Founded in 1970 as the Institute of Medicine, the National Academy of Medicine is one of three academies, alongside the National Academy of Sciences and the National Academy of Engineering, that provide independent, objective analysis and advice on scientific, medical, health and public-policy issues. Members are chosen by their peers for outstanding professional achievement and a commitment to service. Academy president Monica M. Bertagnolli said the new members’ talent and commitment to advancing evidence-based guidance and solutions for major health care challenges would strengthen the academy’s work.

Ettner, a distinguished professor in general internal medicine and health services research at the David Geffen School of Medicine and in health policy and management at the UCLA Fielding School of Public Health, is also dean emerita of UCLA’s graduate education. Her pioneering health economics research helped establish connections between socioeconomic status and health and advanced the field of behavioral health economics. According to UCLA, her work has helped inform policies intended to improve access to mental health and substance-use disorder treatment while reducing financial barriers to care. Among her foundational contributions, she was the first researcher to apply innovative statistical methods to estimate the causal relationship between income and multiple measures of physical and mental health.

Her research has also examined how insurance coverage can ease the financial burden of behavioral health treatment. Ettner led a comprehensive evaluation, funded by the National Institute on Drug Abuse, of the federal Mental Health Parity and Addiction Equity Act, which requires certain health insurance plans to provide comparable coverage for mental health and substance-use disorder treatment and medical and surgical care. The evaluation found that the legislation significantly improved insurance coverage and treatment for mental health and substance-use disorders. “I am truly honored to accept this tremendous recognition of my work establishing the deep connections between socioeconomic status and health and the critical role of insurance policy in ensuring financial access to behavioral healthcare,” Ettner said. She also described the recognition as especially meaningful as a first-generation college graduate and University of California alumnus whose research ambitions were realized with support from an undergraduate faculty mentor.

Ettner joined UCLA in 1999 after serving on the faculty of Harvard Medical School. She has authored more than 230 peer-reviewed publications and served as principal investigator on 34 research grants or subawards. In 2021, she was recognized as one of the most highly cited researchers in her field. During her tenure as dean of graduate education, Ettner oversaw more than 12,000 graduate students across more than 130 academic and professional degree programs. She earned bachelor’s degrees from UC Santa Barbara and a doctorate in economics from the Massachusetts Institute of Technology.

Kohn, a distinguished professor of microbiology, immunology and molecular genetics in the UCLA College and of pediatrics and molecular and medical pharmacology at the Geffen School of Medicine, has spent nearly four decades developing blood stem cell gene therapies. These treatments use a patient’s own genetically modified stem cells to correct the underlying causes of inherited immune and blood disorders. A member of the UCLA Broad Stem Cell Research Center and the UCLA Health Jonsson Comprehensive Cancer Center, Kohn is also a pediatric bone marrow transplant physician. His work has focused on eliminating the need for matched donors and reducing risks associated with conventional transplants.

One of Kohn’s most significant achievements is a gene therapy for adenosine deaminase–deficient severe combined immunodeficiency, or ADA–SCID, a rare inherited disorder that leaves children without a functioning immune system. Kohn and his colleagues treated their first patient in 1993 and spent more than three decades refining a technique that inserts a healthy copy of the defective gene into blood-forming stem cells, enabling the body to produce healthy immune cells. Long-term results published in 2025 showed that the treatment restored and maintained immune function in 59 of 62 children. Kohn also led UCLA’s participation in a multicenter clinical trial of a gene therapy for severe leukocyte adhesion deficiency-I, another potentially fatal inherited immune disorder.

In March 2026, the U.S. Food and Drug Administration approved the latter treatment, known as Kresladi, after all nine children in the trial survived and showed sustained restoration of immune function. It became the first FDA-approved therapy for severe leukocyte adhesion deficiency-I and the first gene therapy Kohn helped develop to receive FDA approval. Kohn’s laboratory continues to investigate gene therapies and gene-editing technologies for sickle cell disease and other inherited disorders. “It’s a great recognition of a lifetime of work and research,” he said of his election. “We don’t do this to get awards — we do it because we’re trying to accomplish something for our patients.” He joined UCLA in 2009 and has served as president of both the American Society of Gene and Cell Therapy and the Clinical Immunology Society.

Slamon, professor and chief of hematology-oncology in the Geffen School of Medicine’s Department of Medicine and director of clinical and translational research at the UCLA Health Jonsson Comprehensive Cancer Center, helped establish targeted cancer treatments as a cornerstone of modern care. His work demonstrated that treatments directed at specific molecular drivers of cancer can improve outcomes while limiting damage to healthy cells. In the 1980s, Slamon and his colleagues discovered that the HER2 gene plays a critical role in driving an aggressive form of breast cancer that represents approximately 20% of cases. That finding provided the biological basis for developing trastuzumab, marketed as Herceptin, a drug designed to target cancer cells carrying excess amounts of the HER2 protein.

Slamon led the first human clinical trials of trastuzumab at UCLA in 1990, and the drug received FDA approval in 1998. Since then, Herceptin has been used to treat nearly 3.5 million people worldwide, significantly improving survival for patients with HER2-positive breast cancer. Slamon also helped pioneer CDK4/6 inhibitors, drugs that block proteins involved in cancer-cell division. His research contributed to the development of palbociclib, marketed as Ibrance, and ribociclib, marketed as Kisqali, which have substantially improved outcomes for patients with hormone receptor-positive breast cancer, the most common form of the disease. Over more than four decades at UCLA, Slamon has continued to lead international clinical trials of next-generation HER2-targeted therapies and approaches to overcoming drug resistance.

“It is a tremendous honor to be elected to the National Academy of Medicine and to be recognized alongside so many individuals whose work has advanced medicine,” Slamon said. He credited the researchers, clinicians and patients involved in the work over the years, adding that seeing discoveries translate into treatments that have made a meaningful difference in patients’ lives has been the most rewarding part of his career. His honors include the 2026 Albany Prize in Medicine and Biomedical Research, the Lasker-DeBakey Clinical Medical Research Award, the Szent-Györgyi Prize for Progress in Cancer Research, the Sjöberg Prize and the Canada Gairdner International Award. Their election brings together three distinct areas of achievement: economic conditions and health, gene therapy for inherited immune disorders and molecularly targeted breast cancer treatment.

Subject of Research: National Academy of Medicine recognition of UCLA faculty research in health economics, gene therapy and breast cancer treatment

Article Title: National Academy of Medicine welcomes 3 new UCLA faculty members

Article References: National Academy of Medicine welcomes 3 new UCLA faculty members. Original publication (Bibliographic details unavailable.)

Image Credits: AI Generated

DOI: Not provided

Keywords: National Academy of Medicine, UCLA, Susan Ettner, Donald Kohn, Dennis Slamon, health economics, gene therapy, ADA-SCID, leukocyte adhesion deficiency, HER2, breast cancer, targeted therapy

Kohn is a distinguished professor of microbiology, immunology and molecular genetics in the UCLA College and of pediatrics and molecular and medical pharmacology in the David Geffen School of Medicine at UCLA. He is also a member of the UCLA Broad Stem Cell Research Center and the UCLA Health Jonsson Comprehensive Cancer Center. A pediatric bone marrow transplant physician as well as a gene therapy researcher, he has spent nearly 40 years developing and advancing treatments through clinical trials, with the aim of improving care, expanding treatment choices and reaching more patients. “It’s a great recognition of a lifetime of work and research,” Kohn said. “We don’t do this to get awards — we do it because we’re trying to accomplish something for our patients.”

The foundation of Kohn’s career was shaped by several influential mentors. Richard Hong, whose work treating children with severe combined immunodeficiency, drew Kohn into the field, provided his initial inspiration. R. Michael Blaese mentored him during a fellowship at the National Institutes of Health, while Robertson “Robbie” Parkman, his division chief at Children’s Hospital Los Angeles, later guided his professional development. Kohn also credited the research collaborators and clinical colleagues who worked alongside him, describing himself as the conductor in an orchestra of “virtuoso players.” He was recruited to UCLA in 2009 by stem cell and gene therapy leaders Owen Witte, Judith Gasson and James Economou, who he said helped create the interdisciplinary environment and research resources needed for his work to flourish.

