Monoclonal antibodies (mAbs) have become an important class of therapeutics in modern medicine, used to treat cancers, autoimmune diseases, and infectious threats ranging from Ebola to COVID-19.¹ But producing these powerful biologics is only half the battle. The real challenge—and increasingly the defining step—lies in purification.

Over the past decade, upstream bioprocessing has advanced dramatically. Modern expression systems routinely generate high titers of antibody from mammalian cell cultures, pushing productivity to levels that were once unattainable. However, this progress has shifted the burden downstream. The resulting product streams are denser, more complex, and filled with impurities that must be removed to meet strict regulatory and safety standards.

As Alejandro Becerra, PhD, principal applications scientist and global purification technical lead at Thermo Fisher Scientific, notes, “Cation exchange chromatography is one of the key polishing steps because antibodies have relatively high isoelectric points, or pIs, and many impurities have lower pIs.” His point underscores a broader reality: Although anion-exchange chromatography (AEX) is somewhat standardized, the increased impurity burden of more complex biologic feed streams needs to be addressed by intermediate polishing, usually CEX.

Traditional purification strategies, anchored by affinity capture followed by polishing steps, are increasingly being pushed to their limits. While Protein A chromatography can deliver high purity for conventional antibodies, more complex molecules such as Fc fusion proteins, Fab fragments, bispecific antibodies, and antibody-drug conjugates, often emerge from capture with significantly lower purity—sometimes below 80%. If optimization of the capture step is deemed too much of a challenge, the burden of achieving final product quality therefore shifts to downstream polishing, where subtle differences between molecules must be resolved with precision.

Hydrophobic interaction chromatography (HIC) can be used for aggregates and/or HCPs, but CEX is the more common and powerful tool used to remove charge variants or other impurities with similar pIs. The mechanism is also well understood in the context of the separation, and a well-developed CEX unit operation can advance a candidate molecule toward clinical use.

Why CEX matters

What sets CEX apart is its ability to remove product-related impurities that closely resemble the target molecule. Among these, high molecular weight aggregates are particularly crucial. These multimers can form during cell culture, downstream processing, or even within the chromatography columns themselves. Because they are structurally similar to the desired antibody, they are difficult to remove using traditional purification steps.

Purity is “one of the main product-quality measures that we look for,” says David Brown, PhD, associate director, process development at KBI Biopharma. “Aggregates can form during production, and they are a key measure of product quality.” These aggregates are closely monitored because they can trigger immune responses or compromise therapeutic efficacy.

CEX chromatography also plays a role in removing other types of challenging impurities, including charge variants and residual contaminants that persist after affinity capture. Its versatility and precision make it an indispensable component in the modern antibody-purification workflows.

CEX provides a degree of flexibility that is particularly valuable in development environments. Because separation can be tuned through relatively simple adjustments in buffer composition and the correct CEX resin selection, scientists can rapidly explore different operating conditions to optimize performance. This adaptability is especially important when working with novel or poorly characterized molecules, where prior knowledge might be limited and iterative experimentation is required. It also allows teams to respond quickly when upstream changes introduce new impurity profiles that must be addressed downstream.

The resin decision

The effectiveness of CEX chromatography depends heavily on the resin used. Resin selection is not merely a technical choice; it is a strategic decision that influences process efficiency, scalability, and cost. Developers must consider multiple factors simultaneously, including binding capacity, resolution, robustness, and pressure-flow behavior.

Becerra explains that the process begins with defining what the purification operation should accomplish. As he adds, this end goal must be attained “without losing sight that these processes will be eventually scaled up.” This dual focus ensures that conditions optimized during development can be translated into manufacturing environments.

Brown highlights the practical considerations: “We’re looking at aggregate removal, step yield, binding capacity, and pressure/flow dynamics.” Each of these factors plays a crucial role. High binding capacity reduces the amount of resin required, lowering cost. Strong resolution ensures effective separation of impurities. Favorable pressure/flow characteristics enable high flow rates without excessive backpressure, supporting efficient large-scale operation.

To navigate these trade-offs, many organizations adopt systematic approaches to resin selection. KBI Biopharma, for example, uses a “resin toolbox strategy, screening multiple resins against a library of molecules to build a robust dataset,” Brown says. This allows rapid decision-making when new programs arise, reducing development time while maintaining confidence in performance.

An example of screening a CEX resin toolbox is the comparative study of several commercially available CEX resins, “Streamlining cation exchange chromatography process development for therapeutic monoclonal antibody purification” published by Lau et al in the peer-reviewed Journal of Chromatography A.  From their study of 3 mAb feeds and 5 CEX resins, the authors concluded that for industrial applications POROS XS had outperformed the other resins tested, “demonstrating outstanding column performance and impurity clearance. Application of Poros XS contributes to a highly efficient and robust manufacturing process, enhancing productivity while maintaining high product quality.”²

Moreover, the resin’s rigid poly(styrene-divinylbenzene) backbone provides mechanical strength and supports high flow rates with minimal pressure increase. This enables stable operation and scalability across different process scales.

Importantly, the robustness of POROS XS resins extends beyond performance metrics. Its chemical stability across a wide pH range and tolerance to harsh cleaning conditions allow for extended resin lifetime and reuse. This contributes to lower overall cost of goods and improved process sustainability—factors that are increasingly important as biologics manufacturing scales globally. In large-scale facilities where chromatography columns are cycled repeatedly, durability translates directly into fewer resin replacements, reduced downtime, and more predictable manufacturing schedules.

