Bioengineers at Stanford University have unveiled a new way to read proteins – by converting them into DNA. The approach, dubbed “reverse translation,” allows protein sequences to be decoded using fast, low-cost DNA sequencing platforms, achieving single-molecule sensitivity with minimal sample requirements.
The method works by chemically tagging amino acids with DNA barcodes as they are sequentially cleaved from a peptide, building on principles from Edman degradation and antibody-based detection. These barcoded fragments are then amplified and read as DNA, effectively transforming protein sequencing into a DNA sequencing problem. In validation experiments – alongside conventional mass spectrometry workflows used for characterization – the technique achieved ~98 percent accuracy and could detect extremely rare peptides, even at ratios as low as one in a million.
Unlike mass spectrometry, which typically samples only a fraction of the billions of protein molecules present, the new approach dramatically boosts detection sensitivity – potentially revealing previously invisible, low-abundance proteins and post-translational modifications. This could prove critical for understanding cellular heterogeneity and why therapies such as CAR-T work in some patients but not others.
“What really is different is how much from the same sample we can see,” said Liwei Zheng, research engineer at Stanford and first author of the study in a press release. “With mass spectrometry, you’re shooting 1 billion to 10 billion protein molecules and see, typically, a million molecules out of it. With our method, you can potentially see 1,000 times that amount.”
Although still in early development, the researchers aim to translate the workflow into a push-button instrument. If successful, the technology could enable comprehensive, single-cell proteome mapping – bringing protein analysis closer to the scalability of genomics.
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