Bacteria that infect the lungs of cystic fibrosis sufferers lose their ability to work together, becoming more selfish and less cooperative the longer the infection, say scientists.

X-ray of lungs

Researchers hope that by better understanding how the potentially-fatal infection changes over time it will make it easier to treat.

The team wanted to confirm whether Pseudomona aeruginosa bacteria become more inactive during chronic lung infections in cystic fibrosis patients.

‘This infection is fairly special because it’s very long-lived. You can normally cure a bacterial infection in a week but for people with cystic fibrosis, a lung infection can persist for years,’ explains Dr Ashleigh Griffin of the University of Oxford, lead researcher on the study published in Plos One.

‘During chronic infections, bacteria will change their behaviour towards each other. It’s interesting, because we can watch the change over time in patients.’

Griffin and her colleagues looked at four different so-called cooperative traits to see how the bacteria evolved during infections.

These included production of signal molecules bacteria use to communicate with other – called quorum sensing molecules, the concentration of protein-digesting molecules called proteases, the production of bright green pyoverdine, which is used to bind iron, and how good the bacteria were at forming biofilms. Biofilms are formed by groups of microorganisms in which cells stick to each other on a surface, in this case, a Cystic Fibrosis patients’ lungs.

They found that the longer the bacteria had been infecting the lung, the fewer signals they sent out to other cells, the less biofilm they formed and the less pyoverdin they produced.

Pyoverdin is a bright green secretion which the bacteria use to bind iron, which is essential for their respiration.

‘When cystic fibrosis sufferers first contract Pseudomona aeruginosa, it’s what you might call healthy. It’s making lots of this bright green pyoverdin, but over time it becomes very pale and quiet, as it’s not making this molecule and it doesn’t send out many signals. It seems odd because not communicating is not usually in the bacteria’s best interest,’ Griffin says.

Griffin explains that people have been very sceptical of the idea that the bacteria are getting themselves into a hole, where they can’t make these molecules and the team have encountered resistance to this idea.

The team are now interested to understand whether the bacteria are adapting to the lung environment or forced to behave in a way that may harm them by competition with neighbouring bacterial cells of their own species. They think there may be alternative explanations for what they’ve seen.

‘If bacteria don’t need iron because the lung is an iron-rich environment, then they won’t need to make this pyoverdin, or something else may be happening that means they don’t need to signal to one another as much,’ Griffin explains.

By understanding how these bacteria evolve, and why they choose certain behaviours over others, will make it easier for treatments to eventually be found.

He has toured 47 states and 23 countries to increase awareness of cystic fibrosis (CF)—a genetic disorder that causes mucus to build up and clog some organs of the body, primarily the lungs—and he gets hugs everywhere he goes. This furry advocate is Burke P. Bear, a cuddly teddy bear named in honor of Burke P. Derr, who died two days before his 19th birthday in 1997 from complications of CF.

As a special gift for Burke Derr, a lifelong teddy bear collector, his friends asked a teddy bear company to create a bear for Burke. Today Burke P. Bear is the world-traveling mascot for PACFI.Today Burke’s memory lives on through the work of his father, Bob Derr, for Pennsylvania Cystic Fibrosis, Inc. (PACFI), and the CF researchers it supports, including Antoinette Moran, M.D., a renowned pediatric endocrinologist in the University of Minnesota Medical School’s Department of Pediatrics.

Burke was a pretty typical kid in most regards, but his CF landed him in the hospital about three times a year for weeks at a time. Some of his friends, on top of their CF, also had cystic fibrosis-related diabetes (CFRD), which affects about 20 percent of adolescents and 40 to 50 percent of adults who have CF.

In the past, people with CF who developed diabetes faced a much higher mortality rate than those without diabetes. Gradually, as doctors have become more aggressive about screening for diabetes, the number of deaths stemming from CFRD has decreased.

Much of that progress is thanks to Moran’s work. She pioneered CFRD research during her residency at the University of Minnesota in the 1980s when she noticed that a surprisingly high number of CF patients were developing diabetes. And much of Moran’s progress was made possible by PACFI, which has supported her CFRD studies for the last decade.

Moran has used the PACFI funding to get fledgling research ideas off the ground. Currently, she’s putting the organization’s money toward a study focused on updating mortality rate trends in CFRD patients.