Driving efficiency

Although resin performance is crucial, process design can further enhance efficiency. In “Cation exchange chromatography performed in overloaded mode is effective in removing viruses during the manufacturing of monoclonal antibodies,” which was published in Biotechnology Progress, by Masuda et al, scientists investigated alternative operating modes for CEX chromatography.⁴

Traditionally, CEX polishing is performed in bind-and-elute mode, where the antibody binds to the resin under low-salt conditions and is later eluted by increasing salt concentration or pH. Although effective, this approach requires significant resin volumes, increasing costs at scale.

To address this, Masuda and her colleagues evaluated an overloaded mode of operation. In this approach, the column was intentionally loaded with POROS XS resin beyond its nominal binding capacity. Instead of relying solely on binding, separation was driven by differences in binding affinity between the antibody and impurities.

The results were striking. Even at extremely high loading levels (up to 2,000 grams of antibody per liter of resin), viral clearance remained effective. Viruses such as murine leukemia virus were found to bind more strongly to the resin than the antibody, remaining on the column while the purified product was eluted.

This behavior enabled the simultaneous removal of multiple impurities, including aggregates, HCPs, and viruses—all in a single step. Importantly, viral clearance performance was not significantly affected by resin type nor by antibody variant, suggesting that the approach is broadly applicable.

The implications are substantial. Overloaded operation reduces resin requirements, lowering costs and improving process efficiency. It also simplifies workflows by combining multiple purification functions into a single step. At the same time, it highlights the importance of understanding molecular interactions, as these interactions ultimately govern separation performance.

Beyond cost savings, the study also underscores a shift in thinking about purification design. Rather than treating each step as a fixed unit operation, researchers are increasingly exploring flexible modes that adapt to process needs. Overloaded CEX represents one such innovation, demonstrating how established techniques can be reimagined to meet modern manufacturing demands.

Precision separation

Advanced purification will also be required for next-generation therapeutics. Bispecific antibodies present unique purification challenges because they require the correct pairing of multiple heavy and light chains. Mispaired variants so closely resemble the desired product that they can be difficult to remove.

Through high-throughput screening and careful optimization of pH and salt conditions, the team identified a process that enabled clear separation between the desired product and mispaired variants. The result was a significant improvement in purity, with the final product reaching 94.78%.⁵

What makes this work particularly notable is the integration of computational modeling with experimental chromatography. By analyzing electrostatic surface properties, researchers predicted how different variants would interact with the resin. This predictive capability enabled more targeted optimization and reduced reliance on trial-and-error experimentation.

The study demonstrates how subtle differences in molecular structure, such as changes in surface-charge distribution, can have a profound impact on purification outcomes. It also highlights the potential of combining structural biology and chromatography to address increasingly complex purification challenges. As antibody formats continue to diversify, such integrated approaches are likely to become standard practice, particularly for molecules where traditional purification heuristics fall short.

Toward smarter, integrated processes

The development of advanced CEX processes is undergoing a transformation driven by data, automation, and modeling. High-throughput screening platforms allow researchers to test multiple conditions simultaneously, exploring a wide range of pH, conductivity, and loading parameters. Statistical design methods help define optimal operating windows, while mechanistic models provide insight into the underlying processes.

One of the key insights from these approaches is the trade-off between yield and purity. Conditions that maximize binding strength might not produce the cleanest separations, while conditions that improve purity may reduce recovery. The optimal process lies in balancing these competing factors within a defined operating space.

Mechanistic modeling is playing an increasingly important role in achieving this balance. By simulating how molecules move, bind, and separate within a chromatography column, these models can predict process performance under different conditions. Once calibrated with experimental data, they provide a powerful tool for reducing development time and improving process understanding.

At the same time, advances in resin chemistry are expanding the capabilities of chromatography. New materials are being developed to address specific challenges associated with next-generation therapeutics, including higher levels of aggregation and increased structural complexity.

In addition, integrated approaches could transform purification from a reactive process into a proactive, design-driven discipline. Increasingly, developers are viewing purification as an interconnected system rather than a sequence of isolated steps, enabling more holistic optimization across the entire workflow.

From bottleneck to advantage

Purification is no longer a downstream bottleneck struggling to keep pace with upstream production. It is becoming a strategic advantage—one that determines not only product quality, but also development speed and manufacturing efficiency.

This shift reflects a broader change in mindset. Purification is no longer viewed as a necessary but secondary step. Instead, it is recognized as a crucial component of therapeutic development, one that requires the same level of innovation and attention as upstream production.

As biologics become more complex and production scales continue to rise, the importance of precise, efficient purification will only grow. In this evolving landscape, the ability to separate what is nearly indistinguishable and helping to remove important impurities will define success.

CEX chromatography now stands at the forefront of that effort. By enabling the removal of crucial impurities and supporting scalable, cost-effective manufacturing, it helps modern therapeutics to be purified with the precision required for improved therapies.

