You are heavily involved in genomics. In some of your recent work, you and your colleagues conducted genome-wide association studies of P. falciparum genomes. What did you learn about the population structure of P. falciparum from this study?
The populations of P. falciparum can be clustered according to their continental origins. Parasites from South America, particularly from the Amazon area, are very similar, which could be the result of drug (chloroquine) selection. Parasites from Africa are diverse, reflecting an older population and a high rate of genetic recombination. Parasite populations in Southeast Asia, particularly the Thai-Cambodia border, can be complicated. For example, we found 2-3 unique populations in Cambodia, with one population that appears to be highly resistant to many antimalarial drugs.
You’ve also used a high-throughput strategy for studying malaria traits related to the response to potential antimalarial drugs. How did that work and what did you find?
One of the purposes of studying parasite populations is to provide population structure information for genome-wide association studies. Studying drug resistance or identifying drug resistance genes can also be done using genetic crosses [of P. falciparum]. However, performing a genetic cross of P. falicparum is quite expensive, requiring a non-human primate (chimpanzee).
In one of our recent studies, we developed a high throughput microarray to genotype thousands of single nucleotide polymorphisms or SNPs. We then used the array to genotype 189 P. falicparum isolates. We also tested parasite responses to seven antimalarial drugs. We identified candidate genes that were associated with responses to artemisinin, mefloquine, as well as the well-known genes conferring resistance to chloroquine (pfcrt) and pyrimethamine-salfudoxine (pfdhfr). We are testing some of the candidate genes experimentally, e.g. genetic transformation of parasites such as gene knockout. We would like to see how the parasite responds to the drugs after gene knockout. Preliminary results are promising.
What is your lab working on these days?
Our major focus is on using genetic and genomic tools to study drug resistance, pathogenesis, and parasite development. One of the projects following this direction is to study parasite response to small molecules using genome-wide association and high throughput chemical screening. One of the issues that bothers me a lot is the lack of malaria traits or phenotypes to study even though we have all the tools we need. It is like I have a hammer, but no place to nail or to build my projects. Malaria parasites are very small; we cannot tell much difference between individual isolates or ‘strains’ under a microscope. Use of chemicals will help to display the differences between individual parasites.
Drugs are small chemicals. If parasites can be resistant to antimalarial drugs, they will show differences in their responses to other chemicals too. So the idea is to use large numbers of chemicals to display as many differences as possible between parasites, and then use genetic/genomic tools to locate the genetic differences. Hopefully we can study gene function after locating the genes.
We also work on a rodent malaria parasite, Plasmodium yoelii. We are studying parasite virulence, drug resistance, and differences in host immune response in this mouse parasite model.
If you had to change careers today and you could do anything, what would you do?
I guess I would still be working on parasites. Another parasite I would like to work on is Schistosoma.
What’s your favorite science book?
“Fundamentals of Molecular Evolution” by Dan Graur and Wen-Hsiung Li. I learned a lot from the book when I read it. It actually got me into some studies of the molecular evolution of malaria parasites and population genetics. I don’t read a lot of books; too many papers to read and write.
What is something about you that most people don’t know?
I like to play and watch basketball, hike, and fish.