biosecurity group had suggested looking into the risks posed by mirror life. In 2019 the organization began funding research by Kevin Esvelt, who leads the Sculpting Evolution group at the MIT Media Lab, on biosecurity issues, including mirror life. He began reading up to see whether mirror life was something to worry about.
Esvelt made waves in 2013 for pioneering the use of CRISPR to develop a gene drive, a technology that could spread genetic changes introduced into a living organism through a whole population. Researchers are exploring its use, for example, to make mosquitoes hostile to the parasite that causes malaria—and, as a result, lower their chance of spreading it to humans. But almost immediately after he developed the tool, Esvelt argued against using it for profit, at least until proper safeguards could be set and its use in fighting malaria had been established. “Do you really have the right to run an experiment where if you screw up, it affects the whole world?” he asked, in this magazine, in 2016. At the Media Lab, Esvelt leads efforts to safely develop gene drives that can be deployed locally but prevented from spreading globally.
Esvelt says he’s often thinking about the security risks posed by self-sustaining genetically engineered technologies, and research led him to suspect that the threat of mirror organisms hadn’t been seriously interrogated. The more he learned about microbial growth rates, predator-prey and microbe-microbe interactions, and immunology, the more he began to worry that mirror organisms, if impervious to the innate defenses of natural ones, could cause unstoppable infections in the event that they escaped the lab.
Even if the first experimental iteration of such a germ were too fragile to survive in the environment or a human body, Esvelt says, it would be a light lift to genetically engineer new, more resilient versions with existing technology. Even worse, he says, the results could be weaponized. The possible path from 2019 to global annihilation seemed almost too direct, he found.
But he wasn’t an expert in all the scientific fields involved in research on mirror life, so he started making calls. He first described his concerns to Relman one night in February 2022, at a restaurant outside Washington, DC. Esvelt hoped Relman would tell him he was wrong, that he’d missed something over the years of gathering data. Instead, he was troubled.
When Relman returned to California, he read more about the technology, the risks, and the role of chirality in the immune system and the environment. And he consulted experts he knew well—ecologists, other microbiologists, immunologists, all of them leaders in their fields—in an attempt to assuage his concerns. “I was hoping that they’d be able to say, I’ve thought about this, and I see a problem with your logic. I see that it’s really not so bad,” he says. “At every turn, that did not happen. Something about it was new to every person.”
The concern spread. Relman worked with Jack Szostak, a professor of chemistry at the University of Chicago, and a group of researchers to see if it was possible to make an argument that mirror life wasn’t going to wipe out humanity. Included in that group was Kate Adamala, a synthetic biologist at the University of Minnesota. She was a natural choice: Adamala had shared the initial grant from the NSF, in 2019, to explore mirror-life technologies.
She also became convinced the risk was real—and was dumbfounded that she hadn’t seen it earlier. “I wish that one sunny afternoon we were having coffee and we realized the world’s about to end, but that’s not what happened,” she says. “I’m embarrassed to admit that I wasn’t even the one that brought up the risks first.” Through late 2023 and early 2024, the endeavor began to take on the form of a rigorous scientific investigation. Experts were presented with a hypothesis—namely, that if mirror cells were built, they would pose an existential threat—and asked to challenge it. The goal was to falsify the hypothesis. “It would be great if we were wrong,” says Vaughn Cooper, a microbiologist at the University of Pittsburgh and president-elect of the American Society for Microbiology.
Relman says that as the chemists and biologists learned more about one another’s work and began to understand what immunologists know about how living things defend themselves, they started to connect the dots and see an emerging picture of an unstoppable synthetic threat.
Some scientists have pushed back against the doomsday scenario, suggesting that the case against mirror life offers an “inflated view of the danger.”
Timothy Hand, an immunologist at the University of Pittsburgh who hadn’t participated in the 2019 NSF meeting, wasn’t initially worried when he heard about mirror life, in 2024. “The mammalian immune system has this incredible capability to make antibodies against any shape,” he says. “Who cares if it’s a mirror?” But when he took a closer look at that process, he could see a cascade of potential problems far upstream of antibody production. Start with detection: Macrophages, which are cells the immune system uses to identify and dispatch invaders, use chiral sensing receptors on their surfaces. The proteins they use to grab on to those invaders, too, are chiral. That suggests the possibility that an organism could be infected with a mirror organism but not be able to detect it or defend against it. “The lack of innate immune sensing is an incredibly dangerous circumstance for the host,” Hand says.
