Genomics

Posts in this category speak to research in population genetics, microbiomes and other large-scale genomic projets.

The Hidden Costs of “Good Enough” Extraction

Posted on by Promega

The translational oncology landscape has changed dramatically in the past two decades, and with it, the demands on the laboratories doing this work. Today’s translational oncology workflows require DNA and RNA from the same FFPE tissue section, cell-free DNA from large plasma volumes, and nucleic acids from heterogeneous batches of sample types processed in a single run. The analyte diversity has increased dramatically, and at the same time, the downstream assays interrogating those samples have grown more sensitive. The operational pressures have grown alongside the scientific ones. Labs are processing more samples than ever, but not with proportionally more staff. Same-day extraction to analysis is increasingly the expectation, not the exception. All of that change and complexity lands at the extraction step first.

Scientist holding up an FFPE tissue sample. Such samples are vital for nucleic acid extraction required for retroactive studies.

Extraction has long been treated as the step before the experiment, the part you complete before the real work begins. However, as these pressures on the translational laboratory grow, overlooking potential issues with extraction could be disastrous, particularly for labs working with limited, irreplaceable samples, because pre-analytical variability at the extraction step propagates through every downstream process. When extraction is overlooked, information in a sample can be lost and with it the insight into the biological question your downstream assay is asking.

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The Molecular Blueprint for Virus-Resistant Cowpea

Posted on by Anna Bennett

Cowpea (Vigna unguiculata), a humble tan and black legume, is one of the most important food crops in the world. Grown across sub-Saharan Africa, Asia, and parts of the Americas, Cowpea provides protein-rich nutrition for hundreds of millions of people, making it a cornerstone of smallholder agriculture. But cowpea production faces a persistent threat: the cowpea aphid-borne mosaic virus (CABMV), a common virus that can devastate yields across entire growing regions.

A dark background with a wooden spoon holding tan and black beans scattered on the spoon and on the background.

What makes CABMV particularly difficult to combat is how the virus infects its host. Instead of relying on viral translational machinery, the virus hijacks the plant’s systems to replicate. CABMV targets a protein called eIF4E, a translation initiation factor that the plant needs to read its own genetic instructions and produce proteins. The virus produces a protein, VPg, that binds directly to eIF4E and redirects the plant’s translational machinery to produce viral proteins instead. The plant can’t simply get rid of eIF4E. Without it, protein synthesis stalls. So how can cowpea defend itself against a virus that exploits one of its most essential proteins?

A new study published in Agronomy by researchers at the Federal University of Pernambuco, the Federal University of Minas Gerais, and Embrapa Recursos Genéticos e Biotecnologia takes a comprehensive look at this problem from the inside out1. The team characterized all three members of the eIF4E gene family in cowpea  (eIF4E, eIF(iso)4E, and nCBP) across six cultivated varieties (cultivars) with known contrasting responses to CABMV infection. Two of those cultivars (Bajão and IT85F-2687) are resistant to the virus; the other four (Boca Negra, BR14 Mulato, Pingo de Ouro, and Santo Inácio) are susceptible to the virus.

Using a multi-omics approach that combined genomic, evolutionary and structural analyses, the researchers set out to answer a fundamental question: what makes some versions of eIF4E exploitable by the virus, and others not?

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Beyond the Liver: How Liposomal LNPs Are Expanding the Reach of mRNA Delivery

Posted on by Simon Moe

Introduction

Lipid nanoparticles (LNPs) have transformed mRNA delivery. From COVID-19 vaccines to the first approved RNAi therapeutic, ONPATTRO (Patisiran), LNPs have proven their ability to ferry nucleic acid cargo into cells with speed and efficiency (Huang, 2019). Despite this transformation, most clinically deployed LNP formulations share a significant constraint: following intravenous administration, roughly 90% of the injected dose clears to the liver within an hour. If your target is a hepatocyte, that is hardly a hindrance. It’s a serious limitation if you need to reach the spleen, lymph nodes, pancreas or other extrahepatic tissues, all of which are organs of major interest in immunotherapy, vaccine development and metabolic disease research.

A new paper from Pieter Cullis’s laboratory at the University of British Columbia (UBC) offers a structural solution to that problem. Their design, termed a ‘liposomal LNP’, reengineers the architecture of the particle itself to achieve dramatically longer circulation lifetimes and improved transfection in tissues that standard formulations have largely missed.

What are Lipid Nanoparticles?

