Most investigations begin at the crime scene and follow evidence to the suspect.
But for years, researchers have worked backward, starting with the prime suspect — the CFTR gene — and attempting unsuccessfully to trace it to the scene of the biological crime, which, in this case, is a form of chronic idiopathic pancreatitis characterized by inflammation and scarring of the pancreas.
A CFTR gene mutation already is known to cause cystic fibrosis and the potentially deadly buildup of thick mucus in the lungs and other organs, including the pancreas, but researchers have had trouble linking the same gene to the form of pancreatitis. It has been a difficult scientific puzzle to solve. If the same gene mutation caused pancreatitis, why don’t those with pancreatitis also have cystic fibrosis?
“What we saw were thousands of people across the United States who had pancreatitis without lung disease, and it raised the question: Why don’t these people have lung disease?” said David C. Whitcomb, chief of the University of Pittsburgh School of Medicine’s division of gastroenterology, hepatology and nutrition.
So Dr. Whitcomb’s team did what good detectives do. They started at the crime scene by genetically testing patients with pancreatitis and tracing the process, step by step, to the prime suspect — that same CFTR gene.
As in any good crime mystery, there’s another plot twist.
The gene mutation that causes cystic fibrosis in the lungs, pancreas and other organs was not the same mutation or mutations that caused the chronic pancreatitis.
The team instead discovered nine genetic variations of CFTR, and they, singularly or in combinations, were linked not only to pancreatitis but other fluid secretion problems including a form of sinusitis and changes in semen leading to male infertility.
The Whitcomb team now has evidence that mutations of the CFTR gene cause two distinct diseases, cystic fibrosis of the lungs and cystic fibrosis of the pancreas, which has no effect on the lungs.
With the cause of one form of chronic pancreatitis now known, researchers can turn to developing treatments that delay or prevent mutations in proteins that gene variations produce.
It also raises the potential that cystic fibrosis of the pancreas could be treated with the same drugs now used or involved in human clinical trials for cystic fibrosis of the lungs.
The study, which Dr. Whitcomb led, was published online Thursday in the journal PLOS Genetics.
Miklos Sahin-Toth, a gastroenterologist at Boston University whose research focuses on proteins produced by CFTR mutations, described the study as “significant with a very novel hypothesis.”
“I would consider this a very significant step in the field, which is an indication of a good study,” Dr. Sahin-Toth said.
“This is not the holy grail, but it is a worthy hypothesis that now can be investigated further. The data are very solid in this paper.”
Scientists already knew there were various mutations of the CFTR gene, but most of those mutations “were deemed to be harmless because they didn’t cause lung problems,” Dr. Whitcomb said. “We examined whether these variants could be related to disorders of the pancreas and other organs that use CFTR channels” to secrete substances necessary for proper organ function.
Cystic fibrosis of the lungs occurs when a child receives a severely mutated CFTR gene from each parent.
Before treatments were available, the genetic effect was known to interfere with production of chloride channels needed for fluid secretion by the pancreas, intestines, male reproductive organs, sweat glands of the skin, sinuses and lungs.
The pancreas is the most sensitive of all organs to CFTR gene mutations, making it unable to secrete fluids that push digestive enzymes from the pancreas into the intestine for food digestion. Without pancreatic enzymes, the child could not digest food and would starve.
Now medications containing digestive enzymes from ground-up pig pancreases can be taken orally to help such children digest their food, but as they grow, they proceed to develop a thick mucus buildup in the lungs, as a result of mutations in the same chloride channels.
A normal CFTR gene produces proteins that fold to produce channels necessary to move chloride from inside cells to the outside, where they attract water through osmosis, resulting in fluid secretion. This flushes duct systems in organs such as the pancreas, sweat glands and male reproductive organs, and moistens mucus in the sinuses and lungs so that it is not thick and sticky, but some mutated proteins don’t fold properly, resulting in channels that hinder secretion of chloride, resulting in mucus buildup in affected organs including the lungs and pancreas.
The pancreas uses channels going through protein molecules to transport secreted bicarbonate, which expels digestive juices from the pancreas, draws water and develops healthy digestive chemistry. To figure out how the gene variants might affect bicarbonate secretion, Dr. Whitcomb recruited Min Goo Lee of Yonsei University College of Medicine in Seoul, South Korea. His team is studying the WNK-1 cell responsible for turning on the switch to convert the chloride channel into one that secretes bicarbonate.
Dr. Whitcomb said the nine variants of CFTR disrupt the effects of the WNK-1 signal, which means that channels cannot transform to transport bicarbonate. As a result, digestive enzymes are not flushed out of the pancreas. If they become active, they begin digesting pancreatic tissue instead of the meal in the intestine, resulting in the inflammation and scarring of pancreatitis.
During the study, the team conducted genetic testing on nearly 1,000 people, all with idiopathic pancreatitis, and compared their CFTR genes with an equal number of healthy volunteers.
That is what led to the discovery of the nine gene variations, along with evidence that, based on the type of variation, some of those with pancreatitis also had sinusitis, with a notable number of males being infertile. These patients did not have lung disease and were not thought to have abnormal sweat chloride levels, so they did not have classic cystic fibrosis.
“If you have severe mutations, both the bicarbonate and chloride channels are wiped out and don’t work,” Dr. Whitcomb said. “So what we found was a different type of cystic fibrosis.
“New drugs can make the CFTR gene work better. If it is defective, medicines can compensate and make the protein work better, but they’ve never been tested before on pancreatitis, and that is the type of thing I’m excited about. We know what the problem is, and now we can start working on the solutions. This is the first time that there’s hope for patients and their descendants.”
David Templeton: email@example.com or 412-263-1578. First Published July 17, 2014 2:33 PM