Researchers at Baylor College of Medicine, the Duncan Neurological Research Institute (Duncan NRI) at Texas Children’s Hospital, and collaborating institutions have identified new genetic candidates that help explain why autism is diagnosed about four times more often in boys than it is in girls. The study, involving tests in induced pluripotent stem cell (iPSC)-derived neurons (iNeurons), revealed that small changes in the gene MECP2 on the X chromosome might help explain part of this difference.
Huda Zoghbi, MD, Distinguished Service Professor at Baylor, director of Duncan NRI, and a Howard Hughes Medical Institute investigator, is senior and corresponding author of the team’s published paper in The American Journal of Human Genetics, titled “A massively parallel reporter assay of MECP2 cis-regulatory elements reveals genetic candidates for male-biased autism.” In their paper, the team concluded, “These findings suggest noncoding MECP2 variants can cause idiopathic, male-biased autism and provide a framework for uncovering regulatory variants in other X chromosome neurodevelopmental genes that may contribute to autism’s missing heritability.”
“Autism is a common, heritable neurodevelopmental trait that affects how a person communicates, interacts with others, and experiences the world, and is characterized by altered social interactions and restricted, repetitive behaviors or interests,” Zoghbi explained. “It is diagnosed about four times more in male individuals than in female individuals, suggesting sex-specific factors may increase male vulnerability,” the researchers added in their paper.
In the current study, the researchers drew from their long experience with gene MECP2, which is on the X chromosome and has been associated with neurodevelopmental conditions, including autism. “We tested the idea that the predominance of autism in males could be explained in part by mild mutations in an X chromosome gene’s regulatory regions,” commented Rebecca Meyer-Schuman, PhD, a postdoctoral associate in the Zoghbi lab. “Females might be protected from such a mild mutation because of their second X chromosome, but males, who have only one copy, would be more vulnerable. The regulatory regions are like dials that control whether a gene will be expressed and by how much. And what better place to start looking at these regulatory regions than the gene MECP2, where brain health depends on how much of the gene is expressed, and where mutations can cause neurodevelopmental disorders that include autism.”
Previous murine studies by Zoghbi lab and others have taught researchers that MECP2 produces a Goldilocks protein, meaning that it must maintain a “just right” concentration or activity level for a healthy brain. Having too little—about 50% or less of the normal levels—leads to Rett syndrome, and having twice the normal levels causes a different neurodevelopmental condition called MECP2 duplication syndrome. “Both loss-of-function and gain-of-function variants lead to severe neurodevelopmental conditions—Rett syndrome (MIM: 312750) and MECP2 duplication syndrome (MDS; MIM: 300260[intellectual developmental disorder, X-linked, syndromic, Lubs type (MRXSL)]), respectively,” the authors commented. “Because MECP2 is on the X chromosome, hemizygous male individuals have a more severe phenotype than heterozygous female carriers with the same variant.”
Meyer-Schuman also noted, “Previous studies in mice also showed us that milder changes in MECP2 levels, for instance reducing the expression by 30% or increasing it by 50%, do not cause the more severe features of Rett syndrome or MECP2 duplication syndrome like seizures or motor problems, but lead to autism-like behaviors.”
For their current study the team used a massively parallel reporter assay (MPRA) to screen the regulatory regions of the MECP2 gene in induced pluripotent stem-cell (iPC)-derived neurons. “This allowed us to identify and manipulate the regulatory regions and determine what kinds of changes would alter their function,” Meyer-Schuman said. The researchers also screened MECP2 regulatory regions in autistic individuals and tested the genetic variants they identified using the MPRA assays.
“We identified two regulatory regions where male autistic individuals inherited a variant from their unaffected mother that altered regulatory activity,” Meyer-Schuman said. “One of these variants reduced MECP2 expression by approximately 30% in human neurons, a magnitude that produces social deficits, hyperactivity and anxiety-like characteristics in mice. As predicted by the mouse model, this individual was diagnosed with autism and ADHD but had none of the defining characteristics of Rett syndrome.”
In their paper, the authors commented that their work supports a broader hypothesis that altered dosage or expression of sex chromosome genes are a major source of the male bias observed in autism. Zoghbi added, “These findings, a result of integrating human and animal studies, suggest that MECP2 regulatory variants can contribute to male-biased autism and reveal just the tip of the iceberg, providing a framework for uncovering regulatory variants in other X chromosome neurodevelopmental genes that may contribute to autism’s missing heritability.”
Biotechnology firm Enodia Therapeutics has announced a research collaboration and licensing agreement with pharma giant Pfizer to discover and develop small molecule inhibitors of Sec61, using Enodia’s proprietary platform.
Under the terms of the agreement, Enodia will perform discovery activities to screen, optimize, and develop Sec61 inhibitor candidates against multiple collaboration targets. Following the collaboration term, Pfizer will be responsible for all clinical, manufacturing, regulatory, and commercial activities. Furthermore, Enodia will receive an upfront payment and is eligible for future research, development, and sales milestone payments, as well as tiered royalties on net sales, bringing the total potential value to more than $500 million.
Enodia develops novel small-molecule therapies for targeted protein degradation using its platform, which is designed to identify small molecules that enable selective Sec61 translocon modulation, a novel approach to inhibit disease-driving proteins when they are synthesized and before pathological effects occur. To date, the company has built a broad chemical space that spans multiple Sec61 inhibitor families and is supported by biological datasets including proteomics and cryo-EM data as well as tailored cell-line libraries.
“Enodia has built a broad platform that enables selective Sec61 translocon modulation, a novel approach to inhibit disease-driving proteins while preserving essential physiological functions,” said Yves Ribeill, PhD, Enodia’s CEO. “We look forward to collaborating with Pfizer, combining their deep expertise and clinical resources with our approach for precisely targeting pathological proteins to bring forth potential new medicines.”
Earlier this year, Enodia announced that it had purchased assets from Kezar Life Sciences’ Sec61-based discovery and development program. At the time, Enodia said that the acquisition helped advance its understanding of Sec61 selectivity mechanisms. The company also said that insights from Kezar’s programs would further strengthen Enodia’s core focus on Sec61-driven selectivity for targeted protein degradation. Under the terms of the purchase agreement, Kezar received an initial upfront payment totaling $1 million, and was expected to receive future payments upon achievement of certain development, regulatory and commercialization milestones.
The emergence of increasingly complex biologics such as multi‑specific antibodies, cytokines, fusion proteins, and other structurally demanding modalities has exposed the limits of conventional bioprocessing. Many of these molecules are difficult to express at commercially viable yields, and their quality attributes can be highly sensitive to the cellular environment. As a result, productivity, consistency, and cost remain major constraints across the industry.
Traditional cell line development (CLD) relies on constitutive promoters that drive static expression throughout development and production. Because production is always on, cells must divide and manufacture protein simultaneously, even when the product is burdensome or toxic. While this model worked relatively well for easy-to-express monoclonal antibodies, it does not work well for next-generation biologics, where the inherent trade-off between higher specific productivity and rapid cell growth, both competing for the same cellular resources, is increased. Light‑controlled gene expression using optogenetics is emerging as a credible alternative.
This article explores the ten most important questions facing optogenetic biomanufacturing as it moves from proof‑of‑concept demonstrations toward mainstream adoption in modern bioprocessing.
1. What is optogenetics, and why is it relevant to biologics manufacturing?
Optogenetics uses light‑responsive proteins to control specific cellular functions. In biomanufacturing, the key application is regulating gene expression with light instead of relying on constitutive promoters or chemical inducers. When light‑controlled gene expression systems are engineered into production cell lines, illumination at defined wavelengths can switch expression on, off, or to intermediate levels.
This is important because it introduces a fundamentally different control modality. Conventional systems provide static expression, whereas optogenetics enables dynamic, reversible, and tunable control. As biologics become more complex and more sensitive to expression conditions, having a way to precisely modulate transcription directly, rather than perturbing the entire cell by modulating process parameters such as temperature, will become increasingly valuable.