By early 2024, Glass had become concerned as well. Relman and James Wagstaff, a structural biologist from Open Philanthropy, visited him at the Venter Institute to talk about the possibility of using synthetic cell technology—Glass’s specialty—to build mirror life. “At first I thought, This can’t be real,” Glass says. They walked through arguments and counterarguments. “The more this went on, the more I started feeling ill,” he says. “It made me realize that work I had been doing for much of the last 20 years could be setting the world up for this incredible catastrophe.”
In the second half of 2024, the growing group of scientists assembled the report and wrote the policy forum for Science. Relman briefed policymakers at the White House, members of the defense community, and the National Security Agency. Researchers met with the National Institutes of Health and the National Science Foundation. “We briefed the United Nations, the UK government, the government of Singapore, scientific funding organizations from Brazil,” says Glass. “We’ve talked to the Chinese government indirectly. We were trying to not blindside anybody.”
A year and a half on, the push has had an impact. UNESCO has recommended a precautionary global moratorium on creating mirror-life cells, and major philanthropic organizations that fund science, including the Alfred P. Sloan Foundation, have announced they will not finance research leading to a mirror microorganism. The Bulletin of the Atomic Scientists highlighted considerations about mirror life in its most recent report on the Doomsday Clock. In March, the United Nations Secretary-General’s Scientific Advisory Board issued a brief highlighting the risks—noting, for example, that recent progress on building mirror molecules could reduce the cost of creating a mirror microbe.
“I think no one really believes at this stage that we should make mirror life, based on the evidence that’s available,” says James Smith, the scientist who leads the MBDF, the nonprofit focused on assessing the risks of mirror life, which is funded by Coefficient Giving, the Sloan Foundation, and other organizations. The challenge now, Smith says, is for scientists to work with policymakers and bioethicists to figure out how much research on mirror life should be permitted—and who will enforce the rules.
Not everyone is convinced that mirror organisms pose an existential threat. It’s difficult to verify predictions about how mirror microbes would fare in the immune system—or the larger world—without running experiments on them. Some scientists have pushed back against the doomsday scenario, suggesting that the case against mirror life offers an “inflated view of the danger.” Others have noted that carbohydrates called glycans already exist in both left- and right-handed forms—even in pathogens—and the immune system can recognize both of them. Experiments focused on interactions between the immune system and mirror molecules, they say, could help clarify the risks of mirror organisms and reduce uncertainty.
Even among those convinced that the worst-case scenario is possible, researchers still disagree over where to draw the line. What inquiries should be allowed and what should be prohibited?
Andy Ellington, a biotechnologist and synthetic biologist at the University of Texas at Austin, doesn’t think mirror organisms will come to fruition anytime soon. Even if they do, he isn’t sure they will pose a threat. “If there is going to be harm done to the human race, this is about position 382 on my list,” he says. But at the same time, he says it’s a complicated issue worth studying more, and he wants to see the conversations continue: “We’re operating in a space where there’s so much unknown that it’s very difficult for us to do risk assessment.”
Even among those convinced that the worst-case scenario is possible, researchers still disagree over where to draw the line. What inquiries should be allowed and what should be prohibited?
Adamala, of the University of Minnesota, and others see a natural line at ribosomes, the cellular factories that transform chains of amino acids into proteins. These would be a critical ingredient in creating a self-replicating organism, and Adamala says the path to getting there once mirror ribosomes are in place would be pretty straightforward. But Zhu, at Westlake, and others counter that it’s worth developing mirror ribosomes because they could possibly produce medically useful peptides and proteins more efficiently than traditional chemical methods. He sees a clear distinction, and a foundational gap, between that kind of technology and the creation of a living synthetic organism. “It is crucial to distinguish mirror-image molecular biology from mirror-image life,” he says. That said, he points out that many synthetic molecules and organisms containing unnatural components, including but not limited to the mirror-image subset, might pose health risks. Researchers, he says, should focus on developing holistic guidelines to cover such risks—not just those from mirror molecules.
