Seven technologies to watch in 2023 –

From protein sequencing to electron microscopy, and from archaeology to astronomy, here are seven technologies that are likely to shake up science in the year ahead.

Single-molecule protein sequencing

The proteome represents the complete set of proteins made by a cell or organism, and can be deeply informative about health and disease, but it remains challenging to characterize.

Proteins are assembled from a larger alphabet of building blocks relative to nucleic acids, with roughly 20 naturally occurring amino acids (compared with the four nucleotides that form molecules such as DNA and messenger RNA); this results in much greater chemical diversity. Some are present in the cell as just a few molecules — and, unlike nucleic acids, proteins cannot be amplified, meaning protein-analysis methods must work with whatever material is available.

Most proteomic analyses use mass spectrometry, a technique that profiles mixtures of proteins on the basis of their mass and charge. These profiles can quantify thousands of proteins simultaneously, but the molecules detected cannot always be identified unambiguously, and low-abundance proteins in a mixture are often overlooked. Now, single-molecule technologies that can sequence many, if not all, of the proteins in a sample could be on the horizon — many of them analogous to the techniques used for DNA.

Edward Marcotte, a biochemist at the University of Texas at Austin, is pursuing one such approach, known as fluorosequencing1. Marcotte’s technique, reported in 2018, is based on a stepwise chemical process in which individual amino acids are fluorescently labelled and then sheared off one by one from the end of a surface-coupled protein as a camera captures the resulting fluorescent signal. “We could label the proteins with different fluorescent dyes and then watch molecule by molecule as we cut them away,” Marcotte explains. Last year, researchers at Quantum-Si, a biotechnology firm in Guilford, Connecticut, described an alternative to fluorosequencing that uses fluorescently labelled ‘binder’ proteins to recognize specific sequences of amino acids (or polypeptides) at the ends of proteins2.

Researchers can now make synthetic embryos in the laboratory (bottom) that resemble natural, eight-day-old embryos (top).Credit: Magdalena Zernicka-Goetz Laboratory

Other researchers are developing techniques that emulate nanopore-based DNA sequencing, profiling polypeptides on the basis of the changes they induce in an electric current as they pass through tiny channels. Biophysicist Cees Dekker at Delft University of Technology in the Netherlands and his colleagues demonstrated one such approach in 2021 using nanopores made of protein, and were able to discriminate between individual amino acids in a polypeptide passing through the pore3. And at the Technion — Israel Institute of Technology in Haifa, biomedical engineer Amit Meller’s team is investigating solid-state nanopore devices manufactured from silicon-based materials that could enable high-throughput analyses of many individual protein molecules at once. “You might be able to look at maybe tens of thousands or even millions of nanopores simultaneously,” he says.

Although single-molecule protein sequencing is only a proof of concept at present, commercialization is coming fast. Quantum-Si has announced …….


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