A polymer science revelation about how liquid mixtures separate could have major implications for human health, metabolism and disease, new research indicates.
In a brief report published today in the Proceedings of the National Academy of Sciences , University of Chicago Pritzker School of Molecular Engineering (UChicago PME) Prof. Matthew Tirrell and Freie Universität Berlin Prof. Matthias Ballauff revealed previously overlooked factors at play in the separation of charged polyelectrolytes polymers in water, challenging assumptions that have dominated the field since the 1950s.
Research into this liquid-liquid phase separation has been “given new urgency,” Tirrell said, by recent work highlighting the process’ role in creating biomolecular condensates. These membraneless cellular structures, straddling the gap between biomolecules and cells in both size and function, perform many tasks necessary for life.
“Biomolecular condensates play important roles in stress response, signal transduction, metabolism, gene regulation and many human diseases,” said Tirrell, director of UChicago PME’s Institute for Materials and Sustainability . “Understanding the mechanisms that help them form makes understanding phase separation as important to biology as it is to physics or chemistry.”
A growing body of research over the past decade has shown that liquid-liquid phase separation helps create these living subcellular blobs, but the new work dives into how the process works.
“Biomolecular condensates formed in biological systems have virtually become an exploding field in recent years,” Ballauff said. “We know a lot about their importance in biology but seem to have much less insight into the basics, namely the equilibrium phase diagrams.”
To study this issue, the pair revisited a trove of experimental data Tirrell’s lab published in 2018. The data, once confounding, became illuminating given recent insights in the field.
“Ballauff and Tirrell expose fresh insight into the phase behavior of aqueous mixtures of negatively and positively charged macromolecules,” said University of Minnesota Department of Chemical Engineering and Materials Science Regents Prof. Frank Bates, who was not involved in the research. “They revisit previously published, but puzzling results, dealing with phase separation of polyions, attributable to molecular clustering in dilute solution.”
Polyion clusters
Liquid-liquid phase separation is the process by which a homogenous mixture of liquids separates into two distinct phases. Shaking a bottle of salad dressing and watching the blend split back into oil and vinegar shows the process at work.
In 1929, scientists found a similar separation when mixing highly charged polyelectrolyte polymers of opposite charges in water. The Voorn-Overbeek model developed in 1957 taught decades of researchers to model the reaction as a single variable, a simple peeling away of two symmetrical polymers of equal chain length and charge fraction. The components would separate into what they once were, no matter the composition of the mixture. In the salad dressing analogy, oil would separate back to oil, vinegar to vinegar.
Tirrell and Ballauff’s research shows this model, while valuable in certain cases, neglects a major factor that can impact how two liquids separate. They found that polyions – charged molecules or bonded atoms that act as a single unit – clump and cluster in different sizes and concentrations during the process, showing the process to be much more complicated than had been assumed since the 1950s.
“The field had overlooked the fact that this clustering will make the composition of the phase-separated components depend on the initial composition of the mixture we start with,” Tirrell said. “Without clustering, this would not occur.”
While this current research revisited previous data on polypeptides – long chains of amino acids – Tirrell and Ballauff are looking into how this process works in other polyelectrolyte systems, Tirrell said. But the pair anticipate that changing scientific assumptions locked in for seven decades will be a long process.
“It will take some time until people in the field realize that phase diagrams of biomolecular condensates look different than generally assumed,” Ballauff said. “We believe that our result will ultimately have a considerable impact in the field.”
Citation: “Macromolecular association creates dispersity of components that determines liquid-liquid phase separation of oppositely charged polyions,” Ballauff and Tirrell, Proceedings of the National Academy of Sciences, Oct. 20, 2026. DOI: 10.1073/pnas.2628217123
Proceedings of the National Academy of Sciences
Macromolecular association creates dispersity of components that determines liquid–liquid phase separation of oppositely charged polyions
21-Oct-2026