LNPs enable fast transfection of a wide variety of cells, facilitating the transport of mRNA, DNA and siRNA into cells to induce transient expression in a short period of time (mere hours for mRNA and one to two days for DNA). They are a powerful tool that rose to broad public awareness through their use in COVID-19 vaccines, which delivered spike protein mRNA as cargo. Beyond vaccines, LNPs have been applied therapeutically as the delivery vehicle for ONPATTRO, which treats polyneuropathy of hereditary transthyretin-mediated amyloidosis (Huang, 2019).

The most widely studied LNP formulation, such as the ONPATTRO-like composition, consists of four components: an ionizable lipid, a helper lipid, cholesterol and a PEG-lipid. At physiological pH, the ionizable lipid is neutral and resides in a hydrophobic oil-like core surrounded by a lipid monolayer. This structure is highly effective at transfecting hepatocytes, but its rapid hepatic clearance limits its utility for reaching other tissues.

A Structural Redesign: What Makes the Liposomal LNP Different

Standard ONPATTRO-like formulations have a lipid monolayer surrounding an oil droplet core. The UBC team’s publication reasoned that dramatically increasing the proportion of bilayer-forming lipids, specifically equimolar egg sphingomyelin (ESM) and cholesterol, could fundamentally change what the LNP looks like (Cheng, 2025).

The authors explored various bilayer-to-ionizable lipid molar ratios (RB/I) to see how they modified the structure of the particle. They found that an RB/I of 4 resulted in particles that transition to a true liposomal architecture consisting of a lipid bilayer enclosing an aqueous interior with a solid core suspended inside. Cryo-electron microscopy confirmed that approximately 84% of particles at this ratio adopt this bilayer structure, with the solid core occupying roughly 30% of the interior. LNP sizes across all tested ratios remained in the 40–60 nm range, confirming that the structural shift happens without meaningful changes in particle size.

Why the Structural Change in Liposomal LNP Affects Assembly and Delivery

The liposomal LNP exploits pH-driven structural transitions at both the assembly and delivery stages, explaining how a particle dominated by bilayer lipids can remain transfection-competent.

Assembly: When an ethanol-lipid mixture meets an acidic aqueous buffer (pH 4) containing mRNA, the positively charged ionizable lipid binds the negatively charged mRNA, forming a core complex. This complex acts as a nucleation point for the deposition of ESM/cholesterol bilayer lipid. As pH rises to 7.4 during formulation, ionizable lipids in the outer monolayer shift to a neutral form and migrate inward, expanding an oil droplet core. The mRNA dissociates from the oil core and resides in the aqueous interior where it is protected within the bilayer.

Delivery: After endocytosis, the acidic endosomal environment reverses this process. The ionizable lipids become positively charged again and migrate to the outer surface of the LNP, causing the solid mRNA-containing core to extrude outward from the liposomal bilayer. This positively charged protrusion interacts with the negatively charged endosomal membrane, triggering fusion and releasing the mRNA into the cytoplasm for translation. The authors describe this as a localized “warhead” mechanism—a structural consequence of the bilayer architecture, rather than a simple membrane-disruption event.

Exploring the Performance of the Liposomal LNP

The authors utilized NanoLuc® mRNA as a reporter payload throughout the study. From in vitro transfection efficiency to whole-animal imaging, it allowed the authors to detect differential expression that would have been difficult to detect with less sensitive reporters.

The performance of the Liposomal LNP tells a compelling story. In vitro, the RB/I = 4 formulation matched or exceeded the transfection potency of the ONPATTRO-like composition in Huh7 cells across a wide dose range, while also proving to be the most stable on the shelf. After 63 weeks at 4°C, it maintained greater than 80% mRNA encapsulation with less than 20% size increase, and produced the highest mRNA integrity and translatability of any tested ratio.

SPECT/CT imaging of whole animals with the Liposomal LNP showed a circulation half-life approximately 15-fold longer than the standard ONPATTRO-like formulation, a direct consequence of the bilayer exterior adsorbing roughly half the plasma protein load. This reduced exterior plasma protein load means less macrophage recognition, less clearance and more time in circulation to reach tissues beyond the liver. That improved lifetime in circulation translated into improved tissue access. Ex vivo organ analysis showed 50-fold greater luminescence in the spleen and 150-fold greater in the inguinal lymph node compared to the standard formulation. Meaningful signal was also detected in the pancreas, a tissue rarely reached through conventional LNP formulations. Immunofluorescence confirmed delivery was localized to macrophages at the marginal zone of the spleen and subcapsular sinus of the lymph node.

It is also worth noting that the liposomal morphology held up when tested with the ionizable lipids used in the BNT162b2 and the mRNA-1273 COVID vaccines, suggesting this is a generalizable design.

