If you had a previously incurable genetic condition and scientists
came up with a treatment for it, you’d jump at the chance to take
advantage. That’s a no-brainer. But what if you had the opportunity to
invest in a company deeply involved in just such cutting-edge research?
In classical drama, as well as real life, the bearer of bad news is
often executed, simply for having brought it; in modern medicine,
though, messenger killing is not only acceptable, it represents a major
breakthrough in our approach to genetic disorders.
It boils down to this: Scientists now have a technique for selectively,
and reversibly, turning off the behavior of certain pieces of the
genetic code in humans. The key word being reversibly.
Ever since the mapping of the human genome in recent years, researchers
have been digging ever deeper into the genetic causes of many
diseases. The idea was simple: find the gene responsible for a malady,
then alter or remove it from a person’s body and cure the disease. A
severe course of action, but one many patients were willing to risk for
the chance to cure a dreadful condition. In the 1990s, using a number
of techniques collectively known as gene therapy, doctors started
putting these new treatments into practice.
But the gene therapy route involves genetic mutation, a risky
proposition at best... After you’ve deconstructed the gene, you can’t
put it back together if problems develop, which they often did. The
genetic manipulations that were performed unleashed all kinds of side
effects – many of them lethal. Too many people were dying, so scientists
began looking beyond full-bore genetic assaults.
There had to be a better way, and there is…
The current preferred alternative – as yet still in its infancy – is
about as close to the polar opposite of the old approach as possible.
It doesn’t touch the gene at all. It’s not only temporary and easily
reversible, and thus good for the patient’s peace of mind, it’s also
well suited for experimentation on outside threats such as cancer, or
possibly even bacterial and viral infections.
It’s called RNA interference (RNAi), and as the name
implies, the technique involves interrupting the function of RNA
(ribonucleic acid), one of the key components of all living cells. In
order to understand exactly how it works, you first have to know just a
little about an extraordinarily complicated subject, human cell
dynamics. Here’s the short version.
At the center of the cellular action is the familiar,
twisted-ladder-shaped double helix structure known as DNA
(deoxyribonucleic acid). It consists of two very long chains of
molecules (polynucleotides), paired together. One chain is called the sense strand; its complement on the other side is called the anti-sense strand.
DNA is further subdivided into 23 chromosomes, and they in turn are sliced into about 25,000 smaller bits called genes.
Genes are the source of all top-level commands in the body. They direct
the production of proteins that make everything run smoothly or, in the
case of a genetic malfunction, run amok. And they do it through a
two-part process, transcription and translation.
First, transcription: Crawling all over the DNA are enzymes, little
ladder-climbing robots that dock at the boundaries between genes. Once
an enzyme locks on, it transcribes the code of a gene into a
particular form of single-stranded RNA (or one half of a tiny piece of
DNA). This RNA is always derived from the DNA’s sense strand. It mimics the gene that encoded it, except for a small chemical marker that designates it as a “messenger” RNA (mRNA), a sort of carrier pigeon used to send genetic instructions from the command center of a cell to its parts.
Then, translation: The enzyme releases the mRNA, and it travels to another part of the cell, the ribosome, a kind of all-purpose life-maintenance factory. It’s the ribosome that translates the instructions carried by the RNA and starts building proteins – the
essential chemicals that support a healthy body – in accordance with
the underlying DNA command.
Message sent; message received.
However, when the ribosome’s protein production is not working
correctly or is genetically faulty to begin with, the body essentially
turns on itself. The mRNA is carrying the wrong message. This results
in diseases that have been very difficult to treat compared with their
virus- or bacteria-based counterparts.
Historically, fighting those diseases has been a matter of isolating
the offending protein and neutralizing it. No small feat. There are
about a hundred thousand different proteins in the body, interacting
with each other in billions of ways. And once you find the one you’re
looking for, you have to test compound after compound against it,
trying to identify the haystack needle that actually affects it (if
there is one). Modern high-speed computers have simplified this random
task, but it’s still incredibly time consuming.
Now all that’s changing – and the change is producing one of the most exciting developments in medicine today: anti-sense technology.
Once genetic mapping became a reality, researchers quickly discovered
that it was possible to sabotage wayward mRNA before it ever gets to
the ribosome. All you had to do was synthesize the anti-sense form of the undesirable mRNA and inject it into the cell, where it would bond with the sense sequence automatically, effectively “switching off” the message. If
the ribosome can’t read it, you’ve achieved RNA interference, and the
offending proteins will never be produced at all.
You’ve killed the messenger.
That’s excellent in itself. But the added bonus is reversibility. The
effect lasts only as long as the anti-sense agent is present. If
counterproductive complications arise, you simply stop treatment and
the mRNA is returned to its previous state, once the supply of reacting
chemicals is exhausted.
It works. But establishing the theoretical basis, then proving it out,
those were the easy parts. Next came the difficulties, which divide
into two broad areas.
Of these, the toughest is that you need a pinpoint delivery system.
It’s obviously impossible to inject the anti-sense compound into
individual cells, one by one. Maybe in a Petri dish. But not in a human
Then, once you do get it inside, you have to protect it from the body’s
natural defenses against invaders. After that, it must encounter its
target. Finally, it must align itself properly with the elaborately
folded RNA and generate the enzymes that will deactivate it.
Thus there’s a furious arms race underway, with plenty of companies
vying to develop the gold standard in delivery systems. So far, there’s
no clear winner – though it looks like multiple options for delivery
will eventually be available to therapy manufacturers, as recent
successes using lipids and polymers to deliver anti-sense molecules in
humans have demonstrated.
The other half of the equation is the need for the proper anti-sense
sequences. But before you can synthesize them, you have to identify
proteins associated with different diseases. That can be tricky.
Protein signatures differ among diseases, and can even differ among
patients with the same disease.
Zeroing in on the right target protein is not enough, either. You have
to then backtrack to the mRNA that causes its production. Only then can
you design your anti-sense messenger.
It’s not high school lab work, but still... Lock down on the right mRNA
and you don’t need to bombard it with randomly chosen compounds. You
only have to design one that features a complementary structure –
properly combining the four simple molecules that are the building
blocks of all DNA – and you’re done. Comparatively, it’s a walk on the
beach. Not to mention that you don’t have to tinker with the underlying
Hand-crafted cures for nearly every genetic malady, possibly extending
even to non-genetic ones – that’s the promise. If only we didn’t have
to wait for a reliable delivery system to make its way through the
scientific process and the regulatory gauntlet. But we do. In the
meantime, however, researchers are taking great strides forward with
mRNA identification and the development of specific anti-sense
molecules. There’s no reason not to stockpile them against the day when
they can easily be applied.
And one innovative biotech company – the leader in the field of
anti-sense therapy – is doing just that. Though it’s only at the
beginning of this exciting road, the company is already being courted
by major pharmaceutical companies and bringing in tens of millions in
revenue per year. As RNAi takes off, they stand to make billions, not
only for themselves, but for investors as well. Try a no-risk
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