WormBase: expanding the reference resource for helminth research

Many developments in modern medicine are based on the enormous progress made over the last 50 years in our understanding of how our genes work. Many diseases are caused by genes malfunctioning in some way, and understanding the function of genes allows to design diagnostic tools and treatments against specific malfunctions. Much of the research that has led to this progress is difficult to do in humans. Because all animals are related by evolution, study of simple animals helps to understand human biology. Certain key model organisms have been the focus of intensive study. One of these is the tiny roundworm, or nematode, Caenorhabditis elegans. C. elegans research has been supported by the MRC for over 50 years, leading to two Nobel prizes, and is a key contributor to our understanding of basic processes such as cell death and ageing. In addition to its relevance for understanding human biology, research on C. elegans is particularly important to our understanding of the biology of parasitic worms. Globally, more than one billion people are infected with parasitic nematodes, including filarial nematodes, such as Onchocerca that causes river blindness, and Brugia that causes elephantiasis; intestinal nematodes such as hookworms, whipworms and giant roundworms. Typically infections are associated with and promote poverty. Genetic research has been revolutionized by obtaining the complete DNA sequence (the genome) of the organism being studied, which contains all the gene sequences. C. elegans was the first animal to have its genome sequenced and now major programmes are collecting genome sequences for parasitic species. To use genome sequences and all the new information about genes requires information resources that tie together DNA information with experimental data, and relate corresponding genes across animals. This application will support the development of WormBase, the reference information resource for all genomic and biological data for C. elegans that is essential for fundamental research using this model organism. The application will also support the expansion of WormBase to include the curation of genomic and experimental information for increasing numbers of parasitic nematodes, and an expansion in scope to include Schistosoma mansoni, a parasitic flatworm. Research into both types of parasitic worms (flatworms and nematodes) has much in common despite their evolutionary distance and WormBase will now support fundamental research in both these areas. By relating parasitology and basic science research, WormBase is uniquely placed to enable community-wide exploitation of data emerging for parasites by applying information, technological infrastructure, and curatorial expertise developed for C. elegans.

We will integrate, curate, analyse and disseminate (through the community website wormbase.org) molecular and other research data from C. elegans - a widely used model organism - and eight important species of parasitic worms. Our approach is to import (especially sequence-based) data from relevant public archives, analyse it automatically using state-of-the-art tools (particularly for the structural and functional annotation of reference genome sequences), to revise these data by manual review and to supplement them by abstraction of functional information and experimental metadata from the scientific literature into ontological vocabularies that can be used for semantic querying. We will support this process using a mixture of community-standard and in-house bioinformatics tools and technologies, including the WormBase database infrastructure (which is in the process of migrating to a new backend using the Datomic database); the Apollo annotation tool; InterProScan for annotation of protein domains; the Gene Ontology and other, worm-specific ontologies; in-house software for literature-identification and triage; state-of-the-art tools (e.g. Kallisto) for RNA alignment. We will use common formats (e.g. FASTA, GFF, BAM/CRAM, VCF, track and assembly hubs) to collect, share and disseminate data according to type. We will scan the molecular archives to automatically identify important new data sets, and additionally keep in regular communication with members of the research community to ensure that no recent or forthcoming data is overlooked. Where requested, we will help community members prepare new data for submission to the public archives.

We will coordinate these efforts with other projects of the UK WormBase team, and with our international partners on the WormBase project, managing a series of regular data releases in an efficient fashion and making a significant contribution from the UK to the global development of the WormBase resource.

The potential beneficiaries of this research are, in the short term, academic researchers interested in helminth-mediated disease in humans (and farm animals), and more generally researchers interested in human biology using C. elegans as a model. Basic molecular insights in C. elegans have driven major fundamental advances in modern medicine, illustrated by 2 Nobel Prizes: the 2002 prize to Brenner, Sulston and Horvitz for identifying genes that regulate organ development and apoptosis in C. elegans, along with the equivalent genes in man; and the 2006 prize to Fire & Mello for the discovery of RNA interference.

Parasitic worms are studied with the aim of killing or controlling them. WormBase will significantly facilitate the direct exploitation and application of large-scale data from sequence based experiments towards this aim, through the provision of accessible, accurate, well-described reference data. Furthermore, the proposed resource will leverage the in-depth and highly organised knowledge-base of C. elegans into the poorer-resourced areas of parasitic nematode research, and from the reference data produced in this project to even less-well studied diseases.

In the longer term, potential beneficiaries include drug companies, farmers, and most strikingly the millions of individuals whose lives are currently blighted and or curtailed but which could be remedied by appropriate programs of treatment or remediation. The application of genomic science towards medical improvements is still in its infancy, but for pathogens with smaller and simpler genomes such as viruses and bacteria, genomic insights are already being translated into tangible benefits e.g. tracking pathogen transmission and the monitoring of drug resistance. For parasitic nematodes, genomic research is expected to deliver significant benefits in the medium term, for which ready access to the data is a clear requirement. The primary beneficiaries will be the people directly suffering from nematode infections, which includes about 2 billion people infected with soil-transmitted helminths alone (WHO 2012). Advances in drug treatment, transmission reduction or vaccination could improve the lives of many people who may otherwise suffer from serious gastrointestinal disease, stunted growth and mental development, malnutrition and fatigue, disfigurement, blindness, or liver and bladder pathologies. Although some effective anthelmintics exist, the available arsenal of drugs is limited and the spread of drug resistance a real danger. Furthermore, large-scale improvements in the treatment and control of helminthiases are likely to bring huge socio-economic benefits to some of the least developed countries.

In addition to the direct health improvements from a reduction in helminth infections, people in endemic areas could also benefit indirectly e.g. by an improved response to vaccinations, by reduced transmission or by an improved disease outcome for other diseases such as tuberculosis, malaria, and HIV/AIDS, as co-infections with helminths have been shown to have potentially adverse effects (see Elliott and Yazdanbakhsh, 2012, and other articles in the same issue of this journal for recent reviews).

Looking further into the future, a thorough understanding of nematodes and their interactions with the human immune system may lead to fundamental new insights that will allow a much more sophisticated manipulation of the human immune system for medical purposes. Such knowledge may ultimately be exploited for and benefit the effective treatment of allergies and other (autoimmune) diseases.

Secondary beneficiaries include UK school children (through their participation in the IRIS project, which we will support), and the UK science community more generally, which benefits from the involvement of young people in actual scientific work, which is likely to kindle interest in scientific careers.