Learn more at: thermofisher.com/porosXS

REFERENCES

1. Lu, R-M., Chiang, H-L., Yuan, J. P-Y., et al. Technological advancements in antibody-based therapeutics for treatment of diseases. J. Biomed. Sci. 32:98 (2025).
2. Lau, W.Y., Mi, X., Dumont, A., Yang, L. Streamlining cation exchange chromatography process development for therapeutic monoclonal antibody purification. J. Chromatogr. A. 1762, 466391 (2025).
3. Thermo Fisher Scientific. POROS XS Strong Cation Exchange Resin. https://documents.thermofisher.com/TFS-Assets/BPD/Flyers/poros-xs-resin-flyer.pdf
4. Masuda, Y., Tsuda, M., Hashikawa-Muto, C., et al. Cation exchange chromatography performed in overloaded mode is effective in removing viruses during the manufacturing of monoclonal antibodies. Biotechnol. Prog. 35(5), e2858 (2019).
5. Cha, M., Xu, A., Williams, A.J. Structural study of a light chain mispaired bispecific predicts mechanism of downstream separation. J. Chromatogr. A. 1730, 465117 (2024).

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Hyperphosphorylation and aggregation of tau are hallmarks of primary and secondary tauopathies including frontotemporal dementia (FTD) and AD, and potentially also Huntington’s disease and Parkinson’s disease. Such disorders also share another common pathology, which is deteriorating performance of the cell’s mitochondria. The powerhouses may number in the dozens or in the tens of thousands within a single cell, depending on the cell type’s energy needs. Nerve cells have especially high mitochondria demand.

To date the connection between tau and mitochondrial pathologies has been unclear. Working in cells and in preclinical animal models, the Stanford and UCSF scientists have now shown that phosphorylated tau can enter mitochondria and interfere with the electron transport chain, initiating a vicious cycle of pathological events and triggering reverse electron transport (RET) and the detriments that ensue.

“This is the first demonstration of exactly what tau does inside mitochondria,” said Bingwei Lu, PhD, Stanford professor of pathology, “Our discovery of a whole new mechanism driving tauopathies renders these disorders amenable to new therapeutic interventions.” Lu is senior author of the researchers’ published paper in Neuron, titled “Tau-induced mitochondrial reverse electron transport drives neurodegeneration,” in which they concluded “Our results suggest that RET may serve as a common pathogenic mechanism linking tau abnormalities to mitochondrial dysfunction across diseases.”

Tau is a soluble protein enriched in neuronal axons but is also found in neuronal dendrites, cell bodies, and non-neuronal cells, the authors explained in their report. Tau is also increasingly viewed as one of the strongest instigators of Alzheimer’s disease.  The appearance of telltale forms of the protein in cerebrospinal fluid or in the bloodstream strongly predicts impending Alzheimer’s symptoms. Neuroimaging studies and postmortem inspections indicate the presence of neurofibrillary tangles—long filaments largely composed of tau—inside Alzheimer’s patients’ nerve cells.

Neurofibrillary tangles and other aspects of tau’s misbehavior—notably, a tendency to rack up chemical modifications that shift that protein’s disposition—have been reported in Parkinson’s disease and Huntington’s diseases and in other tauopathies such as frontotemporal dementia and progressive supranuclear palsy. “Tau is phosphorylated at many sites under normal conditions but becomes hyperphosphorylated in disease,” the team also commented.

Tauopathies share another common pathology, which is deteriorating mitochondrial performance. “Mitochondrial dysfunction is also a common feature of tauopathies,” the investigators stated. “The mechanistic link between tau abnormalities and mitochondrial dysfunction and its relationship to the physiological function of tau, however, is unclear.”

In its healthier manifestation, tau is believed to play a role in stabilizing microtubules, skeletal structures in nerve cells that are critical to these cells’ proper operation. Tau molecules do indeed spend some of their time sitting on microtubules, straddling those structures’ identical subunits. So, not unreasonably, the consensus is that tau’s perch on microtubules helps keep them from falling apart.

The newly discovered pathological pathway is entirely independent of both neurofibrillary tangle formation and microtubule instability. Instead, it involves a switch in the directionality of mitochondria’s energy-production line, with a resulting disruption of mitochondria’s primary function, that being the conversion of calories from glucose or fat to energy by the electron-transport chain. This multiple-component complex passes electrons from one to the next of its components, the last of which converts a precursor molecule into ATP, the cell’s universal energy currency.

The new study shows that when the hyperphosphorylated tau molecule interacts with a key mitochondrial component it jams up the electron transport conveyor belt, causing electrons to flow backward. Aptly named reverse electron transport (RET), this snarl produces large amounts of reactive oxygen species (ROS), with accompanying inflammation and damage to proteins.

Reverse electron transport is an area of intense recent interest in biology. Although it was first discovered in the 1960s, there’s still no clear evidence that it serves any constructive physiological role. “In healthy cells, very little reverse electron transport is happening,” Lu said.

The new study shows that reverse electron transport is activated under stress. It may initially serve some beneficial function—for example, providing short-term adaption to that stress—but nothing like that has been proven. “Here, we demonstrate that tau regulates mitochondrial reverse electron transport (RET), which produces excess reactive oxygen species (ROS), reduces the NAD+/NADH ratio, and is activated by aging or stress,” the investigators noted.

The team carried out an extensive series of experiments in fruit flies, mice, human brain tissue and cultured human nerve cells that in some cases contained mutated genes for tau identical to those found in tauopathy patients. They also employed lab-generated nerve cells carrying a well-studied gene duplication that promotes accelerated acquisition of Alzheimer’s disease.

Through their studies they demonstrated that reverse electron transport was occurring in animal models of tauopathy as well as in tauopathy-afflicted human brain tissues. Healthy nerve cells, largely spared of hyperphosphorylated tau’s malevolent presence, showed no sign of reverse electron transport or its downside effects.

