Salt Wars

Is the new mouse the ticket for CF research?

At times, reaching a breakthrough in cystic fibrosis research can feel a lot like winning the lottery – only to wake up the next morning and hear about the guy in Peoria who claims he has the right combination of numbers. So you go back and see if your six was really just an upside-down nine the whole time. You make sure. And then it happens again a few years later, same guy in Peoria.

Breakthrough, go back, make sure. Breakthrough, go back, make sure. Catchy rhythm if you’re dancing, but when you’re trying to solve one of science’s most maddening mysteries and thousands of lives are at stake, not so much.

Eventually, you just have to believe in your six. You have to believe you have the disease’s number.

And that’s precisely what researchers at UNC’s Cystic Fibrosis Pulmonary Treatment and Research Center are betting on after their announcement in April of finally creating a genetically engineered mouse that mimics the course of CF lung disease. Few searches for answers in medical science are as competitive as the one that would explain why people born with a single defective gene are fated to die by age 30. By fits and starts, answers have revealed themselves, notably the discovery of the gene that goes awry in people with cystic fibrosis, the so-called CFTR, in 1989. But 15 years have passed, and that treasure map has yet to yield its gold.

For years, researchers at UNC and elsewhere believed that CF patients could not clear the thick mucus that builds in their airways because they lacked the miniscule layer of fluid there that healthy people have, fluid that moves inhaled debris along, with the aid of coughing. In CF, the mucus just sticks, clogging airways like a bathtub drain filled with scum and leading to 95 percent of all CF deaths. The reason, the UNC team said, was that the airway cells had too little salt, or sodium chloride, which acts as a magnet for water and helps move it across airways.

The CFTR gene regulates the amount of sodium absorption and chloride secretion in airways – those two actions have to work together to create just the right amount of salt. But in CF patients, the chloride channel doesn’t hold up its end of the bargain, leaving sodium to play an aimless game of one-man Ping Pong and leaving a mess in lung airways.

Without chloride to regulate its actions, sodium absorption skyrockets and fluid levels drop.

At least, that’s what UNC thinks.

Enter Peoria. A team of researchers at the University of Iowa published a paper in 1996 that showed utterly different results from UNC’s. The problem wasn’t low fluid that might be fixed by adding the salt and water back into the airways. The problem with CF, Iowa said, was that the fluid already was far saltier in CF patients than in normal lungs; that, indeed, that salt was blocking the lung’s innate warriors against bacterial agents. It wasn’t a matter of over-absorption but of defective absorption.

Go back, make sure. The tango with Iowa, dubbed the Salt Wars and continuing in 1998 and 1999 after successive papers by UNC and Iowa (both further supporting their dueling hypotheses), is no dance party. It makes treatment options – adding salt or taking it away – a matter of life, death and millions of dollars in research money. But even in normal lungs, the layer of fluid on airways is so thin, just seven-thousandths of a millimeter in depth, that extracting it from organisms for study in lab cultures can alter it.

That’s why the creation of an over-absorbing mouse that mimics the mucus plugs and bacterial infections of a CF patient has many scientists excited. UNC’s previous attempt at a mouse model in 1992, in which the defective CFTR gene was bred in the animal, failed because the mouse’s airways responded differently to the gene, never developing deadly infections. Richard Boucher, the director of UNC’s CF center, says the new mouse, which has a fully functioning CFTR gene but over-absorbing sodium channels, can be used to test more effective treatments – not only for CF patients but for people who suffer from asthma and chronic bronchitis.

“The question is, how much more definitive can you get?” added Marcus Mall, the principal investigator on UNC’s latest finding and a German postdoctoral scholar who came to UNC specifically to create the mouse. “The whole salt war argument in Iowa was all made by cell culture. This one is the first time in an in-vivo model, a living model, that you have hyper-absorption of salt and water.”

And the word from Iowa? Not so fast.

Jeffrey Smith, associate professor of pediatrics at the University of Iowa and one of the school’s prominent CF scientists, said leaving the CFTR gene in – giving the mouse a functioning chloride channel to go along with rigged sodium over-absorption – will result in less fluid simply because chloride helps quicken absorption. Even normal lungs would have clearance problems in such a setup, he said.

“I don’t disagree with their data,” said Smith, who thinks UNC is ignoring Iowa’s research. “They’re doing good science. But they’ve stacked the cards against the mouse, and it doesn’t reflect what truly happens in a CF lung.”

Boucher said he values Iowa’s work; if not for Smith’s 1996 findings, UNC might have assumed its hypothesis was correct and never endeavored to make this new mouse model, would have “just put it in cruise control,” as Boucher explained. Still, he said, “Operationally, we decided a few years ago that you just have to move on.”

They have moved on, creating therapies based on their low-volume hypothesis that are being tested in humans by a small pharmaceutical research firm. One, INS37217, posted unexpectedly positive results in studies reported in late April.

Smith also is moving forward with research to further Iowa’s hypothesis. The Salt War may be turning into more of a Cold War, but that’s OK with scientists – as long as a cure is left standing.

“Science is very competitive,” Boucher said. “But it’s better that way. It makes you think. And as long as it’s done the right way – and on both sides, that’s true here – it’s useful for the field.”

Copyright 2004 UNC General Alumni Association

Published in Carolina Alumni Review, JulyAugust 2004