GENETIC SCREENING FOR CYSTIC FIBROSIS

Terri Mullin was born in 1969 and diagnosed with cystic fibrosis (CF) at age 4. Throughout her life she remained optimistic about her own possibilities, yet resentful about the disease that had stricken her. She resented the lower grades that came from missing school for weeks at a time to receive large intravenous doses of antibiotics. She resented the fact that the friends she made in the hospital died one by one as she grew into her teenage years. She resented modern science, which put men on the moon but offered her no cure. Nonetheless, she was the first chronically ill student at prestigious Exeter Academy, graduated from Harvard with a degree in journalism, and worked as a reporter for the Boston Globe. In her work she was doggedly persevering. She once apologized to a friend that one of her stories was muddled because she had coughed up blood onto her notes in the midst of the interview. In spite of her strength and optimism, she experienced a long, steady decline. On May 10, 1991, she died in a London hospital while waiting for a transplant of her heart and lungs. She was 22 years old. In the United States, a cystic fibrosis sufferer dies every eight hours.

CF has long been known to be a 'genetic disease,' a fact that somehow seemed to increase the sense of hopelessness and inevitability. CF is caused by a single gene that is expressed when an individual has two CF alleles and no normal ones. In spite of all the personal tragedy associated with CF, the story of cystic fibrosis is one of triumph for recent genetic research. In 1985, the chromosome carrying the gene was identified as number 7, the seventh longest. By 1987, its position on chromosome 7 was localized to a specific region that contains about 2 million genetic subunits. Soon afterward, other genetic markers were found that further localized the gene's position. Scientists identified more than 200,000 pieces of genetic code in this region looking for the gene! Then in 1989, workers announced that they had identified both the location and structure of the CF gene.

However, this was only the first step. What did the gene do? How was this gene related to the disease? In this case the gene itself gave clues to its function: it is similar to other genes that create "transport" proteins which use energy to move materials across cell membranes. The protein made from the gene was named the cystic fibrosis transmembrane regulator (CFTR). CFTR appears to form a channel that normally moves salt across the cell membrane and helps regulate water balance. In normal people, this protein consists of a long chain of 1480 amino acids; in the "D F₅₀₈" mutation one of these has been deleted at position 508. This single deletion is enough to change the function of the protein, and cause CF. The cells lining the patient's airways are unable to transport salt (and water). As a result, the protective mucous layer becomes thick and sticky, creating a great breeding environment for bacteria and interfering with breathing. CF patients also have other difficulties, such as an inflamed and dysfunctional pancreas, that add to their debilitation.

It is now possible to take a sample of a person's genes and identify the alleles that an adult, or a fetus, carries. A recent technique also makes this possible for individual unfertilized eggs.  From this "genetic screening," we now know that CF is caused by more than 20 different mutations. The most common mutation, D F₅₀₈, accounts for more than 70% of CF patients; the four most common account for a total of 85%. Only these four are detected by normal genetic screens. The remainder are caused by a variety of rarer mutations, some of which occur only in a single family.

The genetic basis of CF now is clear and we have the technology to explore the genetic makeup of people in ways that were impossible only a few years ago. Now we are faced with other problems. What genetic information should we collect? from whom? How should we use this information? How should we use our financial resources to achieve the greatest effect in the case of CF?

Widespread population screening for CF was advocated as soon as the D F₅₀₈ test became available.  Routine testing of newborns would allow prompt access to customized health care as well as identify carriers. The anxiety of prospective parents with a family history of CF must be excruciating; many want to have all the information that is available to them. A test of the parents would allow them to estimate more realistically the chances of their having an afflicted baby. A prenatal test of the fetus would give parents the choice of terminating the pregnancy.

We might even reasonably ask whether parents who chose to avoid such tests are acting responsibly toward their offspring and toward society. Fletcher, for example, argues that we should protect our future progeny against genetic defects in the same way we protect our children against infection. The cost of providing health care is staggering: a CF patient may incur health care costs in excess of $60,000 per year during an average life span now approaching 20 years. This enormous cost for one person means that health care of all sorts must be limited for many other people. A parental decision to have children in a high risk situation may thus create a million dollar debt that is normally paid by charitable organizations, insurance policyholders and taxpayers.

Doctors feel ethical pressure to use all available technology to help their patients. They may also feel legal pressure in the form of fear of malpractice suits. In the case of Schroeder v. Perkel, the parents of two CF children sued their pediatrician for failing to diagnose CF in their first child while the wife was pregnant with their second. In 1974, this doctor had to use a feces test for CF diagnosis. The parents alleged that the "defendants' negligent failure to diagnose their child's illness denied them the right to make an informed decision as to whether they should conceive a second child." The doctor was found to be guilty of "wrongful birth" and was required to pay the medical expenses the parents incurred for the second child. The possibility has also been raised of a "wrongful life" suit in which an afflicted child could try to sue the doctor for wrongfully allowing him/her to be born! In our litigious society, what doctor would not want to err on the side of caution? With current screening tests, how certain can a doctor be of a diagnosis?

