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.
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.”
The team from the Science study was led by co-senior authors Jay Shendure, PhD, professor of genome sciences at the University of Washington School of Medicine and a Howard Hughes Medical Institute investigator, and Chengxiang Qiu, PhD, a molecular and systems biologist at Dartmouth College. Their approach centered on DNA Typewriter, a lineage-tracing technology developed by Shendure and Junhong Choi, PhD, that uses a cell’s DNA as a recording medium.
The researchers redesigned the system’s recording “tape” to make its history easier to recover from individual cells, then inserted it into the genome of a fertilized mouse egg. As cells divided, “a burst of editing unequivocally marks the daughters of the first cleavage, which serve as inline replicates,” the authors wrote in the Science paper. Because daughter cells inherited the marks already written before acquiring new ones, shared patterns revealed common ancestry and the order of developmental branching.
DNA Typewriter is injected into the genetic material of a fertilized mouse egg. This technology taps into the genetic material in the fertilized egg and resulting embryonic cells as a recording device of the cells’ histories. It tracks their relationships as the embryo develops. [Kyle O’Conner/Seattle Hub for Synthetic Biology]
“Most biological measurements are based on either live imaging, which is limited by the fact that most animal tissues are not transparent, or genomics, which are destructive and only measure a single timepoint,” Shendure said. “Recording techniques like the ones in these studies enable measurements over time including in settings that we can’t directly visualize.”
The experiment was attempted in 100 fertilized eggs and yielded 10 embryos for examination. One embryo carried the most informative record, allowing the team to trace nearly every profiled cell back to one of the first two cells formed after the fertilized egg divided. Although one founding cell produced more descendants, the two branches generated diverse cell types in nearly equal proportions.
The ordered recording also allowed the researchers to estimate when cell types diverged from shared developmental paths. Blood and retinal cells committed relatively early, whereas cells forming the skin’s outer layer committed later. The results indicate that cell identity is not fixed in a single coordinated step; instead, different lineages become restricted on distinct schedules.
Earlier lineage-tracing approaches often relied on DNA-cutting enzymes that could damage cells, erase previous records, exhaust recording capacity, or leave unordered marks whose chronology had to be inferred. “DNA Typewriter avoids all of this,” said co-first author Haedong Kim, PhD, a postdoctoral scientist in genome sciences at UW Medicine. “It writes without fully severing the DNA, keeps recording relatively steadily, and writes everything in strict order, so we can record cell lineages at much higher resolution for a longer time.”
In the Cell paper, Jonathan Weissman, PhD, and colleagues used a prime-editing system called PEtracer to map lineage dynamics across more than 1.4 million cells from 16 mouse embryos. Together with the DNA Typewriter study in Science, the work demonstrates that mammalian cellular family trees can be reconstructed at unprecedented scale. “It’s really proof of principle that we can do what was done with the roundworm in 1983, but for mammals like you and me,” Weissman said.
The work provides a framework for investigating how normal organs form and where development can go awry. More complete lineage records could help researchers study congenital malformations, neurodevelopmental and genetic disorders, and cancer, as well as guide stem cell engineering. As Shendure explained, “Recording techniques like the ones in these studies enable measurements over time including in settings that we can’t directly visualize.” Scaling the methods across additional embryos and experimental conditions could support more quantitative—and eventually predictive—models of mammalian development.
The Advanced Research Projects Agency for Health, (ARPA-H), an agency within the United States’ Department of Health and Human Services (HHS), recently announced awards and teams involved in its BioStabilization Systems (BoSS) program, an initiative that aims to develop new methods for producing, storing, and transporting cell-based biologic medicines at room temperature. ARPA-H has committed to provide up to $87 million across the four-year program. This round of funding will support Phase I of the program.
The teams have been tasked with pursuing new technologies that confer long-term, shelf-life stability to cell-based therapies and biologics making it possible to store and ship them without refrigeration. To accomplish this goal, BoSS teams will work across two technical areas. They will work on interventions to stabilize cells for storage and then reactivate them on demand as well as on creating novel processing systems that ensure these interventions are efficient and scalable for manufacturing.
This week, members of the Reversible Ambient Temperature (RAB) team said that they have been awarded up to $7.3 million initially from ARPA-H. The RAB team includes representatives from Draper, a non-profit research, development, and manufacturing company, which serves as the administrative lead,and Likarda, a biotechnology company that develops hydrogel technologies for delivering and preserving cell therapies and biologics, which serves as the technical lead for the team. Other members of the team include scientists from CaseBioscience, CPSI Biotech, Fresenius Kabi, MiNK Therapeutics, and University of Colorado.
