New Metabolite Detection Method Using DNA Sequencing Could Transform Diagnostics

Metabolites play a vital role as biomarkers that provide insights into our health, and when their levels go awry, it can lead to diseases such as diabetes and phenylketonuria. Quantifying metabolites remains challenging due to their biochemical diversity, making them difficult to amplify using methods like PCR. The major hurdle in metabolomics is to efficiently measure a broad range of molecules across various samples, such as tissues, plasma, or single cells, rapidly and effectively. Researchers have now created a method that leverages DNA sequencing to measure metabolite or drug levels, thus incorporating the capabilities of DNA sequencing into metabolomics.

The new DNA sequencing-based approach for metabolite measurement was developed by scientists at the University of Toronto (Ontario, Canada), and their findings were published in Nature Biotechnology. This method facilitates the swift and precise analysis of biological compounds, including sugars, vitamins, hormones, and numerous other metabolites crucial to health. The novel platform for small molecule sequencing, named “smol-seq,” utilizes short DNA sequences called aptamers to detect metabolites. Each aptamer is specifically engineered to bind to a target metabolite and carry a unique DNA barcode. When an aptamer binds to its designated target, the aptamer’s structure changes and releases its DNA barcode. For instance, an aptamer designed to detect glucose releases one barcode, while an aptamer targeting the stress hormone cortisol releases a distinct barcode. By sequencing these released barcodes, researchers can determine which aptamers have successfully found their targets. The more of a metabolite present in the sample, the more barcodes are released, providing a way to measure the concentration of various molecules within a mixture.

Although aptamers have been previously used to measure metabolites, those methods generally only allowed the measurement of a limited number of metabolites at once. The researchers recognized that by using DNA barcodes as tags for metabolites, they could measure hundreds or even thousands of metabolites simultaneously. With the smol-seq platform now operational, the next phase is to develop aptamers for metabolites with potential biomedical significance. Over time, the expanding aptamer database will support machine learning approaches for predicting new aptamer designs capable of binding novel metabolite targets. In addition to enhancing the aptamer database, the research team will refine the platform to improve the precision of aptamer binding. This will be achieved by fine-tuning aptamer development at the nucleic acid level, ensuring the specificity required as the platform’s capacity to study an increasing number of metabolites grows.

“DNA sequencing is millions of times faster than it was 20 years ago, and we wanted to harness that power for metabolite detection,” said Andrew Fraser, principal investigator on the study and professor of molecular genetics at U of T’s Temerty Faculty of Medicine. “Smol-seq could transform diagnostics and biotechnology by making metabolite detection as easy and rapid as DNA sequencing.”