In 2019, Sebastiaan van Heesch was trying to pry apart the secrets of a broken heart. A systems biologist, van Heesch used a newish method to analyze the contents of ribosomes, cellular protein factories, in a collection of frozen hearts donated by 80 people, many of whom had died from end-stage heart failure. By uncovering all the proteins being produced in each heart, he and his team hoped to learn what had gone wrong.
What they found with this “ribosome profiling” tool produced more questions than answers. In addition to proteins encoded by known genes, the ribosomes also seemed to be making hundreds of never-before-seen mini-proteins — molecules just a few dozen amino acids long whose code could be traced back to portions of the genome that weren’t thought to produce proteins. The main destination for many of these “dark proteins” was the mitochondria, raising the possibility that they were influencing the energy production process necessary for the muscles of the heart to beat properly.
“All of a sudden we could look at all of these noncoding RNAs getting translated,” van Heesch said. “All of these weird things we didn’t know were happening before suddenly became visible.”
Van Heesch is part of an international team that has since gone on to find thousands of these mini-proteins and started to decipher what exactly they do. In a paper published Wednesday in Nature, the group reports the discovery of some involved in critical roles like cell division and DNA repair, as well as several unique to cancer cells that they display on their surfaces. A number of such molecules have already caught the attention of biotech and pharma companies as potential targets for immunotherapies and other disease treatments.
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