Some people simply don't want to know. Ten percent of the pregnant women in one survey agreed with the statement "If there is something wrong with my baby I'd rather not know." They could have many reasons for such an opinion. The test can, however, suggest "non-paternity of the putative father" in uncertain situations that may represent as much as 15% of the population.

Others point out problems with earlier screening efforts. Sickle cell screening efforts was "launched with the best of intentions and a great deal of zeal." In some cases, testing was even required by law. The program created a variety of problems. Many sickle cell carriers mistakenly believed that they had the disease. In some cases, test results were made public and individuals were stigmatized. Some were denied health insurance. Double-carrier couples warned about the risks for their children often failed to use the information and some saw the whole program as a vehicle for racism.

Some feel that the current level of test sensitivity would create unacceptable ambiguity and anxiety among patients. Increasing test sensitivity reduces ambiguity about the risks to child-bearing couples, but does not eliminate it. Some ambiguity is probably inevitable. Others point out that ambiguity and anxiety on the part of some patients is no reason to effectively deny testing to a wider audience.

There are great financial and personal implications of screening programs. First of all, widespread screening could create a billion dollar testing industry. Fenerty and Garber (1989) compared the costs and benefits of alternative prenatal screening regimes in more detail. The first regime is the use of the $150-$225 test for the D F₅₀₈ mutation in families with a CF child, a very high risk population. In this case screening of 1000 pregnancies would save about $150,000,000 in health care costs if CF fetuses were aborted, at a cost of about $5000 per CF fetus discovered. Misdiagnoses would be expected to result in the abortion of 15 normal fetuses. In screening the general population, detection of each CF fetus would have a net cost of $64,000. They also estimated the consequences of a test that detected 98% of CF mutations with 98% accuracy. In screening 3 million pregnancies, 1765 CF fetuses would be detected, but 241 normal and 110 CF fetuses would be misdiagnosed. How would these figures change using available 71% and 85% sensitive tests?

Terri Mullin, among others, suggested that using resources for developing genetic testing procedures are misdirected at the present. She wrote that news of the discovery of the CF gene and its mutation was a "red herring", that has "lulled the patient community and the public into believing that some of the urgency of our circumstances has been taken away." She suggested that efforts must be directed toward alleviating the suffering of existing CF patients even though "clinical research holds little remaining prestige at a time when CF physicians are placing their hopes in a genetic miracle."  In response to the suggested use of screening in prenatal diagnosis, she commented, "We are somewhat appalled at the notion that a problem would be solved if fewer of us were born."

Chest physical therapy, exercise, aerosols and antibiotics are still the most common therapies. "Chest physical therapy is used to prevent blockage of  the airways by the thick sticky mucus caused by CF. It is often combined with bronchial drainage, or postural drainage, where the chest is clapped while the person with CF lies in a position where gravity helps the mucus drain from the small airways to the larger
airways. Physical exercise helps loosen mucus in the lungs so it can be coughed up more easily. Exercise stimulates coughing which help clear the lungs, builds up the strength and endurance of
the breathing muscles and increases the general level of cardiovascular fitness. Aerosols, treatments in the form of mist which are inhaled through a mouthpiece or mask, include bronchiodialtors (widen breathing tubes), mucolytics (thin mucus), decongestants (reduce swelling of breathing tube membranes) and antibiotics. Antibiotics, taken orally, intravenously and as aerosols, are used to kill infectious bacteria in the lungs.Some promising therapies are in the early stages of development and experimental clinical trials. A virus has been used to insert a normal allele into a CF patient's cultured cancerous pancreatic cells, which then began producing normal CFTR. Another group inserted the gene into airway lining cells in a lab culture; they are exploring the idea of spraying a viral aerosol in into a CF patient's airway in the hopes that the virus infection will insert the normal allele into those cells.

The medical community is in general agreement that pilot studies are needed before any larger programs are put into place. Although such studies are under way in England and Canada, none have been started in the US. Studies have been proposed but none have been funded. Robert Beall, president of the Cystic Fibrosis Foundation, says they cannot fund such an effort because their "mission is to find a treatment and cure for the disease - not to prevent it." Responsibility for funding government programs has been elusive for investigators. Scientists feel they have gotten the run-around. While Beall and others deny they are trying to avoid the abortion controversy, insiders say that is the reason for all of this sidestepping.