2. What core limitation in biologics manufacturing does light‑based control address?
The main limitation is the inherent competition between cell growth and protein production. In constitutive systems, cells must divide and manufacture protein at the same time, drawing on the same finite pool of metabolic resources. This creates a structural trade‑off: clones that produce strongly have a slow doubling time and/or do not grow to viable densities, while clones that grow well often produce only modest titers. This trade‑off becomes much more pronounced for challenging molecules such as multi‑specific antibodies, cytokines, and fusion proteins that are aggregation‑prone or place a significant burden on the host cell.
Optogenetics addresses this by separating the growth and production phases. Cells can grow in an uninduced, low-burden state and then transition into a productive state upon illumination. As light acts directly on transcriptional regulators in a dose-dependent manner, expression can be tuned precisely rather than modulated indirectly through temperature shifts or coarsely and irreversibly by chemical induction. Chemical inducers can also negatively affect cell performance through off-target effects and are difficult to remove during downstream processing, which has limited their adoption in mammalian biomanufacturing. The direct, tunable control by light also enables more deliberate modulation of pathways that influence critical quality attributes such as post-translational modifications (PTMs), which is increasingly important for complex biologics and biosimilars.
3. How does optogenetic light exposure work, and is it safe for cells and media?
Optogenetics uses light as an informational cue rather than an energy source. Because photoreceptors respond to brief, low-intensity pulses and stay “on” for a tunable period of time before reverting to the off state, optogenetic systems can maintain precise control without continuous or high-power illumination.
The wavelengths used in bioprocessing are in the visible range and non-ionizing, operating well under established phototoxicity thresholds. At these levels, light does not harm cells or DNA, nor does it disrupt cellular physiology. Although certain media components are known to be light-sensitive, the illumination used for optogenetic induction has not shown detrimental effects on cellular performance.
4. What is the impact of optogenetics on lab operations?
Optogenetic workflows use standard lab equipment with the addition of illumination devices compatible with existing infrastructure, such as plates, shake flasks, or bioreactors. The main operational difference occurs during pool generation and single-cell cloning, where cells must remain uninduced. This is achieved by working under “safe light” conditions, visible wavelengths that do not activate the specific optogenetic system but allow the operator to handle the cell culture. Only small areas of the lab need to be adapted for this purpose. For all other operations, including biomanufacturing, local interventions to shield cells from room light are typically sufficient.
5. How many cellular functions can be controlled with light in a single cell line?
Current systems can independently regulate cellular functions using two or three different wavelengths. For example, one color may control production while another modulates a critical quality‑related pathway. Functions that require coordinated timing can be linked to the same wavelength. As genetic circuit design advances, the number of independently controllable functions is expected to increase.
6. When might optogenetically manufactured biologics reach clinical and commercial stages?
Optogenetic cell line development is already being explored for multiple programs. Regulatory agencies have established pathways for evaluating emerging bioprocess technologies, and optogenetic systems are beginning to move through these mechanisms. If early development proceeds as expected, optogenetically controlled processes could support clinical filings in the next two years, with commercial adoption following thereafter.
7. Can optogenetics be integrated into existing facilities?
Yes. Optogenetic manufacturing does not require new bioreactor designs; illumination hardware can be added to standard single‑use or stainless‑steel systems. For single‑use bags, light is delivered externally through the bag without breaching the sterility barrier; for stainless‑steel tanks, cultures can be circulated through illuminated loops. No cleanroom redesign is required.
8. How does optogenetic manufacturing scale to larger bioreactors?
Scaling optogenetic systems depends on three factors: the sensitivity of the photoreceptors, the lifetime of their activated state in the dark, and the mixing and light-scattering characteristics of the bioreactor. Modern optogenetic systems for biomanufacturing are designed to respond to very low light intensities, and once activated, they gradually return to the off state in the dark at a characteristic rate, typically over tens of minutes.
Since stirred-tank bioreactors mix continuously and scatter light throughout the vessel, cells receive sufficient illumination over the photoreceptor’s characteristic activation lifetime even at large volumes. Simulation studies and early pilot-scale experiments up to the 200 L scale suggest that optogenetic activation can be achieved at commercially relevant scales, including stainless steel and single-use systems.
9. What has convinced established players to evaluate this technology?
Biologics development and manufacturing are intentionally conservative, with new technologies adopted only when they demonstrate clear, reproducible benefits and maintain patient safety. For any emerging bioprocess platform, the threshold for evaluation is data showing that it can deliver meaningful improvements without introducing new risks or operational complexity.
In comparative studies, optogenetic induction has produced more than two‑fold increases in titer for standard monoclonal antibodies as well as for more difficult‑to‑express therapeutic proteins. These gains have been achieved while maintaining or improving critical quality attributes, including those influenced by folding, assembly, and post‑translational modification.
As the next generation of therapeutics become increasingly complex, leading biopharma and CDMO players see the need for novel biomanufacturing platforms capable of meeting that complexity without compromising titers, and for that reason several key players are actively evaluating optogenetic technology for potential integration.
10. Where is optogenetic biomanufacturing headed in the next decade?
If current trends continue, optogenetic control may become a standard tool for managing expression, quality, and other cellular functions in biologics manufacturing. The ability to modulate gene expression dynamically opens possibilities for more efficient production of complex therapeutics, more predictable quality profiles, and more flexible facility design. As the technology matures, it is likely to be adopted across CDMOs, biotech, and biopharma companies seeking greater control over their manufacturing processes.
Maximilian Hoerner, PhD, is the head of optogenetics at Prolific Machines
UCB has dedicated the Rowen, GA, site where it plans to build a $2 billion biologics manufacturing campus that is set to open as the Belgian-based drug developer’s first U.S. manufacturing site.
When completed in 2032 or 2033, the campus is expected to support commercial production of recently approved and future biologic medicines, applying artificial intelligence, automation, and advanced manufacturing technologies. The campus is intended to further integrate UCB’s U.S. patient value chain from research and development through manufacturing and delivery.
Some 330 permanent jobs are expected to be based at the approximately 460,000-square-foot campus, which will occupy 79 acres within the Rowen innovation district in Georgia’s Gwinnett County. UCB bought the 79 acres from the Rowen Foundation, which is developing a 1,900-acre campus on Highway 316, launched in 2020 as a “knowledge” community for biopharma and other innovation-based fields.
In its announcement of the campus site dedication, UCB said it chose to build its first U.S. manufacturing campus in Georgia because of what it called the Peach State’s strong life sciences ecosystem, highly skilled workforce, robust infrastructure, and access to leading academic and research institutions.
Another factor in the decision: Gwinnett County has committed $174 million in incentives and infrastructure investments to support UCB’s project.
UCB’s project is the brightest recent success of Georgia life sciences leaders, who worked through industry group Georgia Life Sciences to lay out a 10-year “Roadmap” last year with the aim of “positioning Georgia as the scale-up manufacturing hub of the Southeast.” The UCB project, announced in March, helped place Georgia among the “Next 5 States” within GEN’s Next 10 U.S. Biopharma Clusters A-List.
“Long-term commitment”
“Our manufacturing investment in the United States reflects our long-term commitment to patients, strengthening our ability to serve them while contributing to scientific innovation, highly skilled jobs, and economic growth in Georgia,” UCB CEO Jean-Christophe Tellier said in a statement.
UCB executives and dignitaries cut a ceremonial ribbon to mark the dedication of UCB’s future biologics manufacturing campus in Rowen, GA. Jeffrey Kessler, U.S. Department of Commerce Under Secretary for Industry and Security, stands at left. At the center are Georgia Gov. Brian Kemp (R); UCB CEO Jean-Christophe Tellier; Katherine Raeymaekers, Consul General of Belgium in Atlanta; and Nicole Love Hendrickson (D), Chairwoman of the Gwinnett County Board of Commissioners. [UCB]
Tellier and other UCB leaders were joined at a dedication ceremony by dignitaries that included Georgia Gov. Brian Kemp (R); Jeffrey Kessler, U.S. Department of Commerce Under Secretary for Industry and Security; Nicole Love Hendrickson (D), Chairwoman of the Gwinnett County Board of Commissioners; and Katherine Raeymaekers, Consul General of Belgium in Atlanta.
