The team includes scientists from Innovative Genomics Institute and the California Institute for Quantitative Bioscience, both at the University of California, Berkeley, and collaborators at other institutions.The findings highlight AI’s ability to expand the CRISPR toolbox to include RNA-guided nucleases with novel properties beyond those found in nature. It is a task that has been challenging for protein design methods because of the complexity of multi-domain proteins, “whose activity depends on coordinated RNA and DNA recognition, activation, and cleavage by distinct conformational states,” the scientists wrote. As such, seemingly small changes can disrupt enzyme activity. 

Sequence-based biological language models have been used to successfully design new nucleases by inferring sequence-function relationships, but they often produce versions of these proteins that closely resemble the reference sequences used to train them. Meanwhile, structure-guided rational design approaches, which “offer a robust strategy to sample highly divergent protein sequences” as well as “structures not found in nature” have been used to generate things like dynamic switches and DNA binders. However, designing complex proteins like RNA-guided nucleases with multiple functional domains and conformations has remained challenging for these methods.

In the Science paper, the scientists present an alternate strategy for generating novel functional proteins that combines the ESM Inverse Folding (ESM-IF1) model with evolution-informed residue constraints. As a test case, they used it to generate new variants for TnpB, a family of CRISPR-cas12-like nucleases that mediate RNA-guided DNA cleavage and regulate transcription among other tasks. Members of this enzyme family are “an attractive target for protein design because they couple programmable DNA targeting and a variety of natural functions to a minimal architecture,” the scientists explained in the paper.

The results showed that compared to sequence-based biological language models which generated proteins with binding domains with over 99% identity to natural homology, their approach created “DNA- and RNA-interacting lobes with AI-generated contacts that had 83% and 72% identity to their closest counterparts in nature.”

As part of the study, the scientists screened the activity of the designed proteins, dubbed SynTnpBs, first in the bacterial cells and then selected the most active ones for further testing in plant and human cells. They also used cryo-electron microscopy to determine the structures of the most divergent variants. Their analysis showed that many AI-designed nucleases either retained or surpassed the activity of natural TnpB in multiple cell types. Microscopy studies further revealed that the engineered proteins formed new electrostatic and hydrogen-bonding networks that stabilize interactions at the RNA-DNA interface across different conformations. 

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The newly developed compounds, called prosthe6, mimic the function of light sensing photoreceptor cells, which degenerate in blinding diseases such as age-related macular degeneration (AMD) and retinitis pigmentosa (RP).

The prosthe6 compounds target ON-bipolar neurons and in tests were found to successfully restore saccadic eye movements (optokinetic reflex) in blinded zebrafish larvae, a widely used model for studying visual acuity. Even more strikingly, the researchers demonstrated recovery of innate light-avoidance behavior in mouse models of age-related macular degeneration and retinitis pigmentosa.

Test results suggest that the prosthe6 compounds may be administered by injecting them in the eye, or administered as eye drops. In animal studies the photoswitchable molecules also showed promising preliminary safety profiles, pointing to the development of potential drug candidates for restoring vision in patients with degenerative retinal diseases, without the need for genetic manipulation or implanted devices. Importantly, these compounds are designed to work under normal lighting conditions and do not require light-enhancing devices as optogenetics. They are small, water-soluble molecules that respond to ordinary visible or white light, such as indoor lighting or daylight, without requiring intense or specialized light sources.

“These molecules do not cure blindness, because they do not address the cause of photoreceptor degeneration,” said study co-lead Pau Gorostiza, PhD, ICREA Research Professor at IBEC, leader of the Nanoprobes and Nanoswitches group, member of CIBER-BBN. “But they are remarkably effective at restoring sight, and they do so using a very simple and potentially patient-friendly approach.”

Rosalba Sortino, former PhD student at the University de Barcelona, and currently post-doctoral researcher at Gorostiza’s group at IBEC, added, “Our goal was to restore vision using a molecular mechanism that is as close as possible to how the healthy retina works … Instead of bypassing retinal processing, we aimed to reactivate it right at the same level of the retinal circuit than the lost photoreceptor cells.”

