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The Times of India/ New Delhi/ 02/ 11/ 07
RNA A Brave New World
Scientists across the world are waking up to the power of ribonucleic acid, which may be
the catalyst in the quest for cures of dreaded diseases likes AIDS, cancer and even
common colds. Subodh Verma investigates
Asilent revolution sweeping through the obscure world of molecular biology could be
the beginning of finding cures for some of the most dreaded diseases like AIDS, cancer,
hepatitis and even common colds. Scientists working in dozens of research labs across
the world, including in India, have discovered that RNA (ribonucleic acid), long thought
of as an important but lowly ‘messenger’ in the complex biochemical factory called the
cell, is actually a manager and regulator with wide-ranging powers. Philip Sharp, who got
the Nobel Prize for medicine in 1993, says that these discoveries are “the major
breakthrough of the last decade and perhaps of several decades”.
Indian scientists have been involved in this cutting edge research. A Hyderabad based
husband-wife duo - Utpal Bhadra of the Centre for Cellular & Molecular Biology and
Manika Bhadra of Indian Institute of Chemical Technology – were among the first to
discover gene silencing by RNA interference. The 2006 Nobel Prize was awarded to two
American scientists for this discovery. Sunil Mukherjee of International Centre for
Genetic Engineering & Biology at Delhi is working on manipulation of genes in plant
cells and in developing virus resistant crops.
For over half a century it was believed that RNA merely carries the blueprint of
proteins from DNA to ribosomes and helps in assembling the desired protein molecules.
Recent discoveries have substantially changed, if not overturned, this belief. Now it has
been found that besides doing this, RNA molecules regulate many important processes,
including shutting off the blue-print carrying genes themselves.
DNA carries the genetic code in the form of precise sequence of four chemical units
(A, T, G and C). Each DNA molecule contains millions of these units. Some specific
sequences are used for making proteins – these are called genes. The rest of the DNA was
considered junk, leftover from millions of years of evolution. One of the crucial
discoveries is that even these non-coding portions of the DNA are used to create small or
micro RNA molecules. Ronald Breaker, of Yale University says, “The recent discoveries
of non-coding RNA functions, such as microRNAs and riboswtiches, are remarkable
because they reveal a far greater role for RNA in cells”.
There are hundreds of RNA molecules floating around in the cell, performing a variety
of functions. They regulate what combines with what, they switch processes on and off,
and they control rates of reaction. According to Sidney Altmann, winner of the chemistry
Nobel Prize in 1989, the main task of scientists in the immediate future will be to find out
what all these hundreds of types of RNA are doing in the cell.
Some of the activities of RNA have been deciphered. One of them is called RNA
interference (RNAi). It has been found that introducing a double strand RNA (dsRNA)
into a cell sets of a chain of events resulting in the destruction of messenger RNA. This
effectively ‘silences’ the gene, which was sending out the messenger. RNAi has immense
possibilities. It is based on a naturally occurring process and it is very precise. Using it,
one can silence any gene and thereby stop protein production related to that gene. So, it
can be deployed to kill off viruses, or bacteria. It can provide a potent tool of silencing
rogue genes, say, those causing cancer. RNAi is also being used to selectively switch off
genes to observe what happens to the body.
Scientists had been tweaking genes through more difficult means till now – introducing
bits of DNA into cells to change the genetic code. This was easy in plants which have
less complicated structures. So, genetically modified (GM) crops developed. But the
RNAi method can be used much more effectively and in animal cells too.
Research indicates that small RNA is involved in other crucial tasks too. According to
Peter Seeburg of the Max-Planck Institute, Heidelburg, they play a role in regulating
organ specification, that is, development of different organs, and also in running the
body’s immune system.
However, all experts agree that it’s early days yet. One of the major issues scientists
are grappling with is: how to deliver the suitable short interfering RNA at the precise
place where it will perform its function. Claes Wahlestedt of the Scripps Research
Institute, Florida says that, “delivery (is) a hurdle that nobody has been able to overcome,
other than in very small incremental advances.” Utpal and Manika Bhadra have found
that RNA plays a key role when cells divide rapidly, as in cancerous cells. This could
lead to a method for controlling cancer. They have also developed nano-tubes for
delivering the required small RNA. “At this point we have only explored the tip of the
RNA iceberg and most still lies below the surface,” says Stephen Holbrook of the
Lawrence Berkeley Laboratory. However, international cooperation between scientists,
using new IT tools to scan and catalogue molecules is driving research at a furious pace.
So much so that commercialization of RNA based medicines is already on the horizon.
The New Pharma Jackpot?
Within a decade and a half, what was a mere twinkle in the eyes of scientists has
turned into a multi billion dollar flood. But that is because one of the cornerstones of
genetic science got upturned.
Scientists in public funded universities and research institutions spread across Europe,
North America, and even India carried out the basic research. As the momentum
gathered, and Nobel Prizes started flowing in, the focus began to turn to applications.
This was understandable: with the rising trend of metabolic disorders like diabetes,
heart diseases, arthritis, cancer in the West, and also the widening sweep of unconquered
diseases like AIDS, there was a growing panic both in the public at large and among
pharmaceutical manufacturers. Few drugs were coming out of the research pipeline.
Discoveries about RNA’s key regulatory role held out hopes for breakthroughs.
First, many of the scientists themselves set up firms to commercialise the nascent
discoveries. Thus, Nobel laureate Philip Sharp of MIT set up Alnylam, while another
group of scientists led by Stephen Fodor launched Affymetrix. These start-ups are
making tools for research based on bio-informatics or actively researching delivery
mechanisms for RNA-based therapies.
Meanwhile, big pharmaceutical companies moved in with big bucks. In a series of high
profile take-overs through 2006 and continuing this year, Merck acquired Sirna
Therapeutics Inc, a specialist in RNA interference (RNAi), for $1.1 billion, Pfizer entered
into a multi-million dollar deal with Mirus Bio to push research on RNA, AstraZeneca
bought MedImmune for $14.6 billion, Novartis purchased NeuTec Pharma for $576
million, and Schering-Plough acquired Organon for $14.3 billion. Drug industry watchers
say that big pharma is now raring to grab the burgeoning bio-tech market. From
cloistered university labs to the billion dollar limelight – RNA has come a long way. But
people will have to wait longer before actual therapies hit the market.