How a new gene targeting technique provided Eric Hendrickson with $6 million in federal grants, a biotech contract and new ways to treat life-threatening conditions.
If you’re looking for an expert at using recombinant Adeno-Associated Virus (rAAV) to modify human somatic cells, head on over to Eric Hendrickson’s laboratory on the 6th floor of the Molecular and Cellular Biology Building.
Hendrickson, professor of biochemistry, molecular biology and biophysics, has become one of the world’s leading experts at using the technology since he learned about it eight years ago.
Adenoviruses are the pathogens that cause the common cold. Adeno-Associated Virus (AAV) is an infectious, but non-pathogenic, agent that hitches a ride with adenoviruses yet doesn’t trigger an immune response. Approximately 85 percent of Americans today are seropositive for AAV, with no obvious pathogenic consequences. Importantly, the recombinant form of AAV can be manipulated to target genes but it has a distinct advantage over other gene targeting vector strategies since the immune system doesn’t chase it off.
The original description of the rAAV technique was made in David Russell’s laboratory (University of Washington) in 1998. Many researchers dismissed the report as too good to be true. But then Bert Vogelstein, a world-class cancer researcher at John Hopkins University, demonstrated that rAAV could be used to target oncogenes. When Hendrickson read this follow-up report his interest in the technology was piqued and he decided to try it in his own laboratory.
“I was skeptical at first that a truly wimpy, somewhat bizarrely structured single-stranded DNA virus could target genes with high efficiency but I decided to try it,” he says. “It not only worked, but it spawned everything that has happened in my laboratory since then.”
“Everything” includes about $6 million in federal grants to use the family of genes he studies to understand the molecular mechanisms that underlie the rAAV technology and to apply it to treat serious conditions, such as immune deficiency disorders, DNA damage caused by radiation therapy and cancer predisposition syndromes. Besides the federal research contracts, the Hendrickson laboratory is also supported by a research contract with Horizon Discovery, Ltd. Horizon is the company that owns the patents for using rAAV to target genes. The Hendrickson laboratory is working on methodologies to improve and expand the uses of rAAV.
Hendrickson’s field is DNA repair. His research has long focused on a pathway called C-NHEJ that is involved in DNA repair. C-NHEJ (classic non-homologous end joining) constitutes the major pathway for repairing double-stranded breaks in DNA. Double-stranded breaks, in which both the “Watson” and “Crick” strands of DNA are broken, are the most serious kind of DNA damage because there isn’t a strand left to serve as a template for repair. C-NHEJ is a highly evolutionarily conserved mechanism that has been extensively studied in many model systems from bacteria to mice. Unfortunately, while the basic C-NHEJ mechanism has been conserved, the specifics of the process haven’t been and thus many of the observations garnered in these model systems have not proven relevant to human cells. Hendrickson’s use of rAAV to manipulate the C-NHEJ pathway has thus filled an important void in understanding how the C-NHEJ pathway functions specifically in human cells.
His attention is now focused on three areas, all of which involve using rAAV technology:
- The connection between DNA recombination and immunity in humans. When immunity is functioning normally, DNA makes site-specific rearrangements to protect the host from bacteria, viruses and tumor cells. But some people are born without this ability, which makes them extremely vulnerable to opportunistic infections and disease.
- The repair of double-stranded DNA breaks caused by radiation treatments for cancer patients. The C-NHEJ gene family repairs double-stranded breaks resulting from the radiation exposures used during cancer therapy. Hendrickson is seeking to understand how C-NHEJ regulates this process and to ultimately use that knowledge to protect cancer patients from side-effects of radiation.
- How C-NHEJ knows how to skip telomeres. Telomeres are natural double-stranded breaks that occur at the ends of chromosomes. Paradoxically, C-NHEJ is required for normal telomere maintenance, a process that is critical for genomic stability. How C-NHEJ “knows” that a telomere is a double-strand break that needs to be maintained and not repaired is unknown. Understanding how this discrimination works might help improve or restore DNA repair mechanisms in situations where they are needed.
“I have always considered myself a very basic research scientist and as such I have never really expected to see our research results make their way expeditiously into the clinic or industry,” Hendrickson says. “In the past five years, however, my laboratory has developed a biotechnology component that is almost entrepreneurial in nature. This aspect has been very unexpected, but actually quite rewarding—both for my own laboratory and for the University of Minnesota—and for that I’m exceedingly grateful.”
In short, “life is good” in the Hendrickson lab, thanks to a “truly wimpy” virus that hitchhikes on common cold viruses.
– Peggy Rinard