The progress holds special meaning for Bob Derr and for everyone who knew Burke. “To lose someone you love and to have something like this come out of it is remarkable,” Derr says.

- Grace Birnstengel

Cutting edge aircraft engineering and pulmonary medicine might seem to have as much in common as chalk and cheese, but they both involve air flow dynamics, and scientists at the University of Cincinnati are researching the use of computer simulations developed for aircraft design to improve treatment of human airways in a variety of diseases such as cystic fibrosis, asthma, sleep apnea and snoring.  A UC release reports that a more accurate and successful, yet complex approach used in designing an airplane is now taking off in the health care industry. The end result is helping patients with pulmonary disorders breathe easier, and their surgeons in considering novel treatment approaches.

Goutham Mylavarapu a senior research associate in the University of Cincinnati Department of Aerospace Engineering, and Ephraim Gutmark, PhD,, Ohio Eminent Scholar and UC distinguished professor of aerospace engineering and engineering mechanics, presented their research involving Computational Fluid Dynamics at the 39th American Institute of Aeronautics and Astronautics (AIAA) Dayton-Cincinnati Aerospace Sciences Symposium held on March 5 in Dayton, Ohio.


[Photo caption: Goutham Mylavarapu, left, and Ephraim Gutmark - Image credit: Jay Yocis]

Computational Fluid Dynamics, or CFD, uses computer algorithms to solve the flow of air or fluids for various applications. These algorithms are typically applied in aircraft design where CFD is often considered both an accurate and less expensive means of testing theories prior to investing in building physical models and testing in air tunnels.


However, over the past decade or so, CFD has also been applied to biological flows in the study of certain medically-related problems, including respiratory disorders like cystic fibrosis, and has gained a great deal of interest. Computer simulations originally developed in the field of aircraft design are finding new use in treating health conditions such as cystic fibrosis, asthma, sleep apnea and snoring.

The human respiratory tract is a pathway of hard and soft structures that take in and push out airflow. Dr. Mylavarapu explains that several pulmonary upper airway disorders are associated with vibration and/or deformation of the soft structures around the airway, leading to partial or complete collapse of the airway, as in the case of sleep apnea. In more severe cases, these airway obstructions or deformations can significantly impact quality of life and can even lead to death.


The researchers are using CFD simulations crossed over from the aerospace industry on actual medical data from patients with breathing disorders. Applying the equations to analyze the information being sought in an MRI can provide surgeons with a better idea on how to treat the problem, increasing the potential success of any surgical approach as well as reducing the number of surgeries (therefore a better recovery and less of a medical expense) for the patient.

“Historically, the evaluation of a patient’s airway is limited to clinical diagnosis with medical imaging,” explains Dr. Mylavarapu. “But the variability and complexity in the airway anatomy can limit the success rate of surgery. CFD provides a better understanding of respiratory flow and enables individualized treatment when applied to what we’re seeing with medical imaging.”

“Surgery is sometimes based on experience-based intuition, and it’s not always guaranteed that the end result will be effective,” says Dr. Gutmark. “CFD is another tool to provide surgeons with more quantitative information about the possible outcome during the planning of a surgical procedure.”


Last year, Dr. Gutmark was recognized for his outstanding contributions to physics with the award of an American Physical Society (APS) Fellowship — a designation limited to no more than one half of one percent of the APS membership and therefore a distinct honor signifying recognition by one’s professional peers.

According to APS, Dr. Gutmark’s “pioneering contributions to the fundamental flow physics of noise, combustion, and propulsion, and the development of flow control methodologies to achieve quiet aircraft engines, clean, stable and efficient combustion, and innovative propulsion systems” earned him the honor of fellowship in the society.

Spanning 30 years, Dr. Gutmark’s research and development of innovative fluid engineering applications have impacted diverse technical areas including turbomachinery for power generation and automotive turbochargers, aerodynamic flight control, and biomedical applications, among others. Since joining UC, Dr. Gutmark has been instrumental in generating over 30 new research projects in a range of interdisciplinary topics with a budget of over $27 million.

Dr. Gutmark credits UC for steadily backing his research efforts. “I get a lot of good support from UC,” he commented in a release. “From the beginning, I was given a nice space to develop my lab and the basic infrastructure to start activities was here so that really helped a lot to develop my ideas.”