Sortino is co-first author of the team’s published paper in Journal of the American Chemical Society, titled “Restoration of saccadic eye movements and visually guided behavior in ambient white light with photoswitchable small molecules.”

Diseases such as age-related macular degeneration and retinitis pigmentosa affect 200 million people worldwide and are the leading causes of visual impairment and blindness. Beyond the personal impact on quality of life and independence, vision loss places a global economic burden estimated at over US$400 billion per year in healthcare costs and lost productivity.

More recently, optogenetics and light-responsive drugs have entered clinical testing, the latter with encouraging safety results. “Photopharmacology can develop photoswitchable small molecules to restore vision impairment by conferring light sensitivity to ion channels that are widely expressed in the remaining inner retinal neurons, and a first-in-human clinical trial is ongoing,” the team noted. However, achieving high-quality vision at ambient illumination levels remains a major challenge.

The (IBEC)-led consortium has now developed a new class of photoswitchable small-molecule drugs that are capable of restoring key visual functions in animal models of blindness. The team’s photopharmacology-based technique involves modifying a drug’s chemical structure by adding a light-activated molecular switch, enabling control of the pharmacological action using light. “Unlike (opto)genetic manipulation and surgically implanted retinal electronic prostheses, pharmacotherapy is noninvasive, readily reversible, and can be upgraded when new drugs are approved,” the authors noted. “Medicines are preferred by patients, clinicians, and public healthcare systems, they  can be developed and manufactured at lower costs than other approaches and assessed by conventional regulatory procedures and clinical assays.”

The reported work builds on more than a decade of research and was carried out in collaboration with the team co-led by Pedro de la Villa at the University of Alcalá (UAH), as well as researchers from the Institut de Química Avançada de Catalunya (IQAC-CSIC), the University of Barcelona (UB), the Institute Ramón y Cajal of Health Research (IRYCIS), the Autonomous University of Barcelona (UAB), and the Fundació Eduard Soler.

By targeting a protein (mGlu6) in this preserved part of the retina, prosthe6 compounds can take over the role of the missing photoreceptors. “… we have targeted metabotropic glutamate 6 (mGlu6) receptors, which are exclusively expressed in ON bipolar cells (OBCs) and localized postsynaptic to PhR cells, thereby leveraging a privileged position to drive physiological visual circuit,” the investigators explained. When light enters the eye, the molecules respond by changing their shape, triggering signals inside the retina in a way that closely resembles natural vision. In this way, the drugs effectively act as “molecular prostheses,” helping the eye process light again without the need for implants or genetic modifications.

Healthy mice naturally prefer to remain in dark environments and instinctively avoid brightly lit areas, a behavior that relies entirely on a functional visual system. Blind mice, by contrast, lose this preference and move indistinctly between light and dark spaces, as they are unable to perceive light. The team showed that after treatment with prosthe6, blind mice once again showed a clear and spontaneous preference for dark areas, indicating that they could perceive light and use this information to guide their behavior.

This recovery occurred without any training and under light levels comparable to those found indoors or on an overcast day, demonstrating that the treatment restores functional light perception capable of driving natural, visually guided behavior.

Two lead compounds, prosthe6-12 and prosthe6-15, showed particularly promising results. The restored behaviors were observed not only after intraocular injection, but also after topical administration as eye drops. “… at least two compounds (prosthe6-12 and -15) appear to be devoid of adverse effects and restore sight by topical administration, which is linked to higher overall clinical success rate than systemic routes for neurological drugs, and to stronger patient adherence,” the investigators pointed out.

The prosthe6 technology is protected by patent and the researchers are now evaluating its safety and formulation to extend the duration of visual rehabilitation. The team is working with Eyelumina, a spin-off company in formation to secure investments that support translational development and future clinical trials.

“Turning this into a therapy is a long and laborious process,” says Gorostiza. “But the results show that there is a realistic possibility of restoring high-quality vision with drugs, non-invasively, reversibly and with a mechanism that is independent of the specific retinal disorder or genetic mutation to reach a majority of patients.”

