Background: Suicide helplines increasingly employ chat services to aid those in urgent need, but the wording and structure of text-driven exchanges may affect their effectiveness. Objective: Given the association of cognitive distortions with depression and anxiety, this study investigated their prevalence in the language of individuals seeking help from the Dutch 113 suicide helpline. Methods: We observed the prevalence of cognitive distortions for both help seekers and counselors in a large volume of chat sessions (N=71,148) of the Dutch 113 suicide chat helpline using natural language processing. The results were compared to 2 large collections of online text data from Dutch social media and web content. Results: We found that nearly all types of cognitive distortions are more prevalent in the language of help seekers compared to the control group of helpline counselors. Distortions of the personalizing, emotional reasoning, and mental filtering types were, respectively, 20.22, 7.87, and 4.53 times more prevalent among help seekers, revealing a distinct pattern of thought and language among individuals affected by suicidality. Conclusions: Our results raise the prospect of improving the effectiveness of online therapeutic interventions that target cognitive distortions through lexical analysis that detects the cognitive and lexical markers of suicidality.
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STAT+: AIDS group sues Trump administration over undisclosed agreement with Gilead
An AIDS activist group filed a lawsuit against the Trump administration for failing to disclose a research and development agreement that was at the heart of a settlement between the U.S. government and Gilead Sciences over patents for HIV prevention.
The settlement resolved a contentious lawsuit that was filed six years ago by the previous Trump administration after the Centers for Disease Control and Prevention maintained that Gilead infringed its patent rights. The agency had helped fund academic research that later formed the basis for two Gilead HIV pills, Truvada and Descovy.
The administration had alleged that Gilead ignored the contributions by CDC scientists, exaggerated its own role in developing HIV prevention drugs, and refused to sign a licensing agreement despite “multiple attempts” at reaching a deal after unfairly reaping hundreds of millions of dollars from research funded by taxpayers.
WHO Designates Network of Regional Biomanufacturing Training Centers
The World Health Organization (WHO) has designated a network of regional training centers for biomanufacturing across all six WHO regions, which is intended to mark a major step forward in strengthening the global workforce needed to produce vaccines, biotherapeutics and other biological products.
As global efforts continue to expand manufacturing infrastructure and advance technology transfer, WHO is placing equal emphasis on the people and systems required to make these investments sustainable and impactful.
The designation follows a global selection process conducted through two calls for expressions of interest and forms part of the WHO Biomanufacturing Workforce Training Initiative established in 2023. This flagship effort addresses critical skills gaps across the biomanufacturing value chain, enabling countries to translate technological advances into sustainable local production.
![Yukiko Nakatani, MD, PhD [WHO]](https://www.genengnews.com/wp-content/uploads/2026/04/yukiko_nakatani_portrait-3-1024x1011-1-300x282.jpg)
“Building a skilled biomanufacturing workforce is fundamental to advancing equitable access to health products and strengthening global health security. By designating regional training centers across all WHO regions, we are investing in people and systems that enable countries not only to produce quality-assured essential health technologies, but to sustain and scale them,” said Yukiko Nakatani, MD, PhD, WHO assistant director-general for health systems, access, and data. “This network reflects a strategic shift towards more resilient, geographically diversified manufacturing capacity, grounded in science and collaboration.”
The newly designated regional training centers will operate as part of a coordinated global network, delivering context-specific training aligned with regional priorities, regulatory environments and languages, according to Nakatani. By partnering with academia and industry, they plan to expand access to training, strengthen regional expertise and foster collaboration across countries, supporting the development of a skilled and sustainable workforce. While operating independently, they will work in close collaboration with WHO under agreed frameworks to ensure quality, alignment, and accountability, note WHO officials.
The selected institutions are:
- African Region: Institut Pasteur de Dakar, Senegal; Council for Scientific and Industrial Research, South Africa
- Region of the Americas: Oswaldo Cruz Foundation (Fiocruz), Brazil
- South-East Asia Region: Translational Health Science and Technology Institute, India
- European Region: National Institute for Bioprocessing Research and Training, Ireland
- Eastern Mediterranean Region: Center for Continuing Professional Development, Egyptian Drug Authority, Egypt Western Pacific Region: Peking University, China
These centers will complement the Global Training Hub for Biomanufacturing (GTH-B), established in 2022 in collaboration with the Ministry of Health and Welfare of the Republic of Korea.The Global Hub delivers standardized training programs that combine hands-on experience and classroom-based learning, while also supporting the WHO initiative through training-of-trainers programs.
