"But you know what would have been the best present of all...A cure for my disease. I have often thought about that, Mother. Just what it would be like not to have this disease. I wouldnıt even ask for forever. Just for a day Iıd like to wake up one morning, and not have any pain or be sick or anything. Just once to be free." --ALEX: The Life of a Child, (164)

Introduction

What is Cystic Fibrosis?

But what exactly is CF? Essentially, cystic fibrosis is a genetic disease characterized by a failure of the exocrine glands. In healthy people, the exocrine glands produce thin, slippery secretions including sweat, tears, mucus and saliva. These secretions are carried through small ducts to the external surface and, in turn, they play a crucial part in maintaining the normal functions of the body. But in CF patients, the exocrine glands often yield thick, sticky secretions which plug up ducts and passageways; mucous builds up in the lungs and the intestinal system and interferes with vital body functions, such as breathing and digestion. Because of this, CF often leads to the destruction of the pancreas and respiratory system. In addition, CF patients give off an excess of salt as evidenced by abnormally high amounts of sodium and potassium in patientıs sweat. A German idiom says, ³Woe to the child which when kissed on the forehead tastes salty. He is bewitched and soon must die.² While this adage certainly rings true today, there are numerous treatments to combat this overabundance of salt. Currently, there is no cure for cystic fibrosis, but relative health is maintained through antibiotics, aerosol sprays and physical therapy.

This article explores cystic fibrosis-- its cause, its effects, its treatment and the possibility of a potential cure. The article is segmented to address all these issues as well as give background on the disease itself. We will see how the disease destroys the respiratory system of its sufferers; we will see how CF patients are treated in order to live in relative health and normalcy; and finally, we will see how gene therapy has revolutionized applied research in the medical community. Since the CF gene was discovered in 1989, the pace of research has greatly accelerated. Indeed, cystic fibrosis is terminal disease but with medical advances, we may see a cure in the near future.

In order to see how the disease affects its victims on a more personal level, we will refer to the book ALEX: The Life of a Child. This book, written by Frank Deford, chronicles one man's battle with his daughter's cystic fibrosis. It is a touching and heartfelt memoir that will bring the disease to a more personal level. We will see how, after the fact, new medicines and treaments are in the works to make people like Alex be free.

Incidence and Symptoms

Discovering that one of your children has been diagnosed with CF is devastating. Indeed, cystic fibrosis tears parents apart as they typically feel guilty and responcible for passing this lethal gene on to one of their own children. Frank Deford discusses the incidence of cystic fibrosis and the remorse he felt for giving this deadly disease to Alex.

The laws of genetics are pretty unyielding, of course. One out of every four children born to two carriers will have the disease. One out of every four will be free and clear. The other two will be carriers. But itıs like flipping coins. There is no reason for the unlucky ones to pop up in the order that they do. Surely, many undiagnosed CF carriers have numerous children, none afflicted. Similarly, others have a sick child right away, their first born. And some of these parents, by ignorance or design, go on having babies. Many families have two CF kids, a few even three or more. --Frank Deford, from ALEX, The Life of a Child, (37)

Defordıs description of the incidence of cystic fibrosis is entirely accurate. CF, inherited as a recessive trait , has a 1 in 4 chance of developing in a child if both parents are carriers. In other words, a child must inherit a defective copy of the CF gene-- one from each parent-- to have cystic fibrosis. Most doctors recognize the incidence of CF to be 1 in 2,500. In the United States, these figures translate into about 1,000 new cases each year. The disease is usually recognized in infancy, but interestingly, a small number of patients escape detection until adolescence or early adulthood. The median life expectancy of a CF patient is 29 years.

Currently, the sweat test is the most reliable diagnostic test for CF. The sweat test simply measures the amount of salt in sweat; and a high percentage indicates that the patient does indeed have cystic fibrosis. The sweat test, however, is not used on infants because babies do not sweat enough to give an accurate reading. As mentioned above, the symptoms of cystic fibrosis are very salty tasting skin, persistent coughing, wheezing or pneumonia and excessive appetite but poor weight gain. But it is imperative to note that more than 12 million Americans are unknowing symptomless carriers of the gene.

Here it is imperative to note that the gene for cystic fibrosis may actually protect against cholera. Scientists are now speculating that the infamous CF mutation that has survived through hundreds of human generations, may have the benefit of making its carriers immune to cholera and possibly other genetic diseases. In fact, studies have shown that "laboratory mice carrying cystic fibrosis genes did not suffer the life-ending severe diarrhea that is typically caused by cholera" (New York Times). This might explain why CF is one of the most common gene defects.

