Tag: Academic research

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CD169-Positive Macrophages Attacking Melanoma Imaged in Living Tissue

Australian researchers at the Garvan Institute of Medical Research have identified a population of immune cells in the skin that actively interacts with melanoma cells and limits tumor growth. Using intravital imaging in a mouse model of melanoma, the team observed macrophages at the tumor margin engulfing live cancer cells. The research, published in the Journal of Experimental Medicine, identified a subset of tissue-resident macrophages marked by CD169 expression that appear to contribute to local tumor control through direct phagocytosis of melanoma cells and containment of tumor expansion.

“This is the first time anyone has captured a macrophage attacking and engulfing a live cancer cell in real time,” said first author Yuki Keith, PhD, a research officer at Garvan. “We always suspected macrophages were doing more than we gave them credit for—now we have the video footage to prove it. Studying this in a living system is crucial because it is more representative of what happens in real life, showing the complexity of the immune system and paving the way for the treatments of the future.”

Melanoma is an aggressive skin cancer arising from melanocytes. It is influenced by the tumor immune microenvironment, where cancer cells interact with immune and non-immune cells, and the extra-tumor environment, including tumor-draining lymph nodes where adaptive immune responses are initiated. Immune checkpoint blockade therapies, which rely on T cells to recognize and kill cancer cells, have improved outcomes in advanced melanoma, but currently only around half of patients respond to these treatments. Tumors that limit T cell infiltration, sometimes described as immune “cold” tumors, remain particularly difficult to treat.

For their work, the Garvan researchers used intravital two-photon microscopy to visualize immune activity in living mouse models with melanoma tumors. They identified CD169-positive macrophages concentrated at the tumor periphery and in the hypodermis, where they were seen physically engulfing melanoma cells. Functional experiments showed that depletion of these macrophages using CSF1R blockade led to increased tumor growth, indicating these macrophages suppress tumor progression. Importantly, the anti-tumor effect appeared independent of T cells and B cells, suggesting an innate immune mechanism operating at the tumor edge engulfs and kills tumor cells.

The study shows that in this context, CD169-positive macrophages represent a distinct tissue-resident population positioned near blood vessels in deeper skin layers, where they appear capable of directly interacting with emerging tumor cells.

Within this environment, tumor-associated macrophages have previously been associated with both tumor-promoting and tumor-inhibiting roles, depending on context and cellular subtype. The identification of CD169-positive macrophages that directly engulf live melanoma cells helps explain this heterogeneity and indicates there is a spatially defined immune function in the hypodermis.

“We have revealed a novel phagocytic tissue-resident macrophage subset in the skin that suppresses tumor growth in the mouse melanoma model,” Keith said. “Importantly, we showed that analogous subpopulations of CD169+ macrophages are also present in normal human skin and in patients with melanoma, highlighting the therapeutic potential of targeting this specific subset.”

The findings could provide a new path for the development of immunotherapies targeting melanoma. By enhancing the activity or abundance of CD169-positive macrophages, or improving their ability to tag and ingest tumor cells, it cold be possible to strengthen innate immune containment of melanoma. The team also indicated these cells could influence adaptive immunity by presenting tumor antigens to other immune populations, although the mouse model indicated tumor control could occur independently of adaptive responses.

Keith said the Garvan researchers will now look to define how CD169-positive macrophages communicate with T cells and how they might be modulated by new therapies. There is also the potential to develop targeted drugs that increase the activity of CD169-positive macrophages, or to combine macrophage activation with existing checkpoint inhibitors as a method of improving treatment response, particularly in tumors resistant to T cell–focused therapies.

The post CD169-Positive Macrophages Attacking Melanoma Imaged in Living Tissue appeared first on Inside Precision Medicine.

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Guardant Nabs Key ACS Nod and Liquid Biopsy Approval 

Colorectal (CRC) detection has become a red hot field, as concerns about rising numbers of young adult cases and competition among multi-cancer panels heat up. Guardant Health took two giant steps forward recently with first the approval of its liquid biopsy test, Guardant360 Liquid CDx, and then the listing of its blood-based Shield test by the American Cancer Society (ACS) as a choice for CRC screening of adults age 45 and older who are at average risk of the disease.