Expanding Use of NanoLuc® mRNA: UBC RNA and Formulation Core

Throughout this study, NanoLuc® mRNA served as the reporter payload. In vitro, NanoLuc® luminescence normalized to total protein provided a sensitive, linear measure of transfection efficiency across a wide dose range. In vivo, it enabled whole-animal IVIS imaging using the Nano-Glo® Fluorofurimazine substrate, with quantification extended to ex vivo organ homogenates using the Nano-Glo® Luciferase Assay System. NanoLuc® Luciferase sensitivity enabled detecting differential expression in tissues as small as inguinal lymph nodes and the pancreas. Detecting meaningful signal from a lymph node or pancreas can be challenging and thus successful detection demonstrates the exceptional performance of NanoLuc® Luciferase.

The authors synthesized their NanoLuc® mRNA in-house, a capability not universally available to research groups. We have partnered with the University of British Columbia RNA and Formulation Core to close that gap, enabling distribution of NanoLuc® mRNA across the core’s academic and industry network. Researchers who want to investigate LNP delivery, optimize formulations or validate mRNA constructs can now work with the RNA and Formulation Core to acquire NanoLuc® mRNA without the overhead of in-house synthesis. Work from UBC has contributed foundational understanding for LNP formulations, and now through their core they enable NanoLuc® mRNA development for any interested scientist.

Conclusion

The work from UBC demonstrates what becomes possible when mRNA delivery can reach beyond the liver, but the findings are only useful if researchers can access the tools to replicate and build on them. That’s where the UBC RNA and Formulation Core comes in. By partnering with Promega to distribute NanoLuc® mRNA, the Core gives researchers direct access to the same reporter used in this study, without the overhead of in-house synthesis. Whether you’re optimizing an LNP formulation, validating extrahepatic delivery or exploring mRNA constructs for a new application, you can now work with the Core to get started.

Interested in learning more about the UBC RNA and Formulation Core? Explore their website.

Learn more about the full NanoLuc® portfolio.

Citations

Cheng, M.H.Y. et al. (2025) Liposomal lipid nanoparticles for extrahepatic delivery of mRNA. Nature Communications 16, 4135.
Huang, Y.Y. (2019) Approval of the first-ever RNAi therapeutics and its technological development history. Prog. Biochem. Biophys. 46, 313–322.

Piecing Together the Primate Gut Microbiome: Known Residents and Novel Species

Posted on by Anna Bennett

If you’ve read anything about the gut microbiome in the last decade, you’ve probably encountered a familiar setup: researchers collect stool samples, sequence the microbial DNA, and draw conclusions about gut health based on what microbes populate the gut. It’s a practical approach because stool is relatively easy to collect and doesn’t require invasive procedures. But how well does a stool sample represent the health of the entire intestinal tract?

A team of researchers at the Quadram Institute Bioscience and UK Health Security Agency set out to answer this question in primates1. They characterized the intestinal microbiome of cynomolgus macaques, a primate commonly used in biomedical research because of its genetic and physiological similarities to humans. Rather than relying on stool alone, the team collected samples from six distinct regions along the intestinal tract in 24 captive-bred animals ranging in age from 4 to 20 years.

Four hands putting jigsaw puzzle pieces with image of large intestine together.
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When Cancer Research Depends on Quality RNA: Maxwell® RSC in the Lab

Posted on by Promega

Reliable molecular research starts with reliable sample preparation. Two recently published cancer biology studies illustrate this well, and both studies relied on the Maxwell® RSC platform to extract RNA from formalin-fixed, paraffin-embedded (FFPE) tissue, the archival format that makes up the bulk of clinical pathology material.

With Maxwell Instruments and chemistries for FFPE samples, RNA quality is suitable for many critical assays.

Mapping Molecular Targets in a Rare Thyroid Cancer

A 2025 study published in Endocrine Pathology focused on poorly differentiated thyroid carcinoma (PDTC), a rare and aggressive thyroid cancer subtype with limited treatment options once surgery is no longer curative (1). The research question was straightforward but clinically urgent: how many PDTC cases harbor mutations that could be targeted with existing or emerging therapies?

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Ancient RNA From a Woolly Mammoth?

Posted on by Shannon Sindermann

Most of us first meet woolly mammoths as Manny from Ice Age (a gentle giant with main character energy) or as towering skeletons in museum halls. In the lab, though, mammoths can show up in many ways: such as fragile molecules preserved in permafrost for tens of thousands of years.

Woolly Mammoth

Ancient DNA has already helped scientists piece together mammoth genomes. Now scientists have done something wilder: they’ve pulled ancient RNA out of a ~39,000-year-old woolly mammoth and used it to see which genes were being expressed in its muscle tissue. In a new study, researchers showed that not only can woolly mammoth DNA survive tens of thousands of years in permafrost, but RNA, the fragile, quick-to-degrade “live feed” of the cell, can too.

