A biologist at The University of Texas at Arlington is using a new grant to look for ways to finish off a disease that has stubbornly resisted all attempts to eradicate it.
Todd Castoe, associate professor of biology, is co-investigator on a five-year, $3.4 million grant from the National Institutes of Health for a study titled, "Schistosomiasis at the edge of elimination: Characterizing sources of new infections in residual transmission hotspots." Castoe's portion of the grant is $1.159 million.
The project uses cutting-edge genomic approaches--which are being conducted by Castoe and his students on equipment in his laboratory and in the state-of-the-art North Texas Genome Center housed on the UTA campus--to learn why the parasitic disease schistosomiasis persists in areas where extensive control measures against it have been implemented.
Schistosomiasis is an acute and chronic disease caused by parasitic worms and is second only to malaria as the most devastating parasitic disease. It affects more than 200 million people worldwide, mostly in tropical and subtropical areas and especially in poor communities without access to safe drinking water and adequate sanitation.
Epidemiologists in China and other countries have been studying schistosomiasis and attempting to eliminate it for more than a decade. They have been able to achieve eradication rates of 99 percent in some areas, but the disease has resisted being wiped out entirely.
"We want to find out what it is about this disease that allows it to persist even in the face of aggressive control measures," Castoe said. "It's important to get rid of schistosomiasis, but the scope of the project is much larger than learning how to eliminate this disease in any one area of the world.
"The real importance of the study is in learning why we can't totally eliminate this parasitic disease, and then using that knowledge to help guide eradication campaigns for this and other parasitic diseases elsewhere. There's something about transmission patterns that perpetuate this disease that we don't understand yet. We want to know what's unique about the biology of this and other parasitic diseases in the end-game, when control has been fairly effective at reducing the disease but eradication cannot be achieved."
Castoe is working on the project with principal investigator Elizabeth Carlton and co-investigator David Pollock, both from the University of Colorado School of Medicine. Castoe spent five years as a postdoctoral fellow in Pollock's lab prior to coming to UTA in 2012.
"Dr. Carlton contacted Dr. Pollock for help on the project, and he got in touch with me because the research I've been doing to generate genome data from many individual samples complemented their goals well," Castoe said. "Using genomic sequencing, this project will provide unprecedented insight into the detailed patterns of transmission across hosts, across geographic areas and through time. This will help us to understand how to prevent infections and advance efforts to achieve permanent reductions in schistosomiasis and other human helminthiases [worm infections]."
The parasites that cause schistosomiasis live a portion of their life in certain types of freshwater snails. The infectious form of the parasite, known as cercariae, emerges from the snail into the water, which then infects people during routine agricultural, occupational and recreational activities. Lack of proper hygiene and activities of school-aged children such as swimming or fishing in infested water make them especially vulnerable to infection.
"One of the more exciting parts of this project is leveraging advances in sequencing technologies to improve our ability to reduce, and possibly eliminate, neglected tropical diseases," Carlton said. "Dr. Castoe was an obvious choice due to his expertise in sequencing technologies. He is on the cutting edge of the field and one of the things that is so great about having him on the team is that he is always thinking about how we might leverage the latest advances in genomic sequencing to answer our research questions efficiently and effectively."
Carlton explained that the researchers are using new genomic sequencing technologies to map the ancestry of parasites, in an effort to identify human or animal hosts that may be acting as sources of new infection. They are following human and animal populations over time, testing them for infection and measuring risk factors.
"We're looking at new areas of infection, hotspots where we can't eliminate it," Castoe said. "Many of the things we learn in this project could apply globally, to various parasitic diseases in many low- and middle-income countries. That's the goal."
College of Science Dean Morteza Khaledi praised the work that Castoe and his colleagues are doing and said it has the potential to have a far-reaching impact on health and the human condition, one of the main pillars of UTA's Strategic Plan 2020: Bold Solutions | Global Impact.
"Dr. Castoe is a leader in the field of genome sequencing and this project will benefit greatly from his expertise in this area," Khaledi said. "It's possible that the work he and his colleagues are doing in this study could be applied worldwide and be of tremendous benefit in the fight against parasitic diseases."
Castoe also has two other major federally funded projects underway, both involving genomic studies of snakes but seeking to answer fundamentally different questions.
NSF project to understand the roles of selection and gene flow in speciation in rattlesnakes
The first of these projects, titled "Systematics, introgression and adaptation in Western Rattlesnakes: A model system for studying gene flow, selection and speciation," is funded by a four-year, $867,402 grant from the National Science Foundation's Division of Environmental Biology. Castoe is principal investigator; co-PIs are Matthew Fujita, UTA associate professor of biology; Stephen Mackessy, professor in the School of Biological Sciences at the University of Northern Colorado; and Jesse Meik, assistant professor of biological sciences at Tarleton State University, who earned a Ph.D. in Quantitative Biology from UTA in 2009.