The WHO Biomanufacturing Workforce Training Initiative was designed to directly support the implementation of World Health Assembly resolution WHA74.6 on strengthening local production of medicines and other health technologies. By investing in workforce development, WHO states that it is helping to address longstanding inequities in access to health products and to ensure that all countries are better equipped to respond rapidly and effectively to future health emergencies.
As global health systems move from crisis response to long-term resilience, building a skilled and geographically distributed biomanufacturing workforce is emerging as a cornerstone of pandemic preparedness and health security, points out a WHO spokesperson.
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Restoring Gut Barrier Function in Crohn’s by Targeting ISR Activation
Researchers at the University of Houston, working with collaborators at Baylor College of Medicine and The University of Texas MD Anderson Cancer Center, have identified a mechanism that identifies epithelial cell stress as a one of the main drivers of Crohn’s disease, a finding that runs counter to much current thinking of Crohn’s disease as immune-mediated and instead frames it as a failure of within the intestinal barrier. The study, published in Gastro Hep Advances, shows that chronic integrated stress response (ISR) activation and a related cell death pathway, necroptosis, form a feedback loop that damages intestinal epithelial cells and prevents cell regeneration leading to sustained inflammation.
“It’s a paradigm shift from the way we’ve thought about the disease,” said senior author Seema Khurana, PhD, a professor of biology and biochemistry at the University of Houston. “Existing therapies primarily manage symptoms because we don’t know what causes the disease. We believe our research brings us closer to identifying those drivers.”
Crohn’s disease is typically treated with anti-inflammatory therapies aimed at suppressing immune activity, but only a minority of patients have long lasting benefits. This current study may help explain why anti-inflammatories only have limited benefits by showing that intestinal barrier dysfunction is not simply a consequence of inflammation but is a factor in disease development.
For their research, the team sought to discover how stress signaling within certain epithelial cells contribute to disease progression. The ISR is a conserved cellular pathway that helps cells respond to stress by temporarily reducing protein production and activating processes that restore cellular balance, including stress-response gene expression, protein quality control, and metabolic adaptation. While short-term ISR activation is a temporary response to cellular stress, the researchers found that in Crohn’s disease, ISR signaling becomes chronically activated.
“Our results identify ISR activation as a unifying hallmark of epithelial stress in CD, regardless of whether the initiating insult is intrinsic (loss of villin-1/gelsolin) or extrinsic (TNF-α dysregulation),” the researchers wrote.
The result of this chronic ISR activation is that instead of helping epithelial cells become healthy, they are instead kept in a dysfunctional state. This leads to mitochondrial stress and triggers necroptosis, a form of programmed cell death that releases inflammatory signals. The combination of ongoing stress signaling and cell death prevents epithelial regeneration and weakens the intestinal barrier, allowing microbes to infiltration tissue in the intestine further increasing inflammation.
Prior studies have focused on this form of dysfunction to Crohn’s disease, but ISR activation had not been clearly characterized as a central driver of disease development. To address this, the team used a number of different models of Crohn’s disease, including genetically engineered mice with epithelial-specific ISR activation, mice with chronic inflammation driven by TNF-α dysregulation, and patient-derived intestinal organoids. The organoids allowed the researchers to directly study human epithelial responses.
The resulting data showed that for all the models, the same pattern of chronic ISR activation, increased necroptosis, impaired epithelial survival, and failure of regenerative growth emerged.
To begin finding potential therapeutic approaches based on these new findings, the investigators then tested whether blocking these pathways could reverse intestinal damage. Using both experimental inhibitors and two FDA-approved cancer drugs, pazopanib and ponatinib, repurposed at low concentrations, they were able to suppress ISR signaling and necroptosis. This restored epithelial cell survival, improved regeneration, and reestablished barrier integrity.
“A major advance of this work is the demonstration that pharmacologic inhibition of ISR or necroptosis restores epithelial homeostasis by promoting regenerative growth of the epithelium in both murine and human models of CD,” the researchers wrote.
If additional studies can establish ISR inhibition as safe and effective for human use, this research could be the beginning of a shift in how Crohn’s disease is treated. Instead of focusing only on controlling inflammation, a new class of treatments could aim to repair the epithelial barrier directly. This approach aligns with emerging evidence that permeability barrier healing is a stronger predictor of long-term remission than traditional measures such as mucosal healing.
