On Jul 21, 9:56 pm, chazwin <chazwy...@yahoo.com> wrote:

"The raison d'etre of the gene is to make an organism that survives."

     If he wants to have his cake and eat it too, that's fine by me.

   Also, to set the record straight, in the above passages he's
cobbled together and removed the context.  I had also put a link in to
an article entitled: When RNA Rules.  Here's the TEXT of that article
(if you want to find it, Google "RNA rules" and look for 'Whitehead
Institute'.  It was the sixth link when I did it.):

 When RNA rules

A newly discovered class of molecules plays an astonishingly powerful
role in biology

What do newly discovered molecules called microRNAs and the Internet
have in common? Both reshaped entire fields in the past decade, says
Whitehead postdoctoral fellow Andrew Grimson.

“That’s a fairly grandiose claim for microRNAs,” acknowledges Grimson,
who studies them. “But the discovery of the widespread role of these
molecules changed the landscape of biology very quickly.”

“Labs across the world, working on a variety of biological questions,
are now integrating microRNAs into their research,” says David Bartel,
Whitehead Member and Howard Hughes Medical Institute investigator.

Bartel and his colleagues have helped to fuel the frenzy by
identifying hundreds of the small RNA molecules and providing
compelling evidence that they regulate the production of thousands of
proteins in plants and animals.

“Computational work has produced a very big picture of what microRNAs
are likely to be doing in a very short time,” says Nobel laureate and
MIT Institute Professor Phillip Sharp.

Until the early 1990s, no one had a clue about microRNAs, which flew
under the radar because of their tiny size. Each one contains only 21
to 24 nucleotides, or letters of the genetic alphabet, so scientists
simply missed them. Victor Ambros’s group found the first microRNA—
lin-4—in 1993 at Harvard Medical School while studying a mutation in
the worm Caenorhabditis elegans.

Another Harvard researcher detected a second microRNA in 2000. One
year later, the floodgates opened with the discovery of nearly a
hundred in worms, insects and humans. At this point researchers began
calling these tiny regulatory molecules “microRNAs.”

The discoveries changed conceptions of RNA. Scientists have known for
decades that RNA molecules serve as messengers and translators,
building proteins from DNA sequences. But microRNAs determine which
DNA sequences get translated in a given cell, a responsibility once
considered the purview of proteins known as transcription factors.
MicroRNAs essentially choreograph biological ballets, helping to
determine where and when proteins can appear to perform. Thus RNA can
add “regulator” to the roles listed on its résumé.

MicroRNAs bind to messenger RNAs that code for proteins involved in
activities ranging from development to cancer, and disrupt the
production of these proteins. In humans, microRNAs regulate roughly
one-third of protein-coding genes, and that’s a conservative estimate.

Going through the genome
“This is the first discovery of a broad biological mechanism that’s
been made since genomics,” says Nobel laureate Phillip Sharp, who is
investigating how microRNAs work at MIT, where he is an Institute
Professor.

Scientists determined the scope of microRNA activity in a matter of
years by mining recently published DNA sequences. Bartel, an RNA
biochemist, and computational biologist Christopher Burge of MIT
played a leading role. They collaborated to develop computer programs
that scanned genomes to identify microRNAs and their messenger RNA
targets. Their work helped to ignite interest in microRNAs as
biologists in labs around the world realized the tiny molecules
regulate a large portion of the protein-coding genes in plant and
animal cells.

“Computational work has produced a very big picture of what microRNAs
are likely to be doing in a very short time,” says Sharp. “ “It feels
like the field is moving at warp speed,” agrees Burge, a Whitehead
Career Development Associate Professor of Biology. “Genomic approaches
have provided a number of important insights, and there has been nice
synergy with molecular and biochemical studies.”

Finding the first microRNAs
Rosalind Lee and Rhonda Feinbaum, researchers in the Ambros lab, were
conducting painstaking experiments on C. elegans when they bumped into
the first microRNA.

They knew that early development of worm larvae required proper levels
of the novel protein lin-14. They also knew that something was
regulating those levels and assumed it was another protein, so they
set out to isolate the gene for that protein. The result amazed them.