One of Kohn’s most consequential contributions is his work on adenosine deaminase-deficient severe combined immunodeficiency, known as ADA-SCID. In this rare disorder, the absence of functional ADA enzyme cripples the immune system by preventing healthy immune cells from developing normally. Kohn and his colleagues treated their first patient with gene therapy in 1993 and have spent more than three decades refining an approach that adds a healthy copy of the ADA gene to a patient’s own blood-forming stem cells. Once modified, those stem cells can generate immune cells capable of restoring immune function. Long-term results published in 2025 from the largest study of the therapy to date found that immune function was restored and maintained in 59 of 62 children. Kohn and his collaborators are now working to move the treatment toward approval by the U.S. Food and Drug Administration so that it can become more widely available.

The rationale for this strategy lies partly in the limitations Kohn observed while performing bone marrow transplants. A conventional transplant can depend on finding a sufficiently well-matched donor, and donor immune cells may attack the recipient’s body, producing graft-versus-host disease. Reusing a patient’s own genetically modified stem cells avoids that donor-recipient mismatch and can require substantially less chemotherapy than a donor transplant. It may also eliminate the need for immune-suppressing medication after treatment. The approach illustrates a central principle of ex vivo gene therapy: a patient’s cells can be removed, genetically corrected in a laboratory and returned to the body to rebuild a deficient system. The technical simplicity of that overview conceals the considerable work involved in delivering genes effectively, preparing patients for therapy and demonstrating that any immune recovery will endure.

That same platform has produced another historic regulatory milestone. Kohn led UCLA’s participation in a multicenter clinical trial of a gene therapy for severe leukocyte adhesion deficiency type I, or LAD-I, a potentially fatal immune disorder that impairs the ability of white blood cells to move from the bloodstream into tissues. In March 2026, the FDA approved the therapy, called Kresladi, after all nine children enrolled in the trial survived and showed sustained restoration of immune function. Kresladi is the first FDA-approved treatment for severe LAD-I and the first gene therapy in which Kohn has been involved to secure regulatory approval. The result also demonstrates how a rare-disease trial can validate multiple parts of a treatment strategy at once: the biological mechanism, the procedure for modifying stem cells, the conditioning regimen required before reinfusion and the durability of the immune correction.

Kohn’s decade-long work on gene therapy for sickle cell disease has yielded additional insights even though the source does not describe that program as having reached approval. His research helped clarify the effects of chemotherapy conditioning, inflammation and gene delivery, knowledge that may improve future treatments for sickle cell disease and related blood disorders. These issues are central to translating a promising laboratory result into a tolerable and effective clinical treatment. Conditioning makes space for corrected cells to take residence in the bone marrow, but it can also provoke inflammation and other adverse effects. Efficient gene delivery is likewise essential for achieving a clinically meaningful level of functional protein. By examining those barriers across diseases, Kohn’s laboratory has helped refine the platform rather than treating each inherited disorder as an entirely separate scientific problem.

The broader laboratory is now extending blood stem cell gene therapy to additional conditions while investigating gene-editing technologies such as CRISPR-Cas9 and base editing. Current projects include potential treatments for alpha thalassemia major, mucopolysaccharidosis type IIIB, also known as MPS IIIB or Sanfilippo syndrome type B, Angelman syndrome and X-linked agammaglobulinemia. Conventional gene addition supplies a functional copy of a gene, whereas editing seeks to alter DNA directly, including correcting a disease-causing mutation or changing a regulatory sequence. These complementary approaches could expand the range of disorders addressable by stem cell therapy. They also raise distinct safety and delivery questions, making the long-term clinical data generated by earlier programs important for evaluating where correction, addition or precise editing offers the most benefit.

Beyond laboratory and clinical research, Kohn has held prominent leadership positions in gene and cell therapy. He has served as president of both the American Society of Gene and Cell Therapy and the Clinical Immunology Society, and as a member and chair of the National Institutes of Health Recombinant DNA Advisory Committee. His previous honors include the American Society of Gene and Cell Therapy’s outstanding achievement award, a career achievement award from the International Society for Cell and Gene Therapy, the Distinguished Clinical Scientist Award from the Doris Duke Charitable Foundation and a lifetime achievement award from the Pediatric Blood & Marrow Transplant Consortium. He has also been recognized for mentoring the next generation of physician-scientists and gene therapy researchers, extending his influence beyond his own laboratory and clinical trials. Kohn said election to the academy is not a reason for him to stop. “This is what I like doing. This is what I’m good at,” he said. “And so I plan to keep doing this, trying to bring new treatments to the clinic for patients.”

Subject of Research: Donald Kohn’s development of blood stem cell gene therapies and election to the National Academy of Medicine

Article Title: UCLA gene therapy pioneer Dr. Donald Kohn elected to National Academy of Medicine

Article References: UCLA gene therapy pioneer Dr. Donald Kohn elected to National Academy of Medicine. Original publication (Bibliographic details unavailable.)

Image Credits: AI Generated

DOI: Not provided

Keywords: Donald Kohn, gene therapy, blood stem cells, ADA-SCID, severe LAD-I, Kresladi, sickle cell disease, CRISPR-Cas9, base editing, UCLA, National Academy of Medicine, rare immune disorders

Alpha-ketoglutarate is a central player in cellular chemistry. It sits inside the tricarboxylic acid cycle, the series of reactions that cells use to extract energy from nutrients, and it also serves as an essential cofactor for a family of enzymes that remodel the epigenome, the layer of chemical marks that determines which genes are switched on or off. Among these are enzymes that strip methyl groups from histones, the protein spools around which DNA is wound. Because αKG participates in both energy metabolism and gene regulation, researchers have long suspected that raising its levels could influence cancer, but how supplementation would affect lung tumor growth in living organisms remained poorly understood.

To find out, the UCLA team turned to mice genetically engineered to develop lung adenocarcinoma driven by a mutation in KRAS, one of the most frequently mutated cancer-driving genes in this disease. The animals received either a control diet or a diet containing 2 percent Ca-αKG for 16 weeks. The results were unambiguous and sharply divided by sex. Female mice on the supplemented diet developed significantly smaller tumors with lower levels of tumor-cell proliferation than their control-fed counterparts. Male mice given the identical supplement developed larger tumors and showed higher proliferation. Notably, the number of tumors did not change significantly in either sex, indicating that Ca-αKG primarily altered how fast existing tumors grew rather than how many tumors formed in the first place.

When the researchers examined the molecular fingerprints of the treated tumors, the explanation for the divergence began to emerge. In female tumors, the supplement reduced two repressive histone modifications, H3K27me3 and H3K9me3, chemical marks that normally dampen the activity of certain genes. In male tumors, Ca-αKG instead increased H3K27me3. The same molecule, delivered in the same dose, therefore produced opposing epigenetic effects in the two sexes, rewiring gene regulation in opposite directions rather than simply feeding or starving the cancer cells energetically.

Gene-expression analysis reinforced this picture. In female tumors, Ca-αKG activated a suite of genes associated with myogenesis, the biological program that builds cardiac and skeletal muscle. Such genes are rarely expressed in epithelial tumors, making their appearance in lung adenocarcinoma particularly striking. In male tumors, that same muscle-development program was suppressed. A potential conductor of this response was TBX5, a transcription factor that governs cell identity and development. Ca-αKG raised TBX5 protein levels in female tumors, and laboratory experiments showed that an alpha-ketoglutarate derivative also increased TBX5 expression in human lung cancer cells derived from female patients, hinting that the mechanism could extend beyond the mouse model.

To probe the clinical relevance of TBX5, the team analyzed data from The Cancer Genome Atlas, a large public repository of human tumor profiles. TBX5 expression was higher in tumors from women, and among female patients, higher TBX5 levels were associated with better five-year overall survival. Elevated TBX5 also correlated with lower expression of genes driving tumor-cell proliferation and higher expression of genes marking a more differentiated, less aggressive tumor state. The researchers were careful to stress, however, that this human analysis was purely observational. The patients in the dataset were never treated with Ca-αKG, so the data cannot demonstrate that the supplement raises TBX5 or improves survival in people.