Next, the investigators showed how reverse electron transport is activated, finding that tau molecules enter mitochondria, but only when they’re phosphorylated. There, they can bind to a component of the electron-transport chain called NDUSF3, warping that protein’s shape. When this happens, electrons drop off the conveyor belt and start flowing backward. “Mechanistically, tau enters mitochondria and directly interacts with the complex I subunit NDUFS3 to promote RET in a phosphorylation-dependent manner,” they continued. “Elevated RET further drives tau hyperphosphorylation, establishing a self-perpetuating pathological loop.”

Studies showed that genetically or pharmacologically depleting tau halted this defection. An experimental drug called CPT prevented hyperphosphorylated tau from binding to NDUSF3, blocking reverse electron transport without impairing normal electron flow. Experimental animals that were genetically altered to produce no or little tau, suffered none of the cognitive or other behavioral deficits or brain pathophysiology exhibited by tau-producing, but otherwise genetically identical animals under stress conditions. “In flies, mice, and human induced pluripotent stem cell (hiPSC)-derived neurons, tau depletion eliminates stress-induced RET and confers resilience,” the authors stated.

Deleting the gene for tau, for instance, protected fruit flies from the severe, life-shortening nervous-system damage that normally results from prolonged exposure to elevated temperatures. CPT treatment of the tau-producing normal flies not only protected them against heat stress but extended their lifespan.

The study showed equivalent findings in mic engineered to not produce tau. Cognition in these animals was protected by CPT treatment from the detrimental effect of heat stress. CPT also protected tau-producing normal mice subjected to heat stress.

Tau hyperphosphorylation proved critical for promoting reverse electron transport. Only tau molecules that had undergone particular phosphorylation events could get inside mitochondria, bind to NDUFS3, and induce reverse electron transport.

In tauopathy mice with severe cognitive deficiencies, an extended CPT regimen inhibited reverse electron transport in the brain mitochondria. This significantly improved the animals’ performance on a wide range of behavioral tests and prevented nerve-cell inflammation as well as several characteristic markers of neurodegeneration, such as diminished cortical thickness and total brain volumes.

“Crucially, therapeutic inhibition of RET mitigates tau-induced neurotoxicity in multiple models, without observable detrimental effects on normal animals,” the authors noted. “The RET inhibitor CPT effectively disrupts the pathological loop between RET and tau phosphorylation, ameliorating neurotoxicity across species. In fly and mouse models of tauopathy, CPT treatment rescues behavioral deficits, reduces neuroinflammation, and mitigates neurodegeneration.”

Reverse electron transport is a textbook example of a vicious circle, Lu said. The massive release of highly reactive chemicals dramatically boosts the odds that individual tau molecules will get hyperphosphorylated, leading to additional activation of reverse electron transport. “Once this gets started, it can become self-perpetuating,” he commented. Reverse-electron-transport inhibition holds promise as a therapeutical strategy for tauopathies and, potentially, other maladies characterized by aberrant tau phosphorylation and mitochondrial dysfunction, such as brain tumors, stroke and traumatic brain injuries, Lu suggested.

“RET regulation thus represents a previously unrecognized normal function of tau that becomes pathological in disease, providing a therapeutic target for various conditions characterized by tau abnormalities and mitochondrial dysfunction,” the authors stated in their paper. “These findings suggest that RET inhibition holds promise as a therapeutic strategy for not only tauopathies but potentially other brain diseases characterized by aberrant tau phosphorylation and mitochondrial dysfunction.”

Lu added, “The main results we observed in our animal models were also seen in patient brain tissues and in the laboratory generated nerve-cell models we derived from tauopathy-patients’ cells. This suggests that what we learned from this study is applicable to the human nervous system. In fly and mouse models of tauopathy, CPT treatment rescues behavioral deficits, reduces neuroinflammation and mitigates neurodegeneration. In hiPSC-derived neurons carrying pathogenic tau mutations, CPT protects against stress-induced cellular abnormalities.”

These are early days for this compound’s clinical development, he stated. “Much more work remains to be done before it can undergo clinical trials.” Lu is co-founder and sits on the advisory board of Cerapeut, a company that is developing CPT as a therapeutic drug for the treatment of neurodegenerative diseases.

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Led by GE HealthCare, the FLASH program aims to develop a modular, automated platform for the rapid, distributed manufacturing of high-fidelity DNA to support research and potential future applications in personalized medicines, vaccines, and other genetic health technologies. DNA Script’s EDS technology supports this goal by enabling faster and more flexible DNA manufacturing workflows.

DNA Script, which is contributing its EDS technology and acting as the technical solution integrator for the project, says the company has adapted its solution to incorporate GE HealthCare’s proprietary DNA scaling technology, complementing DNA Script’s EDS technology, with the goal of eventually deploying the integrated platform across U.S. medical research centers, universities, and federal agencies.

“ARPA-H solutions are designed to address hard problems with bold, practical approaches,” says John Schiel, program manager, ARPA-H. “Projects like FLASH exemplify how scalable, platform-based technologies can transform the way health solutions are developed, produced, and delivered.”

“Our enzymatic DNA synthesis platform is ideally suited for the on-demand manufacturing model FLASH is pioneering,” adds Marc Montserrat, CEO, DNA Script. “Collaborating with GE HealthCare on an ARPA-H program of this scale shortens the path from research bench to patient bedside for next-generation therapies, personalized vaccines, and the broader genetic-medicine pipeline.”