If successful in humans, the drug-based approach would offer a widely accessible and affordable alternative to existing vision restoration technologies, especially relevant for patients with advanced retinal degeneration for whom no effective treatments currently exist.

In their paper the team further stated, “From a fundamental perspective, prosthe6 constitute new tools for ophthalmology to study the physiopathology of mGlu6 receptors and retinal circuits in vitro and in vivo and contribute to the medicinal chemistry of allosteric modulators. They also achieve the prediction that upstream targeted photopharmacology can deliver nearly native output signals, taking full advantage of the retinal circuit for high-quality vision restoration.”

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Cellular Origins’ Constellation^® automated platform was created to enable cell therapy manufacturing, integrating mobile robotics, existing bioprocessing technologies, and sterile fluid transfer into a coordinated operation. Its flexible, modular architecture allows developers and manufacturers to scale manufacturing capacity as demand grows while maintaining standardized processes, avoiding therapy redevelopment and reducing scale-up risk, notes Edwin Stone, CEO of Cellular Origins.

Autolomous’ digital autoloMATE^® platform was designed to allow real-time data exchange and integration across existing software and AI systems, as well as devices and robotic platforms across the entire manufacturing process and supply chain, while safeguarding intellectual property. The modular architecture allows each deployment to be configured to customer needs.

The combined solution overcomes fragmentation, limited visibility, and the absence of standardized, interoperable data flows without replacing existing processes, enabling manufacturers to scale to commercially viable levels,  maintains Alexander Seyf, CEO of Autolomous. First integrations have already been achieved at the Cell and Gene Therapy Catapult Digital and Automation Testbeds, as part of an Innovate UK-funded project.

“Scientific ambition has never been the bottleneck in bringing innovative cell therapy to patients, but the delivery infrastructure has brought many challenges,” continues Seyf. “Together with Cellular Origins, we enable fast and efficient scaling from research through to patient administration, ensuring standardization, automation and digitization across the entire process.”

“Scaling cell therapy manufacturing is not just a question of employing automation. It requires a manufacturing system that can evolve with demand,” adds Stone. “Our collaboration with Autolomous, and joint work with the Cell and Gene Therapy Catapult, clearly demonstrates how robotic platforms and digital infrastructure can operate as one.”

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Headed by teams at Sapienza University of Rome, at the University of Verona, and at the Research Centre on Environmental Pollution and Cardiovascular Diseases at the University of Campania “Luigi Vanvitelli,” the study included 61 patients at Sant’Andrea University Hospital or Azienda Ospedaliera Universitaria Integrata of Verona, diagnosed with either a heart attack, chronic ischemic heart disease, or normal coronary arteries.

The researchers say their study adds to growing evidence that environmental pollution may affect cardiovascular health. Research lead Emanuele Barbato, MD, PhD, at Sapienza University of Rome, said, “These findings do not prove that microplastics cause heart attacks, but they reveal a strong association between environmental exposures, microplastics in the blood and cardiovascular disease. In our study, smoking history was strongly linked to microplastics in the blood. Our findings suggest that smoking might make it easier for micro and nanoplastics to enter the blood stream via the lungs. Air pollution may act in a similar way.”

Barbato is director of the Cardiology Unit of Sant’Andrea University Hospital, Rome, Italy, and senior author of the team’s published paper in European Heart Journal, titled “Micro- and nano-plastics in the coronary circulation and air pollution exposure in ischemic heart disease presentation.”

Cardiovascular diseases are increasingly related to lifelong environmental exposures, the authors noted. Among such exposures, MNPs are ubiquitous environmental pollutants, and evidence is increasing that they accumulate in human tissues following exposure and are emerging as a risk factor for health. Pasquale Paolisso, MD, PhD, at Sant’Andrea Hospital Sapienza University of Rome, said, “Micro and nanoplastics are tiny plastic particles that are found virtually everywhere in the environment, including the air we breathe, the water we drink, and many foods we consume. In recent years, scientists have begun to detect these particles in human tissues and organs, raising concerns about their potential health effects.”