In an updated guideline released today, the ACS added blood-based screening tests, and specifically Shield, to its list of recommended choices for the patients in this subset who have not completed or have declined visual exams and stool tests. The group specifically names Shield, which was approved by the U.S. Food and Drug Administration in 2024.

Shield is an in vitro diagnostic test that detects CRC-derived alterations in cell-free DNA from blood collected in the Guardant Blood Collection Kit. The test is performed at Guardant.

These two advances put Guardant in an excellent position in the cancer liquid biopsy market, which is currently valued at between $7B and $12B and expected to double over the next ten years. 

A spokesperson for Guardant told Inside Precision Medicine, “Our current focus is on ensuring the approval and successful launch of the Shield test, with an initial focus on eligible adults age 65 and older across the U.S. who are enrolled in Medicare. In parallel, we are continuing to optimize and improve the performance of the Shield test, with the goal of upgrading the test post-approval.”

This week also, Guardant announced that the Molecular and Clinical Genetics Panel of the U.S. The Food and Drug Administration (FDA)’s Medical Devices Advisory Committee strongly recommended FDA approval of the Shield blood test for these types of patients.

“The advisory committee’s strong support for the approval of Shield reinforces the crucial role that a blood test option can have in improving CRC screening rates for those at average risk,” said AmirAli Talasaz, Guardant Health co-CEO. “Despite the importance of detecting colorectal cancer early, there are notable barriers that can deter average-risk Americans from completing existing screening methods. Shield effectively detects cancer at an early stage when it is most treatable. Providing people with this blood test alongside other non-invasive stool tests can increase the rate of colorectal screening and potentially reduce preventable CRC deaths.”

Colorectal cancer is the second-leading cause of cancer-related deaths in the U.S. The disease has a 91% five-year survival rate when caught at stage I (localized), but one out of three eligible Americans—50 million people—are not being screened for CRC. 

Current primary non-invasive screening options include stool-based tests which have proven efficacy in detecting CRC; however, studies have consistently found that barriers such as handling stool and challenges performing the test impact adherence. 

“Sadly, 76% of deaths caused by colorectal cancer occur in individuals who are not up to date with their screening,” said Daniel Chung, MD, gastroenterologist at Massachusetts General Hospital and professor of medicine at Harvard Medical School. “Clinical evidence and CRC screening guidelines acknowledge the value of offering choice to individuals at average risk for CRC and highlight the role of patient preference in test selection and CRC screening completion.”

The FDA panel’s recommendation is based on Guardant’s premarket approval (PMA) application for Shield, including the results of the pivotal ECLIPSE study evaluating the performance of the test for detecting CRC in average-risk adults. Results from the study appeared in the March 2024 issue of The New England Journal of Medicine. (Chung was an author on this study.) Shield demonstrated 83% sensitivity for the detection of CRC, with 90% specificity for advanced neoplasia. Guardant notes that this performance is within range of existing stool-based tests used as primary CRC screening options, in which overall sensitivity ranges from 67% to 92%.

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Automation and AI Will Drive Next-Gen CAR T Manufacturing

The remarkable clinical success of CAR T therapies in blood cancers has validated the promise of engineered cell therapies. But according to Adam Janvier, PhD, head of cell therapy at eXmoor Pharma, the industry faces a crucial challenge: transforming highly personalized, labor-intensive manufacturing into scalable, commercially viable production systems.

“The next big thing that really needs to come through is how we can start tackling solid tumors,” Janvier says. “Until solid tumor is truly tackled, we’re always going to be missing that key next step of what CAR T has the promise to do.”

Although scientific hurdles remain, Janvier emphasizes that manufacturing constraints are equally pressing. Today’s autologous CAR T therapies rely on harvesting a patient’s own immune cells, engineering them outside the body, and reinfusing them after a manufacturing process that can stretch to two weeks. For critically ill patients, that timeline can prove devastating.

“We might fail a process because the donation just isn’t good enough,” he explains, referring to inconsistent starting material collected from heavily pretreated cancer patients. “Then we’ve got a four to six week vein-to-vein time due to manufacturing, testing, and logistics, where the patient might pass away during the period.”