During the last five years, Dr. Gutmark has also been working in collaboration with the UC Medical School and Cincinnati Children’s Hospital on researching new and innovative uses for fluid dynamics in biomedical applications. “We use fluid dynamics to understand the formation in voice and how to treat disorders of voice,” he observes.

Dr. Gutmark’s project with Cincinnati Children’s Hospital studies children with Down syndrome who suffer from sleep apnea. “We are looking to understand what leads to sleep apnea, how to prevent it or better treat it and how to help physicians to make good decisions on the treatment,” he says, noting that the common denominator of all of these activities is the application of fluid dynamics. “I see a lot of potential for growth and for more activities in the future,” he observes. Dr. Gutmark is optimistic that the physics disciplines of fluid dynamics will result in a stream of new techniques, procedures and aids to improve these medical treatments, noting that “Surgery is sometimes based on experience-based intuition, and it’s not always guaranteed that the end result will be effective. CFD is another tool to provide surgeons with more quantitative information about the possible outcome during the planning of a surgical procedure.”

The researchers are using CFD to examine both the flow and structure equations of the respiratory challenges of individual patients. They also applied the method to a virtual surgery involving a medical case in Sweden, leading to a successful outcome for the patient.

The research, conducted in UC’s Gas Dynamics and Propulsion Lab, is a partnership with Cincinnati Children’s Hospital Medical Center and the UC Medical Center, and is supported by funding from the National Institutes of Health (NIH #1R01HL105206-01).

Dr. Gutmark’s name and APS fellowship citation were published in the March 2013 issue of APS News for his pioneering contributions to the fundamental flow physics of noise, combustion, and propulsion, and the development of flow control methodologies to achieve quiet aircraft engines, clean, stable and efficient combustion, and innovative propulsion systems, nominated by the Division of Fluid Dynamics

The AIAA Dayton-Cincinnati Aerospace Sciences Symposium showcases cutting-edge aerospace research in the region and covers all general areas of aerospace science and technology. The event is organized and sponsored by the executive council of the AIAA Dayton-Cincinnati section and is sponsored by several organizations including the University of Cincinnati.

UC’s aerospace program is recognized by the Ohio Board of Regents as an Ohio Center of Excellence in Aerospace for its contributions to research and to the state’s economy. UC’s College of Engineering and Applied Science is a leader in engineering education, research and innovation, and is the world founder of cooperative education.

Sources: University of Cincinnati

Photo credits: University of Cincinnati – Jay Yocis

PHIL Lewis knows the life saving work of The Alfred and Australia’s organ donation program inside and out.



Soon after starting work as a medical scientist at The Alfred almost 20 years ago Mr Lewis received a double lung transplant at his own hospital, saving him from cystic fibrosis.

Still working at The Alfred, Mr Lewis has become proof of just how successful organ donation can be: this week he celebrated a 40th birthday nobody dreamt he would get anywhere near.

In the lead-up to his transplant, Mr Lewis was buoyed by statistics showing the operation would give him a good chance of being alive two years later.

He was also cautioned against dreaming of having children, because he might not be able to see many of their birthdays.

Now there is the promise of many more milestones to celebrate with his wife Amy and five-year-old son Kieran.

“I guess my life post-transplant is a pretty good example of what can be done,” Mr Lewis said.

“Before transplant I had a very short-term set of goals. I was just happy to see what came my way and I guess I have been doing that for 18 years now.

“I don’t think anybody could have said anything to me back then that could have prepared me mentally for the possibility that I would still be around and physically capable nearly 20 years later.”

But Mr Lewis has also experienced the tragic side of organ transplants: his brother Jeff died just a year after a double lung transplant because of cystic fibrosis.

“I have been in and out of hospital since I was six or seven years old,” Mr Lewis said.

“I get a lot of value out of the thought that I might actually be contributing something to a system that has benefited me so much

“Even when things look bad on paper, even when you have upsets, mishaps and misfortune, as long as you can push out the other side, the future really is unknown,” he said.

“So you might as well look positively at it, because you may be surprised.”

