Benchmarks
- Scanning the Genetic Horizon Joe Hacia is
pioneering the use of DNA chip technology to uncover cancer-related
genetic mutations.
- by Monika Guttman
If the next stage in the war on cancer is to understand the genetic mutations that make each person's case unique, then Joe Hacia, Ph.D., could be considered something of a Navy Seal.
Like the Seals, who are often the first to explore a strange new territory and then perform strategic strikes, Hacia dives into individual DNA, trying to find the minute genetic mutations that differentiate one case of, say, lymphoma, from another. His weapons: a micro-
array scanner and a fluidic station.
Hacia is an expert in nucleic acid microarrays: pieces of glass the size of a thumbnail with thousands of DNA sequences imprinted on their surface. These glass pieces, also called "DNA chips," can be used to scan for abnormalities in DNA collected from tumor tissue or blood samples. The microarray scanner, as he puts it, is the high-tech equivalent of a supermarket scanner. "It reads off thousands of genetic codes using a laser," he says. The fluidic station prepares the DNA chips for rapid analysis.
Hacia, an assistant professor of biochemistry and molecular biology, recently came to USC's Institute for Genetic Medicine from the National Human Genome Research Institute at the National Institutes of Health (NIH) in Bethesda, Md. He worked as a post-doctoral fellow in the laboratory of Francis Collins, head of the Human Genome Project. While at the NIH, Hacia developed oligonucleotide microarray (DNA chip) technology to efficiently screen cancer-related genes for all possible mutations. Short pieces of DNA called oligonucleotides are present on the chip surface. More than 250,000 different oligonucleotides can be arrayed on the surface of the glass in a checkerboard pattern.
"The manufacturing processes are very similar to that used to create computer microprocessor chips," he says.
Once the DNA is extracted from tumor tissue or blood, it goes through a two-step process: PCR (polymerase chain reaction) and in vitro transcription. The DNA serves as a template to make an RNA "target," which precisely represents the sequence of the patient's gene. This target is applied to the surface of the DNA chip. Each oligonucleotide in the array is a biological sensor. If the RNA target has no mutations, it will bind strongly to a specific subset of oligonucleotide sensors on the chip. However, mutations in the target will cause it to weakly bind to a subset of oligonucleotide sensors designed to recognize a normal target and strongly bind to oligonucleotide sensors designed to detect a mutant target.
By screening for mutations in specific genes, Hacia hopes to correlate mutation status with responsiveness to chemotherapy. He is currently working with clinicians at the USC/Norris Comprehensive Cancer Center on mutations associated with lymphomas, leukemias, and breast and colon cancers.
In addition to his work on human genetics, Hacia devotes significant time and research to evolutionary biology. Francis Crick, the Nobel-Prize winning molecular biologist and co-discoverer of the structure of the DNA molecule, recruited Hacia to this field. In collaboration with the San Diego Zoo, Hacia looks for the genetic differences between humans and apes.
Hacia expects to spend the next few years developing different types of cancer-related chips to screen for cancer mutations, and developing tools for primate genomics such as maps of genetic variations and gene expression patterns.
"The field is so broad and has so many opportunities because we're just beginning to tap the power of new technologies," he says
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