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, could be considered something of a Navy Seal.
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). He worked as a post-doctoral fellow in the laboratory of Francis Collins, head of the Human Genome Project.
Like the Seals, who are often the first to explore a 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 microarray 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 microar-ray 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.
During his post-doctoral studies 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. Over 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 said.
Once the DNA is extracted from a 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 arrays 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 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 lymphoma, leukemia, breast and colon cancers.
In addition to his work on human genetics, Hacia devotes significant time and research to evolutionary biology. He was recruited to this field by Francis Crick, the Nobel-Prize winning molecular biologist and co-discoverer of the structure of the DNA molecule. “In addition to human comparisons, I’m genetic knowledge of non-human primates, such as chimpanzees, gorillas, orangutans and rhesus monkeys,” he said. “There are many exciting research opportunities in this new field.” In collaboration with the San Diego Zoo, Hacia looks for the genetic differences between humans and apes.
“It’s known that there’s about a one or two percent difference in DNA sequences between humans and chimpanzess and gorillas,” he said. “I’m looking for sequence changes that are functionally relevant and contribute to making us human on a biochemical level.” Work in the field so far has uncovered “that there’s actually greater genetic diversity in apes than in humans,” he noted. “The theory is that humans went through a population bottleneck very early on in our history. Diseases or disasters may have wiped out whole groups of humans and thus reduced our genetic diversity. Such events do not appear to have happened in chimpanzees and gorillas.”
The Piscataway, New Jersey native attended Rutgers University and became interested in genetics while doing doctoral work in biochemistry at The California Institute of Technology. He applied to work in Francis Collins’ laboratory and was invited to work on microarrays due to his experience with nucleic acid biochemistry at Caltech.
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 said.