For their part, this team will use AI-assisted design of experiments to optimize formulation, quiescence induction parameters, hydrogel composition, and recovery media as well as freeze-assisted droplet drying to achieve a stable product. Specifically, the RAB team’s biostabilization strategy, led by Likarda, will focus on simultaneous control of cell state, physical environment, and the cellular stress responses activated during freezing, dehydration, storage, and recovery. Meanwhile, the bioprocessing engineering team, led by Draper, will convert the manual steps of biostabilization into an automated, commercially viable workflow and will develop custom instruments to scale up the processes.
Likarda will contribute its proprietary Core-Shell Spherification hydrogel technology, which is designed to encapsulate and protect living cells while maintaining viability and function. CaseBioscience will provide expertise in clinical media formulation, biopreservation, and cellular metabolism to the development and evaluation of novel approaches for long-term ambient stabilization of therapeutic cells.
“The RAB team brings together deep expertise in cryoprotection, encapsulation, and cell state, with a focus on protecting cell viability throughout the stabilization and reanimation process, and the team has direct experience bringing products to market,” said Jason Fiering, distinguished technical staff at Draper. “Working in parallel, our interdisciplinary engineering team will develop the customized instruments needed to transfer these processes to clinical manufacturing environments.”
In his comments, John Baust, PhD, an expert in biopreservation and collaborator on the project with CPSI Biotech noted that “the concept of preserving living cells in a dry state has been pursued for more than two decades, but significant scientific and engineering barriers have yielded limited success.” The BoSS program is an opportunity “to tackle this from multiple scientific and engineering directions simultaneously” that if successful “could represent a paradigm shift in how biologics are preserved, stored, and distributed.”
Other teams announced by ARPA-H include one led by DesiCorp. This team includes members from the University of Louisville, University of Texas at Austin, Via Therapeutics, VeriSIM Life, and Ossium Health. They will leverage high-throughput screening to identify biocompatible formulations that slow cellular metabolism and AI-assisted process optimization to develop a thin-film freeze-drying (TFFD) system that stabilizes cells at room temperature.
DesiCorp will lead integration of the overall workflow by using a high-throughput screening platform to rapidly identify biocompatible formulations that enable cells to survive TFFD and resume function after rehydration. Meanwhile, UT Austin researchers will help optimize the TFFD critical process parameters and composition/material attributes, while also contributing expertise in aseptic processing and scaling up the technology.
A third team is led by the University of California, Davis and includes scientists from Mayo Clinic, Case Western Reserve University, University of Georgia, and Sersense. The team will induce a low metabolic state in cells using light-responsive gels and microfluidic processing techniques to produce cells that are stable at room temperature.
Recently, that team announced that it had been awarded up to $6 million, initially, from ARPA-H to fund its project dubbed CYBORGEL. Their efforts will leverage research done in the laboratory of Cheemeng Tan, PhD, a professor of biomedical engineering at UC Davis. Previously, he and his collaborators formed water-rich polymer networks inside living cells to create cell-material hybrids. This process, called intracellular gelation, forms a gel inside the cell and is capable of halting cell division while preserving cellular function. Tan and his team dubbed this cellular product a “cyborg” since the gelation process combines living cells with synthetic materials.
Through CYBORGEL, the collaborators will investigate whether this intracellular gelation process can be extended to reduce the cost and simplify the storage, transportation and delivery of cellular therapies. The researchers will also test whether CYBORGEL cells remain therapeutically useful after being returned to their original state. For instance, one study will test the effectiveness of reanimated CAR T cells for existing clinical trials on cancer immunotherapies. Another will test it on placental mesenchymal stem cells used to treat spina bifida, a medical intervention being developed by UC Davis researchers.
As part of the initiative, the American Type Culture Collection (ATCC) has been tapped to serve as the IV&V partner. ATCC will provide working cell banks of government-selected cell types that will be used for demonstrations. They will also provide unbiased assessments of both the viability and function of the preserved products and the design features of the preservation systems.
The first phase of the BoSS program kicked off in September and is expected to run for 15 months. Over the four-year multi-phase program, the teams’ approaches will be evaluated against increasingly stringent benchmarks for cell viability, production speed, and shelf-life stability. If successful, work under the BoSS program could enable lower costs for cell-based drugs, reduce the risk of therapeutic and pharmaceutical product losses, and enable domestic reserves for public health preparedness.
