In 2019, systems biologist Sebastiaan van Heesch set out to unravel the mysteries of heart failure. Using a novel technique called ribosome profiling, he analyzed protein production in frozen heart tissue samples from 80 individuals, many of whom had succumbed to end-stage heart failure.
What van Heesch and his team discovered defied expectations. Alongside proteins encoded by known genes, the ribosomes were actively producing hundreds of previously undetected mini-proteins—molecules composed of just a few dozen amino acids. These proteins originated from genomic regions previously dismissed as noncoding, meaning they were not believed to produce functional molecules.
Many of these newly identified ‘dark proteins’ were found to localize in the mitochondria, the cell’s energy powerhouses. This discovery suggests they may influence mitochondrial function, particularly the energy production critical for heart muscle contraction.
“All of a sudden we could look at all of these noncoding RNAs getting translated. All of these weird things we didn’t know were happening before suddenly became visible.”
Van Heesch’s findings underscore the vast, unexplored complexity of the human proteome—the entire set of proteins expressed by the genome. This work is part of a growing global effort to map the ‘dark proteome’, a term describing proteins derived from noncoding regions of DNA, which may hold the key to understanding and treating previously intractable diseases.
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