The gene fell on a stretch of DNA once termed “junk” by some, a
stretch outside the protein-coding region of the chromosome. It
appeared to code for a small RNA molecule— lin-4—that somehow
regulated lin-14 levels.

The researchers wondered if lin-4 was an esoteric molecule or a
harbinger of a new class of RNAs. “We had no basis for saying that
lin-4 was part of something much broader,” says Ambros, who now works
at Dartmouth Medical School.

His lab had no luck searching for additional RNAs in the next few
years. He was thrilled when researchers in the lab of Harvard Medical
School’s Gary Ruvkun discovered another gene in C. elegans that coded
for a small RNA called let-7 in 2000. In addition to cloning let-7,
Ruvkun’s group examined the genomes of a number of other animals and
found the gene for let-7 in most of them. The study foreshadowed the
role of genomics in later research.

In 2001, Rockefeller University associate professor Thomas Tuschl
(formerly a postdoctoral fellow in the Bartel lab), Ambros and Bartel
independently found dozens of additional small RNA genes in worms,
flies and humans and decided to call them microRNAs.

Leveraging genomics
Bartel realized he needed to look outside the toolbox of classical
biology. In 2001, he approached Burge—who had previously developed
algorithms to identify protein-coding genes in the human genome—and
Lee Lim, who had just completed his PhD training with Burge. The
researchers jumped at the chance to explore a new class of genes. Lim
worked jointly with the two labs to write a computer program that
could scan DNA sequences and predict microRNA genes.

He started by examining known microRNAs. Each microRNA is generated
from a piece of RNA that folds back on itself to form a structure that
resembles a hairpin. Lim scanned the genome of C. elegans for DNA
sequences that would give rise to hairpins after being transcribed
into RNA. He then looked for ways to further refine the search.

The double-stranded RNA of a hairpin is chopped and processed into a
single-stranded microRNA by proteins called Drosha and Dicer. But
apparently these proteins don’t recognize every hairpin. Lim whittled
down the list of potential microRNAs by eliminating DNA templates for
hairpins that lacked Dicer-friendly characteristics.

Lim then screened the remaining microRNA candidates by comparing the
genomic sequence of C. elegans with that of the related worm C.
briggsae. He reasoned that most of the genuine microRNAs, those
performing critical biological functions, would be conserved across
species.

Eventually, the team showed that the human genome contains more than
200 microRNA genes. “We were excited to find new microRNAs,” says
Burge. “But then the big question was—what do they do?”

This question had been largely answered in plants. Matthew Jones-
Rhoades, a graduate student in the Bartel lab, had discovered that
plant microRNAs have extensive and highly conserved pairing to plant
messenger RNAs, so he could easily identify many targets of the plant
microRNAs.

“At a time when we had about 50 plant targets, we were still in the
dark regarding which genes were targeted in animals,” says Bartel.

Benjamin Lewis, a graduate student in both the Bartel and Burge labs,
developed a second computer program to bridge this gap. He took the
sequences of known micro-RNAs, scanned animal genomes for
corresponding messenger RNA targets and, like Lim, used conservation
across species to screen the results. The goal was to find many more
conserved microRNA-mRNA pairings than would result by chance. But the
initial program failed to deliver.

The researchers then tried another twist. Previous work showed that
some microRNAs pair only partially with their mRNA targets, so the
team hypothesized that one part of each microRNA sequence might be
particularly important. They were right. Lewis hit the jackpot when he
required perfect pairing near one end of the microRNAs. He found tiny
sequences, matching short stretches of microRNAs, conserved much more
frequently than chance would dictate in the mRNAs of mice, rats and
humans.

Lewis named the critical stretch that matches targeted mRNAs the
“seed” of the microRNA. The discovery of the seed gave scientists
working on the biochemical interaction between microRNAs and mRNAs a
big boost. It also allowed Bartel, Burge and Lewis to move forward
with predicting targets.