Further, because both pazopanib and ponatinib are already approved drugs that are known to be safe and have well characterized pharmacology profiles, the path to these new treatments could be on a fast track.
“If you had to start from scratch to identify and develop a drug, it takes 10 to 15 years and can cost between $1 billion to $2 billion,” Khurana said. “For a patient who is suffering from chronic Crohn’s disease, they’re looking for some immediate relief. Our goal was to make our findings much more translatable to real patients.”
Beyond drug development, the study points to new opportunities for improving clinical care. Biomarkers of ISR activation, such as phosphorylated eIF2α or RIPK3 expression, could help identify patients with barrier dysfunction and guide treatment decisions. Patient-derived organoid systems may also enable personalized testing of therapeutic responses before treatment.
The post Restoring Gut Barrier Function in Crohn’s by Targeting ISR Activation appeared first on Inside Precision Medicine.
Benefit of the N-of-1 Approach Versus Aggregate Analysis in Tracking Individual Trajectories During Pregnancy: Comparison of Longitudinal Wearable Observational Studies
Background: Personal digital health technologies (DHTs) enable real-time monitoring of physiological metrics and behavioral data, including heart rate variability (HRV), supporting analysis of pregnancy-related conditions and personalized care throughout the perinatal period. While recent studies demonstrate the utility of personal DHTs in tracking pregnancy-related symptoms, they often rely on aggregate statistical methods that overlook individual variability. Objective: This study aims to compare aggregate and individual-level analyses of DHT data for pregnancy-related conditions, using the comprehensive BUMP (Better Understanding the Metamorphosis of Pregnancy) dataset to highlight the importance of individual variability and data heterogeneity. Methods: We analyzed wearable and self-reported data from 256 participants enrolled in the BUMP study (January 2021 to May 2022), including HRV, sleep, and fatigue measured via Oura Rings and smartphone surveys. Individual-level (N-of-1) trajectories were evaluated and compared with aggregate results to uncover personal and collective trends. A statistical method was developed to assess the influence of adverse events and severe symptoms, while case studies explored confounding and modifying factors underlying heterogeneity. Comprehensive statistical analysis included the coefficient of determination, Kolmogorov-Smirnov tests, likelihood ratio tests, and Welch tests, with interindividual variability flagged based on high-variability thresholds. Results: Substantial interindividual variability was observed across all features. Only 4.76% (12/256) of participants exhibited an HRV inflection at the aggregate week-33 inflection point, with a coefficient of variation of 14.24%. The median value of the gestational week in individual fatigue troughs was 23 (IQR 8; range 8-38) weeks, differing from aggregate estimates. Distributional comparisons showed no statistically significant differences in individual-level model fit (²) by pregnancy complications or age ( values ranging from .06 to .99 across all model fit comparisons). Case studies further highlighted both intraindividual and interindividual differences, emphasizing the importance of considering external factors, such as adverse events and severe symptoms. Conclusions: Our findings show that aggregate wearable data often fail to generalize across populations, oversimplifying pregnancy-related physiological and subjective changes. This simplification can obscure individual trajectories, leading to generalized insights that may not reflect many pregnant women’s experiences. Our results highlight the impact of heterogeneity on pregnancy outcomes, emphasizing the need to move beyond one-size-fits-all models and leverage DHT for personalized care.
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Sexual Assault Prevention via Bystander Intervention Using Instagram Reels as a Communication Channel: Experimental Design Study
Background: Bystander intervention is one of the most commonly used methods to curb the sexual violence crisis on college campuses. Most universities conduct training among their student bodies to ensure students are familiar with the procedure. However, it is necessary to remind and repeat messages to audiences to underscore their importance and solidify that knowledge among populations. Objective: In this study, the author developed Instagram-type reel messages that consider multiple frameworks used to develop bystander training and programs, such as the social norms approach and bystander barriers. Methods: These messages were tested via a 4×1 experimental design study with college students at a large public university (N=157). The conditions were messages that emphasize norms (norm reinforcement condition, based on the social norms approach; n=39), messages that emphasize behavior (norm readjustment condition, based on bystander barriers; n=39), messages that underscore the discrepancy between perceived peer norm and actual behavior (combination condition, based on both the social norms approach and bystander barriers; n=39), and a control condition (n=40). Results: ANOVA analysis revealed that the norms reinforcement condition and the combination condition seemed to have the greatest impact on participants’ perceived norms and behavioral intentions. In particular, when assessing norms as the dependent variable, the reinforcement group was significantly different from the readjustment group (Δmean 0.682, SD 0.160; 001), the combination group (Δmean 0.675, SD 0.160; 001), and the control group (Δmean 0.432, SD 0.159; =.04). For behavioral intentions to engage in bystander intervention, the reinforcement group was significantly different from the control group (Δmean 0.217, SD 0.073; =.02), and the combination group was significantly different from the control group as well (Δmean 0.221, SD 0.073; 02). Conclusions: The findings indicate that these messages could work in conjunction with training as a way to underscore the importance of bystander intervention behavior. It also highlights the role that Instagram reels can play in the prevention of sexual violence on college campuses.