Vertex Pharmaceuticals has a number of ongoing clinical trials investigating the use of Ivacaftor in cystic fibrosis patients with mutations in the gene coding for cystic fibrosis transmembrane conductance regulator (CFTR). Two of its Phase III trials, which are studying patients homozygous for the F508del-CFTR mutation, recently switched the primary and secondary endpoints. TRAFFIC and TRANSPORT are still evaluating the efficacy and safety of Lumacaftor in combination with Ivacaftor (tradename Kalydeco), but the primary outcome measure is now “an absolute change in percent predicted forced expiratory volume in one second (FEV1).” The original primary endpoint was a relative change in lung function but is now a secondary endpoint.

The switch was made as “part of ongoing discussions with the FDA and was not based on anything going on in the study or anything observed in the study,” said Zach Barber, spokesman for Vertex.

Get more information about Cystic Fibrosis.

Both studies have three treatment arms. The first treatment arm is receiving 600 mg of lumacaftor daily and 250 mg of ivacaftor every 12 hours, the second is receiving 400 mg of lumacaftor and 250 mg of ivacaftor every 12 hours, and the third is receiving placebo throughout the 24-week period. The study began in March 2013, and completion is expected in April 2014. Results of these studies have the potential to generate $6 billion in new sales for Vertex.

Cystic fibrosis affects the lungs and digestive system, and the Cystic Fibrosis Foundation reports that 30,000 children and adults in the United States have the inherited chronic disease. Mutations in the CFTR gene lead to a defective protein that causes a buildup of thick, sticky mucus in the lungs and intestines, causing life-threatening lung infections and poor pancreatic enzyme activity to break down food. The drug Ivacaftor has been approved by the Food and Drug Administration since January 2012 for some subsets of cystic fibrosis patients. It improves the transport of chloride ions through CFTR by increasing the number of open channels.

US-based Proteostasis Therapeutics has extended its collaboration with Cystic Fibrosis Foundation Therapeutics (CFFT), to research, develop and commercialize therapeutic candidates to treat people with cystic fibrosis (CF) who have the most common CF mutation, ΔF508del.

CFFT is the non-profit drug discovery and development affiliate of the Cystic Fibrosis Foundation.

The extension will focus on moving the company’s lead compounds toward a development candidate in 2014.

It will also focus on the company’s ain of filing an investigational new drug (IND) application with the US Food and Drug Administration in 2015.

The deal will continue to focus on the development of small molecule proteostasis regulators that modulate protein homeostasis pathways within the cell to correct the folding, trafficking and functional activity of the Cystic Fibrosis Transmembrane Conductance Regulator (CFTR).

The preclinical results have showed that ability of compounds to increase functional activity in ?F508 human bronchial epithelial cells.

In addition, the company’s lead candidates have shown significant synergistic properties with existing clinical-stage corrector candidates, more than doubling maximal activity and providing a strong foundation for the potential of combination therapies.

Proteostasis Therapeutics chief scientific officer Markus Haeberlein said the company is happy to continue its collaboration with CFFT, which has supported some of the most innovative and successful research in the field.

“This extension represents an endorsement of our novel approach to correcting CFTR activity and of the preclinical results that we have generated during the past 18 months,” Haeberlein said.

What do cystic fibrosis patients and factory workers in microwave popcorn plants have in common? The answer, according to Katrine Whiteson, a postdoctoral researcher from San Diego State Univeristy, is a molecule known as 2,3-butanedione (diacetyl). Cystic fibrosis patients have higher concentrations of diacetyl in their lungs than healthy adults, and diacetyl is a toxic lung-damaging agent.

The motivation behind Whiteson’s study was the mystery of what is different about cystic fibrosis patients’ lungs during times of symptom flare-ups, or exacerbations, compared to periods of relatively calm symptoms. At the doctor’s office, cystic fibrosis patients inhale vaporized salts to induce coughing so that they can produce a mucus sample. When the mucus is cultured to identify microbes, there is no difference in microbes between calm and exacerbated periods. This makes it nearly impossible to help warn patients when an exacerbation is imminent so that they can ward off future lung damage by taking antibiotics.

Knowing that something must be different, Whiteson and colleagues at San Diego State University and the University of California, Irvine, turned their attention to the gases produced by cystic fibrosis patients during breathing. Comparing the gases from healthy individuals, the researchers found a significant >7-fold increase in the levels of diacetyl in the cystic fibrosis patients. This increase was reduced 10-fold by the administration of antibiotics. It was theorized that Streptococcus species in the mouth produce diacetyl during fermentation to avoid lethal acidification, leading to harmful effects of other microbes that exist in the lungs; for example, lung microbe P. aeruginosa increases production of exotoxin and phenazine and improves biofilm formation when exposed to diacetyl, found another study from Cornell University.

