Cystic Fibrosis is the most common genetic disorder among Caucasians. One in 29 Americans carries a CF mutation in their genetic code, and when two carriers have children, each child has a 25% chance of being born with the disease. Our niece L was in that 25%.
L at the Johns Hopkins Children's Center, 2008
L was diagnosed at 8 months of age, after struggling to gain weight for the first eight months of her life. The disease affects all of the mucous-secreting tissues of the body, including those of the digestive tract where thick, sticky mucous clogs the passageways through which digestive enzymes would normally travel to the intestine. As a result, babies born with CF often have trouble digesting their food - particularly fats - and quickly become malnourished. Unfortunately, it wasn't until 2009 that all 50 states included CF in their mandatory newborn screening panel - ten years after L was born. As a result, her CF went undiagnosed and she was one sick baby. Simple pancreatic enzyme supplements are used to alleviate these digestive symptoms, so L must take several pills before every meal to ensure proper digestion.
CF also affects the lungs, where the same thick, sticky mucous lines the airways and incapacitates the hair-like projections called cilia that normally beat rhythmically to circulate mucous up out of the lungs. This normal process keeps air-borne particulates and bacteria from settling in the lungs and causing respiratory infections. In CF patients, not only are the lungs perpetually plagued with thick, sticky mucous that gives rise to a chronic, croupy cough - the environment that this mucous creates is also highly conducive to bacterial colonization. As a result, CF patients are highly susceptible to stubborn respiratory infections that are very difficult for the lungs to clear, since their normal ciliary clearance system is all but paralyzed. In such cases, a Peripherally-Inserted Central Catheter (PICC line) is often placed to administer strong antibiotics directly to the lungs through the right side of the heart. L has had a few of these in her day - she used to go under general anesthesia for placement of her PICCs but she's such a pro now that they can be placed at the bedside.
L at Johns Hopkins Children's Center during PICC insertion, 2008
These lung infections, over time, can result in the development of permanent lung damage in CF patients, and this accumulation of damage is responsible for the majority of serious complications later in life.
The disease can also damage the liver and pancreas, as well as the reproductive tract in males, where small passageways can become blocked by thick mucous secretions and choke off the nutrient supply to surrounding cells. This kind of damage can lead to cirrhosis of the liver, CF-Related Diabetes (CFRD), and infertility in males.
CF hit home for my husband and I in an even bigger way when we discovered, after conceiving our first child, that we are both carriers of the same genetic mutation that causes L's Cystic Fibrosis. We knew that it was a good possibility that B (as her blood relative) might be a carrier, but were shocked to find out that, despite CF never showing in up anywhere in my family tree, I, too, was a carrier. Being a "carrier" means that you have one "good" copy of the gene and one "bad" copy, and one "good" copy is enough to keep us both from actually having the disease. However, it also means that each of our children will have a 25% chance of inheriting both of our "bad" copies and therefore having CF.
CF hit home for my husband and I in an even bigger way when we discovered, after conceiving our first child, that we are both carriers of the same genetic mutation that causes L's Cystic Fibrosis. We knew that it was a good possibility that B (as her blood relative) might be a carrier, but were shocked to find out that, despite CF never showing in up anywhere in my family tree, I, too, was a carrier. Being a "carrier" means that you have one "good" copy of the gene and one "bad" copy, and one "good" copy is enough to keep us both from actually having the disease. However, it also means that each of our children will have a 25% chance of inheriting both of our "bad" copies and therefore having CF.
The underlying defect in Cystic Fibrosis is a mutant chloride channel protein called CFTR. This protein normally inserts itself in the cell membrane of the cells that line the digestive and respiratory tracts. Positioned at the cell surface, it forms a channel through which chloride ions (one of the major components of table salt) can pass out of the cell. When chloride ions move, water moves with them, so maintaining a proper chloride balance outside the cell is an important part of keeping the cell's mucous secretions thin and watery as they should be. Without water, the mucous secretions of these cells are thick and sticky. In CF patients, this protein does not serve its normal function and so very little water is added to the mucous, and it remains thick and sticky.
schematic courtesy of prometheus.mse.uiuc.edu
The defect in this protein arises from a DNA-based mutation, the most common of which (for CF) is called deltaF508. The deltaF508 mutant protein is functional enough to serve its purpose, but unfortunately it never makes it to the cell surface to do its job. Soon after it is synthesized inside the cell, the protein is recognized as a mutant and "tagged" by the cell's quality-control machinery. Once tagged, it is destined for rapid degradation - it is sent to the cell's garbage can and disposed of quickly. This quality control function is vital for keeping other mutant proteins from causing disease and cancer, but in the case of CF, it hurts more than it helps. We know that as little as 10% of normal CFTR function may be enough to provide for normal mucous secretions, so if we could trick the cell into letting just 10% of that mutant protein reach the cell surface, we could restore at least near-normal function to CF patients and dramatically alleviate symptoms.