During the ceremony, the dignitaries joined top UCB executives in unveiling the Emmanuel Janssen Circle, a commemorative stonework installation just completed within the roundabout to the entrance of the future campus. Janssen (1879-1955) was a Belgian businessman who founded Union Chimique Belge (UCB) on January 18, 1928. The company initially focused on industrial chemicals before evolving into a developer of biologics for indications in neurology and immunology.
“UCB’s new biomanufacturing campus builds on the entrepreneurial legacy of Baron Emmanuel Janssen, founder of UCB, while strengthening the transatlantic collaboration that drives economic growth, scientific innovation, and improving people’s lives,” Raeymaekers stated. “Today’s site dedication reflects the strength of the partnership between Belgium, the United States, and the State of Georgia—and our shared commitment to enduring progress, innovation, and opportunity.”
UCB worked with numerous public and private partners to locate its biologics manufacturing campus in Rowen—including the Metro Atlanta Chamber; Georgia Quick Start, which provides customized workforce training through the Technical College System of Georgia; Gwinnett County Government; Georgia Power Company; the public-private economic development initiative Partnership Gwinnett; and the Georgia Department of Economic Development.
Headquartered in Brussels, UCB employs more than 10,000 people in nearly 40 countries—including the United States, where the company employs more than 2,000 people in research, development, manufacturing, commercial operations, and corporate functions.
UCB has maintained a U.S. presence for nearly a century. The company now employs more than 400 people in Georgia, where it established its Stateside headquarters in Atlanta in 1993.
More than 1,000 construction jobs are expected to be created in connection with the campus during the six- to seven-year projected timeframe for design and construction.
“At UCB, our purpose is to create value for people living with severe diseases, and that purpose guides the science we pursue, where we invest, and the choices we make for the long term,” Tellier added.
Caribou Biosciences (Nasdaq: CRBU), whose co-founders include Jennifer Doudna, PhD, capped a one-year 83% freefallof its stock after announcing plans to evaluate strategic alternatives, as investors responded with a selloff that sent shares of the CRISPR genome-editing cell therapy developer plunging 62%this past week.
Caribou announced plans to carry out an unspecified “substantial” reduction of its workforce—which numbered 97 people as of February 27, according to its most recent Form 10-K Annual report, filed March 5—as well as a halt to trials of its two clinical-phase pipeline candidates, both allogeneic chimeric antigen receptor (CAR) T-cell therapy programs, and other cost reduction measures also yet to be specified.
Rachel Haurwitz, PhD, Caribou Biosciences co-founder, president, and CEO
“Caribou’s story has taken a heartbreaking turn,” co-founder, president, and CEO Rachel Haurwitz, PhD, posted on LinkedIn, announcing the company’s strategic review. “This decision is not a loss of belief in our science, our clinical data, or what these programs could mean for patients. It reflects the difficult reality that the current financing environment for allogeneic CAR T-cell therapies has made it impossible to secure the capital required to responsibly advance them.”
Haurwitz co-established Caribou in 2011 along with Doudna and two other co-founders: Martin Jínek, PhD, a former postdoctoral fellow in Doudna’s lab, now at the University of Zurich, who led the seminal 2012 study leading to the Nobel Prize; and James Berger, PhD, professor in the department of biophysics and biophysical chemistry at Johns Hopkins University School of Medicine.
Caribou became operational in 2012, which would make it the oldest CRISPR therapeutics company as far as Haurwitz could recall in a 2021 interview. That year, Caribou went public through an upsized initial public offering (IPO) that raised $321 million in aggregate net proceeds after deducting underwriting discounts and commissions and other offering expenses. Caribou sold 21.85 million shares at an IPO price of $16 a share, up from earlier plans to sell 13.5 million shares.
Two years later, Haurwitz shared with GEN her journey from graduate student in Doudna’s lab to launching a biotech start-up: “This is the only job I’ve ever had!”
Trials halted
As a result of the strategic review, Caribou has halted trials of vispacabtagene regedleucel (vispa-cel, formerly CB-010) a treatment for relapsed or refractory (r/r) B cell non-Hodgkin lymphoma. Caribou has said vispa-cel is the first allogeneic CAR T-cell therapy “to our knowledge” that has reached the clinic with a PD-1 knockout, a genome-editing strategy designed to improve antitumor activity by limiting premature CAR T-cell exhaustion.
To manufacture vispa-cel, Caribou applies Cas9 hybrid RNA-DNA guide or “chardonnay” (chRDNA) to make three edits: A knockout of the TRAC gene to remove the T cell receptor; a site-specific insertion of an anti-CD19 CAR into the TRAC gene; and a knockout of PD-1.
Also halted were clinical studies of CB-011, an allogeneic anti-BCMA CAR-T cell therapy for the treatment of patients with r/r multiple myeloma (RRMM). To manufacture CB-011, Caribou uses Cas12a chRDNAs designed to direct precise genome editing, in order to make four edits:
A knockout of the TRAC gene to remove the T-cell receptor
A site-specific insertion of a humanized anti-BCMA CAR into the TRAC gene
A site-specific insertion of a gene encoding a B2M–HLA-E-peptide fusion into the B2M gene
The resulting knockout of the endogenous B2M
“This method simultaneously eliminates endogenous HLA class I presentation on the surface of the CAR T cells and expresses HLA-E, a minor HLA class I antigen, to blunt both T and NK cell-mediated rejection of the CAR T-cell therapy by the patient’s immune system,” Caribou explained on its website.
Strategic pivot
The development of CB-011 and vispa-cel followed a strategic pivot by Caribou from a platform company for biopharma partners applying genome editing in research or product development, to a developer of genome-edited therapies based on its own next-generation CRISPR technology.
While that pivot has generated positive data readouts, it has not shielded Caribou from the financial challenges faced by numerous gene-edited therapy developers. In April 2025, Caribou chopped its workforce by 32% and pruned its pipeline by ending all preclinical research, the Phase I GALLOP trial (NCT06752876) of vispa-cel in lupus (before the first patient could be dosed), and development of CB-012, including the Phase I AMpLify trial (NCT06128044) assessing the candidate in relapsed or refractory acute myeloid leukemia (AML).
“It was really about right sizing the organization relative to our focused priorities,” Haurwitz explained last year in an interview. Asked how hopeful she was about an improving economic environment over the next 12 months, she replied: “I remain a believer and I remain an optimist. I’d probably be in the wrong job in the wrong line of work if I weren’t.”
“I certainly think for the work that we are doing, I continue to fully believe that doing right by patients is the North Star, because business success falls out from that in terms of nearer term clinical catalysts and opportunities that come from doing right by patients. And longer-term commercial opportunity also comes from doing right by patients,” Haurwitz added.
Caribou has retained Wedbush Securities as its exclusive financial advisor to assist in evaluating strategic options.
Caribou announced its pursuit of strategic alternatives after the closure of financial markets on October 6. The following day, Caribou shares began three days of stock declines, nosediving 46% from $1.14 to 62 cents. Those shares tumbled another 22% Thursday to 48 cents, but closed Friday with another 4% decline, finishing the week at 46 cents.
Cash crunch
Daina M. Graybosch, PhD, senior managing director, immuno-oncology and a senior research analyst with Leerink Partners, reported in a research note that Caribou was facing an increasingly pressing cash crunch at a time when the company needed significant capital to fund its planned Phase III ANTLER-3 trial, designed to assess vispa-cel in second-line auto-CAR T ineligible diffuse large B-cell lymphoma (DLBCL).
Caribou never enrolled patients in the pivotal study, though it reached agreement with the FDA in May on a design for the trial, which was expected to be a randomized, controlled clinical study enrolling approximately 250 CD19-naïve second line (2L) large B cell lymphoma patients ineligible for transplant and not candidates or not eligible for autologous CAR T-cell therapy.