Although the study used only a small number of patients and volunteers, future validation may lead to technology that can detect the presence of diacetyl in the breath of cystic fibrosis patients. Detection would then indicate that patients are about to experience a flare-up of symptoms and should take antibiotics to prevent it. “If you had a device to detect these metabolites, you’d know, ‘Oh, it’s time to take antibiotics again,’” said Whiteson. This technology is not merely a dream, either: Whiteson is working with Metabolomx to develop a microchip that detects diacetyl and other indicators of cystic fibrosis exacerbations. “It’s a constant battle going on,” said Whiteson, indicating that a microchip would not be the end-all for helping cystic fibrosis patients. “There’s not just one thing that keeps you healthy.”

The work was published last month in The ISME Journal Multidisciplinary Journal of Microbial Ecology and was accompanied by a study from Cornell University that describes the effects of diacetyl of P. aeruginosa

Proteostasis Therapeutics Inc. a company developing novel therapeutics that regulate protein homeostasis to improve outcomes for patients with orphan and neurodegenerative diseases today announced an extension of its funded collaboration with Cystic Fibrosis Foundation Therapeutics Inc. (CFFT) the non-profit drug discovery and development affiliate of the Cystic Fibrosis Foundation to research develop and commercialize therapeutic candidates to treat people with cystic fibrosis (CF) who have the most common CF mutation ?F508del. This extension will focus on moving the Company’s lead compounds toward a development candidate this year and a goal of filing an Investigational New Drug Application (IND) with the U.S. Food and Drug Administration in 2015.

The collaboration will continue to focus on the development of small molecule proteostasis regulators that modulate protein homeostasis pathways within the cell to correct the folding trafficking and functional activity of the Cystic Fibrosis Transmembrane Conductance Regulator (CFTR). Preclinical research by Proteostasis Therapeutics including data presented at the North American Cystic Fibrosis Conference in October 2013 has shown that the lead corrector series identified by the Company is able to significantly increase functional activity in ?F508 patient-derived human bronchial epithelial cells. Additionally the Company’s lead candidates have shown significant synergistic properties with existing clinical-stage corrector candidates more than doubling maximal activity and providing a strong foundation for the potential of combination therapies.

“We are excited to continue our collaboration with CFFT which has supported some of the most innovative and successful research in the field” said Markus Haeberlein Ph.D. Chief Scientific Officer at Proteostasis Therapeutics. “This extension represents an endorsement of our novel approach to correcting CFTR activity and of the preclinical results that we have generated during the past 18 months.”

About The Cystic Fibrosis Foundation

The Cystic Fibrosis Foundation is the world’s leader in the search for a cure for cystic fibrosis. The Foundation funds more cystic fibrosis research than any other organization and nearly every CF drug available today was made possible because of Foundation support. Based in Bethesda Md. the Foundation also supports and accredits a national care center network that has been recognized by the National Institutes of Health as a model of care for a chronic disease. The Cystic Fibrosis Foundation is a donor-supported nonprofit organization. For more information go to

About Proteostasis Therapeutics

Proteostasis Therapeutics is developing disease-modifying therapeutics for orphan and neurodegenerative diseases with lead programs in cystic fibrosis and a collaboration with Biogen Idec to develop therapeutics for neurodegenerative diseases. The Company’s platform revolves around the modulation of protein homeostasis pathways within the cell. These pathways are part of the cellular ‘quality control’ machinery called the protein homeostasis network or Proteostasis Network (PN) that regulates protein folding trafficking and clearance. By modifying the function and capacity of the PN the Company’s product candidates correct for imbalances in the PN resulting from the cumulative effects of disease genetic mutations environmental factors and aging. For more information please visit

