A terrorist releases anthrax spores, genetically engineered to be resistant to antibiotics, into
a community. The spores are detected by a sophisticated early warning system. The genetic alteration in
the anthrax is pinpointed, and within hours an antidote is engineered, one that silences the gene responsible
for the antibiotic resistance. Exposed individuals receive the antidote along with their antibiotic. Disaster
Since the September 11, 2001 terrorist attacks in New York, Washington, D.C., and Pennsylvania, biodefense
research has taken on new urgency. And cancer treatment may be an unintended beneficiary.
Gene-silencing technology is a prime example. For at least four years, scientists have been using a new
process known as RNA interference to selectively "silence" a gene turn it off in mammalian cells ,
opening up one of the hottest new fields in molecular biology. Then last summer, Allen Christian, a young
chemical engineer at Lawrence Livermore National Laboratory, developed a way to improve RNA interference,
allowing scientists for the first time to silence genes in bacteria as well as mammalian cells.
For biodefense researchers, the ability to silence a gene in a bacterium anthrax, for instance was
an important achievement. "One of the major concerns has been bioengineering of bioweapons materials,
that terrorists would engineer agents like anthrax or plague to be resistant to antibiotics," Christian
says. "We needed a way to get around that."
For cancer researchers, the method also held potential. In addition to silencing bacterial genes, Christian's
technique, siHybrid, turns off mammalian genes more efficiently than any previous technique.
As Christian was developing his siHybrid method at Lawrence Livermore, Paul Gumerlock and Philip Mack,
molecular geneticists at UC Davis Cancer
Center, were putting together grant proposals to fund what would be the first tests of RNA interference
in certain prostate cancer cells. Through the Cancer
Center's formal research partnership with the national lab, the three scientists frequently exchanged
information about their work. The idea was born to write Christian's siHybrid technique, still unpublished
at the time, into the grant.
Within months, Gumerlock and Mack had secured two new grants totaling almost $1 million from the Department
of Defense's Prostate Cancer Research Program. Over the next three years, the researchers will work to
harness the biodefense technique to fight prostate cancer, a disease that kills almost 29,000 men every
year in this country, many times more than die annually in terrorist attacks worldwide.
To silence a gene, Christian identifies a short sequence of that gene's DNA. Next, he engineers an RNA
molecule that is an exact match of this sequence.
The chemically engineered twin, when introduced into cells containing the target gene, wreaks genetic
havoc. "The cell begins to actively degrade any RNA that matches that sequence," Christian says.
"In effect, it commits gene suicide."
The approach is exquisitely sensitive. Only genes containing the matching sequence are silenced. "We
can even shut off just a mutated gene, without touching the healthy version," Christian says.
Silencing repair genes
Gumerlock, a professor of hematology/oncology, applied to the defense department for funding to develop
a way to silence DNA repair genes and genes that prevent programmed cell death, or apoptosis. The veteran
prostate cancer researcher was awarded a three-year, $557,000 grant to pursue the project.
If he can silence key repair genes and apoptosis-preventing genes in prostate tumor cells, Gumerlock
believes he can make prostate cancers more vulnerable to radiation therapy.
That would be excellent news for the thousands of men who undergo radiation treatment for localized
prostate cancer every year. With current methods, 10 to 40 percent of these cancers recur following radiation.
Blocking androgen independence
Mack proposes another way to use gene-silencing technology to control cancer. The research geneticist
won a three-year, $334,000 grant to determine whether silencing certain mutations of the p53 tumor suppressor
gene can prevent androgen independence, a poorly understood process that renders prostate cancer untreatable.
Prostate cancer cells start out dependent on testosterone, a type of androgen, for their survival. Oncologists
exploit this weakness by giving prostate cancer patients hormone treatments that suppress testosterone
Initially, hormone treatment weakens or even kills prostate cancer cells. Given enough time, however,
the cells adapt to an androgen-depleted environment. They become androgen-indpendent able to grow without
testosterone. When this happens, few treatment options remain.
"Preventing or delaying the emergence of androgen independence, and perhaps even reversing it after it
has occurred, would provide new treatment options and greatly impact overall patient survival," Mack says.
Gumerlock was also awarded a second grant to exploit two other technologies fresh from the Livermore
lab. With this $111,000 grant, he hopes to develop a new test that can detect minute traces of prostate
cancer DNA in the bloodstream.
If it works, the test would be more sensitive than the PSA blood test now used to detect prostate cancer.
The PSA test measures levels of prostate-specific antigen, a protein produced by prostate tumors. Gumerlock's
proposed test might reveal prostate cancer even before PSA surges are detectable.
The test would examine blood for methylated, or deactivated, gene sequences common in prostate cancers.
While scientists have known since the early 1970s that such DNA sequences are often present in blood,
only in the last few years have they determined that some of the fragments are shed by tumors.
The realization has opened a promising new area of cancer research, but technical difficulties have also
emerged. Gathering enough of the DNA bits to allow analysis has been one challenge. Another challenge
has been figuring out how to keep the bits in place long enough to analyze them, without damaging them
beyond recognition in the process.
At Lawrence Livermore, Allen Christian again had answers. He had figured out how to affix tiny gene segments
to chips of glass, without degrading any of the DNA. Mounted on the glass chips, the minute pieces become
easy to study. In addition, Christian had developed a technique in situ rolling circle amplification
that allows DNA fragments from tumors to be detected with much greater sensitivity.
With both technical problems solved, Gumerlock hopes to come up with a test that will allow doctors to
monitor prostate cancer patients and ultimately patients with all types of cancer much more accurately for recurrences following treatment. "Earlier detection will allow more prompt treatment," he says, "and should increase survival of cancer patients."