The study also revealed that the tumor’s own genetics can override the supplement’s effects entirely. When the researchers tested Ca-αKG in mice whose KRAS-driven lung cancer additionally lacked the tumor-suppressor gene TP53, the supplement no longer significantly reduced tumor growth. In human lung adenocarcinoma, tumors carrying mutated TP53 also showed lower TBX5 expression. Together, these results suggest that tumor genotype helps determine whether the Ca-αKG–TBX5 axis can be engaged at all, adding a second layer of complexity to an already sex-dependent response.

One question remains open: why did Ca-αKG accelerate tumor growth in male mice? The researchers do not yet know. Intriguingly, when they repeated the experiment in a different mouse genetic background, Ca-αKG no longer increased tumor burden in males, indicating that the harmful response in males may itself depend on the strain’s genetic background. The finding adds yet another variable, sex, tumor genotype and now host genetics, to the list of factors that can shape how a metabolic intervention plays out in cancer.

Senior author Dr. Claudio Scafoglio, associate professor of pulmonary and critical care medicine at UCLA, framed the work as a window into a tangled biological relationship. These findings, he noted, offer a glimpse into the complicated interplay among metabolism, cancer and biological sex, and the opposite responses observed in male and female mice underscore how sex and tumor genetics shape the outcome of metabolic interventions. He added that the study highlights how a metabolic intervention can have broad effects on the cancer genome, not only by changing the energetic state of cancer cells but also by directly affecting gene regulation, and that cellular metabolism is tightly linked to epigenetic state through a complex network of interdependent pathways.

Lung cancer remains the leading cause of cancer-related death worldwide, and lung adenocarcinoma accounts for a large share of cases. Although targeted therapies and immunotherapies have improved outcomes for some patients, the search for approaches to prevent or slow the disease continues, and metabolism has become one of the most actively explored frontiers. The UCLA results, with first author Martin Alcaraz Jr., a postdoctoral scientist at the Jonsson Comprehensive Cancer Center, leading the work, are an early step toward fully characterizing the metabolic and epigenetic changes induced by nutritional interventions. Future studies will need to determine why the response differs by sex and tumor genotype, and whether these findings could eventually inform prevention strategies tailored to a patient’s biology rather than applied uniformly. For now, the message is one of caution and curiosity: a supplement that is safe, natural and seemingly benign can act as a double-edged sword in cancer, and understanding who benefits and who is harmed may matter far more than the molecule itself.

Subject of Research: Sex-dependent effects of dietary calcium alpha-ketoglutarate on KRAS-driven lung adenocarcinoma growth and epigenetic gene regulation

Article Title: Dietary supplement may influence lung tumor growth differently in females and males, UCLA study finds

Article References: Dietary supplement may influence lung tumor growth differently in females and males, UCLA study finds. (n.d.). Original publication

Image Credits: AI Generated

DOI: Not provided

Keywords: lung cancer, calcium alpha-ketoglutarate, alpha-ketoglutarate, epigenetics, KRAS, TBX5, TP53, lung adenocarcinoma, sex differences, tumor metabolism, histone modifications, UCLA

Brantingham has spent two decades studying car theft, but the Kia and Hyundai episode presented an unusually rich case. The surge began in several U.S. cities, including Los Angeles, before spreading nationwide. To understand it, his interdisciplinary team combined ideas from foraging ecology, social learning theory, criminology, and methods drawn from mathematical modeling and computer science. Working with data from the Los Angeles Police Department, the researchers built forecasts showing that the theft wave is not a short-lived spike tied to a fleeting internet trend, but a slow-moving phenomenon governed by the life cycle of the vehicles themselves.

The root of the problem lies in a manufacturing decision. From 2011 to 2022, Kia and Hyundai left engine immobilizers out of 20 car models. These electronic devices, standard anti-theft equipment in most modern vehicles, prevent an engine from starting without the correct key. Without one, stealing the affected cars became a relatively low-skilled crime. During the COVID-19 pandemic, when cars sat unattended on the street for long stretches and school and business closures left young people with more unstructured time, even inexperienced thieves had hours to experiment. The technique they learned was simple: pry apart the steering wheel casing, expose the starter, and turn the ignition with a plain USB cable.

Social media then amplified what had begun as a localized discovery. Videos tagged Kia Boys or Kia Challenge spread across YouTube and TikTok, some offering step-by-step instructions for the thefts. But Brantingham notes that even clips without explicit instructions were enough to signal to naive thieves that these models could be taken in minutes. Social media, he observed, is remarkably effective at creating experts when the required skill is low. The platforms did not invent the vulnerability, but they broadcast it, standardized it, and glamorized the joyrides that followed.

Perhaps the most counterintuitive finding concerns traditional media. The evidence from Los Angeles indicates that the vulnerability was initially discovered without the help of social media, and the same pattern held in Milwaukee, the birthplace of the Kia Boys posts, as well as in Denver. Print and cable news coverage of the theft wave may itself have encouraged copycats, the researchers suggest, extending the crime spree to places that viral videos never reached directly. The interplay between old and new media, rather than either alone, appears to have shaped the trajectory of the epidemic.

One of the most striking insights from the study is geographic. Crime hotspots, the researchers found, move with the underlying new and used car market. New vehicles tend to be sold in more affluent areas, held for a couple of years, and then resold. As cars age and depreciate, each change of hands shifts them toward less affluent neighborhoods. A vulnerable vehicle that began its life on an affluent street in Los Angeles will, some twenty to twenty-five years later, likely end its life in a far less prosperous one. The same pattern held for Honda Civics and Toyota Camrys, frequent targets in the 1980s, 1990s, and 2000s, and it will hold for the Kia and Hyundai models as well.

For people living in those less affluent areas, Brantingham explained, the crime hotspot comes to them. The movement is not about offenders relocating from one neighborhood to another, he said, but about ripe criminal targets migrating through the used car market. This means that by the time higher-income areas of Los Angeles have long forgotten the Kia Boys vulnerability, lower-income communities will still be absorbing the aging, unprotected vehicles as they drift toward the end of their life cycles. The burden of the crime wave, in other words, is not static; it travels with the cars.

The forecast that thefts will continue through at least 2042, and likely through 2050, follows directly from this logic. Because the vulnerable models remain on the road and continue to change hands, the pool of easy targets persists for decades. The research, funded by the Air Force Office of Scientific Research, offers a quantitative window into how social media shapes offline crime and how long the shadow of a single manufacturing decision can stretch across a vehicle fleet.

There are practical lessons for consumers. Brantingham points to the demonstrated success of electronic engine immobilizers, noting that Toyota introduced them on the Camry in 1992 and Honda on the Civic in 2001, with marked reductions in theft. His advice is straightforward: verify that any car you buy comes with an immobilizer as standard equipment, and if you own an older model without one, buy a steering wheel lock and use it correctly. Owners of vulnerable Kia and Hyundai models should also take advantage of manufacturer recalls that improve anti-theft technology, or consider trading in the vehicle for one with modern protections.

Policy has begun to catch up as well. A class action lawsuit brought by 36 states against Kia and Hyundai led to a settlement in 2025 in which both companies agreed to equip all future cars with industry-standard engine immobilizer anti-theft technology, provide ignition cylinder protectors, and offer some monetary compensation for cars damaged by thieves. For Brantingham, the episode carries a broader significance beyond one brand or one crime wave. We live in one of the safest times ever recorded, he noted, yet crime remains incredibly common, and documenting how people behave in complex online and offline environments is core to a better understanding of the human condition.