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While over 1,900 errors that contribute to cystic fibrosis (CF) have been identified by researchers , thus far, it has remained unclear which of them actually contribute to people passing on the disease through heredity. However, researchers recently reported they have identified an additional 105 inheritable genetic mutations which convert the shape of the cystic fibrosis transmembrane conductance regulator (CFTR) protein, and in turn have increased the number of known CF-causing mutations from 22 to 127, which represent  95 percent of the genetic variations found in cystic fibrosis patients. These findings will allow families to know whether they carry the risk mutations of CF and also accelerate development of new, tailored drug particular to mutations. The study has been published online in Nature Genetics, titled “Defining the disease liability of variants in the cystic fibrosis transmembrane conductance regulator gene” (doi: 10. 1038/ng.2745)

Cystic fibrosis is the most common, lethal, recessive genetic disease among Caucasians, affecting approximately 70,000 to 80,000 people worldwide. CF occurs in children when they inherit two CFTR-defective genes from both of their parents, resulting in production of thickened mucus that stacks in their lungs and digestive system. In 2012, a drug called ivacaftor to treat CF was approved for use in the cystic fibrosis patient population, but the target protein mutation of which ivacaftor enhances the function is found in only 4 % of CF patients.

Researchers studied a genetic database of nearly 40,000 patients with CF and found 159 shared mutations. Then they examined the salt concentrations in the sweat of the patients with those mutations to assess the health conditions — a known signal observed in CF patients. As a result, they identified 127 of the 159 mutations are CF-risky when they are inherited and 105 of the 127 mutations had never been characterized before.

“This new information will give clear answers to tens of thousands of people each year: those being screened as potential carriers, parents of infants who have been flagged during newborn screening and children and adults who are looking for a diagnosis,” said Karen Siklosi, M.G.C., a genetic counselor involved in the study.

“I had actually been thinking about writing a book for probably about 10 years author— and then I had a double lung transplant seven years ago,” recalled Richard Keane, author of the upcoming memoir “Fighting with Crib Gloves.” “I actually wrote the outline for the book five or six days after the transplant.”

Keane, 57, a Rockville Centre resident for 21 years, was born with cystic fibrosis, a hereditary disorder that causes abnormally thick mucus, and can lead to blockage of the pancreatic ducts, intestines and bronchi, as well as respiratory infection. The memoir, published by Oklahoma’s Tate Publishing, chronicles Keane’s years of fighting the disease and the many complications that come with it.

“I’ve had a lot of medical issues aside from CF, all stemming from CF, but there are different strains of the disease,” he said. “I was actually quarantined for seven of the first 10 months of my life with issues, you know — measles, mumps, not digesting. When I was finally diagnosed in 1956, children who were diagnosed didn’t survive more than a year or so.”

Keane, a Rockville Centre resident for 21 years, wasn’t the only member of his family affected by the illness — the second of nine children, he was just one of three with CF. One of his sisters, Valerie, died of its complications in 1976, at age 17. Another sister, Jennifer, is now 45, and while she had a lesser strain growing up, the illness has begun to catch up with her.

Current science has no answer to cystic fibrosis, and the average life expectancy of a CF patient is 36 years. In a way, Keane has been lucky — he has been featured in a number of medical journals as one of the world’s longest-surviving CF patients. The illness tends to predispose its sufferers to other medical issues, including osteoporosis, high blood pressure, diabetes and pancreatitis. Keane has survived them, too.

The title of his memoir is apt. “Fighting with Crib Gloves” reflects the urgency of the disease, and refers to an experience he had as a child undergoing treatment. When he stopped breathing one morning, his pediatrician resuscitated him, and hung a pair of boxing gloves over his crib, calling him a fighter.

“Really, don’t give up,” Keane said when asked what advice he would give those suffering from CF. “Fight — and that word is used a lot. But on my sister’s deathbed, the last thing she said to me was, ‘You’ve got to keep fighting.’”

The book took Keane nearly a year and a half to write, and another year to edit and rewrite a number of passages. “It was emotionally uplifting in parts, but as I do state in the beginning of the book, there were parts that were very difficult to write,” he said. “But some of it was a lot of fun. I grew up in the ’70s. It was a lot of fun. When I got into that writing — when I got into that zone — I could just write. It would flow right out of me.”

Richard and his wife, Mary Anne, manage International Delight Café, and although the book doesn’t officially hit the shelves until April 1, Keane is due to sign copies of his memoir at the restaurant on March 3 at 7 p.m. All proceeds from book sales will be donated to the Boomer Esiason Foundation, which funds CF research.