The dual risks of manufacturing failure and lengthy turnaround times are pushing developers and contract development and manufacturing organizations (CDMOs) toward alternative strategies. Among the most promising are allogeneic, or off-the-shelf, CAR T therapies and emerging in vivo approaches that could eliminate ex vivo manufacturing altogether.

“There’s a lot of work going on now with in vivo CAR T,” Janvier says. “Instead of taking a blood donation as starting material, there is growing evidence that we could use the reprogramming technology directly with the patient, generating functional CAR T cells in situ.” Although such approaches remain early-stage, they represent a potential paradigm shift by reducing manufacturing time, simplifying logistics, and lowering costs.

Analytics and quality control also remain major bottlenecks. Current CAR T testing workflows rely heavily on expensive, time-consuming assays, including flow cytometry, qPCR, and tests to confirm the quality and safety of the lentivirus. Janvier believes that AI could eventually streamline many of these processes.

“One of the exciting technologies coming out is AI-based flow-cytometry approaches,” he says, pointing to emerging platforms that use label-free imaging and machine learning to characterize cells without fluorescent antibodies. “All of a sudden, you’re removing the need for antibodies and fluorophores, reducing the cost,” he says.

Still, Janvier argues that automation might ultimately become the defining factor in whether CAR T therapies can achieve widespread commercial adoption. Current cleanroom manufacturing remains highly manual, requiring specialized staff and flexible—but inefficient—facility layouts. “Once we approach commercial scale, batch costs need to have substantially decreased,” he says. “Automation can really support that.”

Janvier envisions future CDMOs operating sophisticated robotic manufacturing platforms capable of running around the clock while minimizing operator variability and contamination risk. However, implementing such systems will require substantial capital investment and new technical expertise. “These are not going to be inexpensive methods to implement into facilities,” he notes. “They’re going to be a large capital investment, and also a large people investment.”

Beyond manufacturing hardware, Janvier believes structural changes must begin much earlier in therapy development. Many CAR T programs originate in academic laboratories focused primarily on biological innovation rather than manufacturability or commercial scalability. “What can be missed there is the translation starting at the very beginning,” he says. “You need to start with the end in mind.”

That means considering GMP compatibility, scalability, cost-of-goods analysis, and automation readiness long before therapies enter clinical trials. Investors, Janvier adds, are increasingly demanding evidence that therapies can ultimately be manufactured at scale—not simply that the science is compelling.

The post Automation and AI Will Drive Next-Gen CAR T Manufacturing appeared first on GEN – Genetic Engineering and Biotechnology News.

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Real-World Implementation of EndoConnect in Brazilian Primary Care: Formative Study of Usability, Engagement, and Equity in Digital Endometriosis Care

Background: Endometriosis is a chronic gynecological condition affecting approximately 10% of women of reproductive age worldwide and is associated with chronic pelvic pain, infertility, and reduced quality of life. In Brazil’s Unified Health System (Sistema Único de Saúde [SUS]), diagnostic delays frequently range from 7 to 10 years and disproportionately affect socially vulnerable populations, including rural, low-income, Black, and Indigenous women. Digital health interventions have been proposed as scalable solutions; however, most available applications are developed in high-income settings and do not align with the structural and operational realities of low- and middle-income countries (LMICs). Objective: This study aimed to evaluate feasibility, usability, acceptability, and user engagement associated with the real-world implementation of EndoConnect Alpha in primary health care settings, and to explore preliminary patterns of change in symptom burden, knowledge, and care navigation. Methods: A single-arm, prospective, formative implementation study was conducted in 10 primary health care units in Ceará, Brazil. A convenience sample of 60 participants, including women with suspected or confirmed endometriosis and primary care professionals, used the platform over an 8-week period under real-world conditions. Usability (assessed using the System Usability Scale), acceptability (assessed using the Technology Acceptance Model), engagement metrics, and exploratory outcomes were assessed. All analyses were exploratory, with no control group and no causal inference. Results: High usability and acceptability were observed, with strong user engagement, including a 79% completion rate of educational modules and consistent platform use. Observed decreases in pelvic pain and anxiety were identified, alongside increases in disease-related knowledge, self-reported therapy adherence, and reported gynecological referrals. A positive association between usability and acceptability was also observed. These findings should be interpreted as exploratory signals given the study design. Descriptive subgroup analyses suggested more pronounced trends among rural participants and those with a lower education level. Conclusions: The real-world implementation of EndoConnect Alpha demonstrated high feasibility, usability, and acceptability within a public primary care setting in a middle-income country. Observed trends suggest potential benefits, particularly among underserved populations; however, causal inference cannot be established. These findings support further controlled evaluation and highlight the relevance of equity-oriented digital health strategies tailored to LMIC contexts.
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Open-Source Up- and Downstream Modeling in a Unified Environment

