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University of Toronto researchers have developed a new approach for measuring metabolites using DNA sequencing. This makes fast and accurate study of biological molecules such as carbohydrates, vitamins, hormones, and a number of other metabolites vital for health possible.
To recognize metabolites, the new small molecule sequencing platform, known as “smol-seq,” uses short strands of DNA known as aptamers. Every aptamer is made to carry a distinct DNA barcode and attach to a target metabolite.
Because of their importance for our health, researchers must analyze metabolites; nevertheless, studying this large spectrum of compounds can be quite difficult. Mass spectrometry has been the preferred method for assessing metabolite levels until now; however, it is not as quick or as easily available as techniques that sequence DNA. Researchers sought to leverage that amazing sequencing capability by developing a technique detecting metabolites using DNA sequencing.
Once an aptamer hooks itself to its target, its structure changes to release its DNA barcode. The glucose-detecting aptamer, for instance, produces one barcode while the aptamer identifying the stress hormone cortisol produces another barcode.
This allows one to determine which aptamers detected their targets just by running the released barcodes. More of that barcode is released in a sample the more of a metabolite target it contains, therefore enabling researchers to calculate the concentration of various compounds in a combination.
Researchers have previously employed aptamers for the quantification of metabolites; however, these methodologies predominantly allow the measurement of only a limited number of metabolites. Researchers came to discover that they could measure hundreds or perhaps thousands of metabolites concurrently if they tagged them with DNA barcodes.
With the smol-seq platform now operational, the subsequent phase involves the development of aptamers targeting metabolites that possess biomedical potential. The growing database of aptamers will eventually allow machine learning to forecast aptamer designs that interact with new metabolite targets.
Apart from expanding the aptamer database, the study team will modify the platform to improve the aptamer binding accuracy and enhance the precision. This can be accomplished by optimizing aptamer synthesis at the nucleic acid level—a degree of specificity required as the total number of metabolites the platform can be used to examine develops.
DNA sequencing has advanced to a speed that is millions of times greater than it was two decades ago, and researchers aimed to leverage this capability for the detection of metabolites. By allowing metabolite detection as simple and quick as DNA sequencing, smol-seq could revolutionize biotechnology and diagnostics.
Sources:
June H. Tan et al. (2025). Quantifying metabolites using structure-switching aptamers coupled to DNA sequencing, Nature Biotechnology. DOI: 10.1038/s41587-025-02554-7
https://phys.org/news/2025-02-method-rapid-metabolite-dna-sequencing.html
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