UMass Amherst chemists develop tool providing unrivaled look inside cells
First model that allows researchers to dig into the molecular details responsible for neurodegenerative diseases, many cancers
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UMass Amherst chemists Shanlong Li (l) and Jianhan Chen (r)
view moreCredit: Jianhan Chen
AMHERST, Mass. — The interior of a cell is packed with proteins and nucleic acids, such as RNA, all of which need to perform specific functions at the exact right time. If they don’t, serious diseases—ALS, Huntington’s or many cancers—can result. But what exactly is happening inside the crowded cell when it malfunctions, and how can these miscues be prevented? Thanks to a pair of chemists at the University of Massachusetts Amherst, a new publicly available tool, called iConRNA, recently announced in the Proceedings of the National Academy of Sciences, provides an unrivalled look at the mysterious world RNA and could help solve the mystery of how devastating diseases develop.
Think of a cell as a busy traffic intersection. There are many organelles within the cell—lysosomes, the nucleus, Golgi apparatus and mitochrondria—with their own membranes that keep them separate from everything else, in the same way as a car keeps its occupants separate and protected from everyone else in the intersection. But just as there are also pedestrians, bicyclists, skateboards and other obstacles zooming in and among the automobile traffic, a cell has strings of unprotected protein and RNA mixed in with the organelles.
For decades, scientists have wondered how unenclosed proteins and RNAs could self-organize into membrane-less organelles and stay separate from everything else in the cell until just the right time. It wasn’t until 2009 that researchers first determined that, during germline development, some of these unenclosed elements would condense into a self-enclosed, protected droplet due to phase separation—a process similar to how a homogenous mixture of oil and water can separate into two distinct phases.
These “biomolecular condensates,” as they came to be called, have the ability to phase separate under numerous cellular functions and interactions. Their malfunctioning has been linked to the development of various human diseases.
Central to the formation of these condensates are long, floppy biomolecules, including single-strand RNA and what are known as intrinsically disordered proteins, that are both enormously important to cellular function and magnificently difficult to study at the molecular level. While there are currently coarse-grained, low-resolution models that have given some insight into the world of RNA and intrinsically disordered proteins, until now there has been no efficient tool that can offer a more detailed window into how phase separation in RNA condensates work.
“This is a topic with intense interest in the field,” says Jianhan Chen, professor of chemistry at UMass Amherst and the paper’s senior author. “It’s not for lack of effort that a model like ours, iConRNA, hasn’t existed until now; it’s just that it’s extremely hard to build.”
Chen points to the paper’s lead author, Shanlong Li, postdoctoral researcher at UMass Amherst, and his “attention to detail, sharp physics intuition and strong sense of the best mathematical form to model various physical interactions of RNA” as keys to building iConRNA.
Part of what makes their model so powerful is that it resolves the balance of the distinct physical driving force of phase separation and can also predict how this balance is tuned under different cellular situations. “It allows you to ‘turn the knob’ of things like temperature and salt to see how they affect RNA’s phase separation,” Chen says.
Its performance tracks closely to experimental observations conducted in the lab, which means that, for the first time, researchers can get a close look at one of the enduring mysteries inside every human cell.
This work was supported by the U.S. National Science Foundation.
Contacts: Jianhan Chen, jianhanc@umass.edu
Daegan Miller, drmiller@umass.edu
About the University of Massachusetts Amherst
The flagship of the commonwealth, the University of Massachusetts Amherst is a nationally ranked public land-grant research university that seeks to expand educational access, fuel innovation and creativity and share and use its knowledge for the common good. Founded in 1863, UMass Amherst sits on nearly 1,450-acres in scenic Western Massachusetts and boasts state-of-the-art facilities for teaching, research, scholarship and creative activity. The institution advances a diverse, equitable, and inclusive community where everyone feels connected and valued—and thrives, and offers a full range of undergraduate, graduate and professional degrees across 10 schools and colleges and 100 undergraduate majors.
