The Human Proteome Just Got 10% Bigger

The official catalog of human proteins is far from complete.

By analyzing billions of data points, an international team added 1,785 new entries to the human proteome. The work was led by the Princess Máxima Center for pediatric oncology, the University of Michigan Medical School, the EMBL European Bioinformatics Institute, and the Institute for Systems Biology.  

These tiny molecules, termed peptideins, were found in previously overlooked sections of DNA and offer promising new targets for cancer immunotherapy.

Mapping the hidden regions of the human proteome

Previously, scientists had believed that the human proteome consisted of ~19,500 proteins, but this  was based on a binary rule: a section of DNA either encoded a functional protein, or it did nothing. Non-coding regions were often overlooked, forming a biological “dark proteome” that remained invisible with traditional approaches.

However, this knowledge gap hindered the understanding of health and disease, with many genetic conditions and cancer mechanisms lacking clear explanations.

“We know that the current overview of recognized proteins doesn't capture the full picture,” said co-senior author Dr. Sebastiaan van Heesch, a research group leader at the Princess Máxima Center.

Historically, researchers ignored thousands of small genetic sequences, known as non-canonical open reading frames, because they were small or did not appear across different species during evolution. However, it is now understood that these hidden regions are not silent.

The new study aimed to systematically map these previously unknown molecules using large datasets to build a more accurate and functional inventory of the human proteome.

Discovery of peptideins and the microprotein proteome

The team analyzed 3.7 billion raw data points across 95,520 experiments, which required computers to work non-stop for ~20,000 hours.

They used a specialized computational pipeline to identify molecules that had gone undetected for years.

“By deploying our battle-hardened Trans Proteomic Pipeline across nearly 100,000 mass spectrometry experiments encompassing 3.7 billion spectra, we were able to confirm, with high confidence, the existence of more than 1,700 of these newly identified peptideins that would otherwise have largely remained invisible to science,” said co-senior author Dr. Robert Moritz, a professor and the head of proteomics at the Institute for Systems Biology.

The study identified 1,785 new microproteins, expanding the known proteome by nearly 10%. While these molecules are called microproteins because of their small size—65% consist of fewer than 50 amino acids—the team coined the term “peptidein” to describe their unique status. Unlike traditional proteins with known functions, peptideins have ambiguous biological roles that scientists are just beginning to define.

To prove these molecules matter, the team used CRISPR gene editing to switch off specific sequences.

They found several essential peptideins required for cell survival. Switching off one specific peptidein, produced by a sequence called OLMALINC, impaired the survival of 85% of cancer cell lines tested.

Clinical impact of peptideins and the expanding human proteome

Many peptideins appear on the surface of cells, making them ideal targets for cancer immunotherapies and vaccines.

“By classifying these molecules of unknown functionality as peptideins, we’ve given them a formal place in reference databases so the wider community can study them,” said Heesch.

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This expanded view of the human proteome may help clinicians diagnose genetic diseases that currently have no known cause.

“Given their smaller size and the diversity of cellular contexts in which they appear, I believe peptideins may prove to be among the most versatile and consequential regulatory molecules we have yet encountered in human biology,” said Dr. John Prensner, a pediatric neuro-oncologist at the University of Michigan and co-author of the study.

“We’re just beginning to see what this ‘dark proteome’ has to offer. It’s like the trailer to a movie. We see the outline of a game-changing view of human biology. We’re incredibly excited that the coming years will open new doors to help solve and treat human diseases such as cancer.” — Dr. John Prensner.

Understanding the functions of thousands of newly discovered molecules is a significant challenge. It took the team over a year to categorize the initial findings. To speed up the process, the researchers are sharing their data in an open-source format to encourage global collaboration.

“What excites me most is not simply that these molecules exist, but what their existence implies,” said Prensner.

“With growing interest in industry and academia, peptideins are at the center of multiple drug development initiatives,” Heesch added.

“This is not the end of a search—it is the opening of a vast and fertile new territory for the entire scientific community to explore and exploit, and I look forward to seeing what the broader scientific community uncovers as these molecules, and many more that are yet to be confirmed, are brought into the light,” Prensner concluded.

Reference: Deutsch EW, Kok LW, Mudge JM, et al. Expanding the human proteome with microproteins and peptideins. Nature. 2026. doi: 10.1038/s41586-026-10459-x

This article is a rework of a press release issued by the Princess Máxima Center for Pediatric Oncology. Material has been edited for length and content.