Subject of Research: Forecasting the impact of the viral Kia Boys social media trend on Kia and Hyundai car thefts in the United States

Article Title: Car owners beware! Lessons from the ‘Kia Boys’ crime spree

Article References: Car owners beware! Lessons from the ‘Kia Boys’ crime spree. (n.d.). Original publication

Image Credits: AI Generated

DOI: Not provided

Keywords: Kia Boys, car theft, Hyundai, Kia, social media, engine immobilizer, UCLA, criminology, forecasting, used car market, TikTok, COVID-19

The study, published in the journal Cancer Immunology Research, a journal of the American Association for Cancer Research, used a powerful genetic screening technique called a genome-wide CRISPR screen to systematically search for the genes involved in T-cell exhaustion. The research team, led by senior author Dr. Antoni Ribas, professor of medicine at the David Geffen School of Medicine at UCLA and director of the cancer center’s Tumor Immunology & Immunotherapy Program, focused on human CD8+ T cells engineered to recognize a melanoma antigen. By turning off thousands of genes one by one and repeatedly exposing the engineered T cells to tumor cells in a laboratory system designed to mimic the chronic tumor exposure seen in patients with solid tumors, the investigators were able to pinpoint which genetic changes helped the immune cells remain functional, active and capable of killing cancer cells during repeated encounters with their targets.

Justin Saco, a graduate student in the Ribas laboratory and first author of the study, explained that the experimental design was a critical part of the discovery. Instead of studying short-term T-cell activation, the team modeled the chronic, repeated tumor exposure that T cells experience in solid tumors. This repeated tumor rechallenge system allowed the researchers to identify regulators of long-term persistence and exhaustion more effectively than conventional approaches. Saco noted that immunotherapy depends on T cells staying active long enough to continuously recognize and kill cancer cells, and that if they lose function too early, tumors can grow back or escape immune control. The longer T cells remain functional, the better the chance of durable cancer control.

The screening process revealed a strong and consistent signal pointing to a protein-regulating pathway known as the Cullin-5 RING E3 ligase complex, or CRL5. This molecular machinery helps control how cells break down and recycle proteins, a fundamental process that influences many aspects of cellular behavior. Importantly, the signal was not limited to a single gene. Several different components of the CRL5 machinery were independently enriched across experiments and time points, a pattern that often suggests a biologically important pathway rather than a statistical fluke. This convergence of evidence from multiple independent components of the same complex gave the researchers confidence that CRL5 plays a central role in driving T-cell exhaustion.

When the researchers disrupted CRL5-related genes, the modified T cells maintained stronger tumor-killing ability, produced higher levels of immune signaling molecules, showed fewer molecular signs of exhaustion and preserved gene programs linked to survival and long-term immune function. In other words, silencing this pathway helped the engineered immune cells resist the gradual loss of function that normally occurs during chronic tumor exposure. The modified T cells stayed active longer, produced stronger anti-tumor responses and retained the molecular characteristics of functional, persistent killer cells rather than exhausted ones.

The team also tested a drug called MLN4924, which blocks the activation of Cullin-RING ligases, including CRL5. The drug partially reproduced the effects seen with genetic deletion, helping T cells maintain stronger long-term function in laboratory experiments. This pharmacological validation is significant because it suggests that the pathway could potentially be targeted with drugs rather than requiring genetic modification of the immune cells. In mouse models of human melanoma, animals treated with CRL5-deficient T cells showed improved tumor control compared with those receiving standard engineered immune cells, providing preclinical evidence that targeting this pathway could translate into better anti-tumor responses in living organisms.

The findings suggest that targeting the CRL5 pathway could potentially help improve the durability and effectiveness of T-cell-based immunotherapies for patients with solid tumors. By reducing a key biological mechanism that drives T-cell exhaustion, it may be possible to help immune cells stay active longer and maintain their cancer-fighting ability, potentially leading to stronger and more sustained treatment responses. This could be especially valuable for CAR T-cell therapies and other forms of adoptive cell therapy, which often struggle to remain effective over time in solid tumors where the immune cells are exposed to persistent tumor signals.

A companion research article by the research group of Dr. Julia Carnevale of the University of California, San Francisco provides additional support for the findings and for the broader potential of targeting molecular mechanisms of T-cell exhaustion to improve cancer immunotherapy. The convergence of evidence from two independent research groups strengthens the case that the CRL5 pathway is a biologically important regulator of T-cell persistence and that interfering with it could open new avenues for therapeutic development.

The study’s senior author, Dr. Antoni Ribas, is also the director of the Parker Institute for Cancer Immunotherapy Center at UCLA and a member of the Eli and Edythe Broad Center of Regenerative Medicine and Stem Cell Research. Other UCLA authors include Daniel Karin, J.J. Patten, Yichen Fan, Egmidio Medina, Nataly Naser Al Deen, Ameya Champhekar, Katie Campbell and Cristina Puig-Saus. The research was funded in part by the Parker Institute for Cancer Immunotherapy, the National Institutes of Health and philanthropic support. As the field of cancer immunotherapy continues to evolve, discoveries like this one highlight the importance of understanding the fundamental molecular mechanisms that govern immune cell function, and they point toward new strategies for engineering longer-lasting, more effective treatments for patients with solid tumors.

Subject of Research: A UCLA study identifies the Cullin-5 RING E3 ligase complex as a driver of T-cell exhaustion and shows that blocking it improves the persistence and anti-tumor function of engineered immune cells in preclinical models.

Article Title: UCLA researchers identify key pathway that drives T-cell exhaustion in cancer immunotherapy

Article References: UCLA researchers identify key pathway that drives T-cell exhaustion in cancer immunotherapy. (n.d.). Original publication

Image Credits: AI Generated

DOI: Not provided

Keywords: T-cell exhaustion, Cancer immunotherapy, CAR T-cell therapy, CRISPR screen, CRL5, Cullin-RING ligase, Solid tumors, Melanoma, Adoptive cell therapy, Cancer Immunology Research, UCLA, MLN4924

The first study, published in Nature Communications, examined a strategy that many oncologists have considered but few have tested rigorously in brain cancer: giving two immune checkpoint inhibitors instead of one, and giving them before surgery rather than after. In a phase 2 clinical trial, the researchers enrolled 63 patients with recurrent glioblastoma whose tumors had returned after initial treatment and who were already scheduled for an operation. Participants received either the combination of nivolumab, which targets the PD-1 checkpoint, and ipilimumab, which blocks CTLA-4, or nivolumab alone, or a placebo, before their tumors were removed. This neoadjuvant design allowed the team to analyze living tumor tissue harvested during surgery and to see, directly, how each regimen reshaped the immune landscape inside the cancer.

The survival difference was striking for a disease in which incremental gains are the norm. Patients who received the dual combination lived a median of about 13.5 months, compared with roughly nine months for those treated with nivolumab alone. More remarkable still, five patients — about 15 percent of those on the combination — became long-term survivors, while no long-term responders emerged among patients receiving nivolumab by itself. In a cancer where median survival after recurrence is typically measured in months, a subgroup of durable responders is a signal that demands explanation, and the researchers found one written in the tumor tissue itself.

When the team examined the surgically removed tumors, the combination therapy had triggered significantly greater immune activity than the single agent, including increased infiltration of cancer-fighting T cells and higher expression of interferon-related immune genes, the molecular signature of an immune system actively engaged with its target. The most important finding was quantitative: patients whose tumors carried the highest density of T cells lived longer, with T-cell density emerging as an independent predictor of overall survival. The long-term survivors also had substantially higher levels of tumor-infiltrating lymphocytes, suggesting that the physical presence of T cells within the tumor may be the critical ingredient that converts checkpoint blockade from a theoretical therapy into a working one.

“These findings give us a clearer picture of what an effective immune response against glioblastoma may look like,” said Lu Sun, adjunct assistant professor of neurosurgery at UCLA and first author of the study. “The long-term survivors showed evidence of a stronger immune response within their tumors, offering important clues for developing treatments that can help more patients benefit from immunotherapy.” The study also identified early immune changes in the blood that were associated with better outcomes, hinting that blood-based biomarkers could one day allow physicians to monitor a patient’s response without repeated surgery. Imaging added another layer of insight: several patients treated with the dual blockade showed early pseudoprogression on MRI scans, an apparent swelling of the tumor that actually reflected immune cells flooding in, and that pattern was associated with longer survival.

