NYTimes.com Article: RNA Trades Bit Part for Starring Role in the Cell

khare@alumni.caltech.edu khare@alumni.caltech.edu
Wed, 22 Jan 2003 04:15:11 -0500 (EST)


This article from NYTimes.com 
has been sent to you by khare@alumni.caltech.edu.


Just imagine that it's *still* possible to actually discover something wonderful! the very last line is really quite important -- it could have been discovered anytime in the last twenty years, yet no one had "twisted the rubik's cube" to see this perspective on the problem. 

Biology is a frustrating field, personally. I wish I knew what was going on. But it must be like trying to learn computer science by using Windows, this ridiculous bit about learning chemistry by dissecting animals :-)

It is telling, though, that nature's as good|bad a programmer as we are: the oldest code is the most stable and the most fragile; the new stuff is always flaky and optional :-)

Definitely look up the roundworm obesity study -- quite an impressive experimental hack. 

Rohit

khare@alumni.caltech.edu


RNA Trades Bit Part for Starring Role in the Cell

January 21, 2003
By ANDREW POLLACK 




 

In the family of genetic material, RNA has long been the
poor cousin of DNA. DNA makes up the genes, the master
instructions of life, while RNA merely conveys those
instructions to other parts of the cell. 

But surprising new discoveries are showing that cells
contain an army of RNA snippets that do much more than act
as DNA's messenger. The discoveries are helping to refine
the prevailing theories of genetics - or even upend them. 

"It's like discovering the neutrino or something," said Dr.
Gary Ruvkun, a professor of genetics at Harvard Medical
School. "These things were all around us for many years,"
and no one was aware of them. "Now we're discovering they
are all over the place," he added. "Genomes are full of
them." 

The discoveries are having practical applications.
Scientists have found that tiny snippets of RNA with two
strands instead of the usual one can be used to shut off
specific genes. The technique, known as RNA interference,
is being widely used to discover the functions of genes by
turning them off and seeing what happens to the plant or
animal. 

In a paper published in Nature on Thursday, Dr. Ruvkun and
his colleagues at Harvard and Massachusetts General
Hospital used RNA interference to turn off almost all of a
worm's genes, one at a time, to discover those linked to
obesity. Doctors hope that RNA interference will one day be
used for medicine, inactivating genes, say, in tumors or
viruses. 

"This is a gift from heaven," said Dr. Phillip A. Sharp, a
Nobel laureate and a professor of biology at the
Massachusetts Institute of Technology. He is also a founder
of Alnylam Pharmaceuticals, one of several companies
started to exploit RNA interference. Many other companies
are trying to develop drugs based on other aspects of RNA. 

Dr. Stuart Peltz, chief executive of PTC Therapeutics in
South Plainfield, N.J., said RNA had become "sort of a huge
discovery zone." PTC is developing drugs that influence the
way RNA works. 

Scientists have recently reported that Prader-Willi and
Fragile X syndromes, each leading to mental retardation,
and chronic lymphocytic leukemia may be linked to RNA
defects. Biologists studying other species are also looking
to RNA for answers to unsolved mysteries. 

"Everybody wants to look in their favorite organism or
favorite system and see if there's an RNA lurking there,"
said Dr. Susan Gottesman, chief of biochemical genetics at
the National Cancer Institute, who studies E. coli
bacteria. "A lot of the regulatory puzzles in E. coli are
explained by small RNA's we didn't think were there." 

RNA and DNA are strings of chemical units called bases that
embody the genetic code. The bases are represented by the
letters A, C, G and either T in DNA or U in RNA. The C base
always binds to G. A binds only to T or U. So a single
strand of DNA or RNA can bind to another strand that has
the complementary bases. 

Under what is known as the central dogma of genetics,
genes, which are the recipes for making proteins, are part
of the DNA of the chromosomes. When a protein is to be
made, the DNA is copied onto a corresponding piece of
single-stranded RNA, known as messenger RNA, that delivers
the recipe to the cell's protein-making machinery. Proteins
make up most of a cell and perform most of its functions,
including turning genes on and off. 