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Method Identifies Cellular Makeup of Microenvironments Favoring Tumor Metastasis
Researchers at Baylor College of Medicine and collaborating institutions have developed a method that reveals the cellular makeup of tissues that support metastatic cancer growth, which is the primary cause of death for most patients with solid tumors. The technique, sortase A-based microenvironment niche tagging (SAMENT), is designed to selectively label cells encountered by cancer cells during metastasis. The team’s tests using SAMENT not only revealed cellular features shared by metastatic niches of multiple cancer models but also uncovered an unexpected driver of immune suppression in bone metastasis.
“As tumors progress, cancer cells leave the original site and spread or metastasize to other organs where they seed new tumors,” said Xiang Zhang, PhD, William T. Butler, MD, Endowed Chair for Distinguished Faculty, professor of molecular and cellular biology, and director of the Lester and Sue Smith Breast Center at Baylor. “Our lab is interested in better understanding what cellular and molecular features support metastasis as these could guide the development of therapies to prevent, slow down, or eliminate them. In the current study, we first developed a new method to identify the makeup of metastatic niches.”
Zhang, also a member of Baylor’s Dan L Duncan Comprehensive Cancer Center, is senior and corresponding author of the team’s published paper in Cell, titled “Unbiased niche labeling maps immune-excluded niche in bone metastasis.”
During metastasis, cancer cells interact constantly with other normal cells in the body, and these interactions affect cell behavior, fate, and even response to therapies. “Numerous previous studies have elucidated the roles of specific microenvironment niches (i.e., cells that are immediately adjacent to cancer cells) in the progression of metastasis,” the authors wrote.
For their newly reported study the team developed the SAMENT technology. “Our method allowed us to identify specific cells encountered by cancer cells during metastasis,” said co-first author Fengshuo Liu, graduate student in the Cancer and Cell Biology Program working in the Zhang lab. “The method, called Sortase A–Based Microenvironment Niche Tagging (SAMENT), selectively labels normal cells that come into direct contact with cancer cells.”
The authors further explained, “By combining SrtA and synthetic ligand-receptor binding, we aim to label any cells that are physically encountered by cancer cells.”
The investigators’ tests using SAMENT revealed that pro-metastatic microenvironments of multiple cancer models in all the organs studied, including bone, lung, liver, and brain, shared common features, including an abundance of macrophage immune cells and shortage or absence of immune T cells, which typically help fight tumors. “Among all cell types, macrophages occur most frequently surrounding disseminated cancer cells and appear to be phenotypically re-programmed upon interaction with metastases,” they wrote.
Liu added, “However, bone metastases stood out. We were surprised to find that macrophages surrounding cancer cells in bone metastases activated a protein called estrogen receptor alpha (ERα). This protein is best known for its role in hormone-responsive breast cancer but is much less studied in macrophages or other immune cells.” The team added, “It also plays an important role in many other cell types, including macrophages, T cells, osteoblasts, and osteoclasts.”
The study showed that macrophages with active ERα signaling were not detected in normal bone or in primary tumors in other tissues. ERα-active macrophages were also present in human bone metastasis samples from patients with breast, lung and kidney cancers—including male patients. This showed that this finding is not limited to one cancer type or to women.
The researchers also investigated how cancer cells turned macrophages, which would typically fight cancer, into their allies. Cancer cells deliver small molecules called fatty acids (FAs) to macrophages, likely through tiny particles known as extracellular vesicles (EVs). These fatty acids activate a metabolic pathway in macrophages that turns on ERα signaling. “Taken together, our data indicate that ERα expression in macrophages is driven by cancer cell-derived FAs through paracrine interaction mediated by EVs,” they wrote.
