A team of EMBL researchers and collaborators has now created a tool that takes single-cell analysis to a new level. It can capture both genomic variations and RNA within the same cell, offering greater accuracy and scalability than earlier technologies. This approach allows scientists to identify variations in non-coding regions of DNA, the areas most often linked to disease, giving them a new way to explore how genetic differences contribute to human health. With its precision and ability to process large numbers of cells, the tool marks a major step toward linking specific genetic variants with disease outcomes.

"This has been a long-standing problem, as current single-cell methods to study DNA and RNA in the same cell have had limited throughput, lacked sensitivity, and are complicated," said Dominik Lindenhofer, the lead author on a new paper about SDR-Seq published in Nature Methods and a postdoctoral fellow in EMBL's Steinmetz Group. "On a single-cell level, you could read out variants in thousands of cells, but only if they had been expressed -- so only from coded regions. Our tool works, irrespective of where variants are located, yielding single-cell numbers that enable analysis of complex samples."

The important difference between coding and non-coding regions

DNA contains both coding and non-coding regions. The coding parts function like instruction manuals, since their genes are expressed into RNA, which directs cells in building proteins essential to life.

Non-coding regions, on the other hand, contain regulatory elements that guide how cells grow and function. Over 95% of disease-linked DNA variants occur in these non-coding regions, yet existing single-cell methods have not had the sensitivity or scale to study them effectively. Until now, researchers were unable to observe DNA and RNA from the same cell on a large scale, limiting insight into how DNA variants affect gene activity and contribute to disease.

"In this non-coding space, we know there are variants related to things like congenital heart disease, autism, and schizophrenia that are vastly unexplored, but these are certainly not the only diseases like this," Lindenhofer said. "We needed a tool to do that exploration to understand which variants are functional in their endogenous genomic context and understand how they contribute to disease progression."

Deciphering barcodes that track single cells

To perform single-cell DNA-RNA sequencing (SDR-seq), researchers used tiny oil-water droplets, each containing a single cell, allowing them to analyze DNA and RNA simultaneously. This method enabled them to examine thousands of cells in a single experiment and directly link genetic changes to patterns of gene activity. Developing this technology required overcoming major challenges and brought together teams from EMBL's Genome Biology and Structural and Computational Biology units, the Stanford University School of Medicine, and Heidelberg University Hospital.

Collaborators from EMBL's Judith Zaugg and Kyung-Min Noh groups developed a way to preserve delicate RNA by "fixing" the cells, while computational biologists in Oliver Stegle's group designed a specialized program to decode the complex DNA barcoding system needed for data analysis. Although this decoding software was built for this specific project, the team believes it could prove valuable for many other studies.

Researchers from Wolfgang Huber's and Sasha Dietrich's groups at EMBL and Universitätsklinikum Heidelberg were already examining B-cell lymphoma samples for other studies. These patient samples, rich in genetic variation, provided an ideal test case for the new technology. Using these samples, Lindenhofer observed how variations in DNA were linked to disease processes and found that cancer cells with more variants showed stronger activation signals that support tumor growth.

"We are using these small reaction chambers to read out DNA and RNA in the same single cell," Lindenhofer said. "This lets us accurately tell whether a variant is on one or both copies of a gene and measure its effects on gene expression in the same single cells. With the B-cell lymphoma cells, we were able to show that depending on the variant makeup of cells, they had different propensities to belong to distinct cellular states. We could also see that increasing variants in a cell actually were associated with a more malignant B-cell lymphoma state."

The many opportunities from a single-cell sequencing tool

The SDR-seq tool now offers genomic biologists scale, precision, and speed to help better understand genetic variants. While it could eventually play a role in treating a broad range of complex diseases, it may first help in developing better screening tools for diagnosis.

"We have a tool that can link variants to disease," said Lars Steinmetz, a senior author on the paper, an EMBL group leader, and a genetics professor at Stanford University School of Medicine. "This capability opens up a wide range of biology that we can now discover. If we can discern how variants actually regulate disease and understand that disease process better, it means we have a better opportunity to intervene and treat it."

A new study from the Fralin Biomedical Research Institute at VTC, published this month in Scientific Reports, found that GLP-1 agonists appear to slow how quickly alcohol moves into the bloodstream, which in turn delays its effects on the brain.

