PI4D Distinguished Lecture - Anthony James

Purdue Institute of Inflammation, Immunology and Infectious Disease
January 18, 2018
1:30 PM - 2:30 PM


Tentative time.  More information will follow.




Donald Bren Professor, Microbiology & Molecular Genetics
School of Medicine

Donald Bren Professor, Molecular Biology and Biochemistry
School of Biological Sciences
PH.D., University of California, Irvine

Phone: (949) 824-5930
Fax: (949) 824-2814
Email: aajames@uci.edu

University of California, Irvine
Dept. Molec. Biol. Biochem.
McGaugh Hall 3205
Mail Code: 3900
Irvine, CA 92697

Molecular biology of insect vectors of disease, genetics of vector competence, malaria, dengue fever.
URLs Microbiology and Molecular Genetics
  Molecular Biology and Biochemistry
Fellow of the Royal Entomological Society, 1992; Burroughs-Wellcome Award in Molecular Parasitology, 1994; Fellow of the American Association for the Advancement of Science,1994; Burroughs-Wellcome Fund New Initiatives in Malaria Research Award,2000; Foreign Fellowship,Japan Society for the Promotion of Science, 2003; Distinguished Alumnus, School of Biological Sciences, University of California, Irvine, 2004; Member National Academy of Sciences USA, 2006; Distinguished Professor, 2007; Recipient of a MERIT Award, National Institutes of Health 2007; Co-recipient of the Premio de Investgación Médica Dr. Jorge Rosenkranz, 2008; UCI Medal, 2009; Recipient of the Entomological Society of America (ESA); 2009 Nan-Yao Su Award for Innovation and Creativity in Entomology; Fellow of the Entomological Society of America, 2011;Fellow of the American Society of Tropical Medicine and Hygiene, 2012; Recipient of the Athalie Clarke Achievement Award for Outstanding Research, University of California, Irvine, School of Medicine 2013; Rosetta B. Barton Lecturer, University of Oklahoma 2013.
Mosquitoes are arguably the most dangerous animals in the world. Annual human mortality from malaria transmitted by just one species, Anopheles gambiae, exceeds two million, while Aedes aegypti transmits viral diseases such as dengue and yellow fever. While these diseases occur principally in tropical zones, emerging pathogens such as Chikungunya and West Nile viruses may represent future medical and public health threats in more temperate regions. The goal of our laboratory is to develop novel, genetics-based control methods for blocking transmission of human pathogens by mosquitoes. The hypothesis driving our efforts is that the introduction into a population of mosquitoes of a gene that confers resistance to a pathogen should lead to a decrease in transmission of that pathogen. Implicit in this hypothesis is the assumption that less transmission will result in less disease and death. To test this hypothesis, a gene or allele that interferes with pathogen development or propagation must be discovered or developed, and subsequently spread through a mosquito population. Following implementation of this strategy, there should be measurable decreases in incidence and prevalence of the targeted disease.

Research in three areas needs to be done to test the hypothesis. First, we must develop mosquitoes that are resistant to pathogens. Second, we must develop procedures for moving genes developed in the laboratory into wild mosquito populations. Finally, we must have sufficient information about the target mosquito population so that we can model and predict how the gene will behave in the population. This is important for both the introduction of the gene and establishing parameters by which the success of the introduction will be measured.

In parallel lines of research, we are evaluating the genetic control hypothesis using mosquitoes that have been engineered to be resistant to the pathogens that cause malaria or dengue fever. Our research group has focused first on the laboratory component of this strategy and we identified three research goals that must be met in order to make pathogen-resistant mosquitoes. The first goal was to identify as a target of intervention a tissue in which specific interactions occur between the pathogens and host mosquitoes. Our approach has been to isolate and characterize genes expressed specifically in that tissue, and use the control DNA sequences of these genes to express a coding region that will confer resistance to the pathogens. Our second goal was to develop transgenesis technology that would allow the introduction into the genome of mosquitoes a gene or genes capable of interfering with pathogen development. Our final goal was to develop a hybrid gene that interferes with pathogen development when expressed in the mosquito. This will be the gene that is spread through a target population and is expected to affect pathogen transmission. Our laboratory has had much success with these goals using avian malaria as a model. We are working now with the most lethal human malaria parasite, Plasmodium falciparum. Most recently, we have partnered with a network of laboratory and field scientists and modellers to develop genetic control approaches for preventing the transmission of dengue viruses.

Recently we started experiments that investigate the second major research area, the movement of laboratory-developed, pathogen-resistance genes into wild populations of mosquitoes. In collaboration with Valentino Gantz and Ethan Bier (University of California, San Diego), we developed a highly effective autonomous Clustered Regularly Interspaced Short Palindromic Repeats (CRISPR)-associated protein 9 (Cas9)-mediated gene-drive system in the Asian malaria vector Anopheles stephensi. This specific system results in progeny of males and females derived from transgenic males exhibiting a high frequency of germ-line gene conversion consistent with homology-directed repair (HDR). This system copies an ~17-kb construct from its site of insertion to its homologous chromosome in a faithful, site-specific manner. Dual anti-Plasmodium falciparum effector genes, a marker gene, and the autonomous gene-drive components are introgressed into ~99.5% of the progeny following outcrosses of transgenic lines to wild-type mosquitoes. The effector genes remain transcriptionally inducible upon blood feeding. Strains based on this technology could sustain control and elimination as part of the malaria eradication agenda.



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