A broad European industry/academic consortium, Inno4Vac, has developed a robust, open-source modeling platform that unifies upstream and downstream models and predicts product stability, all within a single environment. Unlike many open-source modeling programs, this one, called CADET-Hub, doesn’t need mad programming skills to use.

As Reinhard Liebers, PhD, a project manager at the European Vaccine Initiative, tells GEN, this work shows “that mechanistic modeling, digital twins, and stability prediction can be integrated into one collaborative platform to accelerate bioprocess development, improve process understanding, and reduce experimental workload.”

CADET-Hub is an integrated, modular, cloud-based modeling platform designed to help the biotech industry especially vaccine manufacturers quickly reconfigure their manufacturing platforms in response to emerging demands such as quickly-mutating pathogens. Its developers add that it can be used to help optimize a broad spectrum of bioprocesses.

Integration and ease of use—even for non-programmers—are standout features for this new platform. A key motivation for developing CADET-Hub was “to make the setting up and fine-tuning of biomanufacturing processes more efficient as well as reduce the technical overhead of setting up local software environments for bioprocess modeling,” according to a team led by Eric von Lieres, PhD, head of modeling and simulation at Forschungszentrum Jülich, and Liebers, in a recent paper. Therefore, each of the modules is web-based “in principle, with options for local deployment if desired, and a graphical user interface under development,” they tell GEN.

The upstream models are based on computational fluid dynamics and metabolic models for bioreactor simulations. The downstream models offer insights into centrifugation, filtration, and chromatography. CADET-Hub includes a dedicated stability forecasting model.

The research around CADET-Hub supports a shift from empirical trial-and-error development toward predictive, data-driven biomanufacturing with integrated upstream, downstream, control, and stability models,” Liebers says.

Overview of CADET-Hub and the broader CADET-Hub environment, which integrates standalone modeling, the open-source CADET framework within a JupyterHub-based online platform. [Inno4Vac]

Case studies

The team of authors around Liebers and von Lieres tested CADET-Hub under three scenarios.

As a way to model anion exchange capture of a recombinant subunit vaccine, they report that it functioned effectively as a collaborative workflow to share experimental data and mechanistic models, capturing meaningful nonlinear and multicomponent effects.

When modeling downstream filtration using ion exchange chromatography, CADET-Hub used explicit storage vessel models to close local material balances and transfer component concentrations in a structured way. It showed how upstream variability “can be propagated downstream to predict its impact on subsequent unit operations.” But, they add, “Experimental validation of the filtration model is still required.”

For process optimization and control, they point out, “Vaccine production requires a combination of sequence control and nonlinear model predictive control.” Overall, the case study showed a 50% improvement in upstream yield and a 20% improvement in downstream productivity that is attainable through model-based optimization.

To predict product stability under various conditions, the scientists combined hierarchical and advanced kinetic models within a Bayesian framework. They produced a “robust estimation of vaccine shelf life,” while meeting regulatory expectations and ICH Q12 principles.

“The next steps are to expand CADET-Hub toward fully end-to-end digital bioprocess models; to improve scalability, industrial deployment, and user interfaces; and to continue regulatory validation and adoption,” Liebers says.

CADET-Hub was created as part of the Inno4Vac vaccine development project and received funding from the Innovative Medicines Initiative/European Union/European Federation of Pharmaceutical Industries and Associations (IMI2/EU/EFPIA).