But new evidence suggests that some RNA is not merely the
intermediary between DNA and protein, but the end product.
Some huge stretches of DNA that do not contain
protein-coding genes and have been considered "junk"
actually hold the code for some of this RNA. 

A study published in May by scientists at Affymetrix of
Santa Clara, Calif., a maker of gene chips, reported that
in addition to the DNA's containing the recipes for
proteins, a lot more DNA was being copied into RNA. 

The recently deciphered mouse genome was found to have
about twice as much in common with the human genome as
could be accounted for by protein-coding genes. Areas of
the genome that are similar are thought to have important
functions, explaining why they have not mutated as species
evolved. At least part of this overlap appears to be genes
that produce RNA as their end product. 

What all of this RNA is doing is not clear, and much of it
may have no function. Dr. Sean Eddy, a researcher at Howard
Hughes Medical Institute at Washington University, said
cells might just be sloppy, turning far more DNA into RNA
than they needed. But mounting evidence suggests that at
least some RNA is involved in regulating the way genes are
turned on or off. 

Dr. John S. Mattick, a molecular biologist at the
University of Queensland in Australia, holds the most
radical view: that RNA provides the command and control of
cells. 

Proteins, Dr. Mattick said, are like bricks and beams. But
the RNA determines whether those bricks and beams become
office buildings or houses. This RNA network, he said,
provides the complexity that separates higher life forms
from simpler ones. 

"People have totally misunderstood the nature of genetic
systems in higher organisms," he said. "This will probably
turn out to be the greatest failure in the history of
molecular biology." 

Most scientists say Dr. Mattick's views, although
intriguing, are not backed by much evidence. Rather than
upending the central dogma, they say, the new findings just
add some tenets. 

It has long been known that RNA is more than a messenger.
The ribosome, which makes proteins, is made partly of RNA.
Another type of RNA, called transfer RNA, aids in protein
production. Some scientists say it is not surprising that
RNA has multiple roles, because it is generally believed
that RNA had the role of both proteins and DNA in the early
days of life on earth. 

"We still have a lot of remnants from that," said Dr.
Stephen R. Holbrook, a scientist at the Lawrence Berkeley
Laboratory. 

The recent excitement has been generated by two discoveries
related to small RNA snippets and their ability to turn off
genes. 

Some genes, scientists found, produce tiny RNA's, known as
micro-RNA's or miRNA, which are about 21 to 23 bases, or
letters, in length. The micro-RNA's bind to matching pieces
of messenger RNA, turn it into a double strand and keep it
from doing its job. The process effectively stifles the
production of the corresponding protein. 

The first such micro-RNA was discovered in the early 1990's
by Dr. Victor Ambros and his colleagues at Dartmouth. It
helps control larval development in C. elegans, the
roundworm often used for genetic studies. 

Because the finding was so unexpected, "there was a
considerable amount of legitimate doubt," Dr. Ambros
recalled. It was not until 2000 that Dr. Ruvkun discovered
the second one, which also acts to control development in
roundworms. 

Now micro-RNA's are being found in many species. Dr. David
Bartel, an associate professor at the Whitehead Institute
and M.I.T., and his sister, Dr. Bonnie Bartel of Rice
University, found 16 in arabidopsis, a plant. He also found
50 micro-RNA's in the roundworm and is about to publish his
estimate for humans, which other scientists say is more
than 200. 

The second discovery is known as RNA interference, or RNAi.
About four years ago, Dr. Andrew Fire of the Carnegie
Institution of Washington and Dr. Craig Mello of the
University of Massachusetts found that when double-strand
RNA was given to roundworms, it would silence the gene
corresponding to that RNA. That helped explain a similar
gene-silencing phenomenon noticed in plants years earlier. 

Many scientists theorize that RNA interference is a
protective mechanism against viruses, which sometimes
create double-strand RNA when they replicate. 