Even if the exact risk remains uncertain, Esvelt remains more convinced than ever that the work should be paused, perhaps indefinitely. No one has taken a meaningful swing at the hypothesis that mirror life could wipe out everything, he says. The primary uncertainties aren’t around whether mirror life is dangerous, he points out; they have more to do with identifying which bacterium—including what genes it encodes, what it eats, how it evades the immune system’s sentinels—could lead to the most serious consequences. “The risk of losing everything, like the entire future of humanity integrated over time, is not worth any small fraction of the economy. You just don’t muck around with existential risk like that,” he says.
In some ways, scientists have been here before, working out rules and limits for research. Two years after the start of the covid-19 pandemic, for example, the World Health Organization published guidelines for managing risks in biological research. But the history is much deeper: Horrific episodes of human experimentation led to the establishment of institutional review boards to provide ethical oversight. In the early 1970s, in response to concerns over lab-acquired infections and growing use of biological warfare, the US Centers for Disease Control and Prevention established biohazard safety levels (BSLs), which govern work on potentially dangerous biological experiments.
And in 1975—at the dawn of recombinant DNA research, which allows researchers to put genetic material from one organism into another—geneticists met at the Asilomar conference center in Pacific Grove, California, to hammer out rules governing the work. There were concerns over what would happen if some virus or bacterium, genetically engineered to have traits that would make it particularly dangerous for people, escaped from a lab. Scientists agreed to self-imposed restrictions, like a moratorium on research until new safety guidelines were in place. As a result of the meeting, in June 1976 the NIH issued rules that, among other things, categorized the risks associated with rDNA experiments and aligned them with the newly adopted BSL system.
Asilomar is often hailed as a successful model for scientific self-governance. But that perception reflects a tendency to recall the meeting through a nostalgic haze. “In fact, it was incredibly messy and human,” says Luis Campos, a historian of science at Rice University. Equally brilliant Nobelists argued on either side of the question of whether to rein in rDNA research. Technical discussions dominated; talks about who would be affected by the technology were missing. The meeting didn’t start establishing guidelines, says Campos, until the lawyers mentioned liability and lab leaks.
For now it’s unclear whether these examples of self-governance, which arose from the demonstrated risks of existing technologies, hold useful lessons for the mirror-life community. Three competing images of the future are coming into focus: Mirror life might not be possible, it might be possible but not threatening, or it might be possible and capable of obliterating all life on Earth.
Scientists may be censoring themselves out of fear and speculation. To some, shutting down the work seems necessary and urgent; to others, it is unnecessarily limiting. What’s clear is that the question of what to do about mirror life has been both illuminating and disorienting, pushing scientists to interrogate not only their current research but where it might lead. This is uncharted territory.
Stephen Ornes is a science writer based in Nashville, Tennessee.
File this under “hiding in plain sight.”
Last fall, the Journal of the American Academy of Child & Adolescent Psychiatry issued a so-called expression of concern about a controversial study that was published in 2001 about the widely prescribed antidepressant known as Paxil.
Such a step is taken when a study may have errors or include unreliable information. The notice, which followed a request for a retraction, indicated that a review was underway. Meanwhile, it served as a warning, of sorts, to health care providers who might consult the study when deciding whether to prescribe the medicine.
Around half the outputs from five commonly used artificial intelligence (AI) chatbots could lead users to ineffective or harmful medical choices without professional guidance, suggests research led by the Lundquist Institute for Biomedical Innovation at Harbor-UCLA Medical Center.
As reported in BMJ Open, the researchers tested the free web versions of Gemini, DeepSeek, Meta AI, ChatGPT 3.5 and Grok available in 2024. They created 50 different adversarial prompts intended to test whether the AI models would give a problematic response or not.
The prompts were intended to realistically represent the kinds of queries members of the public might enter about health topics ranging from cancer to vaccines to stem cells, nutrition, and athletic performance. Some prompts required a specific answer and some were more open.
The researchers collected 250 responses to their prompts and categorized them as non-, somewhat, or highly problematic, using pre-defined criteria. Around 50% were problematic, 30% somewhat problematic and 19.6% highly problematic. Open-ended prompts received the most problematic answers.
In terms of the specific models, Grok produced a disproportionate share of highly problematic answers, while Gemini produced the fewest highly problematic and the most non-problematic responses. Topic-wise, the chatbots appeared more accurate when asked about cancer and vaccines, but less so when asked about stem cells, athletic performance, and nutrition.