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Precancerous Adenomas Alter Gut Microbiome for Long Period

Research shows people who have precancerous polyps removed have an altered gut microbiome for around 12 years after undergoing surgery, which may explain why there is a significant risk of progressing to colorectal cancer in these individuals despite the surgery.

“Early detection and resection of adenomas through colonoscopy are critical strategies for preventing colorectal cancer. However, individuals with a history of adenoma resection remain at a higher risk of developing colorectal cancer than those without adenomas,” write lead author Mingyang Song, MBBS, ScD, associate professor of clinical epidemiology and nutrition at Harvard University, and colleagues in Cell Host & Microbe.

“Meta-analyses of stool metagenomes from diverse populations have identified consistent microbial biomarkers largely characteristic of later-stage colorectal cancer… Studies investigating the gut microbiome of adenoma patients and along the adenoma-carcinoma continuum have also reported distinct, dynamic microbial shifts from early neoplasia to advanced colorectal cancer.”

This earlier research suggests a link between the gut microbiome and colorectal cancer. It is possible some of these changes arise early in the disease process and act as drivers of the cancer, but what these changes look like remains unclear.

In this study, the researchers analyzed stool samples from 354 women who had colorectal adenomas removed an average of 12 years earlier and compared them to 354 matched controls without polyps. The team used shotgun metagenomic sequencing to analyze fecal metabolites and the composition of the gut microbiome.

The investigators then compared the microbiome data from the women who had adenomas removed and the controls to those from 1,045 people with colorectal cancer enrolled in earlier colorectal cancer studies.

Women who had precancerous polyps removed still showed some gut microbiome changes similar to those seen in colorectal cancer patients. The similarity was modest: only about 7% of the microbiome differences could be attributed to their disease history while 93% came from individual factors like diet, genetics, and lifestyle.

Overall, 31 bacterial species showed consistent changes in both adenoma and cancer cases compared to controls. For example, levels of Faecalibacterium prausnitzii, a bacteria thought to be protective of the gut due to anti-inflammatory properties, were low and levels of potentially harmful bacteria Flavonifractor plautii were enriched.

“The fact that colorectal cancer-associated gut microbial and metabolic features are still detectable a decade later suggests the gut microbiome may be part of sustained colorectal cancer risk,” said first author Ana Nogal, PhD, postdoctoral research fellow at Harvard, in a press statement. “Diet and lifestyle were closely tied to these microbes, raising the possibility that these habits could influence the gut environment in people at higher risk.”

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STAT+: Kailera’s own ‘triple-G’ drug also looks very powerful

Want to stay on top of the science and politics driving biotech today? Sign up to get our biotech newsletter in your inbox.

Good morning. Today, we have some AI drug development news and an examination of the growing longevity industry.

The need-to-know this morning

  • The FDA has pushed back the decision date for AstraZeneca’s experimental breast cancer drug camizestrant, following a negative vote from a group of agency advisers, the company said. The extra time will allow the FDA to review additional analyses that AstraZeneca is providing. FDA advisers took issue with the study design of the pivotal SERENA-6 trial, though European regulators have recommended the drug be approved. AstraZeneca did not specify the new target date for an FDA decision.
  • Blackstone Life Sciences, a private equity fund, is providing Apogee Therapeutics with up to $1.3 billion to pay for the Phase 3 development and potential commercialization of zumilokibart, the biotech’s long-acting treatment for atopic dermatitis.

Kailera’s own ‘triple-G’ drug also looks very powerful

Kailera said yesterday that its investigational obesity drug that targets three hormones led to significant weight loss in a Phase 1 study. 

Continue to STAT+ to read the full story…

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Heart Health Impacted COVID-19 Deaths

Having a lifestyle that promotes heart health may have been key in determining who died or was hospitalized during the COVID-19 pandemic.

Research in the Journal of the American Heart Association (AHA) suggests these healthy behaviors—involving diet, exercise, smoking, and sleep as well as body measures—could not only protect against cardiovascular disease but also have other benefits.

Specifically, they may help the body cope with the stress of infections such as those caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), even in people without clinical cardiovascular disease.

Adults with the highest heart health scores were nearly half as likely to die or be hospitalized as a result of COVID-19 compared with those who had the lowest scores.

