Cornell University and Harvard Medical School are collaborating to decipher the structures of proteins associated with human cancers.

The goal, says Dan Thiel, Cornell assistant professor of molecular biology and genetics, "is to determine the three-dimensional structures of gene products associated with human cancers, starting with breast cancer." As the Harvard research group identifies and purifies specific proteins, samples will be sent to the Macromolecular Diffraction Facility (MacCHESS) at the Cornell High Energy Synchrotron Source (CHESS), an X-ray diffraction laboratory where the protein's three-dimensional structure will be calculated. Thiel is director of MacCHESS.

The group of structural biologists, cancer biologists and bioinformatics specialists, led by Tom Ellenberger, associate professor of biological chemistry and molecular pharmacology at Harvard Medical School, includes researchers from the school, its affiliated institutions and Yale University.

The project, referred to as the Harvard structural biology of cancer initiative, is part of the ongoing efforts of the Harvard/Armenise Center for Structural Biology at Harvard Medical School. The collaborative enterprise seeks to advance the fast-developing fields of structural and functional genomics – studies of proteins encoded by the entire genome – to improve understanding of the root causes of many cancers. A protein's structure can tell researchers much about its function, information that ultimately is needed to understand a protein's link to cancer. By determining the detailed, three-dimensional structure of proteins, researchers are better able to determine how each protein functions normally and how faulty protein structures can cause disease. "We will be contributing to the understanding of human cancers through looking at structures of proteins involved in the development and formation of tumors," Thiel says.

Much of the research at MacCHESS in recent years has been in the field of structural biology, aimed at understanding protein structures, and the way in which proteins fold, with the goal of creating new pharmaceuticals and diagnostic techniques. Thiel, who has been director since 1999, says the collaboration is "a new direction for MacCHESS that strengthens our ties to the larger community of MacCHESS users."

Each protein will be picked on the basis of the family of cancers to which it relates. At first, says Thiel, the object will be to determine structures of proteins that constitute the discrete biochemical pathways linked to certain types of cancers. This information will be used to create computer models to correlate this structural information with a growing body of functional genomics data. MacCHESS will provide rapid X-ray diffraction analysis of the protein crystals and develop new methods and instrumentation for high throughput structural studies using synchrotron radiation from the Cornell Electron Storage Ring (CESR).

"Our collaboration with Thiel's team creates a wonderful synergy between leading cancer biologists and the world-class structural biology group at MacCHESS, which should translate into a deeper understanding of the molecular bases for many neoplastic diseases," says Ellenberger. (Neoplastic is a term that refers to the abnormal growth of cells that can lead to a malignant tumor.) Given the vast size of the human genome (estimated to contain anywhere from 40,000 to 80,000 genes) he says, "it is likely that we will identify protein folds or combinations of folds that are not present in less complex organisms."

The core operation of the research effort will be housed in Harvard/Armenise Center where protein production, crystallization and preliminary X-ray diffraction analyses will be performed. These crystals will then be sent to MacCHESS for X-ray diffraction experiments, including the multiwavelength anomalous diffraction (MAD) experiments that will be the primary means of phasing the X-ray structures.

The MacCHESS team will assist with the collection of X-ray data and provide expertise in the development of automated methods for protein sample handling and X-ray data collection.

Ellenberger believes this new effort, grounded in cancer biology, will complement an international structural genomics effort involving scientists in at least nine countries who are working to reveal 10,000 structures of protein folds in a decade. "We seek to maximize the amount of functional information that can be derived from protein structures by carefully selecting targets according to their biological importance and focusing on larger proteins and multiprotein complexes," says Ellenberger. "The protein folds elucidated by the structural genomics projects provide the building blocks that assemble into the complicated structures we are studying."

MacCHESS's funding of $1.8 million a year through August, 2003, comes from the National Center for Research Resources, one of the 20 institutes of the National Institutes of Health. The facility is open to researchers from all institutions and since 1998 has welcomed about 200 users from pharmaceutical companies and universities in the United States and overseas.

Other related websites:

• MacCHESS: http://www.chess.cornell.edu/MacCHESS/index.html#About.MC