“As personalized and time-sensitive genetic medicines continue to advance, there is a growing need for manufacturing approaches that are faster, more flexible, and more accessible,” notes John Nelson, senior bioscience principal and FLASH program lead, GE HealthCare’s Technology and Innovation Center. “Our vision for the FLASH program is to develop new DNA-based medicines on demand quickly, safely, and at scale.”

The FLASH program has been designed to bring together expertise in automation, DNA synthesis and scaling, purification, and genomic validation.

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Now, a study including 15 biomedical research institutions across the United States, Boston Children’s Hospital researchers and their collaborators have discovered that COVID-19 reactivates certain dormant viruses in hospitalized patients. These findings expand understanding of chronically infecting viruses and could inform development of strategies to combat their reactivation.

This work is published in a new study in Nature, entitled, “Virus reactivation in acute and long COVID-19.”

The study leveraged multiomic longitudinal data of 1,154 patients with COVID-19 from the Immunophenotyping Assessment in a COVID-19 Cohort (IMPACC) study across 20 U.S. biomedical research hospitals. It was designed to define biomarkers of COVID-19 severity and outcomes.

“This is the largest and most comprehensive biomarker study of COVID-19, in which we followed more than one thousand patients, collected more than 200,000 samples, and generated more than one billion data points over the course of a year for this public resource,” says Joann Diray Arce, PhD, who leads the PVP-Data Management and Analysis Core and is the lead of the study’s Clinical and Data Coordinating Center.

The research team detected 11 reactivated viruses in patients within the first 40 days from admission, with the most detected ones being Epstein-Barr, herpes simplex 1, cytomegalovirus, and Anelloviridae viruses. Notably, reactivation of Anelloviridae, a poorly understood family of viruses typically latent in about 90 percent of the population, was associated prominently with long-term physical disability and long COVID.

“This association with long COVID is an interesting finding as millions around the world suffer from this chronic condition,” says Ofer Levy, MD, PhD, director of the Precision Vaccines Program (PVP) at Boston Children’s. “Having new insight as to the molecular and viral associations with long COVID could point the way to better understanding and ultimately better diagnostics and treatments.”

In an analysis of the blood samples from the patients, Epstein-Barr and cytomegalovirus seemed to activate in response to inflammation rather than immune system suppression.  The researchers say this is a surprising new mechanism, challenging the prevailing view that chronic viral reactivation is primarily a consequence of immunosuppression. This finding demonstrates that reactivations occur frequently in apparently immunocompetent individuals during severe illness and in association with increased systemic inflammation.

In addition, the authors write, the findings “challenge the prevailing view that chronic viral reactivation is primarily a consequence of immunosuppression, demonstrating that reactivations occur frequently in immunocompetent individuals during severe illness and in association with increased systemic inflammation.” They also demonstrate persistence of viral reactivation in convalescence and report an association of Anelloviridae with long COVID.

“Although many no longer think of COVID being a problem, up to 50,000 Americans died of COVID in 2025-2026 respiratory season and some estimates suggest over 10 million U.S. adults suffer from long COVID,” says Levy. “We need to help these patients recover with the best outcomes.” He adds “Moreover, sooner or later, there may be another coronavirus pandemic, which means we need to learn all the lessons we can from COVID-19 to be better prepared.”

Next steps for this work will be to uncover how the immune system responds to these viruses over the course COVID-19, with the aim of identifying effective therapeutics and establishing the optimal timing of any interventions.

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The team’s study, including experiments in mice, identified a central role for the IL-1 family in mediating rapid and protective immunity against C. albicans mucosal infection. If the results of the preclinical study are confirmed in humans, they could help better understand who is at risk of developing fatal fungal infections and also point to a potential therapeutic target.

The results provide the first potential clues as to why only some patients with weakened immune systems—including those undergoing chemotherapy or living with HIV—are at risk of life-threatening Candida albicans infection. James S. Griffiths, PhD, research fellow, King’s College London, said, “Most people carry Candida albicans harmlessly as part of the body’s natural microbiome, but in immunocompromised patients it can spread throughout the body and become life-threatening. A major challenge has been understanding why a fungus that is normally harmless can suddenly spread beyond its natural niche and cause invasive disease. Our study identified the IL-1 family as a critical early immune defense system that helps prevent this fungus from escaping the mouth and gut and spreading to multiple organs. We hope these findings will help identify patients at greatest risk of invasive fungal disease and provide a foundation for developing new ways to strengthen protective antifungal immunity.”

Griffiths is corresponding author of the team’s published paper in Nature Microbiology, titled “IL-1 family signaling drives mucosal defense against systemic Candida albicans infection.”

C. albicans is a fungus that normally lives harmlessly in the mouth and gut but can sometimes spread through the body and cause fatal disease. Fungal infections kill more than 2.5 million people each year, and C. albicans alone kills almost a million. “While mucosal infection is common and contributes to morbidity, it is invasive systemic disease that drives mortality,” the authors explained.

However, scientists haven’t fully understood why fungi can escape their natural locations in the mouth and gut and cause life-threatening disease in around 10% of patients who have a weakened immune system. “With increasing resistance to antifungals, poor diagnostic tools and limited therapeutics, understanding how C. albicans mucosal infections develop and, critically, how they disseminate, is vital to managing C. albicans disease,” the investigators continued.