“Several patients treated with dual immune checkpoint blockade showed early pseudoprogression on MRI scans following treatment, which was associated with longer survival,” said Benjamin Ellingson, director of the UCLA Brain Tumor Imaging Laboratory and professor of radiological sciences. “These findings suggest that early inflammatory changes may occur on imaging in patients that have an effective immune response.” Timothy Cloughesy, distinguished professor and director of the UCLA Neuro-Oncology Program, framed the result in broader terms: “This study shows that we can activate the immune system against glioblastoma in ways we have not previously seen. The increase in T cells within the tumor and the association with longer survival give us important clues about what an effective antitumor immune response looks like. Those insights are helping guide the next generation of therapies designed to make immunotherapy work for more patients.”

But knowing what a successful response looks like raises an obvious question: why do most glioblastoma tumors never mount one? The second study, published in Cancer Research, a journal of the American Association for Cancer Research, tackles that problem with a new preclinical model built to mirror human disease far more faithfully than the laboratory mice traditionally used to test brain cancer therapies. The model was developed using a technology called MADR — Mosaic Analysis with Dual-Recombinase — which allows scientists to introduce patient-relevant genetic changes into developing brain cells. The engineered tumors carry alterations commonly found in human glioblastoma, including EGFRvIII, a cancer-driving mutation that keeps the EGFR growth signaling pathway permanently switched on, along with the loss of the tumor suppressor genes PTEN and CDKN2A.

“Unlike commonly used glioblastoma models, which often respond to immune checkpoint inhibitors despite their limited benefit in patients, the new model closely mirrored the biology of human disease,” said David Nathanson, professor of molecular and medical pharmacology at the David Geffen School of Medicine at UCLA. The engineered tumors grew diffusely throughout the brain, exhibited the hallmark features of human glioblastoma and developed an immune microenvironment dominated by myeloid cells — suppressive immune cells that crowd out help rather than provide it — with very few cancer-fighting T cells. Critically, the model was resistant to immune checkpoint blockade, reproducing the disappointing results seen in clinical trials rather than the false optimism generated by conventional mouse models. The researchers also found that the tumor cells were inherently resistant to T-cell killing and actively promoted T-cell exhaustion, a dysfunctional state in which immune cells lose their offensive capacity, revealing multiple overlapping mechanisms the cancer uses to evade destruction.

The two studies illuminate each other with unusual precision. In patients, tumors with higher T-cell density were associated with longer survival after dual immunotherapy; the new preclinical model, in contrast, consistently exhibited very low T-cell infiltration, faithfully recreating the so-called immune cold environment that has made glioblastoma so difficult to treat. “The tumors have very low T-cell density, which helps explain why they are resistant to immune checkpoint blockade,” said Robert Prins, professor of neurosurgery and molecular and medical pharmacology at UCLA and senior author of both studies. “Similarly, the MADR model and the clinical study highlight how EGFR alterations are linked to shorter survival and treatment resistance.” For years, Prins noted, researchers have known that immunotherapy works remarkably well in some cancers but has consistently fallen short in glioblastoma; these studies, he said, help explain both sides of that equation, one showing what an effective response looks like in patients and the other providing a model that recreates the biology preventing it.

The findings are already shaping the next phase of research. Working with Nathanson and colleagues, the team is investigating whether novel brain-penetrant EGFR inhibitors can create a window of opportunity that makes tumors more susceptible to immunotherapy, attacking the very genetic driver linked to treatment resistance. In collaboration with the laboratory of Caius Radu, the researchers are also developing next-generation mRNA vaccines designed to increase T-cell infiltration into glioblastoma tumors — directly targeting the deficiency that both studies identified as the decisive factor. The logic is elegant: if T-cell density determines who survives, then therapies that force T cells into the tumor, combined with drugs that strip away the tumor’s defenses, could convert the immune cold majority into the hot minority that responds. For a disease that has defeated nearly every therapeutic advance of the past two decades, the convergence of a human trial showing that the immune system can be activated and a model that finally reproduces why it usually is not represents a genuinely new starting point — and a roadmap for turning a 15 percent long-term survivor rate into something far larger.

Subject of Research: Immune checkpoint inhibitor response and preclinical modeling in glioblastoma

Article Title: Scientists identify clues to making immunotherapy more effective against glioblastoma

Article References: Scientists identify clues to making immunotherapy more effective against glioblastoma. (n.d.). Original publication

Image Credits: AI Generated

DOI: Not provided

Keywords: glioblastoma, immunotherapy, immune checkpoint inhibitors, nivolumab, ipilimumab, T-cell infiltration, EGFRvIII, MADR model, tumor microenvironment, biomarkers, pseudoprogression, UCLA

To understand why the study matters, it helps to understand what biosimilars are and how they differ from the generic drugs most consumers know. Conventional small-molecule medications can be copied exactly, and their generics must demonstrate bioequivalence through relatively straightforward testing. Biologic drugs, by contrast, are large, complex molecules manufactured inside living cells, which makes them inherently variable and impossible to replicate precisely. Biosimilars are therefore defined as products that are highly similar to an originator biologic, with no clinically meaningful differences in safety, purity or potency. A federal policy enacted in 2009 established an abbreviated regulatory pathway designed to bring these products to the U.S. market, with the explicit goals of increasing competition, lowering prices and improving access to biologic treatments. By the end of 2024, thirteen biosimilars had been approved for three of the most widely used cancer biologics: bevacizumab, rituximab and trastuzumab, drugs deployed against breast cancer, lymphoma, colorectal cancer, lung cancer and ovarian cancer.

The financial stakes in oncology could hardly be higher. Previous research has estimated that financial toxicity, the measurable hardship caused by the cost of care, may affect as many as half of all patients with cancer in the United States. That hardship is not merely a matter of household budgets; it has been linked to medication nonadherence and poorer health outcomes, meaning that high drug prices can directly undermine the effectiveness of treatment. Biologic drugs are a major contributor to this burden because of their complexity and cost. While earlier studies had shown that biosimilar competition in other therapeutic areas can drive down prices and shift prescribing toward cheaper alternatives, far less was known about what happened across these three major cancer drugs after biosimilar entry, and crucially, whether any market changes actually translated into lower costs for insurers and patients in everyday cancer care.

To close that gap, the UCLA team conducted a retrospective cohort study built on health insurance claims data. They identified 14,655 patient-drug pairs involving people with cancer who initiated treatment with bevacizumab, rituximab or trastuzumab between 2020 and 2023, a period that spans the market entry of biosimilars for all three drugs. The cohort included patients with commercial insurance as well as those with Medicare-related coverage, and the researchers tracked each patient’s treatment and costs for twelve months after the start of biologic therapy. Patients were sorted into four groups: those who exclusively used a biosimilar, those who exclusively used the originator product, those who switched from the originator to a biosimilar, and those who switched from a biosimilar back to the originator. Monthly insurer payments and patient out-of-pocket costs, calculated as the sum of deductibles, copayments and coinsurance, were compared across the groups after adjusting for differences in patient characteristics and treatment patterns.

The adoption patterns the researchers observed were striking. Among the patient-drug pairs, 59.4 percent of patients exclusively used a biosimilar during the first twelve months of treatment, while 32.5 percent exclusively used the originator. Only 6.9 percent switched from the originator to a biosimilar, and a mere 1.2 percent moved in the opposite direction. In other words, biosimilars captured the market primarily at the point of treatment initiation rather than through conversion of patients who were already mid-course on the branded drugs. That distinction carries practical weight: it suggests that the moment a clinician and patient choose which biologic to start may be the single most important leverage point for expanding the use of lower-cost alternatives, since switching established patients appears to be relatively rare.

