MacCHESS moves into cancer research through structural genomics

By David Brand

The new G-Line facility at the Cornell High Energy Synchrotron Source (CHESS), scheduled to start up in about a year, will provide a major platform for a new, streamlined effort at Cornell to understand human cancers by looking at the structure of proteins involved in tumor formation, says researcher Dan Thiel, who expects to be a major user of the new facility.

Dan Thiel, Cornell assistant professor of molecular biology and genetics and director of the university's Macromolecular Diffraction Facility (MacCHESS), places a protein crystal onto an apparatus for X-ray diffraction data collection. The equipment, designed at MacCHESS, is in a lead-lined room next to CESR, the Cornell Electron Storage Ring. Charles Harrington/ University Photography

Thiel, Cornell assistant professor of molecular biology and genetics, for the past year has been director of the Macromolecular Diffraction Facility (MacCHESS), the biomedical research arm of CHESS. He believes that once the Cornell-funded $3 million G-Line building, adjacent to Wilson Laboratory, is fully operational, it is likely that it will consume more beam time for structural genomics, associated with cancer research, than for traditional X-ray crystallography.

The building, which will contain three additional X-ray beam lines funded by a $2.5 million National Science Foundation grant, will house an addition to the nine existing CHESS X-ray beam lines. The additional beam lines, primarily intended for materials science research, also will be useful for Thiel's structural genomics research.

Grounding such research in cancer biology is becoming big academic business around the world. Currently there is 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.

The fast-developing fields of structural and functional genomics -- studies of proteins encoded by the entire genome -- are being brought to bear on the problem of understanding the root 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 understand how each protein functions normally and how faulty protein structures can cause disease.

The involvement of G-Line in this area of genomics is likely, said Thiel, even though "there are a lot of people who don't endorse the science of structural genomics as appropriate in an academic environment because it is seen as too much of a factory type of science, better suited to the national labs."

What is "appealing" about a structural genomics program at Cornell, however, he said, is its application to cancer research. 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. Thus the broadening of research in structural genomics, said Thiel, seems obvious, "even though this might seem to some to reduce our science down to just being a technology of solving protein structures."

Already MacCHESS is collaborating with a research group at Harvard Medical School in a large-scale effort to understand the structures of proteins associated with human cancers.

The goal, said Thiel, "is to determine the three-dimensional structures of gene products associated with human cancers, starting with breast cancer." As the Harvard group identifies and purifies specific proteins, the samples will be sent to MacCHESS where their three-dimensional structures will be calculated. Thiel said the collaboration is "a new direction for MacCHESS that strengthens our ties to the larger community of MacCHESS users."

"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 said.

Each protein will be picked on the basis of the family of cancers to which it relates. At first, said 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.

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.

"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," said project leader Tom Ellenberger, associate professor of biological chemistry and molecular pharmacology at Harvard Medical School. (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 said, "it is likely that we will identify protein folds or combinations of folds that are not present in less complex organisms." Ellenberger is leading a group of structural biologists, cancer biologists and bioinformatics specialists, including researchers from the school and its affiliated institutions and from Yale University.

MacCHESS's funding of $1.8 million a year through August 2003 comes from the National Center for Research Resources, one of 20 in the National Institutes of Health. The facility, now in its 18th year, 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.

Thiel notes that structural genomics is a new direction for MacCHESS that is not yet funded by the NIH. (The collaboration with Harvard Medical School is being funded initially by Harvard.) Currently the agency funds the facility's medical research into large unit cell crystallography, large multimeric complexes, the measurement of viruses and membrane protein crystallography. However, Thiel said, he has been involved in efforts at MacCHESS over the past few years to streamline the crystallography process by improving such equipment as X-ray detectors. As a result, he said, there is increasing automation in collecting data and mounting samples that is well suited to structural genomics.