Reference lists provided to users by the models were limited or inaccurate and the answers required some knowledge to interpret properly and were aimed at college-educated users.
“Despite adversarial pressure, chatbots typically responded in a confident, authoritative tone. Refusals to answer and explicit caveats or disclaimers were rare, reflecting the models’ strong tendency to provide an output even when prompts steered toward contraindicated advice,” write lead author Nicholas Tiller, PhD, a research associate at the Lundquist Institute, Harbor-UCLA Medical Center, and colleagues.
“As the use of AI chatbots continues to expand, our data highlight a need for public education, professional training and regulatory oversight to ensure that generative AI supports, rather than erodes, public health,” they conclude.
The post Popular AI Chatbots Can Provide Misleading Medical Information appeared first on Inside Precision Medicine.
Technology-based interventions in the field of disability and rehabilitation, which serve assistive, therapeutic, and/or service delivery functions, are considered complex due to the skills required of providers and recipients, degree of individual tailoring, and diversity of use settings. Feasibility studies are an important step in the evolution of complex interventions that can help refine the intervention, inform implementation, and prevent wasted resources. However, guidance is lacking regarding specific considerations for feasibility studies of technology-based interventions in disability and rehabilitation, which leaves researchers and developers reliant on resources from other fields that do not address important technology properties. To advance the field, context-specific definitions, considerations, and evaluation dimensions must be explicitly outlined to ensure that feasibility studies are constructively designed to meet the unique needs of these interventions. In this viewpoint article, we (1) propose a definition and framework for feasibility studies within the specific context of technology-based disability and rehabilitation interventions, (2) highlight important and unique imperatives for feasibility studies of these interventions, and (3) articulate relevant feasibility dimensions and associated evaluation criteria for these interventions. Building on previous work, we distinguish between feasibility studies, wherein we focus on iterative intervention refinement by addressing key development questions (eg, usability), and pilot studies, which are small-scale versions of a larger study that will evaluate intervention outcomes. Integrating previous typologies, we present 13 feasibility dimensions relevant to technology-based interventions and provide sample evaluation criteria, focusing on the intervention itself rather than study design considerations (eg, trial management). This information may be useful for research and development communities (academic, clinical, or industry) to inform comprehensive feasibility studies that examine unique aspects of technology-based interventions to promote real-world impact. This contribution encourages greater harmonization of terminology and evaluation methods to streamline interpretation and comparison across studies.
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Background: Artificial intelligence–powered conversational agents (ie, chatbots) are increasingly popular outlets for users seeking psychological support, yet little is known about how users experience early-stage prototypes or which therapeutic processes contribute to clinical improvement. A transparent evaluation of emerging chatbot prototypes is needed to clarify if, how, and why artificial intelligence companions work and to guide their continued development. Objective: This mixed methods pilot study evaluated user experience, acceptability, and preliminary clinical signals for an early-stage mental wellness chatbot. We also examined whether baseline symptom severity moderated clinical improvement. Methods: Three sequential cohorts (n=125) completed a 2-week, incentivized chatbot exposure (approximately 60 min per week). Participants provided first-impression ratings, qualitative feedback, and pre–post assessments of depressive symptoms (PHQ-8 [Patient Health Questionnaire-8]), anxiety symptoms (GAD-7 [Generalized Anxiety Disorder-7]), psychological distress, well-being, and loneliness. Statistical models estimated symptom change and tested interactions with baseline symptom severity. Mixed methods analysis integrated quantitative outcomes with large language model–assisted qualitative content analysis of open-ended responses. Results: Participants described the chatbot as accessible, easy to use, and emotionally validating, while citing limitations in personalization and conversational depth. Qualitative responses consistently highlighted early therapeutic processes such as emotional validation, goal setting, and perceived attunement. Regression models showed significant pre–post reductions in depressive (Hedges =–0.32) and anxiety (=–0.32) symptoms, alongside modest improvements in distress and well-being. Baseline severity moderated improvement, with marginal effects indicating larger predicted reductions at higher PHQ-8 and GAD-7 baseline scores (eg, PHQ-8=15: =–0.84; GAD-7=15: =–0.62). Conclusions: This pilot provides a comprehensive view of early chatbot development and suggests promising user experiences and preliminary symptom improvements under structured pilot conditions. By integrating experiential and exploratory clinical data, the study identifies candidate process targets to inform ongoing refinement. Findings support continued development and demonstrate procedural feasibility for progression to larger, longer-term trials evaluating engagement and clinical outcomes under more naturalistic conditions.
