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.
And major may be a vast
understatement. We’re talking about a development that could not only
revolutionize an entire field and save countless lives, but one that will
make fortunes for savvy investors.
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 being.
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 gene,
either.
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.
Doug Hornig
Senior
Editor, Casey Research
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