Treatment

For a half a century, doctors have been treating cystic fibrosis symptom by symptom, doing their best to stem the rising tide of mucus triggered by the disease. There are various modes of treatment, but unfortunately, none are particularly effective at prolonging the life of CF patients. The most common treatment is physical therapy, but others include medicine, special dietary supplements and an exercise regimen. Frank Deford tells of his daughter's experience with all these methods of treatment; he expresses frustration in the fact that Alex spent most of her life doing therapy or amidst some other regimen.

³Well,² Alex said, ³Iıve thought about that, Daddy, and I decided that I canıt ever be a princess...Because I never heard of a princess having cystic fibrosis.² My heart bounced into my throat, but I managed to carry on. ³Oh, look, Alex, I wouldnıt worry about that. There are probably lots of princesses all over with cystic fibrosis. They take their medicines and do their therapy so well that theyıre getting better all the time.² And this time, she twisted up her face and said, ³No Daddy, I couldnıt ever be a princess because my crown would fall off all the time whenever I did my therapy.² --ALEX, The Life of a Child, (98)

Today, physical therapy is probably the most simple and common treatment of cystic fibrosis. Its primary purpose is to clear the lungs of excess mucus and prevent blockage of the airways by the thick, sticky mucus that characterizes CF. Therapy, sometimes referred to as bronchial or postural drainage, consists of clapping young patients on the back and chest several times a day. The therapist must ³clap² vigorously on the patient in order to vibrate the chest, dislodge mucus and stimulate its movement. Usually, the child lies or sits in a position with their head tilted downward so that a particular portion of the lungs to drain toward the throat, then the thick mucous moves from the small airways into the larger ones where it can be coughed up more easily. Alex was right in saying that her crown surely would have fallen off. It is clear to see why postural drainage becomes the bane of many CF familyıs existence as it is performed one to three times each day and takes about twenty to thirty minutes each time.

Exercise and Diet

CF children are painfully aware that thier disease inhibits them from acting like "normal" children. They cannot run around as they will inevitably need to cough up mucous and they cannot eat as most children do as they need special dietary supplements. Once Alex Deford hit upon a way to make her body behave, she was captivated.

The dance class-- styled authoritatively as ballet by Alex--was her delight, and surely, the first time in her life that she really enjoyed something physical. For once in her life she found out that she could make her body obey, make it work and that enthralled her. --ALEX, The Life of a Child, (98)

Physical activity is very important for children with cystic fibrosis. And most patients can participate in activities without great strain on the body; and a cross-section of CF kids can ride tricycles, play tag and run around like healthy kids. In fact, there are several reasons why exercise is paramount. One, it helps loosen mucus in the lungs so it can be coughed up more easily. Two, it stimulates coughing which helps clear the lungs. And finally, exercise builds up strength and endurance of the breathing muscles as well as increasing the general level of cardiovascular fitness. As mentioned in the introductory section, CF patients tend to have a voracious appetite but gain very little weight. Toward the end of the disease, however, some patients lose their desire to eat completely and eating becomes a project. But when CF affects the digestive system, the body does not absorb enough nutrients. The reason for this is simple: the pancreas ducts that deliver digestive enzymes to the intestines almost always become blocked, impairing the bodyıs capacity to break down food and draw out proteins and minerals. Therefore people with CF may need to eat an enriched diet and take replacement vitamins and enzymes.

Antibiotics

Most CF kids are fed antiobiotic medicine intraveneuously through a needle in their arm. Alex's IV became a permanent fixture in the Deford home. She loved wheeling it around the hospital so that she could say hello to all the doctors and nurses.

Alexıs internal medications were kept in see-through plastic bags that hung from a pole, with the tubes going down into the needle stuck into her hand. The pole-- we just called her IV pole-- was on a little stand, with rollers so that she could be mobile and wheel it about the ward. --ALEX, The Life of a Child, (99)

Antibiotics are an important part of CF therapy as they kill infection causing bacteria and are effective at combating respiratory infection. There are three major types of antibiotics: oral, intravenous and aerosol. Oral antibiotics are used to treat mild flare-ups of lung infection. Although they are ineffective much beyond that, new, more powerful oral medication is in the development process. IV antibiotics, on the other hand, are effective at fighting more serious lung infections. They work well against staph infections and also fight pseudomonas, a complication that will be discussed in the forthcoming section.