“We are sympathetic to management’s stated rationale for exploring strategic alternatives,” Graybosch commented. “Evidently, investors were unwilling to fund the trial on what would have been highly dilutive terms, especially in the context of lingering clinical risk and uncertainty around the strength of vispa-cel’s Ph[ase I/II] outcomes and partial HLA-matching strategy, as well as substantial in- and out-of-class competition.”
That competition, she wrote, included epcoritamab, a bispecific T-cell engager (BiTE) therapy already marketed as Epkinly® by Genmab (Nasdaq Copenhagen and Nasdaq: GMAB) and AbbVie (NYSE: ABBV).
On October 5—the day before Caribou’s strategic alternatives announcement—Genmab and AbbVie reported positive topline data from the Phase III EPCORE DLBCL-2 trial (NCT05578976) showing that the combination of epcoritamab, rituximab, the corticosteroid prednisone, and three chemotherapy drugs showed statistically significant and clinically meaningful improvement in progression-free survival (PFS) in frontline diagnosed DLBCL patients.
The combination therapy, nicknamed R-CHOP, consists of rituximab—the CD20-directed cytolytic antibody marketed by Genentech, a member of the Roche Group (SIX Swiss: RO and ROP) and Biogen (Nasdaq: BIIB) as Rituxan®—plus cyclophosphamide, doxorubicin hydrochloride, vincristine, and prednisone. In DLBCL patients with an International Prognostic Index (IPI) score of 2 to 5, R-CHOP reduced the risk of disease progression or death by 51% (HR 0.49 [95% CI 0.36, 0.67]; p-value < 0.0001).
“Interesting” timing
“The timing of [Caribou’s] initiative is interesting,” Graybosch observed. “We believe there is enhanced strategic value and clinical rationale for allogeneic cell therapies in a world where TCEs [T-cell engagers] become entrenched in the 1L [first-line] setting.”
As for CB-011, it began development much earlier than vispa-cel, “with an appreciably more challenging competitive setup in RRMM, where we saw elevated clinical risk for its post-BCMA therapy development path due to potential efficacy-compromising loss-of-antigen,” the Leerink Partners analyst added.
Single target allogeneic BCMA CAR-T treatments have posed a potential risk of RRMM relapse through antigen loss as myeloma cells mutate or downregulate BCMA to evade the CAR T cells. To minimize that risk, Caribou designed its Phase I CaMMouflage trial (NCT05722418) to limit the therapy dosing to BCMA-naïve patients—an approach that proved successful when the company last year announced positive data from a 12-patient, BCMA-naïve cohort showing a 92% overall response rate (11/12 patients), a 75% or greater complete response rate (9/12), and 91% minimal residual disease (MRD) negativity (10/11 evaluable patients).
To avoid the risk of antigen loss, several developers of allogeneic BCMA CAR-Ts have designed dual targeting CAR Ts. For example, Allogene Therapeutics (Nasdaq: ALLO) is developing ALLO-329, which targets CD19 on B cells and CD70 on activated T cells. ALLO-329 generated positive preclinical data in April, with a data update from the Phase I RESOLUTION trial (NCT07085104) expected later in Q4.
Another challenge to CB-011 and other allogenic therapies for RRMM: The multiple myeloma space has been reshaped by autologous BCMA CAR-T therapies that have won approval by demonstrating safety and effectiveness—including Carvykti® (ciltacabtagene autoleucel), co-marketed by Legend Biotech (Nasdaq: LEGN) and Johnson & Johnson (NYSE: JNJ); and Abecma® (idecabtagene vicleucel), marketed by Bristol Myers Squibb (NYSE: BMY).
Souring on the stock
Graybosch downgraded Caribou’s rating from “Outperform” to “Market Perform” and chopped the firm’s 12-month price target 75%, from $4 to $1. Graybosch was among several Wall Street analysts who responded to Caribou’s news by souring on the company’s stock, downgrading their ratings:
Brookline Capital Markets (Leah Ruch Cann)—From “Buy” to “Hold,” no price target.
H.C. Wainwright (Robert Burns)—From “Buy” to “Neutral,” no price target.
RBC Capital Markets (Luca Issi, PhD)—From “Outperform” to “Sector Perform,” price target slashed 90% from $10 to $1.
Caribou reported $113.8 million in cash, cash equivalents, and marketable securities as of the end of the second quarter on June 30—a 4% dip from the $118.6 million reported at the end of Q1, but a 20% drop from the $142.8 million Caribou had as of December 31, 2025, and a 38% slide from the $183.9 million reported June 30, 2025.
“We expect that our existing cash, cash equivalents, and marketable securities will be sufficient to fund our operations for at least the next 12 months from the date this Form 10-Q is filed with the SEC [U.S. Securities and Exchange Commission],” Caribou stated in its most recent Form 10-Q quarterly report detailing second-quarter results, filed August 13.
Leaders and laggards
Arrivent BioPharma (Nasdaq: AVBP) shares plummeted 47% October 6 from $28.46 to $15.09 after the cancer drug developer announced that its lead pipeline candidate firmonertinib failed the Phase III FURVENT trial (NCT05607550) designed to assess the oral, mutation-selective epidermal growth factor receptor (EGFR) inhibitor in previously untreated, locally advanced or metastatic non-squamous non-small cell lung cancer (NSCLC) harboring EGFR exon 20 insertion mutations. Firmonertinib did not meet its primary endpoint of meaningful progression free survival (PFS) compared to chemotherapy as evaluated by blinded independent central review (BICR). Arrivent said that clinical benefit was seen in secondary endpoints such as PFS by investigator’s assessment and confirmed objective response rate by BICR. A trend toward improved overall survival was also seen, the company added.
Pacira BioSciences (Nasdaq: PCRX) shares soared 44%Thursday from $25.20 to $36.39 after Viatris (Nasdaq: VTRS) agreed to acquire the non-opioid pain drug developer for $1.65 billion. The deal adds to Pacira’s portfolio with two marketed drugs—the postsurgical pain relief therapy Exparel® (bupivacaine liposome injectable suspension), and the osteoarthritis knee pain treatment Zilretta® (triamcinolone acetonide extended-release injectable suspension). Viatris said it plans to apply its intellectual property expertise and ability to extend product lifecycles and sustain meaningful sales post-competition “to maximize the long-term value of the Pacira portfolio” and expects to expand its reach across select markets. Pacira generated approximately $746 million in revenue and approximately $177 million in adjusted earnings before interest, taxes, depreciation, and amortization (EBITDA) during the 12 months ending June 30. Viatris plans to commence a tender offer for all outstanding Pacira common stock shares for $36.50 per share cash. The deal is set to close by year’s end.
A health worker from the Mfou District Hospital collects a blood sample for the study. [Sandrine Nsango, PhD]
Malaria is one of the deadliest infectious diseases on the planet, afflicting people for the entirety of recorded history. In places where malaria is most common, it’s shaped human evolution by driving higher rates of a protective genetic change. Two copies of the genetic change cause sickle cell disease, but one copy helps protect people from malaria. More specifically, sickle cell hemoglobin (HbS) confers protection against symptomatic malaria caused by Plasmodium falciparum.
Now, a new study has found that people with the sickle cell variant are almost exclusively infected by a distinct variety of malaria parasites, which might contribute to their lower rates of disease.
“Sickle cell trait may protect against malaria, not only by changing how the human host responds to infection, but also by shaping which parasites are able to survive and establish infection,” says Sandrine Nsango, PhD, associate professor of molecular biology at the University of Douala and researcher at the Centre Pasteur du Cameroun, Head of the Department of Biomedical Sciences, Faculty of Science, University of Bertoua.
Previous work had discovered the unusual strain of malaria by investigating the rare cases where people with the sickle cell variant develop disease symptoms. The new research extends these findings to asymptomatic infections, in which people are infected by the parasite but don’t get sick. While less visible than the disease itself, asymptomatic infections were extremely common, affecting three-quarters of the healthy study population.
