IT鈥橲 not just what we already know is lurking in the genomes of humans and
other organisms that is exciting, but the surprises they will throw up, says
Phillip Sharp, a biochemist from the Massachusetts Institute of Technology,
Boston. If we hadn鈥檛 spent so much time poking around various gene sequences
lately, he says, scientists might never have discovered a gene-silencing process
called RNA interference.
It was Sharp鈥攁nd, independently, Richard Roberts at Cold Spring Harbor
Laboratory, New York鈥攚ho discovered in 1977 that genes are broken up into
segments and scattered along chromosomes. After being transcribed into RNA,
these segments, or exons, are joined together. The intervening segments, the
introns, are spliced out like unwanted footage from a film. In 1993, Sharp and
Roberts received a Nobel prize for their discovery.
Since then, the RNA-splicing field has blossomed and researchers have learned
plenty. Then, a few years ago, came a surprise. While searching for a way to
alter gene expression in cells, researchers found that if they injected
double-stranded RNA into the roundworm Caenorhabditis elegans, the corresponding
gene would shut down. RNA interference (RNAi) had arrived.
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In this strange process, messenger RNAs from the targeted genes are still
made, but somehow the cell chops them up before they can be made into protein.
The presence of a double-stranded version of a single-stranded message triggers
the process.
For biotechnology, RNAi could be a real boon, allowing researchers to disrupt
gene expression in an organism without laboriously creating mutations in genes.
For basic researchers like Sharp, RNAi opens up a new field. After all, RNAi
must serve some purpose in cells. In plants, for example, it is thought to help
defend against viral infection by shutting down the expression of viral genes.
In C. elegans, RNAi seems to quash the expression of repetitive sequences such
as 鈥渏umping genes鈥�, or transposons. Left unchecked, such sequences can move
about and create mutations, says Sharp.
About 40 per cent of human DNA is repetitive, and not expressed in high
levels in tissues. RNA transcripts from opposite DNA strands in these regions
could pair up to become double-stranded, suggesting a role for RNAi in humans as
well, he says.
With the help of genomics, Sharp hopes to discover the natural role of RNAi
in regulating genes. 鈥淲e will be able to identify cases where transcription from
two genes would generate overlapping double-stranded RNA,鈥� he says. Such genes
would be obvious targets for regulation by RNAi, but finding them without
genomics would be virtually impossible.
鈥淲e know so little, even when we think we know so much,鈥� says Sharp. 鈥淵ou
turn around and suddenly you鈥檝e got a really remarkable new discovery.鈥