WormBase: an evolving resource for nematode biology

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. For example, drugs interact with genes to change how biological systems function. Much of the research that has led to this progress is hard or impossible to do in humans. Because all animals share evolutionary origins, study of simple animals helps to understand human biology. Certain key model organisms have been the focus of intensive study, and some of the most important progress has been made with extremely simple animals. One of these is the tiny roundworm, or nematode, Caenorhabditis elegans. C. elegans research has been strategically supported by the MRC for over 40 years, leading to two Nobel prizes in the last five years, and is a key contributor to our understanding of basic processes such as cell death and aging.

In addition to its relevance for understanding animal biology, research on C. elegans is particularly important to our understanding of the biology of other nematodes. Globally, more than one billion people are infected with nematode parasites, including blood-borne filarial parasites, such as Onchocerca that causes river blindness, and Wuchereria that cause elephantiasis; as well as intestinal nematodes such as hookworms, whipworms and giant round worms. Typically infections are associated with and promote poverty. For most parasitic nematodes, maintaining full life cycles in the laboratory is either difficult or impossible and few molecular tools exist. Thus researchers are highly reliant on functional studies in C. elegans and their extrapolation (via sequence homology) into the parasites of sister taxa.

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 enable the support and development of WormBase, the reference information resource for all genomic and biological data for C. elegans, and its expansion to enable the curation of genomic and experimental information for increasing numbers of nematode parasites. WormBase is essential both for fundamental research that uses C. elegans as a model, and for research into nematodes that cause disease. By relating these two branches of nematode research, WormBase will be uniquely placed to enable community-wide exploitation of data emerging for parasites by applying information, experience, and technological infrastructure developed for C. elegans.

This application will support two of six UK posts working on WormBase, the established community database for the genome and biology of the Caenorhabditis elegans - a key model organism, established through long term strategic support of the MRC - and other medically relevant nematode species. The genomes of several species of parasitic nematodes are already accessible via WormBase and hundreds more are expected over the coming few years. The funding of this proposal will enable the evolution of the resource to maximise the value of these data.

Through this proposal we will (a) curate the genome sequence and core annotation for C.elegans and key parasitic nematodes, actively incorporating new data from the literature, and developing new models for rapid, community-driven curation of newly sequenced genomes; (b) provide computational annotation and comparative genomic analysis for hundreds of nematode genomes; (c) revise the core data management infrastructure, to support the necessary increases in scale that will be required ; and (d) integrate and deliver for public access every two months the entire database, built from data collected and curated at all three WormBase groups. To do this efficiently, we will combine in-house tools with the use of sequence analysis, curation and data management software developed with the joint WTSI/EBI Ensembl project for genome annotation, as well as software and standards developed for the GMOD consortium of model organism databases, of which we are a member. WormBase is freely available for browsing and download from www.wormbase.org, and also contributes the genome sequence and gene sequences to the primary DNA and protein databases, and participates in other core biological information collaborations including the GO consortium. WormBase is co-funded by NIH, who support the two US groups and the remainder of the UK group.

Basic molecular insights in C. elegans have driven major fundamental advances in modern medicine, illustrated by 2 Nobel Prizes in the last decade: 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 nematodes 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. 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.

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.