Rigorous Basic Science Reflects “Hope in Action”

More than 100 basic scientists participated recently in the meeting known by many in the cystic fibrosis (CF) community simply as “Williamsburg.” Held June 2 - 6, 2006 the lively 19th annual conference offered an opportunity for colleagues to make connections—connections to share new laboratory results, and compare results from one scientific discovery to another. The Cystic Fibrosis Foundation invites leaders from diverse fields like cell biology, molecular biology and immunology to come together to identify their common challenges in solving CF research problems and freely share expertise.  Participants plunge into four and a half days of non-stop exchange of research results, whether in the conference room at official “talks” or at less formal venues like the jogging path or over the lunch table.

“We provide this unique forum to generate new ideas to fuel the future of CF research, and hopefully, the future of people battling this disease,” said Robert J. Beall, Ph.D., president and CEO of the CF Foundation. “We are told repeatedly by researchers who attend that the candor of the meeting is unrivalled and serves as a launching pad for new ideas."

All who attends the conference shares the same goal:  to advance CF science toward curing this complicated disease. According to Sherif Gabriel, Ph.D., University of North Carolina at Chapel Hill, “There is no other meeting that stimulates the kind of collaboration and partnership that is so present at Williamsburg. It is reassuring to know that everyone at this meeting is working not just for improvements in care,” he continued, “but rather to develop a cure for CF.”

For more in-depth information about what was discussed in Williamsburg, click on the links below.

CFTR Takes Center Stage

Jeffrey Whitsett, M.D., a veteran CF researcher at the University of Cincinnati, chaired the first session and praised scientists for making inroads into the understanding of the defective CFTR protein made by the CF gene. “No protein has been looked at from so many angles,” he said, “but the intriguing complexity is still there. The protein has a constellation of roles besides that of a chloride channel and we are here to explore these.”

By interacting with other proteins, CFTR could affect how fats are metabolized, for example, or help regulate the inflammatory response or other vital mechanisms in the body. When researchers discussed these possible roles for CFTR they took the logical next step—to anticipate how this information could lead to new ways to intervene in the cascade of disease process that eventually destroys CF airways.

Knowing that the CF lung is particularly vulnerable to chronic infections, scientists have proposed that there are many factors in the bacteria-killing process that could be affected by CFTR. Research from the University of Chicago by Deborah Nelson, Ph.D., indicates that defective CFTR may diminish the ability of macrophages, scavengers of the immune system, to chew up dead cells, resulting in increased inflammation in the airways. Bruce Stanton, Ph.D., from Dartmouth Medical School, reported other evidence that the most common CFTR mutation, ΔF508, may somehow encourage growth of a biofilm, a protective coating formed by Pseudomonas aeruginosa bacteria which prevents drugs from killing this most common cause of CF lung infections.

Yet another result of the defect in CFTR may be an increase in the level of cholesterol accumulation when cells lose CFTR function, according to Tom Kelley, Ph.D of Case Western Reserve University, Cleveland. How can this be reversed? Based on Dr. Kelley’s ongoing work, the CF Foundation has already started a small pilot study using drugs called statins that affect cholesterol and may reduce inflammation, an ongoing challenge in the CF lung.

For CFTR to be functional it needs to be properly folded into shape as it moves through the protein “assembly line” in the cell. The common ΔF508 CFTR mutation causes problems in the protein folding pathway, so researchers like David Clarke, Ph.D., University of Toronto, are looking to see if different compounds may be needed at different steps along the way. Identifying such compounds might suggest a way to improve the folding of the ΔF508 CFTR protein and restore at least some of its function in the CF cell.

However, the cell also has built-in quality control mechanisms to stop a defective CFTR protein from moving along the assembly line.  These efficient quality control mechanisms retain defective proteins in a special compartment called the endoplasmic reticulum (ER). In one session, researchers described a number of molecules that might rescue the protein from the ER, or other molecules that might prevent the degradation of the defective protein while it is held “captive” in the ER.

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On the Therapeutics Track

Other research focused on new ways to address the inflammation that causes tremendous damage to CF airways.  Although the link between faulty CFTR and inflammation in CF lungs remains unclear, many teams of researchers are chipping away at this problem, searching for ways to switch the immune system out of high gear. The answers may come from the study of various inflammatory diseases like peritonitis or rheumatoid arthritis or from the exciting new studies of resolvins.