Journal
Proceedings of the National Academy of Sciences
Article Title
Driving Forces of RNA Condensation Revealed through Coarse-Grained Modeling with Explicit Mg2+
Article Publication Date
23-Oct-2025
Lighting up life: Rice scientists develop glowing sensors to track cellular changes as they happen
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Researchers at Rice University have engineered living cells to use a 21st amino acid that illuminates protein changes in real time, providing a new method for observing changes within cells.
view moreCredit: Photo by Jeff Fitlow/Rice University
Researchers at Rice University have engineered living cells to use a 21st amino acid that illuminates protein changes in real time, providing a new method for observing changes within cells. The technique is effective in bacteria, human cells and live tumor models, making it possible to study complex diseases like cancer more ethically. The findings are pending publication in Nature Communications Oct. 23.
This breakthrough addresses a long-standing challenge in biology: tracking subtle protein changes, known as post-translational modifications, within living systems. These modifications act like on/off switches for various processes, including growth, aging and disease. Rather than breaking open cells or using disruptive techniques, the research team engineered cells to produce a glowing version of lysine. When these switches are activated, the glow provides real-time visibility, offering scientists a new perspective on the inner workings of life.
“This system lets us see the invisible choreography of proteins inside living cells,” said Han Xiao, the study’s corresponding author, professor of chemistry, bioengineering and biosciences and a Cancer Prevention and Research Institute of Texas Scholar. “By equipping cells with the tools to produce and sense a new amino acid, we unlock a direct window into how PTMs drive biological processes in living animals.”
Chromophoric proof of concept
The initiative began with the hypothesis that giving cells the ability to autonomously produce and use a 21st amino acid would outperform traditional methods that depend on feeding cells large quantities of synthetic labels.
The research team identified and harnessed enzymes to produce acetyllysine within the cells. The team then genetically engineered bacteria and human cells to incorporate it into proteins at specific sites. Reporter proteins such as a fluorescent protein or an enzyme emit light when PTMs are added or removed, validating the system’s effectiveness for real-time tracking.
“This innovative method goes beyond previous approaches by eliminating the need for external chemicals and allowing us to watch protein changes happen naturally inside living cells,” Xiao said.
PTMs and cancer research
As a demonstration of its capability, the researchers used the sensors to study the deacetylase SIRT1, a posttranslational regulator that plays a role in modulating inflammation and has long been debated in cancer biology.
Inhibiting SIRT1 blocked its enzymatic activity but contrary to some expectations did not impede tumor growth in certain cell lines.
“Seeing a glow in response to acetylation events inside living tissue was thrilling,” Xiao said. “It makes the invisible world of protein regulation vividly observable and opens new possibilities for studying disease mechanisms and drug actions.”
Broader applications and future outlook
The engineered cells could reshape how scientists study PTMs in areas like aging and neurological disease. Because they work in living organisms, they can track disease or treatment in real time, and their light-based signals are well suited for large-scale drug screening targeting PTM-regulating enzymes.
Future enhancements may extend this approach to other types of PTMs or human-derived organoid systems, increasing the platform’s relevance for personalized medicine and providing deeper insights into cellular regulation.
“With this living sensor technology, our research offers an innovative tool that illuminates the dynamic world of PTMs, promising to reshape our understanding and treatment of diseases rooted in protein regulation by transforming invisible molecular signals into visible biological narratives,” said Yu Hu, the study’s first author and postdoctoral researcher at Rice.
Co-authors of this study include Rice’s Yixian Wang, Linqi Cheng, Chenhang Wang, Yijie Liu, Yufei Wang, Yuda Chen, Shudan Yang, Yiming Guo, Shiyu Jiang and Kaiqiang Yang.
The SynthX Seed Award, National Institutes of Health, Robert A. Welch Foundation, U.S. Department of Defense and Robert J. Kleberg Jr. and Helen C. Kleberg Foundation supported this work.
Journal
Nature Communications
Article Title
Engineering unnatural cells with a 21st amino acid as a living epigenetic sensor
Article Publication Date
23-Oct-2025
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