|
Scientists identify genetic pathways
essential to RNA interference
Research tool for turning off genes
may eventually have therapeutic application
BOSTON - March 24, 2005 - A research team based at Massachusetts
General Hospital (MGH) has identified 80 new genes essential to
the process of RNA interference (RNAi), a powerful new research
tool for inactivating genes in plants or animals. They used the
RNAi process itself to find new genes that participate in the gene-silencing
mechanism, which someday may help to fight human disease. The report
will appear in the journal Science and is receiving early
online release on the Science Express website at http://www.sciencexpress.org.
"The gene activation produced by RNAi is exquisitely specific,
which gives it enormous potential for therapeutic application,"
says Gary Ruvkun, PhD, of the MGH
Department of Molecular Biology, the study's senior author.
"Imagine short, double-stranded RNA molecules that could be
synthesized quickly and inexpensively to silence a single gene.
Promising targets could include viruses like HIV and hepatitis C
or cancer-causing oncogenes. An RNAi-based treatment for age-related
macular degeneration is already in clinical trials." Ruvkun
is a professor of Genetics at Harvard Medical School.
RNAi was originally identified in the C. elegans roundworm
and the flowering plant Arabidopsis thaliana, both of which
are common model organisms for biological research. The process
interrupts the usual transfer of instructions from double-stranded
DNA, through single-stranded messenger RNA and finally into proteins.
Short, double-stranded pieces of RNA bind to the complementary messenger
RNA segments, shutting down gene expression. RNAi occurs naturally
in plants and animals and may help control resistance to viral infection,
among other functions.
For the current study, lead author John Kim, PhD, and his colleagues
developed a strain of C. elegans into which they added a
gene that caused the worms to glow under ultraviolet light but also
turned that gene off using RNAi. They then used RNAi to inactivate
every one of the worms' 19,000 genes by feeding the worms bacteria
that produce double-stranded RNA for each gene. Inactivation of
about 90 genes caused the worms to glow, indicating that those genes
were essential to the RNAi process that had been suppressing expression
of the fluorescence gene.
Some of the identified genes - many of which have human counterparts
- code for proteins involved with the packaging and processing of
RNA, but others may be involved with the regulation of DNA itself,
including the repair of DNA damage. "These new steps indicate
there is more to RNAi than RNA destruction," says Kim. "And
the connection to DNA damage pathways, which was totally unexpected,
suggests a potential connection between RNAi and the control of
cell division in cancer."
The researchers note that better understanding the mechanisms underlying
RNAi could help transform what has been a research tool into a powerful
therapeutic tool. Although the process has worked well in studies
of cultured human cells, it has not yet been effective for experimentally
suppressing gene expression in living mammals. Identifying each
step in the RNAi process could lead to more successful inactivation
of disease-related genes. And in addition to the technique's potential
for gene silencing, controlling levels of RNAi that may underlie
some cancers or be used in viral replication may offer further clinical
potential.
Along with Kim, the study's co-first authors are Harrison Gabel
and Ravi Kamath, MD, PhD, of the MGH Department of Molecular Biology.
Additional authors are Muneesh Tewari, MD, PhD, Jean-Francois Rual,
Nicolas Bertin, and Marc Vidal, PhD, of Dana-Farber Cancer Institute;
Amy Pasquinelli, PhD, of the University of California at San Diego;
Scott Kennedy, PhD, of the University of Wisconsin; and Michael
Dybbs and Joshua Kaplan, PhD, of MGH. The research was supported
by grants from the National Institutes of Health.
Massachusetts General Hospital, established in 1811, is the original
and largest teaching hospital of Harvard Medical School. The MGH
conducts the largest hospital-based research program in the United
States, with an annual research budget of more than $450 million
and major research centers in AIDS, cardiovascular research, cancer,
cutaneous biology, medical imaging, neurodegenerative disorders,
transplantation biology and photomedicine. In 1994, MGH and Brigham
and Women's Hospital joined to form Partners HealthCare System,
an integrated health care delivery system comprising the two academic
medical centers, specialty and community hospitals, a network of
physician groups, and nonacute and home health services.
Media Contact: Sue
McGreevey, MGH Public Affairs
Physician Referral Service: 1-800-388-4644
Information about Clinical Trials
|
|
 |