Aerosolized antibiotics work by delivering a mist made from liquid medication directly into the airways of CF patients; the antibiotic is inhaled through a mouthpiece or mask. This medication is similar to what asthmatics take on a regular basis. These treatments also help control infection and are most often taken after chest therapy. There are three major types of aerosol sprays: bronchodilators which widen the breathing tubes to make mucus removal and breathing easier; mucolytics which thin the mucus, making it easier to drain; and decongestants which reduce swelling of the membranes that line the breathing tubes. At this point, aerosol antibiotics, are used solely in the short term as a common treatment of CF, but new gene therapy via aerosol spray is in the developing stages.

Potential Complications of CF

There are numerous complications and effects of cystic fibrosis, some manifest externally, but most complications involve chronic infections, clogged airways and digestive problems. In addition to the normal coughing and wheezing, CF patients are subject to club fingers and a slew of other heart and lung complications. There are, however, medical treatments and surgeries to correct these problems.

Alex Deford was mortified when the other kids began teasing her about her clubbed fingers. Though clubbing is one of the more benign effects of CF, it might be the most visible complication, and one that really separates CF kids.

As Alex got sicker and her clubbed fingers grew paler and more bulbous from the lack of oxygen, she became more self-conscious about them, sure that everybody was staring. Clubbed fingers really are different, not like coughing or being skinny. And Alex ran home crying. I was there. She fell into my arms. ³They told, Daddy! They told the new kids about my funny fingers.² And I let her cry for a long time, too. --ALEX, The Life of a Child, (82)

The most common external symptom is clubbing, or enlargement, of the tips of the finger and toes. Although the precise cause of clubbing is not known, clubbed fingers appear in heart and lung disease patients, as well, so it seems to be related to pulmonary flare-ups and severe lung problems. Clubbed fingers look fairly normal despite the rounded tips above the fingernails. They are certainly noticeable and occur in virtually all cystic fibrosis patients. There is no treatment for clubbed fingers at this time.

Collapsed lungs, properly known as pneumothorax, are common to CF patients. Frank Deford tells of the distressing time when Alex suffered a collapsed lung. It was a terrifying experience for a seven year old to endure.

³I started coughing really, really hard. Then it felt really hard to breathe. I started to cry. The nurse came in and I said, ŒI think I have a collapsed lung.ı² --ALEX, The Life of a Child, (142)

Pneumothorax occurs in approximately 4 percent of CF patients and it is described as a rupture or break in the lung tissue or airways that allows air to escape from the lung. As air becomes trapped between the lung and the chest wall, it may cause a partial or total collapse of the lung, making breathing nearly impossible. Collapsed lungs are sometimes difficult to detect in CF patients simply because the patients are so young and unable to articulate the internal malfunctioning of their body. The primary treatment for pneumothorax is oxygen therapy, but sometimes surgery is necessary. In mild cases of pneumothrax, the air may re-enter the lung and not require medical treatment to drain the trapped air and allow the lung to expand.

Another frightening complication of CF is hemoptysis, literally meaning to cough up blood. In the following excerpt, Frank Deford tells of time when Alex spit up blood in addition to the normal phlegm. It was a scarey day for the entire family.

When Alex first bled the other day, it scared her so. Blood! My blood! We had not prepared her for blood, nobody had told us about blood. My wife Carol was in tears now, but there was more anger than sadness. ³This beautiful , gorgeous child in her Valentine dress, spitting up blood. My God. My baby spitting up blood.² --ALEX, The Life of a Child, (107)

Hemoptysis is caused by minor bleeding from an inflamed and damaged lining of an airway. The thick, sticky mucus scrapes or tears the lining causing a small amount of bleeding. And as depicted in this excerpt, blood discovered in the normal mucus secretion can be quite jarring for the young patient. In general, though, hemoptysis is not grave. Usually, hemoptysis does not require any specific medical care, but in the more serious cases, medical therapy or surgery is necessary.

In the final chapter, Frank Deford tells of the day when his daughter died. He and his wife Carol climbed into bed with Alex and lay with her while her oxygen compressor hummed on.