HbS carriers with symptomatic malaria harbor parasites enriched for P. falciparum sickle-associated alleles (Pfsa+). While these may partially overcome HbS-mediated protection, their role in asymptomatic infections is unclear. Researchers analyzed the genetics of over 2,246 healthy schoolchildren in a region of high malaria transmission in Mfou, Cameroon, as well as the malaria parasites infecting them. The team found that people with and without the sickle cell variant tend to be infected by genetically different varieties of malaria parasites.
In addition, specific varieties of the parasite infect people with and without the sickle cell variant at similar overall rates. They write, “analyzing the parasite Pfsa and the human HbS genotypes for 1,701 asymptomatic P. falciparum infections confirmed that heterozygous HbS (HbAS) and homozygous non-HbS (HbAA) genotypes have similar rates of asymptomatic infection.” However, despite being infected at similar rates, people carrying the sickle cell variant are much less likely to develop symptomatic malaria.
The researchers found that which parasites are present in an asymptomatic infection differs based on if the infected person has the sickle cell variant. They write, “the HbS genotype is strongly associated with parasites carrying the Pfsa+ alleles at the Pfsa1 and Pfsa3 loci, indicating a selective advantage for these alleles in HbS carriers.” These findings suggest that the sickle cell variant influences which parasites can infect a person, whether or not they develop disease symptoms.
People with the sickle cell variant are just as likely to become infected—albeit with a different variety of the parasite—but they’re a tenth as likely to develop harmful disease. These observations suggest that the biological characteristics of this parasite variety may contribute, at least in part, to the protection against disease conferred by the sickle cell trait.
To understand why people with sickle cell don’t get disease as often—and use that knowledge to develop better therapies—researchers should not only look at the biology of the sickle cell variant but also investigate the differences in the malaria parasite.
Nsango says that their findings emphasize that malaria is an example of a continued evolutionary interaction between humans and the parasite. “The sickle cell mutation is one of the clearest examples of how infectious diseases can shape human evolution, but our findings suggest that humans also shape the evolution of the parasite in return,” Nsango says. “Understanding these interactions may help us anticipate how malaria parasites adapt in the future and design more effective strategies for malaria control.”
Studies of the immune system show that two people born on the same day can have immune systems that age differently, leaving some older adults with resilient defense systems and others with dysfunctional ones that put them at increased risk for age-related diseases. Now a new study led by scientists at Washington University School of Medicine in St Louis, Nationwide Children’s Hospital in Ohio, and King’s College London provides a map of human immune aging that could help explain these different trajectories. Details are published in a new Immunity paper titled “Single-cell analyses of global cohorts outline determinants of immune aging and link the ratio of GZMK⁺ to GZMB⁺ Tem cells to health trajectories.”
According to the paper, a ratio between two immune cell types can reveal whether someone stays healthy or may face risk of future disease. To get to this insight, the scientists first analyzed approximately 12.4 million individual immune cells from the blood of over 2,600 mainly healthy adults ages 20 to 90-plus across eight cohorts in North America, the United Kingdom, Asia, and Australia.
Their analysis showed that while the blood of younger people was uniformly enriched with naive immune cells that had not been exposed to specific pathogens and remained adaptable to new infections or vaccines, older immune systems were more diverse. Specifically, some older participants had a greater abundance of immune cells that reflect inflammation.
To map this shift, the researchers placed each participant on a spectrum based on the ratio between two types of white blood cells: specifically, granzyme B-producing cells and granzyme K-producing cells. Some white blood cells, known as effector memory CD8 T cells, use granzymes to destroy target cells or coordinate immune responses. While granzyme B-producing cells serve as direct destroyers of diseased cells, granzyme K-producing cells have been less studied and may play a role in boosting immune responses.
Next, the researchers evaluated whether participants’ positions on the spectrum, which corresponds to a specific type of CD8 T cell, could dictate their risk of getting sick. In other words, they looked at whether having more of one type of CD8 T cell has an impact on the person’s health as they age. To answer that question, the scientists turned to the UK Biobank.
While that dataset includes protein information from the participants, it lacks counts of CD8 T cells. To get around this hurdle, the scientists used a smaller dataset of seemingly healthy adults that included data on CD8 T cell counts and blood proteins to create a computer model to map out the protein tracks left behind when either granzyme B-producing or granzyme K-producing cells dominated. They then applied this model to the baseline blood protein samples of 50,000 participants from the UK Biobank, calculating their position on the immune cell spectrum.
Using this approach, the scientists were able to draw out some useful insights for their work. Specifically, they found that healthy adults whose immune system leaned heavily toward granzyme B cells at baseline tipped the scale toward a higher risk of death a decade later compared to those with more granzyme K cells. The granzyme B-dominant group also was more likely to develop chronic conditions, including Type 2 diabetes, hypertension, liver disease, and renal failure, among others, over the following decade.
“A higher level of granzyme B cells in a healthy state means the immune system might be already reacting to something,” said Marina Terekhova, MD, a professor in pathology & immunology at WashU Medicine and one of the co-authors on the paper. “It isn’t a formal disease diagnosis, but it may indicate the body is off track.”
A healthy immune system gradually shifts toward granzyme K cells over time, while an immune system that leans toward granzyme B cells signals unhealthy aging. Because individuals can reach this granzyme B state much earlier in life, their immune systems age on different trajectories, explaining why two people born in the exact same year can face different risks for chronic disease and death decades later.
These findings point to “clues in the blood that can tell us whether someone is on a healthy or unhealthy aging trajectory,” said Maxim Artyomov, PhD, the alumni endowed professor of pathology and immunology at WashU Medicine and one of the corresponding authors on the paper. Artyomov and his lab are now adapting their research into a simple blood test that can be processed using standard equipment. “Identifying specific biological red flags in the immune system could pave the way for early-warning tests that spot disease risks years before a clinical diagnosis.”
Molecular movie of penicillin biosynthesis. X-ray free electron laser experiments on isopenicillin N synthase microcrystals capture structural snapshots of key intermediates during the penicillin forming reaction. The film strip illustrates progression through the catalytic cycle, with the monocyclic β-lactam intermediate and reactive high valent ferryl iron species highlighted at the center of the molecular movie. [University of Oxford/Greg Stewart/SLAC National Accelerator Laboratory]
Researchers from the University of Oxford and international collaborators have revealed previously unseen rapid chemical stages in the formation of β-lactam antibiotics such as penicillin, offering insights that could help to support future antibiotic development.
Rather than relying on static X-ray crystallographic structures of the enzyme, the Oxford University team, collaborating with partners from Diamond Light Source, Lawrence Berkeley National Laboratory, PAL-XFEL, and SLAC National Accelerator Laboratory, followed the reaction in real time. To do this they used X-ray free-electron lasers (XFEL) to observe the enzyme isopenicillin N synthase, (IPNS) as it converts its linear peptide substrate into the β-lactam ring system of penicillin.
The study brought together expertise in structural biology, spectroscopy, chemistry, computation and enzyme engineering. The approach, they say, provides a powerful way to study fleeting chemical intermediates that have previously been inaccessible, both in antibiotic biosynthesis and in other biologically important enzyme reactions.
The team captured several rapid stages in the reaction. These included a thioaldehyde intermediate formed just before the β-lactam ring is created, and a monocyclic β-lactam intermediate, representing the first ring-shaped structure on the way to forming the complete penicillin scaffold. These steps provide the clearest picture yet of how the IPNS enzyme assembles the penicillin scaffold. Subtle movements throughout the enzyme help guide these chemical steps, showing that both the enzyme’s shape and its chemistry work together to control penicillin formation.
The results show, in unprecedented detail, how the enzyme IPNS achieves an exceptionally complex transformation in a single step. Christopher Schofield, PhD, Professor of Chemistry, University of Oxford, said, “Penicillin has shaped modern medicine, but there is still much to learn about how nature builds this important antibiotic structure. By capturing these fleeting steps, we can better understand how enzymes control complex chemistry with remarkable precision … As rates of antimicrobial resistance continue to rise, understanding this process will ultimately help us make existing antibiotics more efficient and design new antibiotic structures.”
