Rapid-fire yeast study offers clues to rare diseases, cancer, and other disorders
In a breakthrough that could shed light on the inner workings of human cells and advance the understanding of rare genetic diseases, Israeli and German scientists have discovered the functions of hundreds of previously mysterious proteins — by triggering them to go “on strike.”
Researchers from the Weizmann Institute developed a technique to deactivate specific proteins in yeast cells, leaving the cellular system no time to adapt. This allowed the team to observe the immediate fallout and infer the protein’s original function. The findings were recently published in the peer-reviewed Journal of Cell Biology.
“When you remove a protein suddenly, the cell doesn’t have time to replace it,” said Prof. Maya Schuldiner of the Weizmann Institute’s Department of Molecular Genetics, who led the study. “This lets us see what that protein really does, without any substitutes stepping in to mask its absence.”
The scientists used baker’s yeast — a simple organism used in bread and beer-making that shares about two-thirds of its genes with humans. Of the roughly 6,000 yeast genes, the functions of around 1,200 remain unknown, despite decades of study. To close this gap, the team created a massive genetic library of 5,170 yeast strains, each engineered so that a different protein could be instantly deactivated with a chemical trigger.
The method uses a three-part system: a molecular “tag” to mark the protein, a “destroyer” protein designed to eliminate tagged targets, and an intermediary chemical that activates the destroyer. With this setup, researchers could selectively shut down one protein at a time and observe the effects.
“We built a digital library that anyone can visit and query,” said Schuldiner. “You can find not only the yeast strains themselves but also learn what happened when a specific protein was inactivated.”
The project was spearheaded by doctoral student Rosario Valenti and Dr. Yotam David, and involved several other researchers from the Weizmann Institute, as well as scientists from the University Medical Center in Göttingen, Germany.
One of the study’s most significant discoveries involved mitochondria, the cell’s energy-producing structures. When the team used the library to explore mitochondrial function, they identified 220 genes whose sudden inactivation disrupted the mitochondria’s structure or energy production capacity.
“The cell is constantly reshaping its mitochondria to match its needs,” Schuldiner explained. “When this process fails, it can lead to a variety of diseases. Surprisingly, we still don’t know exactly how this mechanism works or which factors control it.”
Several genes were found to be universally essential for survival, regardless of environmental conditions, which had not been recognized as such before.
Beyond yeast biology, these findings could open doors to understanding the roles of parallel human proteins, many of which are linked to rare genetic disorders.
“Many rare diseases are tied to mutations in genes whose function is still a mystery,” said Schuldiner. “We share with yeast many hundreds of mysterious proteins whose function could be a key to understanding unsolved diseases.”
Several of the newly identified proteins regulate the cell division cycle, a process that often goes awry in cancer. Mapping these control proteins may help researchers find new biomarkers for cancer or targets for therapies that disrupt uncontrolled cell growth.
Mitochondrial dysfunction is associated with numerous conditions, including neurodegenerative diseases, metabolic disorders, and aging. Understanding the genetic controls behind mitochondrial function opens new paths for diagnosis, prevention, and treatment.
The new genetic library is already generating international interest.
“Laboratories around the world have begun to borrow individual strains to study unknown proteins,” Schuldiner said. “I hope this tool helps to unravel some of the mysteries of how human cells function in both health and disease.”