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Solving the AAV Titer Challenge: A New Approach to Gene Therapy Workflows 

Posted on by Darcia Schweitzer

For the success of adeno-associated virus (AAV)-based gene therapies, accurate viral titration is non-negotiable. But as interest in AAVs as delivery vectors soars, so does the challenge of getting consistent, reproducible genome titers—a critical hurdle in biologics workflows where speed and standardization are paramount.

Impact of DNase Digestion on Accuracy

A recent peer-reviewed study pinpoints a surprising source of this variability: the DNase digestion, a common step used to remove contaminating DNA. “[DNase digestion]… led to a significant decrease in genome titers for several AAV serotypes,” the authors write,highlighting concerns around workflow reproducibility and data reliability.The research, published in Molecular Therapy: Methods & Clinical Development, demonstrates how different engineered AAV serotypes respond inconsistently to standard DNase treatment, significantly impacting final titer results. These findings are particularly relevant for scientists developing and optimizing cell and gene therapy platforms, where regulatory expectations for analytical precision continue to rise.

This study addresses the challenge of accurately measuring viral titers in engineered AAVs, which have enhanced transduction efficiency but exhibit lower yields when measured using traditional genome titering methods. Specifically, the authors explored the impact of DNase digestion on the stability of engineered AAV capsids that contain peptide insertions. Through a series of rigorous experiments including electron microscopy, quantitative PCR (qPCR) and digital droplet PCR (ddPCR), they found that the heat-inactivation step commonly used following DNase treatment to eliminate free-floating DNA can compromise the integrity of engineered AAV capsids.

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Growing Our Understanding of Triple-Negative Breast Cancer in Sub-Saharan Africa: Why Comprehensive Population Data Matters

Posted on by Kelly Grooms
A digitally rendered illustration of a cancer cell superimposed over the African continent. The cancer cell, with a textured, reddish-orange surface and extending tendrils, appears to spread across the dark red map of Africa, symbolizing the impact or presence of cancer on the continent.

In the genomics era, the promise of precision medicine and tailored diagnostics is only as good as the datasets, which makes it imperative that those sets reflect the diversity of the human population. Populations from the African continent, the most genomically diverse region in the world, are underrepresented in current genomic data sets.  Nowhere is closing this data gap more urgent than with triple-negative breast cancer (TNBC), which has a disproportionately high incidence in women of African descent and limited therapeutic options.

Highlighting why comprehensive population data is so important are the results of a recent study profiling of 30 TNBC tumor samples from Angola and Cape Verde (1).  Whole-exome sequencing (WES), enriched with untranslated regions (UTRs), showed that 86% of somatic variants in these samples had never been reported before. WES can be especially valuable when working with limited or degraded samples, such as the FFPE samples used in this study, because it allows you to gain valuable insights from samples that are impractical for whole-genome sequencing (WGS). This study’s results emphasize the value in expanding omics cancer research so that it includes all populations and areas of the genome.

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Tuberculosis Genome Mapping in Italy: How 2,520 Strains Are Shaping the Future of TB Surveillance

Posted on by Sara Millevolte

Tuberculosis (TB) remains one of the deadliest infectious diseases globally, with millions of new cases and over a million deaths each year. The rise of drug-resistant strains has only complicated treatment and control efforts, turning TB into a moving target for clinicians and public health officials alike. Understanding how TB spreads, evolves and becomes resistant requires more than just microscopes and cultures—it demands a detailed look at the bacterium’s genetic code.

Secondary tuberculosis in lungs and close-up view of Mycobacterium tuberculosis bacteria, 3D illustration
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Understanding Stress Resilience in Tomatoes: Insights Into the Role of PP2C Genes

Posted on by Kelly Grooms
An illustration of a tomato plant divided between normal and drought conditions. This study looks at the role of PP2C in stress response.

As climate change accelerates, understanding how crops survive environmental stress isn’t just an academic question—it’s a critical challenge for global food security. Tomatoes (Solanum lycopersicum), a staple crop worldwide, face increasing threats from drought, salinity, and extreme temperatures. But how do these plants adapt at the molecular level?

A recent study published in Scientific Reports ​investigated the evolutionary history, genomic diversity, and functional roles of protein phosphatase 2C (PP2C) genes in tomatoes (1). Instead of merely cataloging these genes, the researchers analyzed how PP2C gene expression changes under environmental stress. This information could help inform us about crop improvement strategies.

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