She would have liked to have been in the middle, between her mother and father, but that was not possible because she had to keep her nose prongs on all the time and they were attached on a fairly short tube to the oxygen compressor that was placed next to her side of the bed. The compressor made a horrible kind of wheezing sound, and it would thud at regular intervals. I hated that damn thing even as I had come to accept it as a part of Alexıs room, her life, our house, our lives. --ALEX, The Life of a Child, (174)

Similar to hemoptysis, cor pulmonale is a condition characterized by extensive lung damage causing the right side of the heart to become thicker and larger. The lung damage reduces gas exchange in the lungs so less oxygen gets into the blood. As the heart works harder to receive oxygen and pump blood, the strain causes the right side of the heart to become larger. Treatments include supplemental oxygen and diuretics, to get rid of extra fluid. Many of these treatments are performed on an outpatient basis, but sometimes, they are accomplished at home as most cystic fibrosis families own an oxygen compressor and it blends in with the rest of furniture.

The Cystic Fibrosis Gene

As mentioned before, parents of CF children tend to blame themselves for their child's disease. Parents feel entirely responcible for passing their critically flawed genes on to their kids.

When our child was dying-- when she was dying because of the genes we passed on to her-- no matter how irrational it may have been to flagellate ourselves, there were times in the mustiest corners of self-awareness, when we had to. After all, we quickly enough assumes credit for the genes that make any of our children attractive and bright--she takes after me. Itıs only human nature, then. to accept responsibility when we pass on genes of destruction. --ALEX: The Life of a Child (87)

In 1989, the gene for cystic fibrosis was identified paving the way to a molecular understanding of this disease and opening the door to the envelopment of new treatments, including somatic gene therapy which will be discussed in the next section. In isolating the gene, scientists discovered the defective gene protein product: Cystic Fibrosis Transmembrane Conductane Regulator (CFTR). Inexplicably, this protein serves as conduit through which salt penetrates and exits the cell; injury to the gene barricades the salt and leads to the manifest signs of cystic fibrosis. What makes the CF gene abnormal, though, is a mutation, or change in the genetic material, resulting in a substitution or loss of functioning DNA. Furthermore, there are over 300 mutations in the CF gene and new ones are still being discovered-- scientists have, however, pinpointed the mutation that most often leads to this deadly disease. It is clear that identifying the CF gene is a giant step toward understanding how and why this gene causes cystic fibrosis; in addition, the discovery will be of great facilitation in treating and curing the medical problems of CF. But the question still remains: ³How does a genetic defect turn ordinary sterile lungs into mucus-clogged breeding grounds for harmful bacteria?²(Sternberg 279)

In pondering that question, scientists recently discovered that finding a way to limit salt production in cystic fibrosis patients would be the key to conquering this disease. In healthy people, the lungs produce a natural antibiotic that functions only in a low-salt environment. But CF patients lack a chloride or salt regulator resulting in a surface fluid laden with salt. The deceivingly simple finding of the water-salt imbalance represents a ³paradigm shift in our understanding of cystic fibrosis² (Sternberg 279). The next step, of course, is creating a way to apply this discovery. Researchers agree that the most viable progression will be to trying to ³identify what the lung secretes that has this antibiotic property, isolate it, modify it so that it is not susceptible to salt,² and then test it on those afflicted with the disease. (ibid.)

In 1990, after the initial discovery of the CF gene, scientists were successful in making copies of the normal gene and correcting the defective ones. This of course, was accomplished all within the context of a laboratory dish. But in 1993, another breakthrough occurred when the first experimental gene therapy treatment was given to a CF patient-- scientists modified a common cold virus to act as a delivery vehicle carrying the genes to the CF cells in the airways. And today, researchers are engineering fat capsules or liposomes as the mechanism to deliver healthy genes. Ideally, scientists will be able to add enough normal genes to CF airways to correct a significant amount of defective cells. Ultimately, though, this treatment will be performed every few months to account for the regeneration of cells. These, and other, modes of treatment will be addressed in the next section.

In Pursuit of a Cure: The Prospect of Gene Therapy in CF

She shook her head with determination. ³Oh Daddy, Iım going to keep on hoping. I am! I promise you. You have to hope, donıt you?² ³Yeah, I really think we all have to.² --ALEX, The Life of a Child, (159)

Since 1989, scientists have been working on several ways to attack cystic fibrosis. They are looking at ways to compensate for the loss of ³CFTR chloride channel by increasing the activity of a different class of chloride channel² (Welsh 7). They are trying to administer drugs able to escort ³mutant CFTR molecules from the endoplasmic reticulum through the Golgi apparatus and into the cell membrane² (ibid.). The most promising treatment of CF, however, is gene therapy.

