The Burnham Buzz, February 2009

Partnering for Progress Burnham Institute for Medical Research (Burnham) has signed an assay development and license agreement with Johnson & Johnson Pharmaceutical Research and Development LLC. (J&JPRD). Under this multi-year agreement, Burnham will provide J&JPRD with access to high-throughput assay screening technologies to investigate certain drug targets for inflammatory diseases. The agreement is Burnham's first broad-based partnership with a large pharmaceutical company. Scientists at Burnham's Infectious and Inflammatory Disease Center are already using the institute's state-of-the-art robotic screening center in basic research programs.

Can you hear me now? Digital Drug Search

Giovanni Paternostro, M.D., Ph.D., and colleagues have developed a means to use search algorithms developed for the digital communications industry to identify drug combinations that are safe and effective. This novel approach involves algorithms that use biological measurements and model simulations to search for optimal drug combinations for the treatment of complex diseases such as cancer. In the study, a small subset of the drug combinations identified using the algorithms were tested in fruit fly and cancer cell model systems. Dr. Paternostro's research, published in the December 26, 2008 edition of PLoS Computational Biology, demonstrated that this approach can identify safe and effective drug combinations more rapidly that conventional methods. The conventional approach to finding drug combinations involves trial and error testing.

Gaining Control

Burnham scientists have identified the molecular machinery that regulates DNA replication and the S-phase checkpoint of the cell cycle. Wei Jiang, Ph.D., showed that the protein kinase complex known as Ddk is responsible for initiation of DNA replication, as well as controlling the S-phase of the cell cycle. If damaged DNA or a replication error is identified, Ddk acts as a quality control protein and stops replication at the S-phase checkpoint of the cell cycle. Halting the cell cycle at the S-phase allows for DNA repair enzymes to repair the damaged DNA. Once the DNA damage has been repaired, Ddk re-initiates replication. Ddk has long been thought to be involved in DNA replication and the S-phase checkpoint. However, its exact role had not been elucidated until Jiang's study, which was published in the December 24, 2008 issue of Molecular Cell. The role of Ddk in controlling the DNA replication machinery for genome stability and fidelity may make it an excellent target for the development of new cancer treatments because these functions are often deregulated in cancerous cells.

Suicide Switch

Stefan Riedl, Ph.D., got the first look at the molecular structure of the protein complex that controls apoptosis (programmed cell death). Fas and Fas associated death domain protein (FADD) make up the death inducing signaling complex (DISC). The Fas-FADD DISC is a receptor platform, which once assembled, initiates the induction of programmed cell death. Dr. Riedl determined the X-ray crystal structure of the DISC to 2.7 Angstroms resolution and found that protein-protein interactions between Fas and FADD mechanistically control DISC formation. The structure showed that Fas undergoes a conformational change, creating an open structure that acts as a site for FADD binding, as well as bridging between the Fas molecules in the clustered complex. Dr. Riedl and colleagues propose that the bridging between Fas molecules in the complex acts as a control switch for DISC formation and initiation of apoptosis. Riedl's study was published December 31, 2008 in Nature.

Source: Burnham Institute