Allen M Orville, PhD, group leader of the XFEL Hub, further commented, “The XFEL Hub at Diamond brought specialist expertise in time-resolved X-ray methods and XFEL-based structural biology to this study. Working closely with our colleagues in Oxford and at partner facilities, we helped bring together the experimental approaches needed to capture these fleeting stages of enzyme catalysis. The results show the power of combining complementary expertise and X-ray techniques to move beyond static structures and reveal how enzymes work in real time. It is a great example of how time-resolved structural biology can uncover new principles of enzyme function and, ultimately, inform the design of new catalysts and therapeutics.”
Ever since penicillin was developed into a working drug at the University of Oxford in the early 1940s, β-lactam antibiotics have been among the most important medicines for treating bacterial infections. Their activity depends on a special ring—the β-lactam ring—a highly strained chemical ring system that interferes with bacterial cell wall synthesis, ultimately causing the cell wall to fail and the bacteria to die. “Isopenicillin N synthase (IPNS) catalyses the biosynthesis of isopenicillin N (IPN), forming the fused four-membered β-lactam and five-membered thiazolidine ring system that is characteristic of the penicillins,” the authors explained.
Rising rates of antimicrobial resistance are undermining the effectiveness of existing antibiotics. Today, one in six bacterial infections is resistant to antibiotics, the authors noted, citing WHO figures. With too few new antibiotics in development, understanding how nature builds these molecules is an important step towards replenishing the antibiotic pipeline.
Scientists have been studying how nature constructs this β-lactam ring for decades, but the key fleeting reaction intermediates have been too difficult to observe directly.
To capture the reaction in real time, the researchers used a system in which thousands of tiny droplets containing anaerobic enzyme microcrystals were deposited onto a moving 2 mm wide tape. As the tape entered an oxygen filled chamber, oxygen rapidly diffused into the crystals and initiated the reaction simultaneously across the sample. By precisely controlling the speed of the tape, the researchers could determine how long each crystal reacted before reaching the X-ray interaction point, where an ultrafast XFEL pulse recorded an atomic resolution snapshot.
Combining thousands of these snapshots allowed the team to build a frame-by-frame “molecular movie” of penicillin biosynthesis. This method allows individual reaction intermediates that exist only for tiny fractions of a second to be observed at atomic resolution, and under physiological temperature and pressure, before they disappear.
The newly reported findings help to resolve a long-standing mechanistic question that has remained unanswered for more than four decades. The work also showed that water molecules inside the enzyme play a key role in guiding the reaction. The combined results of their studies, they noted, “… reveal unexpected insight into the IPNS reaction mechanism including the vital roles of active-site water molecules.”
The study ultimately builds on the work of Nobel prize-winning Oxford chemist Dorothy Hodgkin, PhD, who first solved the structure of penicillin in 1945 using X-ray crystallography.
Beyond penicillin, IPNS belongs to a large family of iron-dependent oxygenase enzymes involved in human biology, including those that enable us to sense and respond to changes in oxygen availability. The mechanistic insights from this work could therefore have implications beyond antibiotics, offering new principles for enzyme engineering and catalyst design.
“These findings provide structural insight into IPNS catalysis, inform on the wider Fe(II) oxygenase superfamily and highlight the power of X-ray free-electron laser methods for resolving transient enzymatic intermediates,” the team stated in their paper. First author Patrick Rabe, PhD, Wellcome Career Development Award Investigator, University of Oxford, said, “These insights matter because they can inform how we think about antibiotic biosynthesis and future strategies for developing antibacterial medicines. The ability to capture structural snapshots over milliseconds to seconds of reaction time allows us to connect enzyme motion, iron chemistry and water-mediated proton transfer. This gives us a much richer view of how IPNS controls a difficult chemical transformation. By understanding this process in atomic detail, we can begin to think about engineering these enzymes to produce new or improved antibiotic scaffolds.”
Multiomics analysis combines data from two or more omics layers—such as genomics, transcriptomics, proteomics, and epigenomics. However, published criticisms of multiomics approaches have highlighted concerns about data integration and a tendency toward false-positive findings.1–3
What additional roadblocks might accompany ambitious multiomics projects in 2026? Could any bottlenecks emerge in cost, sample preparation, data integration, or AI implementation? We recently interviewed experts from five companies to gain their perspectives. Here is what they had to say.
Sample preparation
“I sound like a broken record because I can’t stop talking about the importance of sample prep in multiomics work,” says Michael Easterling, PhD, vice president of MALDI/Imaging at Bruker Daltonics.
Easterling stresses challenges such as section-to-section variability, internal standards, FFPE samples, and long sample runs that complicate downstream algorithms. “For multiomics imaging, these issues are not as well defined as some of the bulk methods that have been around much longer,” he notes.
Scott Jelinsky, PhD, senior director of R&D at Thermo Fisher Scientific, agrees. “Different molecular classes have different requirements for sample collection, storage, and preparation,” he says. “Therefore, careful experimental design and standardization are essential.”
Easterling mentions the consequences of inadequate freezing during biopsies, which can disrupt cell structures and lead to ice crystal artifacts. “It is important to really make sure that you have a solid workflow to correctly harvest tissue and provide a good chain of custody from the point that it’s harvested all the way to the analyzer.”
What are some tips for multiomics researchers hoping to prepare their samples in an optimal way? “Community networking is key here,” argues Easterling. “I would say get involved with the overall spatial imaging community and network and find out exactly how to do these things.”
Another practical consideration, according to Jelinsky, is planning the workflow from the beginning so that sample collection, aliquoting, storage, and analytical requirements are compatible across different assays. “Decisions made early in the study can have a significant impact on what can be measured and how confidently the different datasets can be interpreted together,” he notes.
Data integration and analysis
Multiomics technologies generate vast amounts of high-resolution data across modalities that often behave differently from a statistical perspective, notes Najiba Mammadova, PhD, associate director of product management at 10x Genomics. “Multiomics assays have advanced incredibly quickly, and now the analysis and interpretation tools need to keep pace,” she notes.
Mammadova specifically highlights the challenges of computationally aligning multiple omics from different cells or tissues. After all, how can researchers be certain that they are measuring the same cells and biological features?
The 10x Genomics MultiPro Human Discovery Panel, which integrates into existing Flex scRNA-seq workflows, is the largest antibody-based, single-cell protein panel, enabling integrated analysis of 326 protein targets. [10x Genomics]
“That’s why I think measuring multiple modalities from the same cell or tissue is so important,” she adds. “It reduces the need to reconstruct the biology after the fact and gives researchers a more direct view of what’s happening in the sample.”
Vanee Pho-Conners, PhD, vice president of global marketing at Mission Bio, agrees that data integration is often a major hurdle with multiomics work. “Each omics layer has its own data structure, distributions, and variabilities, so combining them isn’t plug-and-play,” she explains. Multiomics analysis also often requires cross-disciplinary expertise in biostatistics, machine learning, and biology—capabilities many labs lack in-house.
“It’s important to ask how you can combine these data sets in a clean way where you preserve all the information, reduce the noise, and start to make biological inferences,” adds Easterling. “It’s not something that’s routine today, but the situation is changing rapidly, and new ways to integrate these datasets of varying dimensionality are starting to appear.”
Timing is yet another important consideration, notes Jelinsky. Proteins, RNA, and metabolites may exhibit different kinetics and respond on different timescales, so measurements collected at the same time may not always align. “Understanding those temporal relationships is essential when integrating and interpreting the results,” he says.
Thermo Fisher’s multiomics solutions include services as well as products for sample preparation, separation, acquisition, and analysis. [Thermo Fisher]
AI and multiomics
“I think the rate-limiting multiomics questions are shifting from ‘Can we measure this?’ to ‘Can we interpret it?’ And that’s where AI has enormous potential,” notes Mammadova. “We’re generating increasingly rich, high-dimensional datasets, and AI can help researchers identify patterns, interpret those data more quickly, and ultimately build models that can predict things like disease progression or treatment response.”
However, Easterling warns that even the most advanced AI technologies often cannot overcome challenges associated with inadequate sample preparation. “Unfortunately, if a model’s trained on an inconsistently prepared section, it’ll give you a confident biological story that’s completely wrong. And the reader of this data may have no way to tell.”
