By David N. Leff
Many of the tummy-soothing antacid drugs on pharmacy shelves rely on one active ingredient - sodium bicarbonate (NaHCO3). This familiar white powder, of course, is baking soda, traditionally taken to sweeten a sour stomach. But the healthy human body also churns out its own bicarbonate, every day.
"An adult human being," observed physiologist Shmuel Muallem, at the University of Texas Southwest Medical Center, in Dallas, secretes about five liters of fluid from his pancreas gland, containing that organ's digestive enzymes. On top of that, the pancreatic fluid we secrete contains a very high concentration of bicarbonate - probably the highest found in any fluid generated by our body. The acidity, or pH, of that fluid, is determined by bicarbonate, which is the buffer of all biological fluids."
He made the added point that "cystic fibrosis [CF] patients do not secrete bicarbonate, and nobody knows exactly how this has happened. People realized its importance, but nobody knew why it was defective."
Muallem filled this knowledge gap in the issue of Nature, dated March 1, 2001. The report, of which he is senior author, bears the title: "Aberrant CFTR-dependant HCO_3 transport in mutations associated with cystic fibrosis." (CFTR, the gene mutated in CF, stands for Cystic Fibrosis Transmembrane Conductance Regulator. Its protein regulates the flow of negative ions in and out of the lung's epithelial cells.)
"People knew for many years," Muallem told BioWorld Today, "that there are two problems in CF: One, its affected tissues do not secrete enough fluid, and two, what fluid they do secrete is quite acidic. One reason is that CF patients don't have a channel, a conductance, a tunnel for transporting chloride ions from a cell's interior to its outer surface. We knew that our secretory glands need to move chloride and sodium - like table salt, NaCl - from one side to the other, in order to secrete fluid. And then the fluid follows.
"Since cloning of the CFTR gene in 1989," Muallem recounted, "it was found that about 75 percent of Caucasian CF patients have defective chloride transport. Once that gene, which causes CF, was identified, it became clear that normal CFTR could code for a protein that functions as a chloride channel. It's like a door. When it opens, it allows chloride to flow from high concentration to low concentration. The 75 percent of CF patients had a mutation in this protein - loss of a single phenylalanine amino acid - which prevents the protein from getting to the cell surface of lungs, pancreas and other ducts. That makes it the root cause of cystic fibrosis.
"In later years," Muallem continued, "a great many other less common CFTR mutations have been found that cause CF. There are now close to 800. When people started analyzing those aberrant proteins, they encountered more and more mutations that have a normal or reduced ability to transport chloride. Yet they cause the disease, and nobody knew how this is possible: If those mutations are so good at transporting chloride, why should they ever cause CF?"
Solving NaCl vs NaHCO3 Equation
Here is how Muallem and his co-authors undertook to solve that puzzle, as reported in their Nature article:
"We selected 17 of these mutations that can cause CF with different degrees of severity - mild to very severe - but all of them had some capacity, normal or reduced, for transporting chloride. When we measured their ability to transport bicarbonate, we found that bicarbonate transport is defective in these mutants. And the more severe the disease, the more it inhibited bicarbonate transport. So, now we can explain why those chloride-competent patients actually get the disease; it's because their cells cannot move bicarbonate."
A potentially therapeutic bottom line of that experiment, Muallem pointed out, is that, "whenever we are trying to find therapies for CF, we have to make sure that bicarbonate transport also has become normal. We cannot just go and deal with the chloride alone. We must also deal with the problem of the bicarbonate." However, he made clear that this mission is for the future, and for hands-on clinicians to tackle, rather than basic scientists such as himself.
"We are still at such an early stage," Muallem emphasized, "that the most important thing, before we go anywhere, is that our findings need to be verified in vivo - in tissues from patients. We didn't use any such tissues. We manipulated the 17 mutations in vitro, to mimic the situation of patients, and we put them in cell lines. The absolutely next thing is to go and see if it is true in patients. Get the tissue from them, measure their chloride and bicarbonate transport, and see that this still holds.
"Not myself, but other investigators have already started doing that," Muallem went on. "They are some of the people I let know about our findings before publication, and they are at the moment looking at these things - obviously trying to verify the finding."
Inhaling Life-Prolonging Bicarb - Someday
Speaking as a fundamental researcher, not a clinician, he ventured that "it would make sense to try to get bicarbonate to the surface of those tissues by artificial means. But I have no idea how this can be done, how to go about it, what drugs are available in the market that can do something like that. I don't know of anyone who is trying to manipulate bicarbonate as therapy in CF.
"As the bicarbonate is lacking in the CF tissue," he speculated, "it would be helpful if we could let a patient inhale a mist or spray containing it."
At present, he said, he and his team "are trying to understand the mechanism by which CFTR-encoded protein transports bicarbonate. If we can appreciate why it is defective in CF, we may try eventually to prevent or remedy that defect. Plugged ducts destroy the pancreas, and pathogenic bacteria eventually destroy the lungs of all CF patients. That leads to death at an early age. Perhaps, delivering bicarbonate to diseased tissues can someday lessen the effects of cystic fibrosis in patients, and even extend their lives." n