The cost differences between the groups were substantial. After adjustment, average monthly payer costs were $8,959 for patients who exclusively used biosimilars, compared with $12,779 for those who exclusively used the originator, a gap of $3,820 every month of treatment. Out-of-pocket savings were smaller in absolute terms but still meaningful: patients on biosimilars paid an average of $118.90 per month versus $158.40 for those on originators, a difference of $39.50 per month. Senior author Tina Shih, director of the Cancer Health Economics Research Program at the UCLA Health Jonsson Comprehensive Cancer Center and professor of Health Economics in the Department of Radiation Oncology, acknowledged the asymmetry but emphasized its human significance. Although the savings were substantially greater for insurers than for patients, she noted, even modest reductions in out-of-pocket costs may be meaningful for people facing the financial challenges of cancer care, since those savings can be directed toward other treatment-related expenses or everyday living costs.

Beyond the patient-level comparisons, the study documented clear market-wide effects of biosimilar entry. The average sales price of the three originator biologics declined by 3.8 percent per year after biosimilars entered the market, evidence that competition pressured the branded products themselves rather than simply carving off a slice of demand. Meanwhile, the originators’ market share fell by roughly 30 percent annually among patients with commercial insurance and 31.5 percent within Medicare Part B. The biosimilars themselves were also becoming cheaper over time: the average sales price of the twelve biosimilar products included in the study declined by 12.4 percent per year, a pattern consistent with intensifying price competition among multiple manufacturers of similar products. Together, these trends indicate that the biosimilar pathway is functioning as intended, reshaping prices across the entire category rather than at the margins.

First author Xiaoyu Liu, a former PhD student in the Department of Health Policy and Management at the UCLA Fielding School of Public Health, framed the findings as timely support for ongoing regulatory efforts. The FDA has continued to take regulatory actions aimed at further unlocking biosimilar competition, Liu said, and the study’s results offer further evidence to support patients, providers and insurers in their consideration of biosimilars. The research team also included Xiaoyi Xu and Z. JohnLu of UCLA. Because the analysis relied on insurance claims rather than clinical records, it speaks primarily to utilization and cost rather than to treatment outcomes, but the regulatory standard for biosimilars, no clinically meaningful differences from the originator, underpins the assumption that the cheaper products deliver equivalent care. The study’s retrospective design also means the associations reflect real-world prescribing behavior rather than a controlled experiment, which is precisely what makes them valuable for policy discussions.

Taken together, the findings sketch a healthcare market in transition. Biosimilars now account for the majority of new treatment starts across three of oncology’s most important biologics, their prices are falling year over year, and their presence is pulling down the prices of the branded originals as well. For the health system, the monthly savings of nearly $4,000 per patient on payer costs represent the kind of aggregate figure that could reshape oncology budgets if adoption continues to climb. For individual patients, the roughly $40 in monthly out-of-pocket relief is modest against the backdrop of cancer’s total financial toll, yet it arrives at a time when financial toxicity affects up to half of American cancer patients and contributes to treatment abandonment and worse outcomes. The study also highlights a practical prescription: because biosimilar uptake happens overwhelmingly at treatment initiation, clinicians, insurers and policymakers who want to widen access to these equally efficacious, lower-cost alternatives should focus their efforts on the first prescription, where the choice between originator and biosimilar is actually made.

Subject of Research: Economic impact of biosimilar competition on cancer biologic drug costs for insurers and patients

Article Title: Cancer biosimilars associated with lower costs for insurers and patients, UCLA study finds

Article References: Cancer biosimilars associated with lower costs for insurers and patients, UCLA study finds. (n.d.). Original publication

Image Credits: AI Generated

DOI: Not provided

Keywords: biosimilars, cancer biologics, bevacizumab, rituximab, trastuzumab, drug pricing, financial toxicity, JAMA Oncology, UCLA, health economics, Medicare Part B, FDA regulation

Now a study led by Dr. David S. Williams, professor of ophthalmology and neurobiology at the David Geffen School of Medicine at UCLA, in collaboration with researchers at the University of California, Santa Barbara and Harvard, reports that the answer for primates is the opposite of what is seen in many other vertebrates. Working with retinal tissue near the fovea of Rhesus monkeys (Macaca mulatta), the team found that the majority of disk membranes in primate cones are closed, self-contained structures, much like the disks found in rod photoreceptors, the cells responsible for vision in dim light. The work, published in the Journal of Neuroscience, represents the first quantitative assessment of the relative proportion of open and closed disk membranes in a mammalian cone, and it settles a debate that has lingered since the earliest electron micrographs of the retina were first interpreted.

The significance of the question is easier to appreciate when one considers what the disks actually do. Phototransduction, the molecular cascade that turns a single photon into an electrical signal, takes place on these membranes. Light-sensitive opsin proteins and the G protein transducin are embedded in the disk membrane, and the second messenger cyclic GMP, along with calcium ions, diffuses in the compartments defined by the disk geometry. Whether the interior of a disk communicates freely with the space outside the cell or is sealed off changes the diffusion pathways available to these signaling molecules, the surface area available for protein trafficking, and the way in which the cell renews its light-sensitive machinery. Structure, in other words, is not a cosmetic detail; it constrains the entire operating logic of the photoreceptor.

Historically, the debate arose because different experimental approaches yielded apparently conflicting pictures. Early transmission electron microscopy of retinal sections produced images that some investigators interpreted as showing continuity between the disk rim and the plasma membrane, while others saw sealed, independent sacs. Preparation artifacts, the extreme fragility of photoreceptor outer segments, and the sheer difficulty of cutting and imaging tissue thin enough to resolve the relevant membranes all conspired to keep the question open. In non-mammalian cones, serial sectioning and physiological measurements converged on the conclusion that the disks are generally open, continuous evaginations of the plasma membrane, and many researchers assumed that mammalian cones would follow the same plan. Without quantitative data from primate tissue, however, the assumption remained exactly that: an assumption.

The UCLA-led team attacked the problem with two independent methods, each capable of addressing the question from a different direction. The first was electron tomography, a technique that goes beyond conventional two-dimensional electron micrographs by reconstructing three-dimensional volumes of tissue from a series of images taken at different tilt angles. Rather than inferring membrane topology from a single thin slice, tomography allows investigators to trace membranes through the volume and determine whether a given disk is sealed or whether it opens onto the extracellular space. Applied to the cone outer segments of the foveal region in Rhesus monkey retina, this approach provided direct structural evidence about the patency, or openness, of individual disk membranes.

The second approach was electrophysiological. If cone disks were open to the extracellular space, the electrical properties of the cell would reflect that continuity in measurable ways, because the membrane area accessible to ion channels and to the diffusion of charged signaling molecules would be organized differently than in a cell with sealed disks. By recording from primate cone photoreceptors and analyzing the electrical signatures of the outer segment, the researchers obtained functional evidence that could be compared directly against the structural data. The power of the study lies in this convergence: two methods with entirely different sources of potential error pointed to the same conclusion, and that conclusion contradicted the pattern established in non-mammalian vertebrates.

Through both approaches, the researchers found that the majority of disk membranes in primate cones are closed, independent structures. This is the configuration familiar from rod photoreceptors, whose disks are well established to be enclosed sacs that are periodically shed at the tip of the outer segment and renewed through new membrane synthesis at the base. The finding means that primate cones, despite their distinct morphology and their role in high-acuity color vision, share with rods the fundamental design principle of sealed disk membranes. It also means that textbooks and models of cone function, many of which have implicitly carried the open-disk assumption into discussions of mammalian and human vision, will need to be revised.

The implications extend into several areas of cell biology and physiology. Disk membrane renewal is one of the most remarkable housekeeping operations in the body: photoreceptors constantly rebuild their light-sensitive stacks, and in rods this involves the daily shedding and phagocytosis of aged disk packets by the retinal pigment epithelium. Whether cones renew their disks through a comparable process has been debated in its own right, and the closed architecture documented in this study provides a structural framework for understanding how such renewal could proceed in primate cones. Similarly, models of phototransduction depend on assumptions about the compartments in which cyclic GMP and calcium diffuse; sealed disks create a distinct intradiskal space whose ionic composition can be regulated separately from the extracellular environment, altering the dynamics of adaptation, the process by which photoreceptors adjust their sensitivity across enormous ranges of light intensity.