Once ERα is active, macrophages become immunosuppressive—instead of helping the immune system attack cancer, they form a barrier that physically and chemically blocks T cells from reaching tumor cells. ERα-active macrophages act as bodyguards for metastatic cancer in bone.
“To test whether ERα in macrophages can drive bone metastasis, we genetically removed the ERα gene specifically from macrophages in mice,” Liu continued. “As a result, cancer cells were far less able to colonize bone in multiple cancer models. Tumors grew more slowly, and metastases in other organs that often arise from bone tumors were also reduced. Importantly, removing ERα from macrophages did not disrupt normal bone health—bone structure and remodeling remained intact.” In their paper the scientists stated, “Taken together, our results strongly support the hypothesis that ERα in macrophages plays an important role in bone colonization.”
“When macrophage ERα was genetically removed or when mice were treated with fulvestrant, an FDA-approved cancer drug that degrades estrogen receptors, T cells were able to enter metastatic lesions in bone and kill tumor cells,” Zhang said. “Our findings support conducting future human clinical trials to assess the value of estrogen-blocking therapies combined with other therapies to treat bone metastases across multiple cancer types, in both women and men.”
The authors added, “Furthermore, as shown in the final set of experiments, inhibition of ERα in macrophages may not be effective by itself but could synergize with immunotherapies because it facilitates T cell infiltration into static lesions.” The team acknowledged that they didn’t see any synergy between Erαknockout in macrophages and anti-PD1 treatment. However, they noted, “… it is still worth exploring the combinatory effects with other immunotherapies. Therefore, our findings may warrant future clinical trials on combined endocrine and immunotherapies on patients with bone metastases, and this combination may be extended to other cancer types and to patients of both genders.”
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Face Photos Offer Window on Cancer Survival
An artificial intelligence tool could identify patients at increased risk of death after cancer treatment from their faces, research findings suggest.
The FaceAge algorithm captures dynamic changes in facial aging from photographs, offering a visible manifestation of the complex interplay between aging, cancer, and survival.
Patients with faces that aged rapidly between radiotherapy treatments according to the tool had a decreased chance of survival, according to the study in Nature Communications.
FaceAge assessments could therefore offer a dynamic, simple, accessible and non-invasive biomarker for cancer prognosis, which could be used to stratify risk and tailor treatment planning in oncology.
“Our study suggests that measuring FaceAge over time may refine personalized treatment planning, improve patient counseling, and help guide the frequency and intensity of follow-up in oncology,” said researcher Raymond Mak, PhD, from Mass General Brigham Cancer Institute.
Facial aging involves alterations in skin texture, loss of volume, and changes in bone structure and advances in deep learning have enabled age to be accurately estimated from visual biomarkers.
To investigate its prognostic value in cancer treatment, Mak and team developed the Face Aging Rate (FAR) biomarker.
This is calculated as the change in FaceAge between two time points divided by the time interval between the two facial photographs that were used, to provide a dynamic measure of aging over time.
A FAR value above one indicates accelerated aging that is faster than expected while a FAR value below one suggests decelerated aging.
The team tested the prognostic value of FAR in 2279 patients with different types of cancer, who underwent at least two courses of radiotherapy at Brigham and Women’s hospital between 2012 and 2023.
Face photographs taken in routine care during different radiotherapy courses at distinct timepoints were associated with survival, they reported. Specifically, a higher FAR is associated with an increased risk of death over different timeframes in stratified analyses.
For photos taken with a short interval in between, of 10 to 365 days, the adjusted hazard ratio (aHR) was 1.25, while for those with a long interval of between 731 and 1460 days, the aHR was 1.65.
The aHR was not statistically significant for the mid interval of photos taken 366 to 730 days apart.
“The association between accelerated facial aging and increased mortality risk may reflect deeper systemic biological processes, such as cellular senescence, DNA damage, and reduced tissue repair; all of which are hallmarks of both aging and cancer progression,“ the authors noted.
They added: “As research progresses, FAR has the potential to become an integral component of comprehensive cancer care and a tool to monitor changes in health more broadly, embodying the future of personalized medicine where serial facial photographs can provide profound prognostic insights.”