Research findings have raised concerns about the potential role that MNPs may play in cardiovascular diseases. “Emerging evidence indicates that MNPs, once considered inert contaminants, are biologically active pollutants contributing to the pathophysiology of cardiovascular diseases, particularly by promoting the development and progression of atherosclerotic plaques and potentially triggering adverse cardiovascular events,” the team stated.

However, as Paolisso further noted, “… very little was known about whether these particles are present in the coronary circulation—the blood flowing through the arteries that supply the heart—or whether environmental exposures such as smoking and air pollution might influence their presence.” As the authors explained, “… current knowledge is predominantly based on in vitro experiments and preliminary ex vivo findings, highlighting the need for in vivo and clinical investigations.”

For their newly reported study the team measured MNPs in coronary and peripheral blood, in 61 patients at Sant’Andrea University Hospital or Azienda Ospedaliera Universitaria Integrata of Verona, who were undergoing coronary angiography for suspected coronary artery disease (CAD). Patients were stratified as those with ST-segment elevation myocardial infarction (STEMI), chronic coronary syndromes (CCS) and controls with normal coronary arteries.

As well as taking blood samples from the vessels supplying the heart and from elsewhere in the body, the team collected data on whether the patients were smokers and their exposure to pollution, both on the day of testing and over the preceding two years. Coronary micro and nanoplastics were analyzed at the Research Centre for Environmental Pollution and Cardiovascular Diseases, University of Campania ‘Luigi Vanvitelli,’ a center dedicated to understanding how environmental pollutants influence cardiovascular health.

The results showed that micro and nanoplastics were detected in 84% of patients diagnosed with heart attack, compared with 40% of patients with chronic ischemic heart disease and 32% of patients with normal coronary arteries. “The observation that IL-6 and TNF-α concentrations were highest in STEMI patients, particularly within the coronary circulation, and were more elevated in the presence of detectable MNPs supports an exploratory association between MNP burden and a localized pro-inflammatory milieu in patients with obstructive CAD,” the investigators suggested.

Heart attack patients also had a greater variety of plastic types in their blood. The most common type of plastic was polyethylene (PE), which is commonly used in packaging and consumer products. “Across all study cohorts, PE was the most frequently identified polymer, being present in 97% of the patients with detectable MNPs,” the investigators added.

Patients exposed to higher long-term levels of air pollution (PM2.5; particles measuring 2.5 μm or less in diameter) were more likely to have microplastics in their blood, and smokers were six times more likely to have microplastics in their blood. All patients who were smokers and were exposed to higher air pollution levels had plastics in their blood, compared with only 12.5% of patients who did not smoke and were not exposed to higher levels of air pollution. “MNPs, PM2.5, and smoking constitute potentially modifiable environmental risk factors for cardiovascular diseases, with significant implications for public health and cardiovascular disease prevention,” the scientists stated. “Future research should aim to quantify individual MNP exposure, assess combined pollutant burden, and validate interventions that target this expanded network of environmental cardiovascular hazards.”

Barbato added, “The results highlight the need to consider microplastic pollution as part of the broader environmental determinants of health. Policies that reduce air pollution, tobacco exposure, and environmental plastic contamination could have benefits that extend beyond environmental protection and potentially improve cardiovascular health.”

In an accompanying editorial Andreas Daiber, PhD, at University Medical Centre of the Johannes Gutenberg University, Mainz, and colleagues pointed to the observation by Paolisso et al. of an association between NMP levels and exposure to air pollution and tobacco smoking. “While the underlying mechanisms remain unclear, this finding underscores a key principle: environmental exposures rarely occur in isolation,” Daiber and colleagues stated. “Individuals are exposed to multiple environmental stressors simultaneously, including air pollution, noise, chemical contaminants, plastics, and climate-related stressors, especially in the urban setting. These exposures may interact through shared biological pathways, leading to additive or synergistic effects on cardiovascular risk.”