The DNA, RNA, and protein workflow on Tapestri’s single-cell platform. Each cell is encapsulated in its own droplet, and a unique molecular barcode (specific to each cell) gets attached to each DNA, RNA, and protein molecule. [Mission Bio]
As an example of recent AI advances, Easterling highlights multiomic workflows pioneered at the Medical University of South Carolina for single-cell analysis. The group has developed an AI algorithm that assists lasers in targeting individual cells rather than clusters of cells.4 Pho-Conners also emphasizes how Mission Bio is using machine learning to jointly cluster DNA, RNA, and protein—referred to as triomics—from the same cell. “We are using a combination of triomics and AI-driven integration to establish disease resistance. This really goes beyond correlations using a single omics layer,” she says.
Although Jelinsky is generally optimistic about AI advances in multiomics, he foresees fundamental limitations. “I see AI as a tool that can help researchers navigate complexity and generate better hypotheses rather than as a replacement for scientific judgment. AI does not remove the need for rigorous experimental design or biological validation,” he stresses.
Challenges with extracellular vesicles
Distinct multiomics challenges also exist in analyzing extracellular vesicles (EVs), small membrane spheres released by cells that contain multiple omics (DNA, RNA, protein, metabolites, and lipids).
“EVs are how cells talk to each other, and a living cell sends up to ten thousand a day. This makes them good biomarkers,” says Pierre Arsène, founder and CEO of Mursla Bio.
However, with traditional EV analysis, each potential omics layer is measured from EVs derived from an unknown blend of cells. There is usually no way to know whether a protein signal and an RNA signal came from the same tissue, for instance.
Mursla’s biomarker discovery workflow for tissue-specific extracellular vesicles. Antibody-coated magnetic beads capture hepatocyte-derived vesicles from under two milliliters of plasma, leaving behind extracellular vesicles from other tissues. [Mursla Bio]
“Tissue-specific extracellular vesicles (TS-EVs) are how we recover that record,” explains Arsène. Mursla’s technology begins with a blood draw. Liver-specific EVs are then captured using antibodies against proprietary surface markers (more specifically, hepatocyte-EV markers). Finally, proteomics and RNA sequencing are performed on two milliliters of plasma for biomarker discovery.
“The great thing about TS-EVs is that they arrive addressed, carrying surface proteins specific to the sending cell and sealed behind a membrane that shields proteins and RNA from the enzymes that would destroy them in blood.”
EvoLiver, Mursla’s blood test for liver cancer surveillance in cirrhotic patients, holds an FDA Breakthrough Device Designation. It analyzes three proteins and five microRNAs derived from hepatocytes. Proteins provide information about tumor surface phenotype and metabolic reprogramming, while microRNAs reveal the regulatory programs driving that phenotype.
As with so many other multiomics platforms, Arsène stresses the importance of TS-EV sample preparation. “Blood handling standards for EVs lag well behind standard liquid biopsy, so our clinical work relied mostly on prospective collection under a common protocol rather than using legacy biobanks.”
The future of multiomics
Mammadova highlights the potential for cost-related challenges in multiomics, particularly as the field moves toward larger studies. “Making these technologies more scalable and cost-effective will be critical to expanding their use across research,” she adds.
“However, I see more overall challenges than roadblocks in multiomics work,” she concludes. “They’re the kind of problems the field works through as technologies mature.”
Detection of the whole transcriptome along with over 64 proteins in a human breast cancer FFPE tissue section using Bruker’s CosMx spatial molecular imager. [Bruker Spatial Biology]
Spatial multiomic layers will also become increasingly critical for decoding the complexity of disease biology, predicts Prajan Divakar, PhD, Bruker Spatial Biology vice president of product management. “Investigators continue to demonstrate the need for more complete spatial datasets, and we are seeing clear applications and momentum for clinical translation,” he says. Divakar highlights Bruker’s CosMx® spatial molecular imager, which measures the whole transcriptome and over 64 proteins.
Finally, Arsène argues that simply adding more layers of analysis without biological resolution is unlikely to advance multiomics research in the future. For instance, in the largest study of a blood-based cancer test ever run (involving around 50,000 participants), incorporating an additional protein layer in advanced adenoma increased the sensitivity only modestly—from about 15% to 16%.5 “More and more layers allow you to gain dimensions, but you end up losing coherence. And no cohort in the world is large enough to train that coherence back computationally.”
Jelinsky agrees that the value of multiomics will lie not in generating more data, but in selecting complementary measurements that address a specific biological question. “I think the future of multiomics will be less about generating the largest possible number of measurements and more about determining which combination of measurements provides the most meaningful biological insight,” he says.
References
Behrens LMP, Fernandes GDS, Gonçalves GF, et al. Limitations and opportunities in multi-omics integration for neurodevelopmental, neurodegenerative and psychiatric disorders: A systematic review. Neuroscience. 2026;599:76-93. doi: 10.1016/j.neuroscience.2026.01.019.
Hayes CN, Nakahara H, Ono A, Tsuge M, Oka S. Genes (Basel). From Omics to Multi-Omics: A Review of Advantages and Tradeoffs. 2024;15(12):1551. doi: 10.3390/genes15121551.
Baião AR, Cai Z, Poulos RC, et al. A technical review of multi-omics data integration methods: from classical statistical to deep generative approaches. Brief Bioinform. 2025;26(4):bbaf355. doi: 10.1093/bib/bbaf355.
Dressman JW, Bayram MF, Angel PM, Drake RR, Mehta AS. Single-Cell Multiomic MALDI-MSI Analysis of Lipids and N-Glycans through Affinity Array Capture. Anal Chem. 2025;97(24):12493-12502. doi: 10.1021/acs.analchem.4c06233.
Shaukat A, Burke CA, Chan AT, et al. Clinical Validation of a Circulating Tumor DNA-Based Blood Test to Screen for Colorectal Cancer. JAMA. 2025;334(1):56-63. doi: 10.1001/jama.2025.7515.
The technology underpinning RNA vaccines1 and therapeutics2 has been around for decades. However, until recently, only a handful of products were on the market.
Everything changed in 2020 when mRNA vaccines proved3 to be effective against SARS-CoV-2, the virus that causes COVID-19. In the years since, many more RNA products entered the clinic as developers recognized both their therapeutic and commercial potential.
The pandemic also kick-started efforts to optimize RNA manufacturing that will likely shape the sector for decades to come, according to David Sokolowski, global workflow manager for nucleic acid therapeutics at Cytiva.
“The COVID vaccines heralded the rapid industrialization of RNA and LNP [lipid nanoparticle] technologies, and due to the nature of a pandemic, large amounts of vaccine safety data were generated. However, it remains a nascent industry with limited applications commercially available, and this space is where developers are rushing to build.
“Manufacturing good quality RNA and LNP became easier with the proliferation of high-quality reports from successful studies, trials, and campaigns occurring all over the world.
“Now, we’re supporting the development of therapeutics with even grander aspirations and increasingly exotic biology—whether they are encoding and producing mAb via RNA, or enabling next-generation in vivo cell therapy, LNP-mediated therapeutics have no shortage of potential advances ahead,” he continued.
Manufacturability
The key to developing any RNA-based product—be it a vaccine or a therapeutic—is to ensure it can be produced in bulk in a cost-effective and efficient manner, says Luis Avila, PhD, a scientist at services firm Novoprotein Scientific.
“RNA design fundamentally determines both manufacturability and biological performance, but optimizing for one often comes at the expense of the other.” The best approach is to design for manufacturability from the start,” he says, adding “the right template architecture can contribute with optimized promoter design, transcription initiation sequences, encoded polyA tails, transcript boundaries, and sequence composition to improve IVT [in vitro transcription] performance while minimizing problematic secondary structures.”
“Combined with other factors, such as engineered RNA polymerases, optimized reaction chemistries and advanced capping technologies, these design strategies will improve RNA yield, integrity, and translational performance all while reducing the generation of dsRNA,” he tells GEN.
