STAT+: How a global effort to explore the ‘dark proteome’ is upending our understanding of human disease

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.