They showed that many animal microRNAs have hundreds of conserved
targets involved in a variety of processes, and in January 2005, they
conservatively estimated that micro-RNAs regulate one-third of protein-
coding genes in humans. This was a shock, as each plant microRNA
appears to have just a few targets linked to development.

By the end of 2005, Kyle Kai-How Farh, another graduate student in
Bartel’s lab, together with Andrew Grimson, showed there is also a
large potential for species-specific targeting, and that in many cases
protein-coding genes are evolving to avoid pairing with microRNAs.
Thus micro-RNAs are affecting the majority of human protein-coding
genes, at either a functional level or an evolutionary level.

Springboard for new studies
While the human genome is clearly full of potential microRNA targets,
scientists in the lab have confirmed only a handful of interactions
between mammalian microRNAs and mRNAs in living cells. Investigators
are just beginning to use classical tools to probe the functions of
the interactions identified computationally by Bartel and Burge, who
are refining their computer programs and designing experiments to test
past predictions.

“We’re improving the prediction programs to make them more inclusive
and more accurate, and we’re sequencing millions of small RNAs in
plants and animals to get a clearer picture of what’s really in the
cell environment,” says Bartel.

Graduate student Graham Ruby, for example, is overhauling Lim’s
microRNA prediction program. The original application missed many real
microRNAs, and Ruby hopes to catch some of the molecules that fell
through the cracks. Lim narrowed the list of microRNA precursors by
scoring each hairpin according to its microRNA-like characteristics.
Ruby adds a new twist. His program includes more than one round of
scoring, like the American Idol show. After each round, he eliminates
the lowest-scoring hairpins from the pool of candidates. He examines
the rejects and uses their characteristics to fine-tune the scoring
criteria for the next round, which should make predictions more
accurate.

Other researchers in Bartel’s lab are working to determine the
mechanism by which microRNAs lower protein levels, as much of it
remains a mystery. The picture is clearer in plants, where microRNAs
pair fully with and direct the cleavage of messenger RNAs.

But most of the new studies on microRNAs deal with their specific
functions. Cancer researchers are particularly interested in the tiny
RNAs, as many of them appear to regulate cell proliferation. Several
papers last year confirmed this link. Gregory Hannon of Cold Spring
Harbor and Scott Hammond of the University of North Carolina, for
example, showed that overabundance of a specific group of micro-RNAs
probably contributes to human B cell lymphomas.

“Studies are beginning to show the relevance of micro-RNAs to human
disease,” says postdoctoral fellow Michael Lam, who is working with
mice in Bartel’s lab to probe some of the other microRNAs connected to
cancer.

“It’s exciting to watch the parallel currents in microRNA research,”
says Ambros. “As a classical geneticist, I find it interesting to know
how particular micro-RNAs work in particular situations. But I’m also
intrigued by the work of people such as Dave Bartel, who are taking a
more genomic view and discerning general patterns of microRNA function
and evolution.”

“This will occupy thousands of people for years,” Sharp says. “It will
take decades to work out the specifics of many different microRNA-
regulated processes and integrate those into whole-organism biology.”

***************
Running interference

RNA interference (RNAi) advanced genomic exploration a few years
before the abundance of microRNAs was recognized. Scientists found
they could knock down the output of genes by introducing double-
stranded RNA into an animal. They soon found that this double-stranded
RNA was processed into short strands of RNA, and that these small
interfering RNAs (siRNAs) pair to and direct the cleavage of messenger
RNA molecules that control protein production.

Sound familiar?

It turns out that microRNAs and siRNAs use similar cellular machinery
to achieve their goals. Both rely on a protein called Dicer for
processing, and a “silencing complex” facilitates their interaction
with mRNAs. Within this silencing complex, the two types of RNA
molecules both can direct messenger RNA cleavage when they have
extensive pairing to the messengers, or dampen protein output by other
means when pairing is not as tight.

However, a microRNA comes from a single strand of RNA coded in the
genome that folds back on itself to form a structure resembling a
hairpin, while an siRNA comes from a long piece of double-stranded
RNA.

 May 5, 2006