And while substantial uncertainties remain, “the convergence of epidemiological, clinical, and mechanistic evidence suggests that plastic pollution may represent a previously underestimated cardiovascular risk factor,” Daiber et al. continued. “Addressing this challenge will require coordinated efforts across disciplines and policy domains. In the era of the Anthropocene, protecting cardiovascular health will increasingly depend on reducing not only traditional risk factors but also the growing burden of environmental pollutants (the detrimental part of the exposome), among which plastics may soon play a central role.”

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In recent years, scientists investigated whether this type of diet might affect the development of cancer. While some research has shown that the diet may protect against the development of colon cancer, a new study suggests that in the small intestine, a ketogenic diet may increase the risk of cancer—with a mechanism through fatty acid oxidation rather than ketone metabolism.

This work appears in Nature in the paper, “Ketogenic diet mediates intestinal tumorigenesis through lipids not ketones.”

“Ketogenic diets have distinct effects on different tissues even within the gastrointestinal tract. I think the message here is that we need to be very careful in generalizing the effects that these diets can have, because what might be beneficial for one tissue may be detrimental for another tissue,” says Omer Yilmaz, PhD, director of the MIT Stem Cell Initiative, an associate professor of biology at MIT, and a member of MIT’s Koch Institute for Integrative Cancer Research.

A 2022 study in Nature suggested that ketogenic diets have a protective effect against colon cancer and that BHB—the most abundant ketone body—is responsible for this effect. In the new study, the MIT team wanted to explore whether ketogenic diets might have a similar protective effect in the small intestine.

The researchers fed mice who were genetically predisposed to developing intestinal cancer either a ketogenic diet, a control diet, or a high fat/high calorie diet. They found that mice on a ketogenic diet were more likely to develop tumors of the small intestine than those on a control diet. While they did not become obese, mice on the ketogenic diet developed tumors at rates similar to or even higher than those of mice on an obesogenic high fat/high calorie diet.

Additional studies revealed that ketone bodies did not play a role in tumor development. Instead, tumor growth was driven by fatty acid oxidation. This pathway activates the PPAR family of proteins, which signal stem cells to multiply more rapidly, increasing the chance that some become cancerous.

Surprisingly, the same ketogenic diet that promoted tumors in the small intestine had the opposite effect in the colon. The researchers found, similar to the earlier study back in 2022, that a ketogenic diet suppressed the development of colon tumors. However, the new findings suggest that ketone bodies are not responsible for this protective effect.

“Given how much attention has been paid to ketone bodies like BHB, both as a commercial health trend and in recent high-profile studies suggesting BHB suppresses colon cancer, we fully expected them to be the direct drivers. Instead, our experiments in genetically engineered mice revealed that these molecules are essentially metabolic bystanders. The real surprise is that tumor acceleration is driven entirely by how stem cells process and burn the heavy influx of dietary fat itself,” Yilmaz says.

The researchers now hope to further study why ketogenic diets have such different effects in the colon and the small intestine. As ketogenic diets continue to gain popularity, understanding these tissue-specific effects will be critical for guiding their use, the researchers say.

The findings carry practical implications. Because the diet’s effects—both the tumor acceleration in the small intestine and the protection in the colon—are driven entirely by fat metabolism rather than the ketones themselves, commercial ketone supplements or drinks would not be expected to mimic either the risks or the benefits discovered in this study. This may be especially relevant given that small intestinal tumors have been rising in incidence in recent decades, with the greatest impact on patients with inherited conditions that predispose them to intestinal cancer, such as familial adenomatous polyposis.

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“A modular modeling approach simplifies the complex IVT reaction network by dividing it into discrete, reusable, mechanistically defined steps,” Xie said. “This structure improves mechanistic understanding by clarifying how each step impacts key quality attributes, including yield, capping efficiency, and transcript integrity.”

