[Possible technical elements for the ultimate nucleotide sequencers].

The DNA sequencing technology invented in 1970's has been a leading tool for genomics and its sequel ─ precision medicine. The needs for advancement of the DNA sequencing technology comes from increasing resolutions in cellular and molecular studies, not only DNA or cDNA sequences but also their covalent modifications, such as various kinds of DNA or RNA methylations. Sequencing single RNA molecules directly without conversion into cDNAs appears to be the last generation of nucleotide sequencers. Some cutting-edge technological elements are clearly expected for the ultimate design of nucleotide sequencers, which must include, but not limited to, nanopores, nanofabrication, surface- or tip-enhanced Raman spectrometry, single-molecule photonics and plasmonics, artificial-intelligence based data analysis tools. The complexity of biological systems is also calling for new syntheses, frameworks, paradigms and more concerted efforts and projects internationally. Here we discuss possible roles and capacities of such technical elements for the fourth-generation nucleotide sequencers in details.