This line of gene therapy research is currently under investigation in a number of labs across the country, including the Guggino lab at the Johns Hopkins Cystic Fibrosis Research Development Center where I spent the summer of 2010. My project with the Guggino lab focused specifically on identifying the regions of the CFTR protein that are "tagged" for degradation by the cell's quality control machinery, as well as exploring the interactions between CFTR and other proteins in order to better understand how CFTR is shuttled to and from the cell surface in both the normal and deltaF508 states.
The Hopkins CF Research Center, in addition to the other 10 CF Basic Research Centers (and many other academic institutions) across the country, is funded in large part by charitable contributions made to the Cystic Fibrosis Foundation. Basic science research is an incredibly expensive endeavor, but it is vital to the continued advancement of CF therapies and medications, not to mention the search for a cure. Even without a cure (yet), the progress made in basic science and clinical research laboratories is yielding promising new treatments to improve symptoms and reduce the accumulation of lung damage over time, which promises to lengthen the life expectancies of patients dramatically. In today's financial climate, with grant dollars dwindling and government funding becoming increasingly competitive, the CF Basic Research Centers need CFF funding more than ever. Click here or use the button in my sidebar to make a donation through CFF's Great Strides program to help keep these vital research programs running at full speed toward a cure!
This line of gene therapy research is currently under investigation in a number of labs across the country, including the Guggino lab at the Johns Hopkins Cystic Fibrosis Research Development Center where I spent the summer of 2010. My project with the Guggino lab focused specifically on identifying the regions of the CFTR protein that are "tagged" for degradation by the cell's quality control machinery, as well as exploring the interactions between CFTR and other proteins in order to better understand how CFTR is shuttled to and from the cell surface in both the normal and deltaF508 states.
In October of 2010, I moved on to another lab at Johns Hopkins to work as a lab tech and clinical research coordinator for Dr. Garry Cutting, a pediatrician and clinical geneticist at Hopkins who was recently awarded the Cystic Fibrosis Foundation's 2010 Lifetime Achievement Award! Dr. Cutting's lab focuses largely on the genetics of CF, and investigates the genetic and environmental differences that seem to affect outcomes for CF patients. In late 2000 Dr. Cutting started the CF Twin & Sibling study, and began recruiting families with two or more children affected by CF with the goal of comparing their genetic similarities and differences as well as environmental exposures that they experienced throughout their lifetimes. Monozygotic (or maternal) twins are genetically identical, while dizygotic (paternal) twins and siblings have genetic variability between them. The environment in which twins and siblings are brought up is usually the same (as far as exposure to second hand smoke, temperature, pollution, humidity, etc), but when the patients grow up and move apart, we are also able to track their progress (lung function, pancreatic status, development of CF-related diabetes, etc) as their environmental exposures begin to diverge. All of this data is collected and maintained in a HUGE database for the clinical fellows in our lab, so that they can ask questions like "Does ambient temperature affect pseudomonas infection rates" or "Why do two kids with the same genetic background often have such dramatically different lung function?" or "Why do some kids develop CF-related diabetes while others don't?". The questions are endless, really. Incredibly interesting stuff!
The Hopkins CF Research Center, in addition to the other 10 CF Basic Research Centers (and many other academic institutions) across the country, is funded in large part by charitable contributions made to the Cystic Fibrosis Foundation. Basic science research is an incredibly expensive endeavor, but it is vital to the continued advancement of CF therapies and medications, not to mention the search for a cure. Even without a cure (yet), the progress made in basic science and clinical research laboratories is yielding promising new treatments to improve symptoms and reduce the accumulation of lung damage over time, which promises to lengthen the life expectancies of patients dramatically. In today's financial climate, with grant dollars dwindling and government funding becoming increasingly competitive, the CF Basic Research Centers need CFF funding more than ever. Click here or use the button in my sidebar to make a donation through CFF's Great Strides program to help keep these vital research programs running at full speed toward a cure!
