New Scholar Award in Global Infectious Disease
Scripps Research Institute
Functional Analysis of the Plasmodium Genome
As the causative agents of malaria, parasites of the genus Plasmodium are major
contributors to global morbidity and mortality. While the disease was once
almost eliminated from many areas of the world, the emergence of drug-resistant
strains and insecticide-resistant mosquitoes has led to a resurgence in the
number of cases. There are now 300-500 million cases per year worldwide. In
order to rationally develop new therapies, more needs to be known about the
molecular development of the parasite. Unfortunately traditional tools for the
determination of gene function are relatively primitive. Though P. falciparum
can be cultured in human erythrocytes, many stages of its lifecycle cannot be
maintained in cell culture. Gene disruptions can now be carried out but they are
laborious and only a few laboratories are currently able to accomplish them. In
1997 a multinational effort was mounted to determine the sequence of the 26 MB
P. falciparum genome, the species responsible for most human mortality. The
genome sequence is now nearly completed and new and untried approaches to
the molecular genetic elucidation of pathogen gene function are now feasible.
My research interests lie in developing and using new sequence-dependent technologies
to functionally characterize small genomes, such as that of the malaria parasite. I am
interested in discovering what this sequence does for the cell. How does the sequence
support replication? What are the genetic regulatory circuits that exist in the genome?
By examining the genome as a whole we hope to make new observations that wouldn't
have been possible if only one example of a cellular entity was studied. While we have
used the yeast Saccharomyces cerevisiae as a test case, we have begun a program to
functionally characterize the genome of the malaria parasite, Plasmodium falciparum.
We are constructing an oligonucleotide array that will carry over 400,000 probes to
specific regions in the Plasmodium genome. The array will be used to assign function to
the proteins encoded by the parasite genome, to identify potential drug targets, to
determine the mechanism of action of active compounds and to identify allelic variation
within Plasmodium species.