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RNAi - Miracle Cure, Silent Killer or Weapon of Mass Destruction?

20th August 2003

A flood of scientific papers has been published recently about an
exciting biochemical technology known as RNAi that promises to
revolutionise medical science. The discovery has the makings of a
terrifying new weapon of mass destruction, too.

The RNA molecule is a less famous ****ogue of DNA, although it plays
an equally important role in the chemistry of life.

Living organisms translate DNA code into proteins via messenger RNA
(mRNA). The mRNA carries coded information from the DNA in a cell's
nucleus to the protein production plants in the cytoplasm. Protein
molecules are made by clipping together a string of amino acids. Each
amino acid is represented by a 3-base-pair sequence of mRNA called a
codon.

The scientific understanding of that mechanism has provided a way of
interfering with the process.

At any one time, a typical human cell expresses anywhere between a few
dozen and several thousand genes. Each gene is translated into a
section of single-stranded mRNA before being transcribed into a
protein.

Over the course of billions of years, rogue mRNA molecules evolved
into parasitic, self-replicating objects known as (retro-) viruses,
which are composed of double-stranded RNA. At the same time, the rest
of the cell evolved various defence mechanisms to detect and destroy
viral RNA.

The cell's viral defence systems lie at the heart of the newly
discovered RNAi technology. The "i" in RNAi stands for "interference".
Scientists have discovered how to hijack the cell's viral defences to
destroy ordinary mRNA and thus silence the expression of the
underlying genes.

It is easy to synthesise RNA molecules that loop back on themselves to
create double-stranded RNA.

Pieces of double-stranded RNA longer than about 30-base-pairs induce
mammalian cells to shut down gene expression temporarily while an
enzyme called RNAse L destroys all the mRNA within the cell.

However, double-stranded RNA less than 30-base-pairs in length does
not induce the shut down response. Instead, an enzyme called Dicer
chops it into a staggered 22-base-pair long fragment and prises the
strands apart. One of the strands (now called an siRNA) becomes
attached to the target site of an RNA-induced silencing complex
(RISC).

The RISC then acts like a magnet for any mRNA that either exactly or
closely matches the target siRNA. If the match is close, the RISC
sticks to the mRNA halting its translation into protein. If the match
is exact an enzyme called Slicer cleaves the mRNA thereby halting its
translation. The sliced mRNA halves are released allowing the RISC to
continue destroying matching mRNAs for several days.

Synthetic double-stranded RNA molecules that dice into siRNA fragments
matching a section of normal mRNA will silence the expression of a
specific gene's protein.

In other words, one or more genes can be switched off for several days
at a time. That ability makes RNAi the silver bullet of cellular
biochemistry. Obviously, such a powerful, gene-specific tool has
enormous research and the****utic potential in medicine. But it also
has a negative side, one that scientists appear not to have
acknowledged yet, in public, at least.

Several methods for delivering and inserting RNAi fragments into cells
are currently under development. RNAi "infection" of cells can be
achieved simply by feeding lower animals with bacteria genetically
engineered to produce suitably coded RNAi molecules. That technique
has not been shown to work in mammals (yet), however, RNAi infection
has been achieved with modified adenovirus vectors, by high-pressure
injection and direct absorption of RNAi encapsulated within
25-nanometre liposome (i.e. fat) globules.

Liposome encapsulated double-stranded RNA molecules can be inserted
into human cells either by injection, inhalation, ingestion or skin
contact via a carrier liniment such as DMSO.

In the wrong hands, RNAi technology can kill in ways that are
currently undetectable. In expert hands, it can kill only those who
happen to possess a particular genetic mutation. A silver bullet par
excellence.

All of the estimated 100,000 plus human proteins are manufactured from
linear sequences of just twenty amino acids. Therefore, it is highly
likely that there are several 22 base-pair mRNA sequences (equivalent
to 7-8 amino acid codons) that are common to many of those proteins.

A double-strand of RNAi carrying a few such common sequences would
disable many essential cellular functions or one could just disable
insulin production, for example. RNAi molecules could be designed to
interfere with one or more neuro-transmitters rendering the recipient
senseless, docile or even insane. Other RNAi sequences could interfere
with motor-neurone synapses, mimicking the effects of nerve agents.
Blindness, breathing difficulties, pulmonary oedema, haemorrhage,
paralysis, heart, liver or kidney failure, fatigue, insatiable thirst
or hunger, disorientation or whatever, just program the RNA
synthesiser as required. Death by numbers.

Unlike regular poisons and biological toxins, RNAi molecules are
virtually undetectable within cells already filled with mRNA. Lethal
RNAi molecules can be obtained from hundreds of biochemical supply
laboratories. Anyone can purchase an RNA synthesiser or simply create
short RNA molecules manually with easily purchased organic compounds
and reagents. RNAi can be as toxic as botulinum or as harmless as
sherbet. It may even cure cancer.

Author's details:
http://www.scandals.org/articles/pkindex.html
http://www.injustice.org/ccrc/

Everything you need to know about RNAi and gene silencing:
http://www.ambion.com/techlib/resources/RNAi/

Comprehensive List of RNAi Publications (updated daily):
http://www.orbigen.com/RNAi_Orbigen.html