Sophie, a 12-year-old dog, isn’t sure what to make of the much larger Homer after Dog Aging Project co-lead and ASU Professor Noah Snyder-Mackler delivered his lecture to residents at Mirabella at ASU on Thursday, August 6, 2026. Sophie lives at Mirabella with her owner, Bonnie Kasel. Snyder-Mackler and his fellow researchers study various health markers in dogs as they age. [Charlie Leight/ASU News]
Domestic dogs offer a useful model for understanding the biology of aging because their lifespans vary dramatically with body size. Large dogs tend to be shorter lived than their smaller counterparts, but why? Headed by a team at Arizona State University, a study of nearly 900 dogs now suggests that the answer may be written into the animals’ epigenomes.
Research professor Noah Snyder-Mackler, PhD, at Arizona State University School of Life Sciences, and colleagues developed an epigenetic clock that predicted mortality in dogs and showed that epigenetic aging is fastest early in life. The study results indicated that male dogs and larger dogs undergo accelerated molecular aging, with male dogs exhibiting pronounced DNA methylation (DNAm) changes on the X chromosome, and larger animals exhibiting methylation changes at transposable elements (TEs), stretches of DNA that can influence genome stability and gene regulation.
Snyder-Mackler is senior and corresponding author of the researchers’ published paper in Science (“Epigenetic aging and transposon dysregulation reflect size-related lifespan compression in dogs,”) in which they concluded, “Our findings broadly establish companion dogs as a translational model for uncovering molecular mechanisms of lifespan variation, epigenomic instability, and age-related disease.”
Genome-wide DNA methylation in 894 dogs from the Dog Aging Project reveals accelerated aging in larger dogs and faster loss of repression of transposable elements. [Blaise Mariner & Brianah McCoy]
Aging is a universal process, but its pace and biological mechanisms substantially differ between individuals within even the same species, the authors wrote. “Whether shorter-lived individuals simply die earlier or instead experience accelerated biological aging throughout life remains unclear,” they noted. And while comparative studies across species have identified mechanisms associated with exceptional longevity, they may not be as well suited to identifying the molecular drivers of aging variation. “Domestic dogs provide a model for addressing this challenge because body size strongly predicts lifespan, with larger breeds living substantially shorter lives than smaller breeds despite sharing many physiological and environmental conditions,” the team continued.
In fact, smaller breeds can live nearly twice as long as larger breeds. And companion dogs live in human environments, consume commercial diets, and receive routine medical care, making them a relevant translational model for studying how genetic background and environmental exposures shape aging, the investigators pointed out.
Professor and School of Life Sciences Associate Director Noah Snyder-Mackler poses for portraits with his two dogs, 7-year-old Homer, bottom, and 4-year-old Juno, top, on the steps of Old Main on the ASU Tempe campus on Monday morning, September 28, 2026. Snyder-Mackler’s recent research focuses on dog epigenetics. [Deanna Dent/Arizona State University]
But how intrinsic factors such as size and biological sex influence variation in dog aging and lifespan remains unclear. “It is well established that size and sex influence lifespan in dogs, but it remains unclear whether shorter-lived dogs experience accelerated epigenetic aging,” they stated. Previous research has demonstrated that DNAm is a useful indicator of biological aging, with “epigenetic clocks” offering a way to understand the factors that accelerate or decelerate biological aging. “DNA methylation (DNAm) has emerged as a robust molecular biomarker of age, with ‘epigenetic clocks’ offering a quantitative framework for identifying factors that accelerate or decelerate biological age.”
For their newly reported study Snyder-Mackler, together with first author Blaise Mariner, PhD, and colleagues generated 1,640 methylomes from a cohort of 894 dogs in the Dog Aging Project. They combined the molecular data with detailed genetic and demographic data. The results indicated that molecular aging occurs most rapidly early in a dog’s life. The study also found that larger and male dogs—both of which have shorter lifespans than their respective counterparts—age more quickly at the molecular level.
The authors identified different epigenetic patterns underlying these effects. According to the findings, sex-related changes were concentrated on the X chromosome, while body-size-related changes were especially prominent in TEs. “Thus, size and sex, two axes associated with shorter expected lifespan in dogs, appear to shape aging through partially distinct epigenetic architectures,” they stated. “Larger dogs show greater methylation loss at TEs with age, consistent with increased immune remodeling and genomic instability … These data address a major gap in comparative epigenomics by providing evidence that, within a species, demographic groups with shorter expected lifespans show faster epigenetic aging.”
![Genome-wide DNA methylation in 894 dogs from the Dog Aging Project reveals accelerated aging in larger dogs and faster loss of repression of transposable elements. [Blaise Mariner & Brianah McCoy]](https://www.genengnews.com/wp-content/uploads/2026/10/low-res-3-300x169.jpeg)