For their reported study they focused on a signal, IL-1, produced by the immune system to trigger symptoms to fight off infection. IL-1 family members are potent regulators of immunity, the investigators noted, and both insufficient IL-1 activity, and excessive activity, may be implicated in disease. “Here, we investigated how the combinatorial IL-1 family shapes the host immune response to mucosal C. albicans infection and explored the role of the IL-1 family in mucosal–systemic dissemination,” they noted.

The scientists’ study showed that mice genetically modified not to produce IL-1 experienced severe disease when exposed to Candida albicans. The study results suggested that the IL-1 immune pathway is critical in preventing Candida albicans from spreading around the body and causing life-threatening disease.

The team investigated this further by injecting IL-1-deficient mice with a drug that removes neutrophils, a type of white blood cell that is among the first to respond to infections and help fight threats such as bacteria and fungi. This approach allowed the researchers to mimic the weakened immune system seen in some immunocompromised patients. By then introducing Candida albicans to the mouths of those mice, the scientists for the first time observed the fungus spread throughout the body and cause fatal disease, confirming that IL-1 is critical in preventing disease spreading. “Critically, absence of IL-1 family signaling coupled with neutropenia permits C. albicans dissemination from the mucosa, first to the liver and then into multiple organs, mimicking disease experienced by severely immunocompromised patients,” they reported.

While the study focused specifically on Candida albicans, the researchers say the IL-1 immune pathway may be a broader defense mechanism that helps keep fungi normally found in healthy microbiomes from spreading and causing fatal disease, and further research is needed to confirm whether this applies to other fungal species. Understanding what causes fungi that are naturally present in our microbiomes, such as Candida albicans, to cause life-threatening disease could help spot at-risk patients earlier.

The researchers suggest that, if confirmed in humans, the findings could lead to a test that identifies which immunocompromised patients have low levels of IL-1 and so are at heightened risk of Candida albicans escaping their microbiomes and causing disease.

While drugs such as antibiotics are currently used to treat life-threatening fungal diseases, more targeted therapies are needed that tackle the root cause of infection. The researchers suggest future clinical studies in humans could test whether drugs targeting IL-1 could work as a personalized therapy for preventing life-threatening Candida albicans infection.

Co-author Lea Lortal, PhD, a postdoctoral researcher in mycology at the University of California, San Francisco (UCSF), said, “Fungal infections are severely overlooked: they affect more than one billion people worldwide. Yet, there are still no clinically approved vaccines against any fungal pathogen, and our understanding of the immune mechanisms that protect us from fungal disease remains incomplete. What normally keeps fungi, such as Candida albicans, in check has remained a major unanswered question. In this study, we identified the IL-1 family as a key early coordinator of the immune response that helps contain Candida before it can become invasive. Understanding how these protective responses are initiated is an important step toward developing better ways to prevent and treat invasive fungal infections.”

In summary, the authors wrote, “Our findings suggest that combinatorial IL-1 family function plays a crucial role in dissemination risk, offering potential for a personalized therapeutic approach. Consequently, therapeutically enhancing IL-1 family function to augment mucosal immunity and reduce dissemination could have substantial clinical implications.”

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GEN: How would you characterize the workforce requirements for bioprocessing?

Frank Fazio: We’re essentially a fully integrated little biomanufacturing company. We need skill sets and education levels that range from jobs requiring a GED or high school diploma to PhDs with postdoctoral experience—and everything in between. We need technicians, new PhDs, and experienced scientists. So it’s not a single pipeline of employees; it’s multiple pipelines.

Geography also plays into it. In markets like Boston, Research Triangle Park, or San Francisco, the candidate pool is deep because there are many bioprocessing companies. In other markets, finding people with GMP experience becomes much more difficult.

Organizations like NIIMBL [National Institute for Innovation in Manufacturing Biopharmaceuticals] are also helping enhance the workforce by supporting workforce development through grants, training, and educational content.

GEN: What are the biggest challenges in attracting and retaining a skilled workforce?

Fazio: They’re really two separate challenges: attracting people and keeping them.

The mission of an organization is often what attracts talent. Whether it’s a startup developing a breakthrough technology or addressing an unmet medical need, people want to be part of something meaningful.

Retention depends on organizational culture. You have to reward people for what they do, provide intellectual challenges, and create opportunities for scientific and career growth.

In highly competitive markets, compensation also matters. A startup may suddenly offer salaries that are 15% or 20% above market rates, changing the competitive landscape. Organizations need strategies to either keep pace with those shifts or successfully ride them out.

GEN: Does the St. Jude mission provide an advantage in recruiting?

Fazio: I think that’s true. The mission is what brought me to St. Jude, and the opportunity to be part of that mission is certainly a benefit. But people can also get excited about the technology itself. Gene therapies, messenger RNA technologies, and other advances have generated tremendous enthusiasm, and that excitement helps attract talented people.

GEN: What strategies are most effective for supporting workforce development?

Fazio: I’m fortunate because Children’s GMP is a 70-person organization within a 6,000-person institute. That creates opportunities for employees to grow within St. Jude.

We want people to gain valuable skills in Children’s GMP and then continue advancing elsewhere in the institute if that’s the right next step. That keeps talented employees within St. Jude while giving them meaningful career opportunities. Many of our employees want to stay in the Memphis area, so providing those pathways helps them grow professionally without feeling limited.

GEN: Do you have additional initiatives that are strengthening workforce development?

