Be it heart disease or liver disease, researchers and clinicians are well used to thinking about disease at the level of organs.

They are also used to thinking of the dysfunction of individual proteins as the molecular underpinnings of diseases -- amyloid beta aggregations in Alzheimer's disease, receptor tyrosine kinases whose hyperactivity drives cancer.

And increasingly, "we are appreciating that there are a lot of defects in this middle ground," Salman Banani told BioWorld Science.

"This middle ground" is the level of subcellular multiprotein structures, and in particular, condensates.

Membrane-bound organelles such as mitochondria or lysosomes are also implicated in disease. But the number of types of condensates, which are protein- and RNA-rich compartments that are not bound by membranes, "just by sheer number far outnumber" the types of membrane-bound organelles, Banani said. "The cell has many different types of biochemical reactions that are happening at the same time, and it needs some way to organize them."

Organization into condensates is more flexible than in organelles, as condensates can form to perform a specific task, and then dissolve as the needs of the cell change.

To date, condensate dysfunction has been heavily linked with neurodegenerative disorders, with few exceptions. But Banani and his colleagues suspected that a broader look might uncover more to see.

Neurons are very vulnerable to protein aggregates, which can be thought of as "a pathological extreme of perhaps a physiological condensate," Banani said.

Banani is a postdoctoral associate in Richard Young's laboratory at the Whitehead Institute for Biomedical Research as well as a clinical fellow in pathology at Harvard Medical School's Brigham and Women's Hospital, and the co-first author of a paper published online on July 8, 2022, in Developmental Cell that takes a comprehensive look at mutations that might affect condensate formation, and linking them to a broader range of diseases.

In the work now published in Developmental Cell, the team took a broad look at whether condensate dysfunction could be linked to other diseases, with a focus on cancer and rare diseases.

The team first used computational methods to catalog mutations in condensate-forming proteins that they predicted would interfere with normal condensate function.

The team also tested a subset of the proteins in the wet lab to verify their bioinformatic predictions, and showed that nearly 90% of those tested mutations across various proteins did affect condensates. The team suspected that a comprehensive look would uncover a broader role for condensates across disorders. But Banani said that he was surprised by the sheer scale of the findings. In their paper, the investigators summarized that they identified "over 36,000 pathogenic mutations that plausibly contribute to condensate dysregulation in over 1,200 Mendelian diseases and 550 cancers."

The work uncovered no particular bias in which disorders condensates show up.

"If you just go organ by organ, the proportion of mutations that likely affect condensates across the board are roughly similar," he said.

In their paper, the authors concluded that "condensate dysregulation may be a pervasive pathogenic mechanism underlying a broad spectrum of human diseases."

Drugging condensates is still in its infancy, but Banani said that "there are now several examples of small molecules that can modulate properties of condensation."

In 2020, research out of the laboratory of senior author Richard Young, who is a professor at MIT and the co-founder of condensate-focused startup Dewpoint Therapeutics Inc., showed that condensates could trap and concentrate cancer drugs. This trapping can lead to drug resistance. But in principle, it could also allow for high concentrations of condensate-targeting drugs at the sites where they are supposed to act.

Banani said that he and his colleagues want to delve deeper into the molecular-level reasons why condensate dysregulation causes diseases, which is still largely a black box for most diseases. And they hope others will as well, he added: "people can take this as a starting point and bear condensates in mind when asking questions about diseases where the mechanisms aren't known." (Banani, S.F. et al. Dev Cell 2022, 57: 1).