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Background: Depression is highly prevalent yet undertreated among people living with heart failure, indicating barriers to mental health services. Although various digital mental health interventions have been developed to detect, treat, and manage depression in this population, these interventions have seen limited integration into clinical care and a lack of implementation research. Stepped care is a service innovation that may promote the implementation of these technologies into clinical settings, but few studies have examined how these services are designed in clinical settings. Objective: This study aimed to identify strategies to address health system barriers to accessing mental health care from the perspective of people living with heart failure, clinicians, and researchers, and to incorporate these strategies into the design of a virtual mental health stepped care service within a heart failure remote management program. Methods: A qualitative description study was conducted using purposive recruitment of people living with heart failure, clinicians, and researchers from a heart failure remote patient management program. As part of a service design approach, semistructured interviews explored potential strategies to address barriers to accessing mental health services. Two researchers coded the data descriptively and constructed themes to guide the development of a virtual stepped care service. Results: A total of 22 participants were interviewed, comprising 13 people living with heart failure and 9 clinicians and researchers. Six themes were identified, comprising 4 requirements and 2 foundational principles. The requirements were to (1) adopt a collective approach to identify distress across methods, people, and time points; (2) maintain a referral-based approach; (3) rely on existing mental health human resources; and (4) offer patient choice among various mental health care options. These requirements were supported by two principles: (1) building on organizational strengths and (2) reducing treatment burden. Based on these findings, a virtual stepped care service was developed, incorporating a depression screening module, referral-based workflows, and, where clinically appropriate, patient choice in treatment selection. Conclusions: The stakeholder-informed design of this virtual stepped care service contributes to the limited literature on stepped care service design and demonstrates how such models can be tailored to their intended contexts. Although each component was designed to address health system barriers to mental health care for people living with heart failure, resource limitations may constrain the balance between feasibility and quality of care. Future research should evaluate the acceptability of this model among people living with heart failure and clinicians.
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Studying mice, researchers at Toronto’s Sinai Health have found that semaglutide—the active ingredient in popular weight loss drugs that mimic the gut hormone GLP-1—acts directly on a subset of liver cells to improve organ function, and does so independently of weight loss. The finding challenges long-held assumptions about how GLP-1 medicines work in the liver and could reshape how physicians treat metabolic liver disease.
Headed by Daniel Drucker, MD, a senior investigator at the Lunenfeld-Tanenbaum Research Institute, the team reported on their findings in Cell Metabolism, in a paper titled “The weight-loss-independent hepatoprotective benefits of semaglutide are orchestrated by intrahepatic sinusoidal endothelial GLP-1 receptors.”
For years, the liver benefits of semaglutide have puzzled scientists. “Glucagon-like peptide-1 (GLP-1) medicines improve metabolic liver disease through weight-loss-dependent and -independent actions,” the authors wrote. The drug was known to lower blood sugar and promote weight loss, but patients’ livers were improving in ways that those effects alone could not explain. And as the authors further noted, “The therapeutic scope of GLP-1 medicines extends beyond glycemic control and weight loss, with benefits evident in people with atherosclerotic heart disease, heart failure with preserved ejection fraction (HFpEF), peripheral artery disease, diabetic kidney disease, knee osteoarthritis, and obstructive sleep apnea (OSA).” However, as the team further pointed out, “… the mechanisms by which GLP-1 medicines improve organ dysfunction remain incompletely understood.”
Drucker has been at the forefront of GLP-1 research since the 1980s when his pioneering discoveries helped lay the groundwork for the development of GLP-1 medicines. After transforming treatment of type 2 diabetes and obesity, semaglutide and other GLP-1 medicines have been approved for other conditions including MASH (metabolic dysfunction-associated steatohepatitis). MASH is a severe form of fatty liver disease in which fat build-up, inflammation, and tissue scarring can lead to cirrhosis and liver failure. It affects about 25% Canadian adults and because it is closely linked with obesity and type 2 diabetes, treatment typically includes lifestyle interventions to reduce weight. “The approval of semaglutide for MASH highlights the importance of understanding the hepatoprotective mechanisms of GLP-1 action,” the investigators stated.
