05 Aug 2025
Holographic microscopy points to new undestanding of role in disease, drug therapy.
A project at New York University (NYU) has combined holographic microscopy and super-resolution imaging to study the tiny cell droplets called biomolecular condensates.
These condensates are essential for cellular organization and function, yet understanding how chemical and physical factors govern their formation and dynamics has been limited by a lack of noninvasive measurement techniques.
In particular, conventional microscopy methods relying on fluorescent labeling and substrate immobilization can perturb the intrinsic properties of the structures, noted the team in its Journal of the American Chemical Society paper.
“It’s been the elephant in the room for scientists,” said NYU’s Saumya Saurabh. “Our research provides a precise and non-invasive way to study biomolecular condensates.”
Seeking a way to examine condensates in real time without damaging them, the NYU project designed a system that slowly flows thousands of droplets through a holographic microscope, so that each particle scatters light from the microscope’s laser beam.
“The scattered light interferes with the remainder of the laser beam, and the intensity of the magnified interference pattern constitutes a hologram of the particle that is recorded with a video camera,” wrote the team in its paper.
The NYU lab of David Grier has pioneered the use of holographic microscopy, using lasers and lenses to create holograms of particles for analysis. This technique allows scientists to image particles in solution so that they can be clearly seen and individually characterized, without the need for fluorescent labels or attachment to a surface.
Big surprises from an important class of systems
In trials, the project applied its holographic microscopy method to the study of condensates formed by PopZ, a bacterial protein crucial for cell growth, aiming to precisely measure the concentration of proteins within the condensates.
Using the volume of a single protein as a way to determine the protein concentration inside condensates, NYU found that relevant biomolecules could concentrate proteins more than ten-fold inside condensates. But the way that the observed condensates grew was unexpected and “defied classical models of growth.”
Subsequent super-resolution microscopy and molecular dynamics simulations showed that the condensates were not simple uniform droplets, but exhibited intricate nanoscale organization. This could be valuable for understanding the role of biomolecular condensates in diseases such as cancer or neurological disorders.
“In a disease like ALS, the proteins that form plaques in disease are fluid condensates in good health,” noted Saurabh. “Understanding how a spherical condensate forms into a deadly plaque is an opportunity to better understand ALS.”
The technique should also benefit drug development, as scientists now know that many drug molecules end up inside biomolecular condensates in the cells. This sequestering of drugs within condensates may help explain why drugs that are made to target a specific protein still cause side effects.
“Being able to see ‘under the hood’ for the first time has revealed some big surprises about this important class of systems,” commented NYU’s David Grier, also founder of spin-out company Spheryx which is commercializing the holographic microscopy platform used in the project.