The research focuses on the Western Rattlesnake and its close relatives as a model system to study the fundamental process of species formation.
"Despite substantial research, the roles of natural selection in the formation of species and in preventing hybridization between species remain poorly understood," Castoe said. "In a rapidly changing world, there is an urgent need to understand the importance of these processes in species formation and the impact of these processes on how scientists identify and name species."
The researchers will study genetic, venom protein and anatomical data to test how natural selection shapes and maintains species, then use the results to test several approaches for appropriately identifying species in nature.
"Essentially, we're using rattlesnakes as a model to understand how some important features of speciation work in nature," Castoe said.
Previous studies have disagreed about how many species should be recognized within this group of snakes, and different populations can produce diverse symptoms from snake bites due to differences in venom biochemistry, the researchers explained. Their goals are to resolve these issues by developing a new system for understanding and appropriately recognizing species; providing new insight into the process of species formation; developing new methods for identifying species; and refining the appropriate medical treatment of snakebites in North America.
The project also includes a public outreach program, which will include educational tools and will be conducted at the Dallas and Denver Zoos, thereby reaching millions of visitors per year.
NSF project on regulation of intestinal form, function, and regeneration
The second project, titled "Collaborative Research: Integrated mechanisms underlying the regulation of intestinal form and function," is funded by a four-year, $1.2 million grant from the NSF's Division of Integrative Organismal Systems.
Castoe is principal investigator and is joined in the study by co-principal investigator Saiful Chowdhury, UTA associate professor of chemistry and biochemistry, and Stephen Secor, professor in the Department of Biological Sciences at the University of Alabama at Tuscaloosa, who is leading concurrent research.
Vertebrates exhibit a broad range of physiological capacities to alter intestinal performance that are adaptively linked to their feeding habits. This project's goal is to understand how and why some vertebrates--including snakes that sometimes go long periods between meals--experience rapid changes in intestinal form and function when feeding, and subsequent intestinal atrophy following the completion of digestion. This is in sharp contrast with snakes that feed more often and experience only modest change in intestinal form and function.
For the widely regulating Burmese python, for example, it is known that feeding triggers the differential expression of more than 1,000 intestinal genes. These snakes experience extreme regenerative intestinal growth with every major meal, and understanding how any vertebrate might accomplish such feats could be key to understanding how to direct regenerative growth in other vertebrates, like humans.
"We don't know the cellular and molecular mechanisms that underlie the structural and functional flexibility of the intestine, and whether such mechanisms are shared across vertebrates that similarly widely or narrowly regulate intestinal performance," Castoe said. "By leveraging the extreme range in intestinal responses exhibited by snakes and other vertebrates and recently available genomic resources, this research program will identify the underlying mechanisms of intestinal flexibility and test if these mechanisms are shared or unique across lineages and regulatory phenotypes.
"Ultimately, studying other vertebrates that exhibit regenerative intestinal growth could lead to breakthroughs in learning how to control regeneration in human tissues."
The researchers are addressing these broad questions by pursuing three aims. First, they are seeking to identify the cellular and structural mechanisms that underlie the modulation of intestinal form and regeneration, and whether form strictly dictates the regulation of intestinal function. Second, they're trying to link transcriptional and post-translational mechanisms to phenotypic changes in intestinal structure and function. Third, they want to test whether shared or unique sets of molecular mechanisms drive similar phenotypic responses among vertebrates.
"Studying gene expression alone does not provide the complete picture of the function of a system. The expression and modification of proteins play significant roles in cellular functions," Chowdhury said. "We are extracting proteins from the intestinal tissues of snakes and sequencing them using mass spectrometry. Using the same mass spectrometry-based proteomics approach, we are also identifying the phosphate modification sites in proteins. Intestinal-tissue proteomics analysis, before and after feeding, is helping us to understand the protein interaction network and signaling cascades linked to intestinal regeneration in snakes."
Chowdhury believes this project is the first to combine genomics and proteomics information to understand the molecular mechanisms which drive major shifts in intestinal function in snakes.
"Ultimately, this research will identify the signaling and structural mechanisms by which vertebrates modulate intestinal form and function, and identify pathways that all vertebrates appear to possess that may direct intestinal regeneration capacity," Castoe said. "We want to understand how vertebrates control, at the molecular level, shifts in intestinal form and function, and test if the regenerative capacities seen in some extreme vertebrate examples, like snakes, could be translated to other vertebrates such as humans."
Together, the NSF projects take advantage of the huge advances made in genome sequencing technology to tackle questions about the processes that drive diversity in form and function in nature. A number of the potential findings of these basic research studies have broad ramifications for understanding human genomic diversity and human health.
"With both of these NSF projects, we're using genomics to answer fundamental questions about biology," Castoe said.