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A number of potentially useful drugs have been banned from the market because of a mysterious and deadly heart reaction. A worm that has no heart may help scientists figure out why.
A simple worm makes a model heart. I'm Bob Hirshon and this is Science Update.
A tiny roundworm known as C. elegans may not have a heart, but it's a boon to heart researchers. That's because its pharnyx, or feeding tube, beats rhythmically like a human heart, has similar electrical properties, and is controlled by similar genes.
Christina Petersen, an anaesthesiology professor at Vanderbilt University, is using the worm to solve a medical mystery: why drugs that block a potassium channel called HERG sometimes trigger fatal heart arrythmias.
These are patients that are taking a drug and simply drop dead. And it's so serious now that the FDA now requires that every drug be tested for HERG block before it's approved for market distribution. So if there was a way to test or predict who was at risk for this, some potentially therapeutic drugs could still be used on the market.
Her team is looking for genes and proteins in the worm that interact with these HERG channels, and comparing them to DNA records from human patients. Recently, they found a mutant protein that appears to protect against the deadly reaction.
And now what we're doing, is we're doing a screen of the entire worm genome, and we're asking, what other proteins are there out there?
It's hoped that this will reveal all the risk factors in this life-or-death issue. I'm Bob Hirshon for AAAS, the Science Society.
Making Sense of the Research
When scientists try to learn about the human body, sometimes it's best to look at other animals first. That's because humans are complicated: we have complicated brains, complicated backgrounds, complicated genes, and complicated bodies. Looking for a few genes that affect a single potassium channel that helps control the heartbeat would be like looking for a needle in a haystack. And then there's the practical problem: you can't deliberately trigger arrhythmias in a beating human heart.
That's why the worm C. elegans functions so well as a model. Even though it doesn't have a heart, its pharynx is like a heart in several ways:
- Worm pharynx cells, like human heart cells, are isoelectric, which means they're connected in a way that allows electrical signals to zap through the entire organ almost instantly.
- The properties of those electrical signals are very similar in the worm pharynx and the human heart.
- When you look at pharnyx cells and heart cells individually in a petri dish, each one will beat on its own just like the whole organ does.
- Many genes that control heart function and development have similar, corresponding genes, or homologs, that are expressed in the worm pharynx.
Now, the drug reaction that Petersen's team is studying is called Long QT syndrome. It's rare, but it can be fatal, and right now there's no way to tell ahead of time who might have the reaction and who might not. So a lot of potentially useful drugs can't be sold because there's a small chance they might cause this reaction. It's as if peanuts had to be taken off the market because a handful of people have life-threatening peanut allergies, but nobody knew who they were.
Since the drugs in question affect a heart potassium channel called HERG, scientists originally checked to see if the Long QT patients had abnormal HERG genes. But it turns out most of them don't. So Petersen and her colleagues used the worm to look for other genetic mutations that cause Long QT. So far, they've found one—a mutation in a gene called KCR1—and they've matched it to DNA records of Long QT patients. It appears that people with a glitch in their KCR1 gene can function normally, unless they take a drug that blocks HERG. If they do, they go into arrhythmia.
Petersen says that KCR1 almost certainly isn't the whole story; there are probably several other genetic risk factors for Long QT. But it's easier to look for them in the worm model first, and then check them against records from human patients, than to look directly at humans. That's just one of the many benefits of the continuity of life: even though a human and a worm may be very different, at the end of the day, we're built from more or less the same stuff.
Now try and answer these questions:
- Define the following terms: isoelectric, homolog, Long QT syndrome, HERG, KCR1. How do they fit into the story?
- Why is a worm a good model for a human heart?
- Why is it important to find out what causes Long QT syndrome?
- Can you think of other examples (not necessarily from science) of simple models that can reveal how a more complicated system works?
The C. elegans WWW server has links to all kinds of research and information dealing with the worm mentioned in this study.
The Texas Heart Information Center offers this page devoted to Long QT syndrome.