When double-strand RNA is detected, an enzyme called dicer,
discovered at the Cold Spring Harbor Laboratory on Long
Island, chops the double-strand RNA into shorter pieces of
about 21 to 23 bases. The pieces are known as small
interfering RNA's or siRNA's. Each short segment attracts a
phalanx of enzymes. 

Together, they seek out messenger RNA that corresponds to
the small RNA and destroy it. In plants and roundworms, the
double-strand RNA can spread through the organism like a
microscopic Paul Revere. 

It did not take scientists long to realize that micro-RNA
and small interfering RNA's were the same length and used
much of the same mechanism. Indeed, micro-RNA's appear to
be formed as longer stretches of RNA that fold back on
themselves like hairpins to create double strands. The
sequence of bases is sort of like a palindrome, so that
when the folding occurs, complementary bases line up, and
the two arms of the hairpin stick together. 

Even more roles for small RNA are being found: in yeast,
for example, small RNA's bind to chromosomes to shut down
genes more permanently than can be done by stifling
messenger RNA. 

At first, it was not clear that RNA interference would work
in humans. Mammalian cells, confronted with long
double-strand RNA, basically destroy themselves as a
defense against pathogens. 

But two years ago scientists at the Max Planck Institute
found that short double-strand RNA, again about 21 to 23
bases, would not set off the self-destructive response but
would silence the corresponding gene. 

"Immediately, it was obvious that the ability to do
experiments in human cells had just changed completely,"
said Dr. David Engelke, a professor of biological chemistry
at the University of Michigan. 

Scientists are now finding that RNAi is a faster way to
turn off genes than other methods like creating so-called
knockout mice that lack a particular gene. Scientists are
also looking to use RNA interference to treat diseases. 

Dr. John Rossi of the City of Hope National Medical Center
in Duarte, Calif., and Dr. Ramesh Akkina at Colorado State
University genetically engineered blood-producing stem
cells to make a double-strand RNA that corresponded to a
part of a gene in H.I.V. When those stem cells were
transplanted into mice, they formed T cells - the target of
H.I.V. - that inactivated the gene in the virus and staved
off infection. 

Others scientists have found in test tube experiments that
they can inhibit infection by knocking out the genes in T
cells that form the receptors used by H.I.V. to enter
cells. 

Still, it will be much harder to make the technique work in
patients, because RNA tends to break down quickly in the
body. 

"It comes down to whether you can deliver the small
interfering RNA to the cells where it is needed and get it
inside the cells," said Dr. David Bartel. 

An alternative is to deliver DNA, which is more stable.
This DNA would be engineered to make an RNA that folded
back on itself into a double strand. But delivering DNA is
gene therapy, which has had little success. 

Viruses that are used to ferry in DNA or RNA could raise
safety questions. Last week, the Food and Drug
Administration suspended 27 clinical trials of gene therapy
after two children in France developed leukemia from such
treatment. 

The inability to deliver a dose high enough has plagued
antisense, a technology similar to RNAi that was once also
hailed as a wondrous way to treat disease. The approach
uses a single strand of RNA or DNA that binds to the
messenger RNA and shuts off protein production. Numerous
antisense drugs have failed, although one is now on the
market, and others are in late stages of clinical trials.
Another gene-silencing technology, ribozymes, has not
worked in patients either. 

Scientists say RNA interference may work better because it
takes advantage of a natural process. "We've done
antisense, and RNAi is about 1,000 times better," said Dr.
Ruvkun. 

As research continues, scientists wonder how the small
RNA's eluded them for so long. One explanation is that
genes that code for RNA are easy to overlook in computer
scans of genomes. But another reason, scientists say, is
simply that no one thought to look. 

"This work could have been done 20 years ago," Dr. Sharp
said. "There's nothing new in it in terms of technology. We
just missed it." 

http://www.nytimes.com/2003/01/21/science/21RNA.html?ex=1044226910&ei=1&en=f2f4c3290f5850fd



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