Research led by scientists at the London School of Hygiene & Tropical Medicine has exploited a revolutionary genetic technique to discover how human African Trypanosomiasis (HAT) drugs target the parasite which causes the disease. The new knowledge could help lead to the development of better treatments for the tens of thousands of people in sub-Saharan Africa who are affected each year.
The findings, published in Nature, are based on the simultaneous analysis of thousands of genes and the action of the five drugs effective against HAT, also known as sleeping sickness. The research was a collaboration between LSHTM, the Wellcome Trust Sanger Institute and the University of Cambridge and was funded by the Wellcome Trust.
The disease - usually fatal if left untreated - is caused by a parasite called Trypanosoma brucei, which is transmitted by the tsetse fly and attacks the central nervous system. Although treatment is available, until now there has been little understanding of how and why the drugs are particularly effective against African trypanosomes and therefore limited scope to tackle resistance when it arises. In particular, an arsenic-based drug called melarsoprol is increasingly ineffective and has the added problem of severe toxicity in patients; it is only because HAT is such a lethal disease that this drug is still in use.
Employing a process of specific gene disruption that prevents the parasite from producing its signature proteins, and targeting one gene in each cell (the parasite is unicellular), the scientists identified which modifications resulted in drug resistance. This implied that the original gene was essential for the drug to work. The technique, called RNA interference target sequencing (RIT-seq), depends upon technology developed by scientists at LSHTM over several years and a high-throughput DNA sequencing approach developed in collaboration with researchers at the Wellcome Trust Sanger Institute.
The team screened the entire T. brucei genome of 7,500 genes and found a total of 50 genes, and therefore 50 proteins, that are linked to drug action and resistance. With this information, the group analysed the biological processes those proteins are involved in and deduced how the drugs interact with the parasite.
Lead researcher Dr David Horn, Reader in Molecular Biology at LSHTM, said: "We now know a lot more about how these drugs work. This new understanding of how these medications kill parasites, or fail to kill parasites, could lead to the development of tests that guide the intervention strategy as well as more active and safer intervention options. What is important now is to begin the process of translating the new findings into clinical advances such as new diagnostics and therapies."
Notes to Editors:
1. Journal Reference. High-throughput decoding of antitrypanosomal drug efficacy and resistance. Alsford, S., Eckert, S., Baker, N, Glover, L., Sanchez-Flores, A., Leung, K. F., Turner, D. J., Field, M. C., Berriman, M., Horn, D., Nature (2012). DOI:10.1038/nature10771
2. A podcast with Dr David Horn is available under embargo on request.
3. The current drugs used in the treatment of sleeping sickness are suramin, pentamidine, nifurtimox, melarsoprol and eflornithine.
4. More information about RNA interference target sequencing (RIT-seq) can be found in the following publications:-
High throughput phenotyping using parallel sequencing of RNA interference targets in the African trypanosome. Alsford S, Turner DJ., Obado SO, Sanchez-Flores A, Glover L, Berriman M, Hertz-Fowler C and Horn D. (2011) Genome Research. 21: 915-924. Doi: 10.1101/gr.115089.110
Featured as a Research Highlight in Nature Biotechnology (2011) 29:330.
Featured as a Research Highlight in Nature Methods (2011) 8:370-371.
Featured in News & Analysis in Nature Reviews Microbiology (2011) 9:401.
5. The London School of Hygiene & Tropical Medicine (LSHTM) is a renowned research-led postgraduate institution of public health and global health. Its mission is to improve health in the UK and worldwide through the pursuit of excellence in research, postgraduate teaching and advanced training in national and international public health and tropical medicine, and through informing policy and practice in these areas. Part of the University of London, the School is the largest institution of its kind in Europe with a remarkable depth and breadth of expertise encompassing many disciplines associated with public health. www.lshtm.ac.uk
6. The Wellcome Trust Sanger Institute is one of the world's leading genome centres. Through its ability to conduct research at scale, it is able to engage in bold and long-term exploratory projects that are designed to influence and empower medical science globally. Institute research findings, generated through its own research programmes and through its leading role in international consortia, are being used to develop new diagnostics and treatments for human disease. http://www.
7. The mission of the University of Cambridge is to contribute to society through the pursuit of education, learning and research at the highest international levels of excellence. It admits the very best and brightest students, regardless of background, and offers one of the UK's most generous bursary schemes. The University of Cambridge's reputation for excellence is known internationally and reflects the scholastic achievements of its academics and students, as well as the world-class original research carried out by its staff. Some of the most significant scientific breakthroughs occurred at the University, including the splitting of the atom, invention of the jet engine and the discoveries of stem cells, plate tectonics, pulsars and the structure of DNA. From Isaac Newton to Stephen Hawking, the University has nurtured some of history's greatest minds and has produced more Nobel Prize winners than any other UK institution with over 80 laureates. http://www.
8. The Wellcome Trust is a global charitable foundation dedicated to achieving extraordinary improvements in human and animal health. It supports the brightest minds in biomedical research and the medical humanities. The Trust's breadth of support includes public engagement, education and the application of research to improve health. It is independent of both political and commercial interests. www.wellcome.ac.uk