Rather than relying on a single monolithic model, the framework separates IVT into individual components, such as initiation, elongation, and termination, as well as parallel processes including mRNA degradation and precipitation. Each module can be independently calibrated, validated, and refined as new experimental data become available, allowing researchers to continuously improve predictive performance without rebuilding the entire model.

The modular architecture also lends itself to the evolving nature of mRNA therapeutics. Because the framework mirrors the modular structure of nucleic-acid sequences, it can be rapidly adapted for new constructs, accelerating process development for emerging vaccines and therapeutic candidates while minimizing redevelopment effort. Beyond improving process understanding, the model provides a powerful diagnostic platform for identifying production bottlenecks that constrain yield, productivity, or product quality.

The framework combines Shapley value-based sensitivity analysis, residual analysis, and simulated reaction trajectories to pinpoint limiting process variables. Sensitivity analysis identifies parameters with the greatest influence on performance, while comparisons between predicted and experimental results reveal missing mechanisms or model deficiencies. Simulated reaction profiles can also highlight issues such as nucleotide depletion or suboptimal magnesium-to-nucleotide ratios before they become significant manufacturing challenges.

“Together, these tools provide a data-driven, mechanistic approach to quickly diagnose constraints and guide targeted process optimization,” Xie explains.

The approach also offers significant advantages during scale-up, one of the most challenging phases of bioprocess development. Because the model is grounded in fundamental molecular reactions and biochemical mechanisms rather than empirical correlations, it maintains predictive capability across different manufacturing scales and can be readily applied to new mRNA sequences, all without extensive redevelopment.

Xie says the framework supports predictive design of scale-dependent control strategies, including dynamic pH regulation and fed-batch nucleotide feeding schemes, helping manufacturers reduce development timelines while improving process robustness during technology transfer.

“A key advantage of the modular architecture is its flexibility and interoperability” Xie says. “New enzymes, reagents, or process steps can be incorporated by simply updating or adding the relevant module, without recalibrating the entire model. The framework’s ability to accommodate heterogeneous datasets generated under varying process conditions further supports rapid evaluation of manufacturing innovations while maintaining model consistency.

Perhaps the greatest impact of Xie’s approach lies in advancing quality-by-design (QbD). Acting as an in silico development platform, the modular model enables researchers to evaluate process variables before entering the laboratory. Coupled with digital twin-based Bayesian optimization, the platform narrows the experimental search space, reducing trial-and-error studies while conserving expensive reagents, such as T7 RNA polymerase.

As mRNA pipelines continue to expand beyond vaccines into broader therapeutic applications, modular mechanistic modeling is emerging as a valuable digital bioprocessing tool, enabling manufacturers to accelerate development, strengthen process understanding, and deliver more consistent product quality with fewer experimental resources.

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Designed for both vat and continuous bioprocessing systems, this bioelectronic sensor network could, ideally “provide spatial information about where they are in a heterogeneous bioreactor platform…as well as multiple measurements of things such as temperature, pH, dissolved oxygen, and dissolved carbon dioxide,” Rabia Yazicigil, PhD, associate professor, Boston University (BU), and lead principal investigator for this project, tells GEN.

Consequently, the network will report data that enable biomanufacturers to determine whether the solution is mixing properly and to identify transit times throughout the process, in addition to specific processing parameters.

“The key innovation…is that these systems integrate living cells into the electronics,” Miguel Jimenez, PhD, assistant professor, BU, emphasizes. The inclusion of microbes—bacteria or yeast cells, for example—“supercharges the sensors,” enabling them to monitor more parameters that are directly relevant to biomanufacturing.

Roughly the size of a chickpea, these sensors never leave the bioreactor. “That allows us to get measurements throughout the reactor… which helps us build a really rich data set that we can then feed into models to help us monitor and predict performance,” notes Mark Poole, PhD, senior director of manufacturing and applied AI, Capra Biosciences.

Paradigm-shifting potential

“Having lots of high-quality measurements at different points in the reactor is game-changing for any biomanufacturing company,” Poole says.