Resolvin molecules, derived from the omega-3 fish oils, appear to be signaling molecules involved in “resolving” inflammation by reducing the generation and release of a number of inflammatory mediators. CF Foundation-supported researchers had previously noted that people with CF have abnormal ratios of the fatty acids docosahexanoic acid (DHA) and arachidonic acid, which may contribute to an exaggerated inflammatory response. Increasing the amount of DHA in the diet may increase the level of resolvins in the body, and reduce inflammation. Ways to increase resolvin levels were discussed at the meeting, including the trials the Foundation is already supporting a study at the University of Massachusetts Medical Center involving infant formula with DHA added.

Thinking of innovative ways to approach the problems of inflammation and infection was enhanced by the mix of seasoned CF scientists, whose careers have centered on the study of the CFTR protein, and experts in other types of lung diseases or inflammation. Together, this professional “stew” took ideas from everywhere and mixed them together to create new views on the CF problem. As one researcher from University College London, Derek Gilroy, Ph.D., stated, once scientists understand the molecular pathways the body uses to respond to injury or infection, scientists will have a “treasure trove for drug development.”

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CF Gene Transfer Update 

CF researchers also gave an overview of gene therapy studies as they continue undaunted to tackle the problems that surround the field. Several scientists offered a progress report on CF gene transfer studies, describing what has been learned and where the research should be headed. They discussed the advantages and disadvantages of various gene delivery systems such as the adeno-associated virus (AAV) compacted DNA, fat capsules (liposomes), and the more controversial retroviruses.  Speakers presented the lessons learned, not only from CF, but also from experts outside the field of CF, who have treated the rare autoimmune disease made famous by the “Boy in a Bubble.”

The lessons learned by these experts from other disease fields were combined with those learned by the CF research teams, informing and shaping further pursuit of this promising area of science for CF. In the wrap-up CF gene therapy panel discussion, researchers agreed that the approach to solving the problems of gene transfer should be more centralized and standardized. The scientists concurred that progress will be quicker if agreement is reached on the appropriate target for gene transfer in the CF trials, such as nasal passages or lungs. Further, there is a need to agree on the molecular and clinical endpoints that measure success for CF gene therapy. By setting criteria for success now, scientists will be able to retool gene delivery systems in the laboratory and advance the field more quickly than in the past.

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Scientists Dismantle Pseudomonas, Piece by Piece 

An investment made in 1997 by the CF Foundation to support the sequencing of the P. aeruginosa genome continues to reap great rewards. Nearly all people with CF will acquire this kind of infection in their lungs, and most cannot rid their airways once colonized with this destructive organism. One particularly confounding factor is that the bacterium can quickly adapt and change its genetic make-up to ward off any innate defenses that a person has. This versatility likewise makes it a formidable foe to common antibiotics.

Once researchers had identified the 5,500 genes found in Pseudomonas, they began the “annotation” stage, determining what each gene does in the life of the organism, allowing it to adapt quickly and change its composition.

Maynard Olson, Ph.D., who directs the Genome Center at the University of Washington (UW) in Seattle, led the effort to map the bacterium. Dr. Olson presented a talk on the molecular evolution of P. aeruginosa, describing how it adapts and changes over years of living in the airways of an individual with CF. He called it an “organism that reflects high genetic complexity” in particular for its ability to adapt rapidly to its host.

“The next step should be to focus on known drugs and learn how they work so that we can exploit the metabolic changes Pseudomonas undergoes early enough to prevent its survival,” said Olson. “That way we have a real opportunity to make a difference in patients’ lives.”

In the lungs of people with CF, the Pseudomonas bacteria often cluster together and form a coating or “shield” called a biofilm that protects them from repeated doses of antibiotics. Researchers have therefore been studying the signaling molecules that call the organisms to group together. Caroline Harwood, Ph.D., a microbiologist from the University of Washington, presented evidence that a small signaling molecule, cyclic-di-GMP, could be the gang leader calling the organisms to meet up. The absence of this molecule leaves the organisms unorganized. The discovery may open the door to screening for therapeutics that would be in essence, anti-biofilm agents, an entirely new type of antimicrobial therapy.

“As a CF physician, it was incredibly encouraging to see some of the best scientific minds in the world spending four intense days discussing, debating an then strategizing together about the next steps needed to lead to improved therapies,” said Michael Boyle, M.D., at Johns Hopkins Medical Institutions.

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Take Home Message

As the meeting concluded, Preston W. Campbell, III, M.D., executive vice president for medical affairs at the CF Foundation, gave participants a note of thanks.

“We greatly appreciate your willingness to share your data and collaborate with your peers to benefit people with cystic fibrosis,” said Campbell. “One common theme, a hallmark really of this conference, is that scientists not only report the latest from their labs, they are oriented to think about the next steps. What could the link be to new therapies for patients?”, he continued. “The advances in science you have made, and will make, provide hope in action for all those living with this disease!”

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