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Virus-X: Viral Metagenomics for Innovation Value

Periodic Reporting for period 3 - Virus-X (Virus-X: Viral Metagenomics for Innovation Value)

Reporting period: 2019-04-01 to 2020-03-31

The Virus-X project was designed to explore and access the genomes of natural viruses, study their diversity and impact in extreme ecosystems, and determine functional roles and the potential of encoded gene products for biotechnological applications. The research and development program employed metagenomics (using collection of genes extracted from environmental samples) and sequence-based bio-prospecting methodologies for accessing diverse environmental genetic material, combining bioinformatics, functional analysis and 3D structure determination of gene products. The Virus-X project put emphasis on developing new tools to strengthen future efforts in the field of metagenomics. This includes new bioinformatics tools for sequence analysis and structure-function analysis of protein families. The Virus-X project has enhanced the understanding of microbial communities and functional dynamics between viruses and microorganisms. The exploration of viruses in natural cold ecosystems in the ocean off the coast of Norway, hydrothermal vents on the North Atlantic ridge and geothermal areas (hot springs) in Iceland was the main focus in the Virus-X project.

The overall objectives in this multidisciplinary project included both scientific and technological objectives. Among the scientific objectives was better understanding of microbial ecosystems, the diversity of viruses in nature and their interaction with their natural microbial hosts. Of special interest in understanding virus-host interactions are instruments of immunity in bacteria against viruses such as the CRISPR system. Also, of importance in this project was the elucidation of the function of gene products that had an unknown function. The metagenomics approach, combined with the development of powerful new bioinformatics tools, structural determinations of gene products and complementary biochemical analysis has provided a way for such scientific discoveries.

A central objective in the project and the mass of the work was the Virus-X biodiscovery pipeline enabling the discovery and utilization of enzymes from selected target genes. Enzymes from bacteria and not the least from viruses have before proved to be the tools that have enabled the revolution we have witnessed in biotechnology, genetics and other biological sciences. Some of the most important tools, for instance heat stable DNA polymerases for use in a Polymerase Chain Reaction (PCR), have been derived from microorganisms that live under extreme environmental conditions. Such environments have been a special focus point in the Virus-X project for the exploration and exploitation of the genetic diversity within the genomes of viruses.

The Virus-X was successfully completed leading to innovations and industrial value in the form of specific marketable products for biotech applications. Furthermore, the wealth of information and scientific discoveries, now evident as a result of the Virus-X project, are immense in both scope and value with an impact that will continue long after the completion of the project. Receiving funding through the European Framework programme for Research and Innovation was absolutely vital to be able to carry out a research and development plan of this scale and ambition.
The Virus-X project was built up as a bio-discovery pipeline fed by genetic resources from microbial ecosystems, the initial phase in the project has focused on environmental sampling for processing and extraction of DNA for subsequent sequencing and analysis of the genetic data. A hallmark of Virus-X was a research approach termed metagenomics that bypasses the conventional isolation and cultivation of organisms in a laboratory and rather involves extracting genetic material directly from environmental samples which is then sequenced. The computational bioinformatics algorithms have identified over 50 million genes in the genetic data obtained so far and to some extent predicted the function of the corresponding gene products. Enzymes that can become new and improved tools for molecular biology applications, such as enzymes that can cut, ligate or amplify DNA (i.e. nucleases, DNA ligases and DNA polymerases, respectively), are among enzymes that were of special interest in the project. Thousands of genes coding for enzymes in this category have been identified from sequence information and some of these genes selected for cloning into gene vehicles (vectors) and subsequent introduction into specific microbial production hosts that allowed the desired enzymes to be produced for further studies. The biochemical characterization involved measuring some functional characteristics of the enzymes such as activity at different temperatures and pH and substrate specificity. This information gives indications of the potential of using these enzymes for new or improved applications and the potential of commercial value for the participating enzyme developers which have obtained specific enzymes that are being developed into marketable products. An important part of Virus-X was to determine the function of the discovered, novel proteins, in particular for those whose function cannot be predicted reliably from sequence. These genes are abundant in viral genomes and often constitute the majority of the genes in a given viral genome. The 3-dimensional structure of a gene product (e.g. an enzyme) has proved to give a better indication of its function by structural similarity than sequence information had previously given. Last but not least, Virus-X has provided invaluable information on ecological aspects of microbial ecosystems to better understand certain aspects, like host specificity and various defense and anti-defense mechanisms, in the interplay between viruses and their hosts in nature.
The Virus-X project has opened up doors to previously unexplored genetic diversity with a large number of genes from the genomes of viruses being targeted for analysis and exploitation. It is expected that the project will continue to facilitate the development of gene products that are both useful and commercially valuable for industry with corresponding societal implications. The project has led to discovery of exciting new biological functions by elucidating the function of gene products with previously unknown function or properties using methods of bioinformatics, crystal structure determination and biochemical characterization. The approach will also promote further development of methods and tools in the field for the benefit of future exploitations of natural genetic resources. The Virus-X project has also involved development of many new bioinformatics tools that will continue to be used for years to come. The scientific impact of the project also includes clearer understanding of microbial communities and discovery of novel genes and proteins. The project is expected to have major impact in numerous areas: exploration of new genetic territory and sequence diversity, further development of new approaches and tools for metagenomics, understanding of microbial communities and continued development of commercially useful genes with corresponding impact on the European biotech industry towards new marketable products and services. The project has also been of paramount value for the education of young scientists and preparation for their future scientific careers for the benefits of society.