Jon Valdez, program manager at BioMADE, which funded the project as part of a $21.4 million investment in 14 projects to advance the bioindustrial manufacturing industry, agrees, calling it potentially paradigm-shifting. Potential applications extend to clinical monitoring—where a prior collaboration focused on human gut monitoring. The technology is solvent-agnostic but may be most effective in a water-based environment, enabling applications that may include soil and water quality monitoring. Benefits, he says, include lower costs per sensor (estimated at $10−$100) and decreased risk of contamination.

The project is two-tiered. The first tier, the electronics-only sensor, is the nearest to commercialization. Industrial-scale testing will be conducted soon at Capra facilities. “That [alone] would signify a big advance,” Jimenez says, citing the ability to field networked sensors capable of measuring multiple conditions throughout a bioreactor or continuous production process.

The second tier adds the bio component to those sensors. This feature is in academic development. Primary challenges are how to design biohybrid sensors that can be autoclaved or cleaned-in-place, and strategies to stabilize and encapsulate the microbes to be compatible with industrial requirements. The researchers are considering possible approaches now.

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A team led by researchers at Northeastern University College of Science in Boston made the case for AI use in a recent paper, arguing that the variability inherent in cell and gene therapy production can be difficult to manage using conventional tech.

Lead author, Jared Auclair, PhD, dean of the College of Professional Studies at Northeastern, tells GEN, “Unlike monoclonal antibodies or recombinant proteins, cell and gene therapies are living or highly complex biological products, making them inherently more variable and difficult to manufacture consistently.

“Every step, from sourcing starting material to manufacturing, analytical testing, storage, and delivery, can influence the final product,” he adds.

Understanding complex, multi-parameter interactions is exactly the sort of challenge at which AI excels, Auclair says, citing the ability to identify critical process attributes as an example.

“AI has the potential to transform cell and gene therapy manufacturing by moving from reactive to predictive manufacturing. Machine learning can optimize process parameters, predict batch failures before they occur, enable digital twins to simulate manufacturing changes, and strengthen quality control through real-time monitoring and anomaly detection,” he adds.

“At Northeastern, our research at the intersection of the Bioanalytical Training Laboratory (BATL), the Center for Bioinnovation and Regulatory Sciences, and AI is exploring how AI can accelerate the development, manufacturing, and regulation of advanced therapies,” Auclair says.

Not plug-and-play

AI’s potential to spot patterns in data is attractive.

However, biopharmaceutical companies looking to adopt the technology are likely to encounter challenges, according to Auclair, who cautions that setting up an AI-driven manufacturing operation is about more than simply buying the right software.

“The technology is advancing rapidly, but successful implementation depends on having high-quality, well-curated data, digital manufacturing infrastructure, and multidisciplinary expertise spanning biology, engineering, data science, and regulatory science.

“AI is not a plug-and-play solution; organizations must build integrated data ecosystems and governance frameworks that regulators can trust,” Auclair says.

AI adoption is a multidisciplinary challenge and should involve people with expertise in all parts of drug development and production, according to study co-author Rominder Singh, PhD, professor of practice, regulatory sciences, & AI at Northeastern.

“Research conducted through the BATL and the Center for Bioinnovation, led by Professor Auclair, has focused on addressing many of these scientific and manufacturing challenges that are unique to advanced therapies.

“This is precisely why Northeastern’s pioneering work in RegSciAI is so important: it brings together regulatory science and AI to ensure these technologies are both innovative and deployable in real-world biomanufacturing,” Singh says.

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That’s according to Mo Heidaran, PhD, chief scientist at Cellx, who is due to give a talk at the upcoming Bioprocessing Summit in Boston.

“Whether something is a cell or gene therapy, from a regulatory perspective, depends on [the nature of] the product that’s administered to the patient,” Heidaran explains.

“And, in the United States, in vivo CAR Ts are gene therapy products and not cell therapies as some people talk about them.”

The better-known CAR T products are ex vivo, delivered via modification of patient cells, he explains. Whereas this emerging class of therapies involves delivery of a genetically engineered virus or lipid nanoparticle (LNP) that, in some cases, is stably integrated into the patient genome.