Fazio: We’ve been working on this aggressively for the past four years through partnerships. We partnered with Southwest Tennessee Community College to create a biomanufacturing-technician internship. Students complete internships during their final semester, gain experience at St. Jude, and have opportunities to apply for full-time positions. We’ve also reached into local high schools to introduce students to careers in biomanufacturing and make them aware of biotechnology programs. At the university level, we partner with the University of Memphis, Rhodes College, and the University of Mississippi through internships, mentoring, presentations, and recruitment efforts. These experiences help students decide whether to pursue graduate school, enter manufacturing, or build careers within the regional biotechnology ecosystem.

GEN: Why are these partnerships so important?

Fazio: I’m an old manufacturing person, so if something isn’t available, you’ve got to make it. That’s how I feel about the workforce pipeline. If the pipeline doesn’t exist, then you have to build it.

We understand the range of skills and educational backgrounds we need, and these partnerships allow us to develop that pipeline. We’re proud of the work we’ve done around workforce development. Creating access to advanced therapeutics is important, but so is education. Being part of an organization like St. Jude means education is in our culture, and our employees take great pride in contributing to that effort.

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No single model excels at every task. Running the same engineering process through different AI models often produces significantly different results. Even repeated runs on the same model can yield inconsistent outputs, Farshid Sabet, CEO and co-founder of Corvic AI, tells GEN.

Variability may be acceptable for low-risk activities, but it becomes problematic when engineering diagrams, flow directions, operational relationships, and other complex data are involved. “Small inaccuracies can compound quickly,” he cautions, leading to unreliable results in production environments.

Corvic AI recently benchmarked leading frontier AI models against Corvic V5’s workflow orchestration platform, assessing their ability to extract piping and instrumentation diagrams (P&IDs) into XML files.

“For general text generation, today’s frontier AI models perform remarkably well and the differences between them are relatively small,” Sabet says. “But engineering workflows introduce an entirely different level of complexity.”

The benchmark found that relying on foundation models alone often resulted in inconsistencies, hallucinations, and poor repeatability. Corvic addresses these challenges by combining semantic data preparation with workflow orchestration that coordinates multiple AI models, validation steps, retrieval, and enterprise context to improve reliability.

Rather than replacing frontier models, Corvic’s platform integrates and orchestrates them, selecting the best model for each stage of a workflow based on the task, performance requirements, and cost.

Like wild horses

As Sabet says, “AI models are like wild horses. They’re incredibly powerful, but they need guidance, structure, and context before they can consistently solve complex enterprise problems.”

Typically, AI developers focus on improving the models themselves through training, fine-tuning, or prompt engineering while assuming enterprise data is already AI-ready. Corvic, instead, focuses on organizing enterprise knowledge through a semantic layer that enables AI systems to understand relationships across engineering documents, databases, diagrams, and operational systems.

“We work with the data independently of whether it’s manufacturing, chemistry, or biology,” Sabet says. “The data has to be organized in a way that allows AI models to recognize context and relationships. That’s the semantic layer.”

Once enterprise knowledge is structured appropriately, organizations can intelligently orchestrate multiple AI models throughout a workflow rather than relying on a single model for every task. Sabet refers to this approach as a “council of models,” where each model contributes its strengths to improve overall accuracy, repeatability, and efficiency.

A former Intel executive, Sabet founded Corvic AI to help organizations operationalize AI across complex enterprise environments. Today, the company works with manufacturers, life sciences organizations, and other enterprises to transform fragmented operational knowledge into reliable AI workflows that improve productivity and decision-making.

For organizations evaluating AI platforms, Sabet recommends looking beyond benchmark scores and considering three factors: how enterprise data is secured and governed, whether the platform intelligently matches AI models to different stages of a workflow, and how success will be measured through meaningful productivity outcomes.

To maximize the benefits of AI, Sabet reiterates, biopharmaceutical manufacturers “need to look at their data from a systems engineering perspective.

“The future of enterprise AI isn’t about finding one perfect model,” he says. “It’s about intelligently orchestrating enterprise data, semantic understanding, and specialized AI models into repeatable workflows that organizations can trust.”

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Monoclonal antibodies (mAbs) are employed in a broad range of therapeutic applications—from the treatment of cancer and autoimmune diseases to the management of viral infections and the prevention of tissue rejection.

They are a major focus of biopharmaceutical industry R&D efforts—13 of the 16 biologic products approved by the FDA in 2024 were mAb-based drugs.

And—based on a recent forecast by McKinsey—demand for mAb therapeutics is set to go on increasing over the next decade.

Various technologies are used to make mAbs—from bubble column to fluidized bed bioreactors. However, the most widely used systems are stirred-tank bioreactors, consisting of a tank, an impeller for homogenizing the culture medium, and a sparger for supplying oxygen to the cells.

Stirred-tank bioreactors are effective for mAb production, but the yields they achieve are still relatively low—typically, less than a tenth of a gram per liter.

Output is largely dependent on a reactor’s ability to make sure cells have the nutrients they need to growth, say researchers at the Italian National Agency for New Technologies, Energy and Sustainable Economic Development (ENEA).

“The main bottleneck limiting the maximal efficiency of these traditional bioreactors is the availability of dissolved oxygen throughout the entire fermentation cycle, due to its low solubility in water.

“As culture density increases, oxygen demand rises, often making oxygen transfer a rate-limiting factor in bioreactor systems. Inadequate oxygen supply can lead to hypoxic stress, resulting in reduced cell growth, decreased protein expression, and shifts toward undesirable metabolic pathways,” they write.

