Seattle Biomedical Research Institute (SBRI) researchers Peter Myler, Ph.D., and Ken Stuart, Ph.D., along with scientists at The Institute for Genome Research (TIGR) in Rockville, MD, Wellcome Trust Sanger Institute in the Hinxton, U.K., and the Karolinska Institute in Stockholm, Sweden, led the sequencing efforts and authored the four resulting papers. Myler and Stuart also serve as faculty at the School of Public Health and Community Medicine and the School of Medicine at the University of Washington, with which SBRI has a formal affiliation.
Three of the papers detail the genomes of Trypanosoma brucei, Trypanosoma cruzi, and Leishmania major, while a fourth paper offers a comparative analysis of the genome sequences of the parasites. Cumulatively, the papers have nearly 250 authors from 46 organizations representing 21 different countries on six continents. The National Institute of Allergy and Infectious Diseases (NIAID), part of the National Institutes of Health, and The Wellcome Trust provided funding for the sequencing.
Collectively referred to as the "TriTryps" because each pathogen is a trypanosomatid, Trypanosoma brucei, Trypanosoma cruzi, and Leishmania major are the causative agents, respectively, of African sleeping sickness, Chagas disease and leishmaniasis. More than 500 million people are at risk for one or more of these diseases, which represent more than 4 million disability adjusted life years (DALYs), a unit for measuring the global burden of disease.
According to Myler, the genome sequences give researchers the "essential playbook" for each of the parasites, offering the basis for new drugs. He pointed out that there are currently no vaccines for these diseases and the available drugs, mostly designed in the early 1900s, are often toxic to patients.
"Now that the genes of these parasites are mapped out, it's much easier to identify genes that are critical for parasite survival," said Myler. "Genes encoding proteins that are involved in critical biological processes often serve as drug targets." Myler is traveling to London along with other authors to take part in a press conference, sponsored by Science, to announce the completion of the genome sequences.
The comparative study offers information about how the parasites infect people, how they cause disease in humans and why different insects carry them. "The original goal of the three genome projects was to decode the genetic blueprint and gain insights into the biology of each of the three parasites," said Najib El-Sayed, Ph.D., a molecular biologist at TIGR, who shared first authorship of two of the Science papers (Trypanosoma cruzi and the comparative paper) with Myler. "The comparative study is a valuable outgrowth of those projects which has yielded important results."
Comparing the three genomes provided scientists with valuable, and somewhat surprising, information. While the diseases caused by the three parasites, which are carried and transmitted by different insects, are very dissimilar, researchers identified a common core of about 6,200 genes that are present in all three in a similar order. "Initially, we believed that the gene organization among the parasites would be very different, but 70 percent of the genes occur in the same order," Myler explained. "The core genome of all three is very similar with the differences mainly at the end of chromosomes. So that tells us that if we focus on the genes that are the same in all three, but different from humans, we have the potential to develop a class of drugs that can target all three diseases."
Myler pointed out that another way to look at drug targets is to focus on the genes that are different in each of the parasites – and also different from the human host – to find drugs that could specifically target each disease separately. An important finding in the Trypanosoma cruzi genome study was the discovery of a novel and large set of 1,300 genes (called the "mucin-associated surface protein," or MASP, genes) that may play a role in the parasite's evasion of the human immune system or in its ability to survive in the variety of hosts it infects.
Last fall, SBRI hosted the 2004 TriTryp Genomes Meeting that brought together approximately 130 scientists from 19 countries to present their work on the sequencing project. "The collaborative nature of this project shows what can be done when we combine the latest technologies with the brightest minds from around the world," said Stuart, president and founder of SBRI. "SBRI's expertise in molecular biology and infectious diseases allowed us to bring critical capabilities to the project."
According to Stuart, as the genomes were being sequenced, data was posted on the Internet so that all researchers could have access. The completed sequences and their annotations are posted at www.genedb.org. This information is being reproduced on a two CD set, along with additional information and analytical software, for use by scientists without access to high-speed Internet services. The Wellcome Trust and the World Health Organization funded the CD set.
Visitors to SBRI's headquarters in Seattle's South Lake Union neighborhood can see a unique rendition of part of the sequence for Leishmania major. Flanking the entryway to the SBRI Building are two large glass panels, comprising artwork called Labyrinth by Seattle artist Linda Beaumont, that depict a portion of the Leishmania major genome sequence.
About Seattle Biomedical Research Institute
Seattle Biomedical Research Institute is the largest independent, non-profit organization in the United States focused solely on infectious disease research. The mission of SBRI's nearly 200 employees is to eliminate the world's most devastating infectious diseases through leadership in scientific discovery. Founded in 1976, SBRI's research targets the world's most underserved populations: the 14 million people who die each year from diseases such as malaria, HIV/AIDS and tuberculosis as well as other lesser known, but equally deadly diseases, including African sleeping sickness, Chagas disease and leishmaniasis. SBRI's discoveries are the basis for new diagnostics, drugs and vaccines that provide long-term solutions to the world's biggest health problems. For more information, visit www.sbri.org.
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