The type of RNA being made should be the key consideration in any assessment of manufacturability, according to Avila, who cites the differences between messenger RNA and self-amplifying RNA to illustrate the point.
“For mRNA, coding-sequence composition, transcript length, GC content, and secondary structure strongly influence IVT efficiency. Whereas optimized UTRs [untranslated regions], cap structures, and poly(A) tails primarily govern RNA stability and translational efficiency.
“For saRNA, the incorporation of the large alphavirus replicase cassette substantially increases transcript length and structural complexity, thus making IVT more challenging while enabling intracellular RNA amplification that dramatically lowers the therapeutic dose required,” he says.
Producing circular RNA—a covalently closed-loop structure that is stable and resistant to exonuclease degradation—can be even harder, according to Avila.
“circRNA presents an even greater manufacturing challenge because linear IVT is followed by an additional circularization step whose efficiency remains a major bottleneck. Following circularization, translation relies on efficient cap-independent initiation through optimized IRES [internal ribosome entry site] elements and RNA architecture.”
Characterization
So, designing an RNA therapeutic or vaccine with manufacturing in mind is critical. However, the ability to realize that optimized blueprint on the factory floor is entirely dependent on being able to characterize the product in real-time, as it is being made.
And, unfortunately for the industry, RNA characterization is a complex challenge, says Matthew Ranaghan, PhD, applications scientist at analysis technology firm Refeyn.
Analyzing multiple RNA molecules in a single pass reduces the experimentation burden on RNA developers. Being able to visualize characteristics within minutes—as shown here—would benefit any developer, says Refeyn. [Refeyn]
“Thorough Characterization of RNA is critical to ensuring the safety, stability, and efficacy of next-generation RNA therapeutics, yet it remains a significant analytical bottleneck.”
“Current methods are limited to various types of chromatography, which struggle with poor resolution for large RNAs, or mass spectrometry, which requires digesting samples into smaller oligos with RNases. While both have advantages, they demand extensive and time-consuming method development.”
Traditional RNA analysis usually consists of separate assays looking at specific characteristics. For example, size exclusion chromatography is used to assess aggregation while enzyme-linked immunosorbent assays are used to check for trace amounts of double-stranded RNA.
One promising alternative is mass photometry (MP), a technique that can analyze RNA molecules within minutes based on only nanograms of material within minutes in a single experiment. There are multiple potential advantages according to Ranaghan.
“A single readout replaces the need for multiple instruments, drastically reducing hands-on time, reagent costs, and the need for extensive method development across different platforms. A single readout also enables at-line process monitoring, allowing for immediate go/no-go decisions during bioprocessing and purification.”
“We envision the faster speed and higher resolution of MP to enable its use as a multi-attribute tool for at-line assessment of the various critical quality attributes (CQAs) of RNA therapeutics,” he says.
“We have already demonstrated how MP can rapidly assess integrity, fragments, multimer, and purity in a single measurement. We are also actively building out more applications,” Ranaghan adds.
Commercial concerns
Manufacturers of RNA products also need to develop commercialization plans as early as possible—in parallel with process development—to ensure they reach the patients who need them and garner the revenues needed to fund future research.
Rajiv Gangurde, PhD Vice President Parexel International
And, for some firms, developing such plans can be a steep learning curve, says Rajiv Gangurde, PhD, vice president of chemistry, manufacturing, and controls (CMC) for cell and gene therapies at contract research organization Parexel International.
“Like many newer modalities, RNA-based therapies typically emerge out of academia or start-up biotech, and transitioning from academia to industry can be challenging due to differences in objectives, differences in expertise, fundraising, etc.”
“In addition, newer modalities require heavier than usual investment in CMC activities to establish proof-of-concept as well as manufacturability. There is heavy reliance on external partners, creating capability and capacity constraints.
“Most importantly,” Gangurde continued, “a phase-appropriate CMC strategy aimed at global approvals can significantly derisk development and help minimize costs and timelines.”
Yet preparing a CMC strategy that will win approval in multiple markets is no small undertaking, particularly, as Gangurde points out, because regulatory guidelines for RNA-based therapies are still evolving.
Another challenge is the lack of consistency. For instance, the U.S. Food and Drug Administration (FDA) and EU EMA use different definitions and guidelines for CMC.
Gangurde told us, “Harmonization of guidelines and expectations across the two agencies will be hugely beneficial to developers of RNA therapies. For example, while both agencies recognize potency/efficacy assessment as a critical quality attribute (CQA), there are some differences in method validation requirements, timing, and regulatory expectations across clinical phases.”
“While the FDA accepts real-world experience and surrogate endpoints, particularly for rare or life-threatening diseases, EMA requires more comprehensive clinical data and demonstration of long-term efficacy for approval. The EMA also mandates an appropriate degree of method validation at each stage of development, whereas the FDA does not expect validation of the potency assays during Phase I,” he added.
The product component designations used by regulatory agencies can also differ. For example, the lipid nanoparticle for the COVID-19 vaccine, Spikevax, consists of four lipids: SM-102, PEG2000-DMG, DSPC, and cholesterol.
The FDA designates each of these components as a “drug substance,” whereas the EMA designates them as “novel excipients”—each designation has differing data submission requirements.
Continuous process
In the future, RNA manufacturing methods are likely to keep improving, according to Novoprotein’s Avila, who says continuous production processes are likely to have a major impact.
“One of the most exciting developments is the emergence of continuous or flow-based IVT manufacturing. This has the potential to improve productivity, reduce costs, and enable more consistent large-scale RNA production through continuous enzyme utilization and process integration.”
“As equally transformative are advances in engineered low-dsRNA T7 RNA polymerases, improved co-transcriptional capping chemistries, and integrated continuous purification. All of which will enable improvements in RNA quality, simplify downstream processing, and accelerate GMP manufacturing,” he added.
RNA characterization is a challenge using current technologies. Refeyn claims its mass photometry system—seen here at lab in Waltham, Massachusetts—reduces the number of assays required. [Refeyn]
This view is shared by Ranaghan from Refeyn, who cites the shift toward continuous flow manufacturing as one of the most exciting advances in the field.
“Moving away from traditional batch processing to a continuous flow model is highly logical because it minimizes the time that the fragile mRNA product spends exposed to active reaction components that drive fragmentation and aggregation. This shift not only improves overall yield and intactness, especially for massive transcripts like saRNA, but it also creates a mandate for faster, real-time analytics.”
For Parexel’s Gangurde, efforts to make production more efficient and sustainable will drive innovation, with the WHO’s recently launched mRNA Technology Transfer Programme Phase 2.04 being a case in point.
“This is a major global initiative aimed at scaling up commercially viable mRNA-based vaccine and therapeutic production in low- and middle-income countries—where the need for these therapies is most critical.”
Launched in 2021 in collaboration with the Medicines Patent Pool (MPP), the initiative has enabled 15 partners across Latin America, Africa, Eastern Europe, and Asia to receive foundational mRNA technology.
Phase 2.0 focuses on building local manufacturing capacity so countries can make mRNA vaccines and therapeutics for future outbreaks and diseases like influenza, TB, HIV, malaria, dengue, and leishmaniasis, as well as oncology drugs and mAbs.
Gangurde says, “By decentralizing production, the program reduces reliance on a few high-income countries for mRNA supply, supporting global access for mRNA-based therapies.”
Chatterjee S, Bhattacharya M, Lee SS, Chakraborty C. An insight of different classes of RNA-based therapeutic, nanodelivery and clinical status: Current landscape. Current Research in Biotechnology 2023;6:100150-100150. doi:10.1016/j.crbiot.2023.100150
Parvin N, Mandal TK, Joo SW. The Impact of COVID-19 on RNA Therapeutics: A Surge in Lipid Nanoparticles and Alternative Delivery Systems, Systems. Pharmaceutics 2024; 16(11): 1366. Doi: 10.3390/pharmaceutics16111366
Detection of the whole transcriptome along with over 64 proteins in a human breast cancer FFPE tissue section using Bruker’s CosMx spatial molecular imager. [Bruker Spatial Biology]
