by MEGHA MAKAM BIO + MED

Cystic Fibrosis A multidimensional discussion

As far as genetic diseases go, ΔF508, a deletion mutation causing loss of
Cystic Fibrosis is complicated. the amino acid phenylalanine at position
Affecting multiple organ systems, Cystic 508.
Fibrosis can originate from any combination
of over 1000 possible mutations of a single A combination of the chromosome’s “Most people throw
gene. The task of finding a cure for such zygosity and the type of CFTR mutation
a disease is understandably daunting, but can result in a wide range of protein out the trash at the
functionalities, from mild dysfunction
despite the seemingly bleak outlook, there
are many researchers devoted to the case. to complete lack of function. The large bottom of the test
Cystic Fibrosis, abbreviated CF, is a genetic
variability in ion-channel functionality
also results in a wide range of possible
tubes. They don’t
disorder that causes dysfunction in glands symptoms and disease severity. One of the
most common diagnostic tests for CFTR
realize there’s a whole
producing mucus, saliva and sweat. As a
result, it is commonly manifested along dysfunction is to measure the concentration different world in
either respiratory or gastrointestinal of salt in a patients’ sweat. For patients with
epithelia. The most common inherited CF, these levels are chronically elevated. there.” – Rabindra
autosomal recessive disease in the United
States, its prevalence in the American CF primarily affects the body’s internal Tirouvanziam, Ph.D.
population has stimulated much laboratory epithelial cells and secretory glands,
and clinical investigation. most often in the lungs, intestines, liver,
gallbladder, and male genital tract.
Stanford Hospital is home to the largest Symptoms arise when the many tubules
CF center in California. Clinical studies and passageways in the respiratory and
conducted here often involve large teams digestive system become obstructed by
of doctors, researchers and both adult and thick, immobilized mucus. The inability to
pediatric patients. Without well-orchestrated clear the airways leaves patients severely
coordination between these three groups, susceptible to colonization by pathogenic
clinical research might be impossible to bacteria and subsequent lung damage. For
conduct. The ability to observe and speak CF patients, even a small cold can easily
with some of the many different players become a serious lower respiratory tract
allows for a unique perspective on CF infection. In the digestive system, the thick
research at Stanford. mucus restricts secretion of pancreatic
digestive enzymes, causing an inability to
A Snapshot of the absorb fat.

Disease Cystic fibrosis currently affects over

One manifestation of Cystic Fibrosis results
30,000 people in the United States, and
from a mutation in a gene that codes for
approximately one in thirty-one people
the CF Transmembrane Conductance
are carriers of a single, non-symptomatic
Regulator (CFTR). Located on the long
copy of the defective gene. Until the early
arm of chromosome 7, CFTR codes for a
1960s, even before developing acute
transmembrane anion channel that affects
disease in the lungs, children born with this
movement of salt and water in and out of
disease would barely survive childhood
cells. So far, over a thousand disease-causing
as they were unable to absorb ingested
mutations have been identified along
Credit: sxc.hu

nutrients necessary to grow. However, life

the gene. The most common mutation,
expectancy has drastically increased thanks
appearing in about 80% of CF patients, is
to treatment of this particular symptom with

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“The persistence and covert activities of

recruited live neutrophils in the lung may be
one of the most misinterpreted and relevant
causes of CF lung disease” – Dr. Rabindra
Tirouvanziam, Ph.D.