"People who drink know there's a difference between nursing a glass of wine and downing a shot of whiskey," said Alex DiFeliceantonio, assistant professor and interim co-director of the FBRI's Center for Health Behaviors Research.

Although a standard serving of each contains the same amount of alcohol (0.6 ounces), a shot causes blood-alcohol levels to rise much faster. That quick spike feels stronger because of how the body absorbs and processes alcohol.

"Why would this matter? Faster-acting drugs have a higher abuse potential," DiFeliceantonio said. "They have a different impact on the brain. So if GLP-1s slow alcohol entering the bloodstream, they could reduce the effects of alcohol and help people drink less."

More than half of U.S. adults consume alcohol, and about one in ten has an alcohol use disorder. Chronic, heavy drinking is linked to conditions such as high blood pressure, heart and liver disease, and several cancers. Earlier this year, U.S. Surgeon General Vivek Murthy identified alcohol use as the nation's third leading preventable cause of cancer, following tobacco use and obesity.

In the study, participants who were taking GLP-1 medications such as semaglutide, tirzepatide, or liraglutide experienced a slower rise in blood-alcohol concentration even though they consumed the same amount of alcohol as those not on the drugs. They also reported feeling less intoxicated based on their own assessments.

Supported by funding from Virginia Tech's Fralin Biomedical Research Institute, the study aimed to explore both the physical and perceived effects of alcohol in people taking a GLP-1 drug. The researchers say these early findings could help shape larger, long-term studies on whether such medications might be used to reduce alcohol consumption.

The study included twenty adults with a body mass index (BMI) of 30 or higher, half of whom were taking GLP-1 medication and half who were not. Participants were asked to fast before the session, then were given a snack bar to keep stomach contents consistent.

Researchers measured each participant's blood pressure, pulse, breath alcohol concentration, and blood glucose levels. Ninety minutes later, they were served an alcoholic drink to finish within 10 minutes. Afterward, participants were asked several times over an hour to describe their level of intoxication, cravings, appetite, and the drink's taste, including the question, "How drunk do you feel right now?" rated from zero to ten.

Those on GLP-1 medication consistently reported feeling less drunk.

After the drinking portion ended, participants stayed in a recovery area while their alcohol levels dropped. Breath alcohol was measured every 30 minutes, blood glucose twice, and after three hours participants again answered follow-up questions. Four hours later, once their breath alcohol measured below 0.02 percent and they were cleared by a study physician, they were allowed to leave.

"Other medications designed to help reduce alcohol intake" -- naltrexone and acamprosate -- "act on the central nervous system," said DiFeliceantonio, the study's corresponding author. "Our preliminary data suggest that GLP-1s suppress intake through a different mechanism."

The drugs slow gastric emptying, which can lead to a slower rise in blood alcohol.

The idea for the study initially bubbled up during a Fralin Biomedical Research Institute faculty retreat and was led by Warren Bickel, professor and director of the Addiction Recovery Research Center, who died in 2024.

It built on an analysis of social media posts on the community network Reddit, in which users reported reduced cravings for alcohol when taking drugs intended to treat type 2 diabetes and obesity.

"His guidance shaped every stage of this research -- from the initial idea to its final form -- and his passion for scientific discovery continues to inspire me every day," said Fatima Quddos, a graduate researcher in Bickel's lab and the first author on both studies.

"Bickel's work had long focused on what happens when you delay rewards, so we asked, 'What if GLP-1s affect how the body handles alcohol?'" DiFeliceantonio said. "Ending this project was bittersweet, because it was my last collaboration with him."

"He was always asking, 'How do we help people the fastest?' Using a drug that's already shown to be safe to help people reduce drinking could be a way to get people help fast," DiFeliceantonio said.

While this was a pilot study, researchers said the findings showed clear differences between groups and provide early data that support larger trials testing the drugs as a therapy for people who want to reduce their alcohol use.

"As a recent graduate, I'm deeply inspired by the potential this research holds -- not only for advancing our scientific understanding, but also for paving the way toward future therapies," said Quddos, who earned her doctorate from Virginia Tech's Translational Biology, Medicine, and Health Graduate Program in May. "The possibility of offering new hope to individuals struggling with addiction is what makes this work so meaningful."