Naked Liquid Blobs Inside Cells Can be a Key Target for Therapies Against Cancer and ALS

Biomolecular condensates, once believed to be simple blobs, are now recognized as a core structure involved in cell division and growth. New research has offered insights into its structure: it is built from complex networks of protein filaments that form a scaffold, and has a defined architecture, unlike previously thought. Scientists hope to target condensate architecture to device therapeutics for cancer and neurodegenerative diseases.

Biomolecular condensates were perceived as average droplets, as they behave like liquids that could coalesce and exchange components quickly. These are not bound by a membrane, unlike traditional compartments. Their primary role is to regulate genetic instructions that control the conversion of DNA into proteins, and to assist in clearing cellular waste that could accumulate and become toxic. Scientists have also found that biomolecular condensates play a role in tumor suppression. Many of these processes are directly linked to various diseases; hence, targeting these low-profile cellular structures can offer new ways to tackle them. 

“Ever since we realized that disruptions in condensate formation are at the heart of many diseases, it has been challenging to target them therapeutically because they appeared to lack structure — there were no specific features for a drug to latch onto,” says Keren Lasker, associate professor at Scripps Research and senior author of the study. “This work changes that. We can now see that some condensates have an internal architecture, and that, importantly, this structure is required for function, opening the door to targeting these membrane-less assemblies much like we target individual proteins.”

To explore how condensates function as membraneless organelles, Lasker’s lab worked with a bacterial protein called PopZ. In some rod-shaped bacteria, or bacilli, PopZ gathers at cell poles, forming condensates that organize proteins required for cell division. Scripps Research professors Ashok Deniz and Raphael Park, who co-led the study, used cryo-electron tomography (cryo-ET), an imaging technique similar to a CT scan at molecular dimensions—Cryo-ET allows researchers to see cellular structures in vivid detail. The images revealed that PopZ proteins assemble into filaments through a coordinated step-by-step process. These filaments then form a scaffold that influences the condensate’s physical features.

Using FRET, a technique that detects small shifts in distance between proteins by measuring energy transfer between externally added fluorescent tags, the researchers collected data on PopZ behavior. The protein changes shape depending on its location, and adopts different conformations inside and outside of a condensate. The difference in conformation can be leveraged in multiple ways to engineer cellular function.

Next, the scientists examined whether PopZ is necessary or just a structural presence in cellular life. To do this, scientists engineered a mutant version of the PopZ gene that failed to form any filaments. The condensates became much more fluid and had lower surface tension. When these changes were introduced into the bacteria, the cells stopped growing, and their DNA didn’t separate properly. The physical properties had more implications for the life cycle of a cell than mere presence.

The findings, although associated with bacteria, have broader relevance. Since biomolecular condensates clear damaged or toxic proteins and control cell growth, they directly influence ALS and cancer. Toxic protein build up is a defining characteristic of neurodegenerative disease like ALS, causing disruptions in neural communication. Cleaning up of such proteins can mitigate the risk of such diseases. Growth-regulating condensates prevent tumor growth, and if they fail, tumor growth can spiral out of control.

A deeper look into biomolecular condensates shows how potent they might be in alleviating cancer or ALS, though a viable treatment based on these wonder blobs is still far off.