Because the tissue examined came from the region near the fovea, the part of the primate retina responsible for our sharpest, most detailed vision, the findings speak directly to human visual physiology. The Rhesus macaque is a well-established model for human retinal structure and function, and the cone-dominant foveal region is precisely where the stakes of the structural question are highest. Understanding that the disks in these cells are closed brings the structural biology of primate cones into alignment with the electrophysiological models that have been refined over decades, and it offers a corrected foundation for studying retinal diseases that target cones, including the macular degenerations that rob millions of people of central vision. The authors declare no competing financial interests, and the research was published as a peer-reviewed contribution to the Journal of Neuroscience under the title describing the ultrastructural and electrophysiological determination of monkey cone outer segment membrane patency.

What makes the study a striking example of basic science at its best is that it resolves, with modern tools, a question posed at the dawn of retinal ultrastructure. The combination of three-dimensional electron tomography with complementary electrophysiology provided the quantitative rigor that earlier generations of microscopists could not achieve, and the answer it delivered, that primate cone disks are closed like those of rods, reshapes how scientists will model phototransduction, disk renewal, and cone physiology in humans. After sixty years of uncertainty, the architecture of the cells that give primates their remarkable color vision is finally clear, and that clarity opens the door to a deeper understanding of how the eye builds sight from stacks of membrane only nanometers thick.

Subject of Research: Structural patency of disk membranes in primate cone photoreceptors

Article Title: Study from the Stein Eye Institute answers long-debated structural question of primate cone photoreceptors

Article References: Study from the Stein Eye Institute answers long-debated structural question of primate cone photoreceptors. (n.d.). Original publication

Image Credits: AI Generated

DOI: Not provided

Keywords: cone photoreceptors, retina, disk membranes, electron tomography, electrophysiology, phototransduction, Rhesus macaque, fovea, vision science, UCLA, Journal of Neuroscience, photoreceptor structure

Interoception, the process by which the nervous system senses, perceives, and models the internal state of the body, has increasingly been proposed as a transdiagnostic mechanism — a single underlying process that cuts across diagnostic categories and contributes to a wide range of mental and physical health disorders. But the construct is inherently multidimensional, spanning everything from the raw detection of visceral signals to conscious awareness of them, and this complexity has created persistent conceptual and measurement challenges. The result, the authors contend, is a field that sometimes talks past itself.

The clearest illustration of that confusion is a recurrent debate over whether more interoception is inherently beneficial. Some studies suggest that people who are more attuned to their bodily signals enjoy better emotional and physical health, while others find that heightened bodily awareness is associated with more anxiety, more symptom reporting, and worse outcomes. For years, researchers have traded apparently contradictory findings without fully resolving why heightened sensitivity to the body could be a blessing in one study and a burden in another.

Savoca and colleagues argue that this tension arises from ambiguity between two distinct constructs that the literature has tended to collapse into a single notion of interoception. The first they label interoceptive modeling: the underlying process by which the nervous system predicts and tracks sensory information arriving from the periphery in order to generate a model of the current or future state of the body. This is, in their framing, a fundamentally predictive enterprise. The brain does not passively receive bodily signals; it actively anticipates them, compares incoming sensory evidence against those anticipations, and updates its internal model of the body’s state accordingly. Good modeling, in this view, means that the brain’s predictions about the body track reality closely — that anticipated heartbeats match actual heartbeats, that expected gastric signals correspond to what the gut is actually doing.

The second construct is interoceptive categorization: the categorization and interpretation of interoceptive information. Once the nervous system has a model of the body’s internal state, that state must be given meaning. A pounding heart can be categorized as excitement, as fear, as the aftereffect of climbing stairs, or as the onset of a medical crisis. The same modeled signal can therefore support very different experiences and behaviors depending on how it is interpreted. Categorization is where bodily sensation meets language, memory, context, and belief — and where individual histories exert their strongest influence.

Crucially, the authors emphasize that these are not independent processes. Modeling feeds categorization, and categorization can, in turn, shape how the system models future signals. But keeping the two conceptually distinct, they argue, dissolves the paradox that has haunted the field. Health risks, on their account, are more likely to stem from poor interoceptive modeling, from maladaptive interoceptive categorization, or from some combination of the two — rather than from an excess of interoception broadly. Better modeling, properly understood, should always be beneficial for mental and physical health, because a model that accurately tracks the body gives the organism reliable information to act on. What harms people is not accuracy itself but either a model that misrepresents the body’s state or an interpretive layer that assigns threatening or otherwise maladaptive meanings to accurately modeled signals.

This reframing has immediate consequences for measurement. Many widely used interoception tasks and questionnaires were designed under the assumption that interoception is a single capacity that can be scored as more or less. If modeling and categorization are distinct, then a heartbeat-counting task, a confidence rating, and a self-report questionnaire about bodily awareness may be tapping different constructs entirely — which would help explain why correlations among these measures are often disappointingly weak. The framework suggests that researchers should specify which construct a given instrument targets, and that studies reporting heightened interoception in clinical populations should ask whether heightened modeling, heightened categorization, or both are actually at work.

To demonstrate the framework’s explanatory power, the authors turn to early-life adversity. Children who grow up in environments marked by abuse, neglect, poverty, or chronic instability encounter bodies and worlds that are unpredictable and, in some cases, genuinely dangerous. The authors propose that features of such early environments can shape both modeling and categorization processes in ways that confer vulnerability to later mental and physical health challenges. On the modeling side, an environment of chronic threat may bias the predictive system toward anticipating danger from the body itself — amplifying the gain on certain visceral signals, or calibrating predictions around states of high arousal. On the categorization side, early experiences supply the interpretive templates through which later bodily states are understood. A child who learned that a racing heart preceded harm may, years later, categorize ordinary exertion-induced cardiac changes as signals of impending catastrophe, a pattern recognizable in panic and anxiety disorders.

The adversity framework also offers a way to think about physical health. Allostatic load — the cumulative wear on physiological systems produced by chronic stress — could interact with interoceptive processes in both directions. Poor modeling might delay the detection of genuine bodily problems, from hunger and satiety disruptions to emerging illness, while maladaptive categorization might amplify symptom perception and healthcare-seeking in unhelpful ways or, conversely, lead individuals to dismiss signals that warrant attention. Because interoception sits at the interface of brain and body, the authors suggest it is a plausible mechanistic bridge between the well-documented psychological consequences of early adversity and its equally well-documented physical health consequences, from cardiovascular disease to metabolic dysfunction.

The implications extend to intervention. If maladaptive categorization is the primary driver of distress in a given individual, then treatments that target interpretation — cognitive reappraisal, exposure-based therapies, or retraining the emotional meaning of bodily sensations — may be most effective. If poor modeling is the problem, then interventions that improve the fidelity of bodily predictions, such as certain forms of body-focused mindfulness practice or biofeedback, may be more appropriate. Distinguishing the two constructs in the clinic could therefore help match patients to the treatments most likely to help them, and could guide the design of prevention programs for children exposed to adversity before maladaptive patterns consolidate.

The authors are careful to present their framework as a conceptual advance rather than a settled empirical conclusion. It generates testable predictions — that modeling accuracy and categorization style should dissociate in specific clinical populations, that adversity should leave distinguishable fingerprints on each construct, and that interventions should show construct-specific effects — and it invites the field to develop measurement tools capable of testing them. But if the distinction holds up, it resolves one of interoception science’s most stubborn puzzles with a deceptively simple insight: the question was never whether more bodily awareness is good or bad. The questions are whether the brain’s model of the body is accurate, and whether the meanings assigned to that model serve the person or betray them. For the millions of people carrying the physiological legacy of early adversity, that distinction could determine which treatments work, which risk factors matter, and ultimately how the dialogue between brain and body goes wrong — and how it might be repaired.