“In many ways, a viral infection is like a cardiac stress test, except it’s not controlled,” explained researcher Elizabeth Oelsner, MD, from Columbia University.

“At the beginning of the pandemic, we immediately saw that COVID-19 was a particularly severe stress on the body. Our results highlight that better heart health, which is something that individuals can work on, likely prepares you better for real-life stress tests such as infectious diseases like COVID-19.”

The findings come from the Collaborative Cohort of Cohorts for COVID-19 Research (C4R), a collection of 14 U.S. studies that accrued extensive health information from participants.

The current analysis included 29,740 adults without clinical cardiovascular disease as of March 2020. Their average age of 66 years, and 61% were women.

Among the participants, just over a third each were White and Hispanic/Latino, while just over a fifth were Black.

Cardiovascular health was measured according to the AHA’s Life’s Essential Eight (LE8), a summary measure that scores diet, physical activity, cigarette use, sleep, body mass index, blood pressure, lipids, and glucose levels each out of 100.

Around 18% of study participants had high heart health(LE8 ≥80), 70% had moderate heart health (LE8 ≥50 to <80), and 12% had low heart health (LE8 <50).

The American Heart Association's Life’s Essential 8 is a wheel shape with 8 wedges representing the eight elements that are essential for cardiovascular health [American Heart Association]
The American Heart Association’s Life’s Essential 8 is a wheel shape with eight wedges representing the eight elements that are essential for cardiovascular health. [American Heart Association]

There were 681 severe COVID-19 cases from March 2020 to March 2023. Just over half the participants were known to have received a COVID-19 vaccination before contracting the virus.

Adults with high LE8 scores had a 46% reduction in risk of COVID-19 hospitalization or death compared with those who had low scores. In addition, every 14-point increase in LE8 was linked with a 20% lower risk of COVID-19 hospitalization or death.

Higher scores for physical activity, weight, blood pressure and sleep patterns were individually associated with lower risk of severe COVID-19.

The benefits of heart heath were similar across different participant groups and continued through the study period and when vaccines became available.

“COVID-19 caused 1.22 million deaths in the U.S. between March 2020 and March 2025, so it’s essential that we understand how important health components, such as heart health, relate to severity of COVID-19 infections,” said lead researcher Tim Plante, MD, from the University of Vermont.

“Our findings suggest that the tremendous impact of COVID-19 on the U.S. could have been reduced if the general population had had better heart health prior to the onset of the pandemic.”

The post Heart Health Impacted COVID-19 Deaths appeared first on Inside Precision Medicine.

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Biohub Releases Protein Biology World Model to Address Disease

Biohub, the non-profit research organization co-founded by Priscilla Chan, MD, and Mark Zuckerberg, has now unveiled the latest update to the ESM protein language model family, with expanded capabilities in binder design and protein function mapping for therapeutic discovery. The release comes just seven months after Biohub recruited the team behind EvolutionaryScale. 

The system includes ESMC (Evolutionary Scale Modeling Cambrian), a language model trained on approximately 2.8 billion sequences drawn from a breadth of life, including organisms adapted to extreme environments, and more than 20,000 types of proteins found in the human body. Evolutionary information encoded in ESMC is translated into atomic-resolution protein structures and interactions using the design engine and prediction model, ESMFold2.  

Alex Rives, PhD, head of science at Biohub and former chief scientist at EvolutionaryScale, presented the work at this week’s “AI in Biology” symposium at Cold Spring Harbor Laboratory.  

These models aim to transform the earliest stages of drug discovery by making biology more programmable. While traditional discovery workflows rely on slow and resource intensive experimental screens to identify promising drug candidates, rational protein design guided by in silico predictions has the potential to dramatically accelerate development timelines. 

“We’re at an exciting point in protein biology where accurate digital representations allow asking experimental questions at a scale that wouldn’t be possible in the laboratory,” Rives told GEN Edge. 

