Think back to your high school biology course and you may remember how important RNA is to every living organism. RNA is the blueprint for proteins and is made within cells by a complex molecular machine, the RNA polymerase, in a process called transcription. Dr. Seth Darst, of Rockefeller University, explores the mechanism and regulation of the process of transcription by determining three-dimensional structures of RNA polymerase and associated proteins. Because RNA polymerase is important for all organisms ranging from bacteria to humans, Dr. Darst is able to study the simpler bacterial versions to understand how transcription and gene expression are controlled in more complicated systems. While much of his research is very basic, seeking to understand the structure and mechanism of the RNA polymerase enzyme, applications for the future are numerous. In fact, Dr. Darst’s study of tuberculosis is likely to lead to novel therapeutic strategies for tuberculosis treatment. In addition to likely therapeutics for tuberculosis, Dr. Darst’s research will allow the development of new therapeutics against a wide range of bacterial pathogens, all of which depend upon RNA polymerase for survival.

Dr. Darst uses many biochemical and biophysical techniques within his laboratory, but uses predominantly X-ray crystallography and cryo-electron microscopy to determine structures of transcription complexes. Using this important variety of techniques, Dr. Darst determined the first high-resolution structure of a cellular RNA polymerase enzyme in 1999. Since, his research has continued to lead the field in innovative and rigorous research as he and his team have made many contributions to the field. While understanding the structures of proteins is an important piece of Dr. Darst’s puzzle, perhaps most impressive is that his research will lead to transformational therapies for many diseases that affect patients worldwide.

Current research includes:

• Tuberculosis Treatment: Tuberculosis, caused by infection with the bacterium M. tuberculosis, continues to pose a major health problem, particularly due to the increase in multidrug resistant strains. It is estimated that 1/3 of the human population is infected with M. tuberculosis. A deeper understanding of M. tuberculosis RNA polymerase its regulation has the potential to identify novel therapeutic strategies for tuberculosis.

• Structural Studies: Dr. Darst works with model organisms, including Escherichia coli (E.coli) for genetic and biochemical studies, and Thermus aquaticus or Thermus thermophilus for structural studies. Structural and functional studies of mycobacterial RNA polymerase are also underway.