According to Heidaran, the risk of integration is higher when viruses are used.

“My colleagues at the FDA want to make sure people understand it’s very important these products must be [designed] to be very specific to the cell type, perhaps based on data about [some of these] therapies having off-target effects,” he says.

Most in vivo CAR T-cell therapies are in very early stages, with none currently approved for patients, although Heidaran says they are increasingly under investigation by larger companies since they are scalable for a wider range of patients. Also, they are believed to be more cost-effective and have similar logistics, as they don’t require lymphodepletion, he adds.

“Essentially the value driver is that you’re pharmaceuticalizing cell and gene therapy since it’s just a vial of the virus or LNP that you can use to treat many patients—almost like a drug or pill,” he says.

Among the challenges for this emerging class is that several ex vivo CAR T-cell therapies are already approved for patients. In vivo CAR T therapies treat some of the same indications, i.e., certain cancers and autoimmune diseases, he says.

“At some point there has to be a decision made by the FDA about how these [new] therapies compare, such as [running] a study or external control as to whether they’re superior or non-inferior to the same or similar approved ex vivo CAR T,” he says.

Other challenges facing this new industry are about batch sizes for manufacturing, as the equipment and processes for treating ten patients are different from needing to treat thousands. Also, he says, in vivo CAR T therapies need to be monitored to look for off-target effects, durability of response, or an immune response by the patient.

“Overall, to develop a safety profile, we need to define what the effective dose is that people are working to, as these therapies may require repeat administration, which is not done with ex vivo-generated CAR T,” he says.

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The authors generated 37 organoids from patients who developed chronic pancreatitis spontaneously. The organoids revealed consistent dysfunction in the protein cystic fibrosis transmembrane conductance regulator (CFTR), which was identified as a therapeutic target. 

“Though patients can have the same clinical diagnosis of chronic pancreatitis, they can have very different underlying molecular drivers of that disease, which makes treatment especially difficult,” said Dannielle Engle, PhD, assistant professor at Salk and corresponding author of the study. “Our work breaks down a major barrier in the field by establishing an experimental model that preserves patient-specific disease biology and can be used to develop tailored therapies.” 

Over the last decade, organoids have become a prevalent tool to bridge the gap between cell and human studies. Each organoid typically begins with stem or progenitor cells from patients. In Engle’s lab, donor pancreas tissues were used to create miniature replicas of the pancreas. Findings based on a patient’s personalized organoid model could improve therapeutic effectiveness. 

“By growing organoids directly from patients, we preserve key features of ductal cells and ask which disease mechanisms are active in each individual patient,” said Victoria Osorio-Vasquez, PhD, a postdoctoral researcher in Engle’s lab and first author of the study. 

The researchers surveyed the molecular signatures in each organoid and found three subtypes of chronic pancreatitis. This biology-based patient stratification can inform optimal treatment. Results showed that approximately half of the organoids demonstrated dysfunctional CFTR. 

“And CFTR dysfunction was not limited to patients with inherited CFTR mutations, suggesting that functional testing may identify therapeutic opportunities that would be missed by genetic testing alone,” Osorio-Vasquez says. 

Existing CFTR modulator therapies treat patients with cystic fibrosis. The findings suggest that these same therapies may offer pancreatic benefits. The researchers tested clinically available CFTR modulators and found that these therapies could stabilize or restore CFTR function and reduce inflammatory signaling in responsive pancreas organoids. 

The platform also revealed rare alterations to genes, KRAS and TP53, in some chronic pancreatitis organoids, supporting future use of the system to study disease evolution, pancreatic cancer risk, and biomarker discovery at the interface of chronic inflammation and pancreatic cancer. 

“These organoids gave us a way to study chronic pancreatitis pathogenesis in human cells for the first time,” says Engle. “Our platform enables a more personalized way of studying and eventually treating chronic pancreatitis, while also blazing the trail for other organoid-based platforms in other inflammatory disease contexts.” 

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