Innovation

To address this, manufacturers typically increase agitation to help cells access oxygen more effectively. However, this can increase shear stress, which is detrimental to CHO cell growth because it can disrupt membranes and induce apoptosis.

A more promising potential alternative, according to the ENEA researchers, is a new rotating drum bioreactor originally designed for bacterial growth for applications in wastewater treatment.

The prototype consists of a horizontal chamber, coupled to a slow-rotating perforated basket. The basket contains two perpendicular paddles, designed to ensure the efficient homogenization of the culture. The chamber is equipped with several inlet and outlet ports and probes for monitoring temperature, pH, foam formation and O₂ level.

According to the authors, “The main innovative principle underlying this prototype involves increasing the liquid surface area exposed to the headspace, thereby promoting gas exchange at low rotational speeds.”

Head-to-head test

Trials of the bioreactor suggest the decision to focus on boosting oxygen availability was the correct approach. In head-to-head comparisons, the bioreactor achieved a titer of 1.3 ± 0.09 g/ L at day 10. In contrast, a titer of 0.71 ± 0.006 g/ L was obtained in a traditional bioreactor.

According to the authors, rotating drum bioreactors are a promising alternative to conventional systems, supporting mammalian cell growth while maintaining high viability and enhancing mAb production.

“Monoclonal antibody production reached 1.3 ± 0.09 g/ L, almost doubling the yield obtained in the stirred-tank reactor. The improved outcomes observed in the innovative bioreactor could be associated with the distinct operating and hydrodynamic conditions established by the system configuration,” they conclude.

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According to Sumit Dutta, associate director of upstream process development at Forge Biologics, AAVs maturing as a technology means the industry should become more focused on how best to bring products to market.

“There’s a very heavy focus and investment on late-stage programs, and we need to bring the focus to [process robustness] and thinking about approaches carefully so therapies can get to market, and become available to patients, sooner,” he says.

Forge Biologics works on multiple different AAV programs, allowing them to spot patterns between programs and learn from that, explains Dutta, who argues that they focus on reducing risk and seamless integration between process development for early- and late-stage clinical programs.

“We have early engagement with our key stakeholders so we’re walking in lockstep about what we’re developing, who we’re developing it for and our final target,” he explains. “We ensure the process and technical solutions the development team are coming up with is what is required for the manufacturing process to succeed.”

That can involve identifying critical process parameters and critical quality attributes early and confirming how to study them with high throughput by developing representative scale-down models, he says.

Forge Biologics have also integrated considerations of U.S. Food and Drug Administration (FDA) and other regulatory guidelines throughout their process development, Dutta says.

“Integrating those approaches and ensuring quality and commercialization needs are [also] met along the way is a [key part of] this approach,” he says.

Dutta will be speaking about Forge Biologics’ late-stage development approach at the Bioprocessing Summit in Boston this month.

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In a study published in Nature, researchers from UCLA Health and the University of Texas Southwestern Medical Center developed an ex vivo platform using human temporal cortex tissue donated by neurosurgery patients and maintained alive in the laboratory for several days. The approach allowed the team to apply electrical stimulation resembling deep brain stimulation, record neuronal activity, and map gene expression changes across individual brain cell types.

The paper, titled “Stimulation modulates gene-linked cell assemblies in the human brain,” addresses a key gap in understanding how stimulation-based therapies affect human brain tissue at the cellular and molecular levels. Although deep brain stimulation is already used for disorders such as Parkinson’s disease and obsessive-compulsive disorder, its effects on different human brain cell types and the genes they activate have not been well defined.

To investigate those mechanisms, the researchers integrated microelectrode array stimulation with simultaneous recording and single-nucleus genomics from resected temporal cortex obtained from neurosurgery patients. In the abstract, the authors wrote that they developed the platform “to directly investigate the mechanisms of neuromodulation elicited by human brain stimulation.” They reported that stimulation strengthened coordinated groups of neurons, or cell assemblies, and then connected those physiological changes to cell-type-specific gene regulatory networks.

After stimulation, brain cells became more synchronized in how they communicated. “These assemblies exhibited stimulation-dependent increases in activation strength and membership flexibility, with analogous properties to compositional drift observed in memory-related assemblies in vivo,” the authors write. The team also found that neurons and non-neuronal support cells, including astrocytes, activated distinct genetic programs in response to stimulation.

“Not only was it a privilege and challenge to work with donated living human brain tissue, but to see it reveal the genes and cell types underlying human brain plasticity as new targets for future therapies makes the work feel even more meaningful,” said senior author Genevieve Konopka, PhD, chair of the department of neurobiology at UCLA Health.

The donated samples came from the temporal cortex, a region on the sides of the brain’s outer layer that is important for memory and related cognitive functions. The authors noted that stimulation of cortical circuits is being explored as a therapeutic strategy for restoring cognitive function, but the biological mechanisms underlying its effects in humans have remained largely unexplored.

The study also points to several open questions. Additional work is needed to determine the molecular effects of long-term stimulation, how stimulated cells influence neighboring cells, and whether similar mechanisms are active in deeper brain regions, which are harder to obtain from living donors. Still, the authors concluded that the work establishes “a foundation for identifying targetable genetic signatures linked with physiology” that could potentially be harnessed through neuromodulation strategies.

“By understanding exactly which genes turn on in which cells during stimulation, we can start to design more precise approaches to deep brain stimulation and potentially augment this clinical strategy with pharmacological therapies to help slow cognitive decline,” added Konopka.

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