Our lab exploits whole genome approaches to tackle problems in yeast molecular biology and human infectious disease. These projects can be classified into three separate areas:
Functional genomics of Plasmodium falciparum, the causative agent of human malaria.
Malaria is one of the most deadly and profound human health problems in existence and results in approximately 1.5 to 2.7 million deaths annually. The most fatal and prevalent form of malaria is caused by the blood-borne pathogen Plasmodium falciparum. Beyond the lives this parasite claims every year, hundreds of millions of people will become clinically ill. The socioeconomic impact of this disease to developing countries, especially those on the African continent, is beyond measure. There exist no vaccines with an operational impact and resistance of the parasite to current anti-malarial drugs has spread worldwide. Because the vast majority of malaria occurs in poor nations, there is little profit incentive for large western and European drug companies to pursue new anti-malarial therapies, yet novel approaches are in desperate need
The paucity of new anti-malarial medications is partly attributable to the lack of validated drug targets. Indeed, all currently approved drugs and those in development are directed against only a handful of gene products and processes. Unlike many bacterial pathogens, both genetic and molecular biological approaches have been difficult in Plasmodia. Fortunately, the completion of the Plasmodium falciparum sequencing project will inherently broaden the range of potential drug targets by identifying all possible open reading frames. Although a great deal of functional annotation may be accomplished by sequence based homology comparisons, this information will not be sufficient to determine whether a gene product actually participates in a function or process at any given time during the development of the parasite. In addition, the majority of gene products discovered through the sequencing of the genome will not reveal significant sequence homology and therefore will remain hypothetical and uncharacterized. We are utilizing the full potential of the completed sequence by implementing a functional genomics approach to the elucidation of metabolic and stage specific gene expression. This is being accomplished by systematic perturbation of P. falciparum cultures in conjunction with genome wide gene expression profiling, exhaustive homology based sequence comparison, pathway analysis, and functional characterization.
Whole genome approaches to the molecular biology of Saccharomyces cerevisiae
We are using DNA microarrays to investigate several different aspects of yeast biology. These include chromatin immunoprecipitation techniques to reconstruct the protein-DNA topology of the genome, gene expression profiles to investigate the action of small molecule drugs, and immunoprecipitation of RNA binding proteins to screen for novel regulatory mechanisms. Other yeast-based projects in the lab seek to elucidate the mechanisms responsible for the various steps of meiotic recombination through genetics and biochemistry.
Searching for a link between asthma and viral infection.
The notion that acute asthma attacks are frequently precipitated by respiratory infection is part of the training of every physician and is well supported in general terms by numerous clinical investigations. However, the prevalence of respiratory infection in acute asthma and the identities of the responsible pathogen(s) have been more controversial. Studies based upon culture and/or viral antigen detection in respiratory secretions of asthmatics have generally recorded rates of infection between 20-40%; these studies typically identify rhinoviruses, coronaviruses, adenoviruses, influenza and parainfluenza viruses. This is likely to be an underestimate and likely define a minimal estimate of the contribution of viral infection to acute asthma attacks.
We are constructing and using a viral DNA microarray based system customized for the goal of detecting and differentiating between pathogens commonly found in the respiratory tract. This technology will allow us to investigate whether there is a positive correlation between viral infection and asthma attacks, if so, which viral types are so associated. To accomplish this goal, we are actively collaborating with an on-going clinical research study of asthma here at UCSF.
Gerton, J. L., DeRisi, J., Shroff, R., Lichten, M., Brown, P. O., and Petes, T. D. Inaugural article: global mapping of meiotic recombination hotspots and coldspots in the yeast saccharomyces cerevisiae [In Process Citation]. (2000) Proc Natl Acad Sci U S A 97(21), 11383-90
Hayward, R. E., Derisi, J. L., Alfadhli, S., Kaslow, D. C., Brown, P. O., and Rathod, P. K. Shotgun DNA microarrays and stage-specific gene expression in Plasmodium falciparum malaria. (2000) Mol Microbiol 35(1), 6-14
Ogawa, N., DeRisi, J., and Brown, P. O. New Components of a System for Phosphate Accumulation and Polyphosphate Metabolism in Saccharomyces cerevisiae Revealed by Genomic Expression Analysis. (2000) Mol Biol Cell 11(12), 4309-4321
Takizawa, P. A., DeRisi, J. L., Wilhelm, J. E., and Vale, R. D. Plasma membrane compartmentalization in yeast by messenger RNA transport and a septin diffusion barrier [In Process Citation]. (2000) Science 290(5490), 341-4
Chu, S., DeRisi, J., Eisen, M., Mulholland, J., Botstein, D., Brown, P. O., and Herskowitz, I. The transcriptional program of sporulation in budding yeast [published erratum appears in Science 1998 Nov 20;282(5393):1421]. (1998) Science 282(5389), 699-705
DeRisi, J. L., Iyer, V. R., and Brown, P. O. Exploring the metabolic and genetic control of gene expression on a genomic scale. (1997) Science 278(5338), 680-6