Drucker and colleagues have now found that semaglutide acts directly on the liver to reduce inflammation and scarring and improve organ function in a way that is independent of weight loss. Their finding overturns a prevailing assumption in the field that liver cells do not carry the receptor that semaglutide binds to, meaning the drug had no direct route to the organ.
Postdoctoral researcher Maria Gonzalez-Rellan, PhD, spearheaded the work that combined sophisticated mouse models of MASH with deep molecular analyses of liver cells. Her work identified two cell types carrying semaglutide receptors: liver sinusoidal endothelial cells (LSECs) and immune T cells. Although LSECs account for only about 3% of liver cell volume, they proved to be the key driver of semaglutide’s liver benefits.
![A pioneer in GLP-1 biology Dr. Daniel Drucker has dedicated his career to understanding how the GLP-1 hormone, and the therapies derived from it, function in the body. His early discovery that GLP-1 stimulates insulin secretion in a glucose-dependent manner paved the way for today's widely popular medications for type 2 diabetes and obesity. Dr. Drucker's ongoing research continues to shine light on the less understood aspects of GLP-1 biology including its effects on the liver and in regulating inflammation. [Colin Dewar, Sinai Health]](https://www.genengnews.com/wp-content/uploads/2026/04/Low-Res_Drucker_LTRI_Colin_Dewar-225x300.jpeg)
LSECs line the tiniest blood vessels in the liver and are studded with pores that allow them to act as a molecular sieve, filtering substances passing between the liver and the bloodstream. Gonzalez-Rellan showed that semaglutide reversed MASH in mice that lacked the brain receptors controlling appetite, demonstrating that weight loss is not required for liver benefits. “Unexpectedly. semaglutide improves hepatic inflammation, fibrosis, and immune remodeling through actions on Glp1r+ pericentral liver sinusoidal ECs (LSECs) independent of changes in body weight (BW),” the team reported. “… we leveraged a unique model of GLP-1R deficiency, Glp1rWnt1-/- mice, which are resistant to GLP-1RA-induced weight loss. Remarkably, semaglutide markedly improved hepatic steatosis, fibrosis, and immune remodeling in the absence of weight reduction.”
In a further test, mice lacking LSEC receptors showed no liver improvement on semaglutide even after losing 20% of their body weight. Detailed molecular analyses of liver cell types showed that semaglutide shifts gene activity in LSCEs, prompting them to release anti-inflammatory molecules that act on the broader liver environment, pushing it toward a state more closely resembling a healthy, disease-free liver. “Together, the data using mouse models of MASH reveal an EC-specific, weight-loss-independent, semaglutide-regulated, GLP-1R-dependent intrahepatic network for improving liver health,” the scientists said.
“It turns out that the receptor responsible for these benefits is in a very specialized population of liver cells,” commented Drucker, who is also a professor of medicine at the University of Toronto. “And this receptor orchestrates the production of molecules that talk to many different types of liver cells to calm down the inflammatory environment that is the problem in metabolic disease.”
The findings carry practical implications. GLP-1 medicines have become widely prescribed, yet their mechanism of action in the body, beyond appetite suppression and blood sugar control, have remained incompletely understood. Knowing that semaglutide improves liver health independently of weight loss could influence prescribing decisions. “We’ve seen in clinical trials that patients who lose very little weight see the same reductions in liver inflammation, scarring and enzyme levels as those who lose a great deal of weight. Now we know why,” Drucker pointed out. In their paper the team concluded “Hence, semaglutide produces a broad proteomic remodeling of the liver, enabling restoration of metabolic homeostasis and suppression of fibrogenic and inflammatory programs. The strong concordance between single-cell transcriptional changes, bulk tissue proteomics, and biomarker signatures underscores the breadth of GLP-1R-mediated hepatic reprogramming.”
Physicians may choose lower doses that avoid the side effects associated with the higher doses needed for significant weight loss, potentially also lowering costs for patients, Drucker suggested adding “We’re not saying weight loss isn’t important because many things improve when patients lose weight. But we now know that weight shouldn’t be the only measure of success, because GLP-1 medicines will improve liver health whether or not the patient loses weight.”
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