ESMC provides a foundation for modeling the sequence, structure, and function of proteins. ESMFold2 predicts the structure of proteins and biomolecular complexes. Features derived from the representations of the model capture fundamental principles of structure and function that form a compositional grammar for protein biology. [Biohub]
ESMC provides a foundation for modeling the sequence, structure, and function of proteins. ESMFold2 predicts the structure of proteins and biomolecular complexes. Features derived from the representations of the model capture fundamental principles of structure and function that form a compositional grammar for protein biology. [Biohub]

ESMFold2 designed high-affinity protein binders against five disease targets in cancer and immunology: receptor tyrosine kinases implicated in tumor growth (EGFR and PDGFRβ), immune checkpoints exploited by cancer cells to evade immune surveillance (PD-L1 and CTLA-4), and a regulator of immune cell signaling (CD45).  

Lab-validated designs achieved hit rates ranging from 36–88% for compact mini-binders and 15–29% for antibody-derived formats, while also demonstrating nanomolar binding affinity, high specificity, and favorable stability profiles consistent with potential clinical utility. Notably, binders for PD-L1 showed therapeutic function and restored T-cell signaling in laboratory tests by blocking the same pathway as approved checkpoint therapies. 

Rather than requiring multiple sequence alignments (MSAs) to build representations, ESMFold2 captures evolutionary information encoded during pretraining. The model also uses a looped transformer architecture, which allows compute to scale at inference time and avoids overfitting that can arise when training is constrained by limited experimental protein structures. 

In benchmarking, ESMFold2 performed favorably when compared against Chai-1 from Chai Discovery, Boltz-1 from MIT (whose developers have since launched a public benefit corporation), and AlphaFold 3 from Google DeepMind. 

The models are accessible under the highly permissive Massachusetts Institute of Technology (MIT) license for both commercial and non-commercial use. The work is described as a preprint that has not yet been peer reviewed. 

“All in” on AI biology 

Last November, Chan and Zuckerberg made the pledge to go “all in on AI-powered biology,” announcing that the organization’s scientific teams will now unite under a single entity, known as Biohub, where the duo would place the majority of their philanthropic effort.  

Concurrently, Rives and EvolutionaryScale colleagues were recruited to tackle disease by decoding the “grammar” of amino acids through billions of years of evolution. That same mission had once secured a whopping $142 million seed round when the startup unveiled in 2024. The raise was led by Nat Friedman, Daniel Gross and Lux Capital, and included participation from Amazon Web Services (AWS) and NVentures, Nvidia’s corporate venture arm. 

Biohub continues to advance virtual biology by building digital representations of molecules, genomes, cells, and living systems. The new ESM release joins Biohub’s growing ecosystem of biology models, including TranscriptFormer, which was published in Science earlier this month.  

The organization recently invested $500 million in the Virtual Biology Initiative, a five-year campaign to accelerate the creation of technologies and multi-modal datasets to build predictive models of biology. The commitment comes a few months after the organization announced a collaboration with Arc Institute and Tahoe Therapeutics to build the largest single cell chemical perturbation dataset to power the virtual cell. 

Evolution is all you need 

Biohub has applied the new ESM models to generate the ESM Atlas, a mapping of 6.8 billion sequences and 1.1 billion predicted structures to protein function using ESMC’s representations. Generating this atlas would have taken “billions of years of experimental work,” but was condensed into a couple of weeks with computational inference. The ESM Atlas is released open-source. 

By probing ESMC’s representations using sparse autoencoders (SAEs), a technique for identifying interpretable structure in large language models, the authors found that the model independently learned hierarchical organization covering the basic chemistry of individual amino acids, local structural interactions, and functional concepts across unrelated proteins, despite being trained only on sequence data. 

Notably, ESM Atlas SAE feature clusters brought together RNA-guided DNA endonucleases, eukaryotic Fanzor proteins and their evolutionary ancestor, prokaryotic TnpB, despite their high evolutionary divergence and low sequence similarity. These insights could support the development of new gene-editing tools. 

While the preprint’s results are still a step away from clinical impact, Rives reiterates the power of open science in placing these tools in the hands of researchers working directly in translational research. 

Biohub is partnering with a number of platform partners, including AWS Bio Discovery, Benchling, Phylo, Tamarind Bio, Modal, Tool Universe, and SandboxAQ, to make the models widely available.

The post Biohub Releases Protein Biology World Model to Address Disease appeared first on GEN – Genetic Engineering and Biotechnology News.