New approaches for archaeal genome-guided cultivation

Archaea, one of the three domains of life along with Bacteria and Eukarya, contains ancient life forms such as methanogen that are observed today on Earth, and one lineage Asgard archaea is also considered the closest ancestor of Eukarya. Recently, with the development of interdisciplinary studies from Earth and Life sciences, archaeal organisms are considered to play pivotal roles in geochemical cycling in nature. However, our understanding of the attributes, origin and evolution, geochemical and ecological functions of Archaea is hampered by the scarcity of archaeal isolates, which has represented a challenge to researchers for the last 40 years. Cultivation-independent sequencing and phylogenomic analyses have demonstrated a considerable diversity of Archaea with more than 20 novel phyla. However, only four archaeal phyla have cultured representatives, leaving large gaps in our knowledge of the metabolic capabilities and ecological functions of the majority of archaeal strains identified exclusively by DNA sequencing. In this review, we summarize the discovery and development of archaeal research, highlight the knowledge gap between uncultured and cultured archaeal microbes, and call on the importance of devoting greater research efforts to archaeal cultivation. Finally, we outlined new ideas and strategic approaches, namely, (1) genome-based methods, (2) microbial network information-based methods, (3) genome-scale model-guided methods, and (4) machine learning methods, to enable the cultivation of uncultivated archaeal microbes using accumulated high-throughput sequencing data.