Subject of Research: Interoceptive modeling and categorization as distinct mechanisms linking early-life adversity to health outcomes

Article Title: Understanding interoceptive modeling and categorization following early-life adversity

Article References: Savoca, P. W., Silvers, J. A., & Callaghan, B. L. (2026). Understanding interoceptive modeling and categorization following early-life adversity. Translational Psychiatry. https://doi.org/10.1038/s41398-026-04517-1

Image Credits: AI Generated

DOI: 10.1038/s41398-026-04517-1

Keywords: interoception, early-life adversity, predictive processing, mental health, Translational Psychiatry, UCLA, body-brain communication, anxiety, measurement, transdiagnostic mechanisms, childhood stress, intervention

The core of the problem is deceptively simple. Certain microbes strip usable nitrogen compounds out of water and return them to the atmosphere as nitrogen gas, a process that cleanses ecosystems of excess nutrients. Measuring that removal, however, has long frustrated scientists. The atmosphere itself is roughly seventy-eight percent nitrogen gas, and an enormous amount of it is dissolved in every body of water on the planet. Any additional nitrogen gas produced by microbes in a lake, an aquifer or a marine sediment is dropped into this vast atmospheric background, where it becomes nearly invisible to conventional measurement. As first author Jiarui Liu, who conducted the research as a postdoctoral fellow at UCLA and UC Santa Barbara, explained, the gas that microbes produce can be very difficult to see against the huge amount of nitrogen naturally dissolved from the air. The answer, the team found, is written in the way nitrogen atoms are paired inside the nitrogen molecule itself.

To understand the technique, it helps to look closely at what nitrogen gas actually is. Every nitrogen gas molecule, or N2, consists of two nitrogen atoms joined by a strong triple bond. Those atoms come in two stable forms, or isotopes: the abundant nitrogen-14, which contains seven protons and seven neutrons, and the much rarer nitrogen-15, which carries one extra neutron. Statistically, the overwhelming majority of nitrogen molecules in nature contain two nitrogen-14 atoms. A smaller fraction contains one nitrogen-14 and one nitrogen-15, and a vanishingly small fraction contains two heavy nitrogen-15 atoms joined together. What makes these rare heavy pairs so valuable is that their abundance in the atmosphere does not follow the laws of random chance. In air, the two heavy nitrogen-15 atoms pair up more often than probability alone would predict, a phenomenon known as isotopic clumping or anomalous pairing.

Microbial nitrogen production behaves very differently. When microbes convert nitrate and other reactive nitrogen compounds into nitrogen gas, the isotopes in the resulting molecules are paired nearly at random, erasing the atmospheric excess of heavy pairs. This distinction is the heart of the new method. When microbially produced nitrogen gas mixes with nitrogen dissolved from the air, it dilutes the atmospheric excess of the rare heavy molecule. The degree of that dilution directly reveals how much nitrogen gas the microbes contributed. In effect, the rare molecule acts as a natural tracer, allowing researchers to separate the microbial signal from the overwhelming atmospheric background without needing to physically distinguish the two sources. Liu described the insight as an answer written into the pairing of atoms, a message that conventional bulk measurements of nitrogen gas simply cannot read.

Detecting such a subtle isotopic signature is an extraordinary technical challenge, and it is here that instrumentation makes all the difference. The team measured nitrogen gas extracted from water and sediment samples using UCLA’s Panorama mass spectrometer, a machine of unusual scale that uses electric and magnetic fields to separate molecules according to their mass and charge. The difficulty lies in the fact that the rare heavy nitrogen pairs are nearly indistinguishable by mass from other molecules with almost identical mass-to-charge ratios. Ordinary mass spectrometers cannot resolve these tiny differences. The Panorama, however, is exceptionally large, giving it the resolving power to separate molecules that differ by minuscule amounts in mass. That capability allowed the researchers to quantify the abundance of the clumped isotopologues with the precision needed to detect microbial nitrogen production in real environmental samples.

The significance of the atmospheric signature itself has deep roots at UCLA. Geochemist Edward Young, a co-author of the study and Liu’s postdoctoral advisor, noted that the anomalous pairing of heavy nitrogen atoms in Earth’s atmosphere was discovered at UCLA, and that the laboratory is now exploiting this signature as a powerful and unique geochemical tool. What began as a curiosity about the isotopic architecture of air has matured into a practical instrument for environmental science, one that can be deployed across dramatically different settings, from frozen polar lakes to tropical ocean basins.

The breadth of the new study is one of its most striking features. The research brought together specialists in groundwater, lake and marine environments, and their combined field and laboratory expertise allowed the clumped-isotope approach to be tested across an extraordinary range of ecosystems. The team applied the method to groundwater in Texas, lakes in Antarctica and Minnesota, coastal basins off Southern California, the Bay of Bengal, and deep-sea sediments offshore from Alaska. Each of these environments poses its own challenges for nitrogen cycling, from the cold, isolated waters of polar lakes to the nutrient-rich sediments of continental margins. The fact that a single isotopic fingerprint could illuminate microbial nitrogen loss across all of them suggests the technique has genuine global reach rather than being confined to a narrow set of conditions.

The practical implications extend directly into environmental management and public policy. In modern times, fertilizer runoff, wastewater discharge and other human activities have played an increasingly large role in the nitrogen cycle, and excess nitrogen from these sources can degrade water quality and fuel harmful algal blooms. When those blooms die off, their decay consumes oxygen and can create the low-oxygen dead zones that threaten fish and other aquatic life. By measuring how much nitrogen microbes remove naturally, the new approach can help assess the impacts of fertilizer and wastewater inputs and inform efforts to protect water quality. Liu emphasized the goal of understanding whether microbes in groundwater can mitigate nitrate pollution and how much nitrogen is removed along the way before it can fuel algal growth in lakes, rivers and coastal waters. The measurements, in other words, give a clearer picture of whether nitrogen stays within an ecosystem or exits the nutrient pool as nitrogen gas.

The technique also addresses a long-standing blind spot in routine environmental monitoring. Alan Seltzer, a co-author and assistant professor of hydrogeology at University College Dublin, pointed out that many routine groundwater-quality monitoring programs do not measure the nitrogen gas produced within an aquifer, which can create substantial biases in accounting for where nitrogen comes from and where it goes. Because the microbial product is invisible to standard water-quality assays, entire pathways of nitrogen removal have gone uncounted. The new method, Seltzer noted, opens the door to a much more complete picture of the sources and fate of nitrogen in groundwater systems, potentially correcting systematic errors in regional and national nitrogen accounting.

At the largest scale, the research speaks to one of the fundamental questions of Earth system science: the pace of the planet’s nitrogen cycle. Scientists construct nitrogen budgets to compare the rates at which usable nitrogen is supplied to the biosphere and removed from it, and that balance influences the growth of the plants and microbes that sustain food webs around the world. David Valentine, a co-author, the Norris Presidential Chair at UC Santa Barbara and one of Liu’s postdoctoral advisors, observed that while scientists know nitrogen removal processes occur, it is very difficult to figure out how quickly they happen in any given environment, which makes the global nitrogen budget hard to work out. The new approach, he said, provides a direct measure of that loss. Combined with information about water transport and how nitrogen gas accumulates in the environment, the measurements allow researchers to estimate nitrogen-loss rates at the ecosystem level. Extending such measurements across environments can link local estimates of nitrogen removal to regional and global budgets, offering an independent way to test whether nitrogen inputs and losses balance across the planet and how that balance shifts over time. Two atoms, paired in a way nature rarely intends, may finally make the hidden half of the nitrogen cycle visible.

Subject of Research: Clumped isotope measurement of nitrogen gas as a fingerprint for microbial nitrogen removal in aquatic environments

Article Title: Where does Earth’s nitrogen go? Two atoms offer a clue

Article References: Where does Earth’s nitrogen go? Two atoms offer a clue. (n.d.). Original publication

Image Credits: AI Generated

DOI: Not provided

Keywords: nitrogen cycle, clumped isotopes, nitrogen-15, mass spectrometry, microbial denitrification, groundwater, water quality, algal blooms, nitrogen budget, biogeochemistry, UCLA, Science journal