It is clear that the isolation of the cystic fibrosis gene has had a huge impact on scientific research. Indeed, the prospect of gene therapy offers the best hope for a life-saving treatment in CF patients; scientists are searching for ways to deliver a normal copy of the CFTR gene to the cells that need it. This section looks at a variety of genetic treatment and early detection of CF, but first, it is necessary to explain the logistics behind gene therapy. As mentioned above, scientists use state-of-the-art biotechnology to manufacture normal genes in the laboratory. Today, research teams are attempting to develop new gene delivery systems to determine the optimal mechanism for depositing these healthy genes-- fat capsules, synthetic vectors, or modified viruses.

Probably the most publicized method of gene therapy capitalizes on the capacity of viruses to enter cells, bringing their DNA with them. Scientists are examining ways to alter mutant genes. The most inviting course would be to remove viral genes to prevent the virus from reproducing in the cells and causing symptoms and then extracted DNA would be replaced with a normal CFTR gene. These normal genes would function properly with regard to healthy chloride channels.

An innovative, new gene therapy created to combat cystic fibrosis was introduced recently in hopes of bringing the gene isolation to the bedside of sufferers. The challenge of medical researchers was to somehow transport the corrected versions of DNA into the lungs of CF patients. A new aerosol spray that provides patients with the protein they lack will supposedly have many beneficial effects. Since the cells that line the lungs shed periodically, this aerosol gene therapy will probably have to be repeated every two to three months.

Now that scientists have determined the genetic mutation leading to cystic fibrosis, prospective parents can easily find out whether their cells harbor a deficient duplicate of the CFTR gene. For better or for worse, by measuring certain proteins in amniotic fluid, couples can potentially learn whether an already developing fetus has inherited two modified copies of the gene and will in turn be afflicted with CF. These tests are not foolproof, though, due to the sheer amount of mutation of the CFTR gene. As a result, an encouraging negative finding may not completely rule out the possibility that someone is a carrier or that a fetus is a affected by CF. Irrespective of the heated debate surrounding the ethics of prenatal testing, this method of early detection is a great relief to CF families and carriers wary of passing on these deadly genes.

Conclusion

Alexıs eyes were drawn to a pair of the ugliest earring you ever did see. It was not enough that they were hideous. ³The trouble is Alex,² Carol said, ³that these earrings are just so pretty, so magnificent that I would never have the right occasion to wear them.² ³Oh, yes, you will....When they find a cure for cystic fibrosis and we have a big family party and get all dressed up-- you can wear them then.² --ALEX: The Life of a Child (32)

Alex Deford died in 1985. She will never have the magnificent occasion to wear those gaudy earrings. Soon, though, there will be a reason to celebrate. Scientific breakthroughs are happening at a rapid pace, enabling many CF families to have hope for curing this disease.

It is an exciting time in cystic fibrosis research. CF patients and scientists alike remain hopeful that this new technology and gene therapy used in treating lung infection, can be adapted to treat other organs affected by CF. But while CF researchers have made stunning advances, much more research needs to be done to actually cure this complex disease. But cystic fibrosis researchers concur that in the next decade, the medical community will see a revolution in treatment for this disease-- possibly even a cure. (Time February 24, 1992)

Works Consulted

Books:

Mueller R. and Young, I. Emery's Elements of Medical Genetics. New York: Churchill Livingstone, 1995.

Deford, F. ALEX: The Life of a Child. New York: The Viking Press, 1983.

Berkow, R. The Merck Manual of Diagnosis and Therapy. Rahway, Merck Sharp and Dohme Research Laboratories, 1977.

Periodicals:

Bedwell, D. "Cystic Fibrosis: An Antibiotic Cure." Science News. v. 149. May 1996.

"Has Gene Therapy Stalled?² Time. v. 146. Oct. 1995.

Welsh, M. "Cystic Fibrosis." Scientific American. v. 273. Dec 1995

Purvis, A. ³Laying Siege to a Deadly Gene.²Time. Feb1992

Scholte, B. ³Genetic Therapy and Animal Models of Cystic Fibrosis.² (publication unknown)

Sternberg. S. ³Grains of Salt Explain Cysric Fibrosis.² Science News. v. 149 May 1996.

Web Sites:

The National Foundation for Cystic Fibrosis Homepage http://www.injersey.com.Living/Health/CysticFibrosis/cfgene.html

Cystic Fibrosis Info-Zone

http://members.aol.com/Doluckie/stuff