a specialized diet rich in lipids and protein called meconium ileus, or a blockage of
and the addition of pancreatic enzyme the intestine, which can fatally prevent the
supplements. Today, advancements in passage of feces. However, there are no
nutritional and respiratory treatments have signs of tissue damage in the prenatal CF
extended median survival to about thirty- lung.
eight years of age. Despite the success of
several combinations of therapies, however, In one landmark experiment, human
there is still no cure. Fortunately, with the fetal tissue from aborted CF fetus was
work of talented scientists and physicians, transplanted into severe combined
the solution may be imminent. immune deficient (SCID) mice. Dr. Rabindra
Tirouvanziam, an instructor in the
One Gene, Many Department of Pediatrics at the Stanford
Opinions School of Medicine and investigator in
Several models attempt to explain the this study, was able to show that there is
physiological symptoms of CF. The most spontaneous recruitment of inflammatory
widely investigated theory holds that a cells to the implanted region. Because
sodium channel (called ENaC) becomes SCID mice are unable to launch an immune
overactive in response to dysfunctional response unless experimentally induced,
CFTR. This results in dehydration of this result indicates the presence of a
the airway surface fluid, increasing the mechanism acting independently of
Even Wider viscosity of the mucous that coats the lung pathogenic infection or immune response
Perspectives epithelium and preventing clearing of the triggers. This important observation has led
lung. Ultimately, inadequate clearance of Tirouvanziam to propose that early, intrinsic
People have been trying to recruitment of inflammatory cells to the
tackle various aspects of Cystic mucus obstructs ciliary beating, trapping
inhaled microbes and particulates and lung may in fact be the principle instigator
Fibrosis for decades, and not of CF lung disease.
only in the basic sciences. Recent allowing them to fester.
socioeconomic considerations
include changes in insurance Another theory suggests osmolarity of Behind the Research
laws and healthcare, historical airway secretions is the root cause of CF Process
significance of the disease, airway disease. Taking into account both Nestled in the basement of the Beckman
epidemiological studies, and even of these schools of thought, there is a new building, Tirouvanziam is motivating a team
population biology. Moreover, branch of research that focuses on the of young researchers to push the limits of CF
with the development of new dysfunction of CFTR in the sub-mucosal research. Sharing his visions for capitalizing
treatments, patients’ lifespans glands of the lung. on the “treasure trove of data” in single
have increased, and the disease microliters of sample material, be it blood,
has progressed from being strictly Although the mechanisms of ENaC over- plasma, urine, or sputum, he has a unique
a pediatric issue to a chronic activity and osmolarity imbalance may finesse for exploiting precious resources.
disease in adults. This in turn has explain severe lung infection in terms of “Most people throw out the trash at the
triggered even more complicated complications with mucus movement, these bottom of the test tubes,” he says. “They
considerations such as the theories do not account for the fact that don’t realize there’s a whole different world
ethics of prenatal screening and CF begins only after birth, even though the in there. We should be using all the parts of
abortion. receptor is defective in the developing fetus. the buffalo to see the full picture of what’s
Babies with CF do often develop a syndrome going on in these patients.”

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Cystic Fibrosis’ most

characteristic symptom is the
thickening of the mucus in
the lungs, which, in occasions,
inhibits the patient’s ability to
breathe normally.

Tirouvanziam currently has supporting be one

studies from a multicenter clinical drug of the most
trial for therapeutic use of N-acetyl-cysteine misinterpreted and
(NAC) in CF and a three-year observational relevant causes of CF lung
study of pulmonary exacerbations in CF disease,” states Tirouvanziam.
patients. In an emerging discipline called Though the defective CFTR
‘metabolomics’—the study of all small- receptor may be causing one
molecule products of metabolism in a suite of symptoms relating to
particular organism—Tirouvanziam’s group salt and water balance, there
uses analytical chemistry methods, such as are almost certainly other
mass spectrometry, to profile biofluids for a factors contributing to CF
range of known and unknown compounds pathophysiology.

Credit: sxc.hu
in the low molecular weight range known
as small metabolites. Using this method to Studying this phenomenon in
identify possible chemical signals, triggers, vivo using human subjects is
or markers, Tirouvanziam predicts that challenging, since the affected
profiling the mileu of CF lung fluid will shed areas are internal, and retrieving
rare light on the dysfunctional activity of sample material from patients’
recruited inflammatory cells in the lung lungs is quite invasive. Although
environment. animal models are frequently used
to study CF, they do not accurately
These metabolite studies arise from an reflect the true pathophysiology
interest in the possible implications of seen in humans. Tirouvanziam’s
neutrophils (a type of white cell that has research, however, sidesteps Pseudomonas bacteria is frequently
the ability to ingest pathogenic cells and animal models, adopting a found in the lungs of CF patients. The
dies after the ingestion) in CF. Many studies method for non-invasive retrieval bacteria form mucoid biofilms, which
investigate the process of neutrophil death of sputum from patients’ lungs. In coat the lung epithelium and insulate
and their subsequent release of damaging this method, patients are asked to the bacteria, making them highly
substances into lung tissue. Few of these inhale a hypertonic saline solution resistant to anti-microbial drugs.
studies, however, consider the phenomenon using a nebulizer, inducing a deep
Credit: Janice Haney Carr

in which ‘renegade’ neutrophils, which can cough that dislodges and expels
only persist in the bloodstream for a matter sputum in the lower airways for
of hours, become long-lived menaces once collection.
entering the lung environment. According
to Tirouvanziam, neutrophils are “designed
‘search and destroy’ pathogens, and are
quite likely being reprogrammed—perhaps
by small metabolite signals—to persist
and continue to wreak havoc on the
lung, releasing destructive enzymes and
degrading the tissue.” To Learn More
For more information, visit the website of
the Cystic Fibrosis Foundation at
“The persistence and covert activities of www.cff.org
recruited live neutrophils in the lung may

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