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Restoring Engagement in Digital Self-Control Tools Using Nudge Reconfiguration Prompts: Quasi-Experimental Study
Background: Digital self-control tools (DSCTs) have emerged as technological interventions to address excessive smartphone usage and promote digital well-being. However, these tools face persistent challenges with user attrition and sustained engagement, compromising their long-term effectiveness. Current literature lacks an understanding of how observable behavioral indicators, as opposed to self-reported measures, are associated with user engagement and readiness to change in DSCTs. Objective: This study addresses three research questions (RQs): (RQ1) whether prompting passive DSCT users to reconfigure nudges increases subsequent user-nudge interaction, (RQ2) how engagement evolves over time and what behavioral divergence emerges between accepting and rejecting users, and (RQ3) whether observable in-app behavioral indicators are more strongly associated with intervention acceptance than traditional self-reported measures. Methods: We conducted a quasi-experimental study (N=252) targeting users who had disabled nudges. Participants were randomly assigned to receive a prompt to reconfigure their nudge settings during daily check-ins (n=138, experimental group) or to a control condition (n=114, no intervention). The experimental group was further classified into acceptance and rejection subgroups based on their response to the intervention. Data collection included DSCT configuration logs, usage-triggered nudge logs, and self-reported questionnaire responses. We analyzed user-nudge interaction ratios using difference-in-differences with permutation tests (RQ1) and nudge configuration parameters and manual app blocking using independent-samples tests with Cohen (RQ2) and compared behavioral indicators against self-reported measures using tests and chi-square tests (RQ3). Results: Of the experimental participants, 46% (63/138) accepted the nudge reconfiguration prompt. Post intervention, the acceptance subgroup’s 7-day average user-nudge interaction ratio increased from 29.7% to 58.5% (peak of 65% on day 1), a significant increase even after controlling for the temporal decline observed in the control group (difference-in-differences=+36.3 percentage points, <.001). The rejection subgroup’s decline was not significantly different from the control group’s decline (=.82). The acceptance subgroup showed preexisting behavioral indicators of higher readiness to change, including 21.53% shorter consecutive usage thresholds (=.03) compared to the rejection subgroup, with a directionally consistent but nonsignificant difference in cooldown length (+20.56%). Behavioral divergence in consecutive usage thresholds widened post intervention, with Cohen increasing from −0.47 to −0.67 (=.002). Acceptance subgroup participants demonstrated a significantly lower tendency to select leisure-oriented daily goals (15.6% vs 26.2%; chi-square =.001, Cramer =0.13). Self-reported measures of screen time goals and scrolling regret were not significantly associated with intervention acceptance (>.10). Conclusions: Observable in-app behavioral indicators, rather than self-reported measures, effectively differentiate intervention receptiveness. Study results suggest that effective DSCT design should incorporate adaptive strategies that recognize and respond to users’ readiness to change, as evidenced by their in-app behaviors, while preserving autonomy. Such systems are likely to outperform static interventions or designs that rely solely on self-reported preferences.
‘Type’ Casting: Flagship-Founded Serif Modifying DNA into New Therapy Class
What happens when the scalability and redosability of messenger RNA (mRNA) is combined with the durability and programmability of gene therapy?
According to Serif Biomedicines, a five-year-old startup that emerged from stealth mode this month, the result is “modified DNA,” a new class of therapeutics designed to be programmable, durable, scalable, and redosable—while minimizing the drawbacks of both mRNA and gene therapy.
Modified DNA builds upon generative protein and mRNA platforms created by Flagship Pioneering, the venture capital giant which founded Serif in 2021. On April 21, Flagship formally launched Serif with an initial commitment of $50 million in financing—capital that Serif intends to use toward developing its scalable platform for optimizing and manufacturing Modified DNA treatments, aided by artificial intelligence (AI), and advancing its first drug discovery programs.
“The reason we’re bringing the company out of stealth mode now is we think we have made progress. We’ve made real progress that we’re excited to share with the world, that we’re excited to get feedback from the broader scientific community on, and we want to tell that story more broadly,” Jacob (Jake) Rubens, PhD, Serif’s co-founder and CEO, and an Origination Partner at Flagship Pioneering, told GEN.
“It’s been on our minds for a long time: What might be possible when DNA becomes an engineerable biotechnology for the first time?”
It’s a question pursued by numerous researchers and companies over the years as they sought to capitalize on DNA’s qualities of being a durably expressing molecule capable of coding for any gene, producing proteins or RNAs in a cell-specific way, as well as being scalable to manufacture and capable of re-dosing for patients.
“Those are, I think, the key differentiating attributes of theoretical DNA medicines. So the question for us became not, would this be valuable if we could do it, but why hasn’t anyone done it yet?” Rubens explained. “We’ve known about the centrality of DNA in biology, the central information molecule in DNA. We’ve known this for 75 years since Watson and Crick’s seminal discoveries around how the structure of DNA enabled it to function as an information molecule.”
Two key problems
“And when we looked at this space,” he continued, “we saw that there were two key problems: The first is that DNA is a highly inflammatory molecule. The second is that DNA needs to be delivered not just into a cell, but into the nucleus, the center of the cell.”
To create Modified DNA, Serif alters the structural and chemical form of DNA in order to minimize innate immunogenicity as lipid nanoparticles drop off the DNA not in the nucleus, but in the cytoplasm of the cell.
Once inside the cell nucleus, Modified DNA reverts to unmodified DNA, enabling transcription into therapeutic RNA and proteins. The resulting treatments are designed to last longer, be given more than once, and be programmed for cell-specific expression. To enhance durability, Serif delivers with its Modified DNA proteins which help the DNA access the nucleus. The proteins, called mRNA co-factors, are designed to transiently express proteins that enhance entry into the nucleus and gene expression.
Pending an announcement it expects to make later this year, Serif isn’t revealing specifics of its initial drug discovery programs, except to say that they focus on rare diseases and immune programming.
“This is not meant to be a limited list of where we could go but the areas that we think we’re going to go first, which are likely in addressing protein deficiencies in genetic diseases,” Rubens said.
Modified DNA has shown itself to be disease agnostic, he added, reflecting DNA’s qualities as a general, programmable information molecule: “One of the reasons we’re so excited about, the future of modified DNA as a new biotechnology akin to RNA, akin to protein, is its centrality in biology. It is the fundamental information molecule inside of all of us, inside of every living thing on this planet. So that is really the existence proof that it is generalizable.”
Tolerability and sustained expression
Also later this year, Serif plans to present data at an as-yet-unspecified scientific conference that will show modified DNA’s tolerability in non-human primates, as well as sustained gene expression with therapeutic effects in preclinical models following intravenous (IV) administration.
Serif aims to transform Modified DNA into treatments as effectively and commercially successfully as Amgen, Genentech (now a member of the Roche Group), and later Regeneron did with engineered proteins, as Alnylam Pharmaceuticals did with small interfering RNA (siRNA), and as Moderna more recently accomplished with mRNA—most notably in developing its SpikeVax® COVID-19 vaccine, which the FDA authorized for emergency use in 2020 and fully approved in 2022.
Flagship launched Moderna in 2010; the company went public in 2018 by raising $604 million, the largest-ever U.S. biotech initial public offering (IPO) until Kailera Therapeutics raised $625 million earlier this month.
At Flagship, Rubens is a scientist entrepreneur who leads the firm’s Pioneering Business Unit, which establishes and grows companies based on new biotechnology. In addition to Serif, Rubens co-founded Quotient Therapeutics, which develops therapies based on its somatic genomics platform; Tessera Therapeutics, which writes therapeutic messages into the genome through a genome engineering approach called GeneWriting
; and Sana Biotechnology, a developer of treatments based on engineered cells. He also launched Kaleido Biosciences, a microbiome therapeutics company that ceased operations in 2022.
Before joining Flagship, Jake received his PhD in microbiology from MIT, working with Tim Lu, MD, PhD, a core member of the Synthetic Biology Center, through the support of a National Science Foundation Graduate Research Fellowship. At MIT, Jake helped enable “intelligent” cell therapies by inventing gene circuits that allow engineered cells to do novel analog, digital, and hybrid computations.
Based in Cambridge, MA, Serif employs about 50 people and as of Wednesday was disclosing five open positions on its website in its three areas of focus: Chemistry (associate scientist and senior scientist, both specializing in LNP formulations), Molecular Biology (research associate and senior scientist), and Research/Discovery (scientist specializing in bioanalytical assays).
“I’m not at this point going to provide any guidance on how much more we will or won’t grow,” Rubens said. “We’re quite agile and responsive to the company’s needs.”
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