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LIZABETH
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D ECEMBER 17, 2013
The cause of cystic fibrosis (CF), as accepted by the scientific community, is a mutation in the CF transmembrane conductance regulator (CFTR) gene on chromosome 7 (Wailoo, 92). Cystic fibrosis results in compromised pancreatic function and the thick mucus in the intestines and lung cavities yield symptoms that include the inability to effectively absorb nutrients, chronic coughing, frequent lung infections, and sterility in males. These all contribute to the classification that cystic fibrosis is the result of a pleiotropic gene, meaning that a single gene is responsible for various, and at times seemingly unrelated characteristics. This pleiotropic gene is the main contributor to the complexity of CF and as this paper suggests, overlooking this simple term, pleiotropic, may be the single most important failure of gene therapy as a treatment of cystic fibrosis.
One of the many intriguing questions involved with cystic fibrosis is, how did a fatal mutation in the
CFTR gene rise to a carrier frequency of 1 in 25 Caucasians and Ashkenazic Jews (Wailoo, 92)? This is a huge percentage and when applied to the American population, leads to a figure to the tune of 10 million Americans carrying the mutated gene. Many historians and researchers alike have attempted to hypothesize probable courses and causes, and of these, a more supported argument is worth mentioning. An article written by Richard
S. Meindl in 1987, two years before the Cystic Fibrosis gene was discovered, revealed an interesting perspective about the possible heterozygote advantage carriers had in terms of immunity to tuberculosis (TB). Carriers that are heterozygote for the CFTR gene only have one copy of the mutation and do not experience severe symptoms typical of a person whose genes contain two copies expressing the mutation, but they can still have slightly thicker mucus in the lungs. If a person carries the mutant CFTR, his or her lungs are coated with unusually thick mucus. Subsequently, the absorbance of the TB bacteria into the blood stream via the mucus lined lungs is unlikely, making them resistant. A person with healthy lungs and normal mucus would absorb the bacteria and become infected with TB. Historically, it has been recorded that “ the worldwide TB epidemic began in England

in the 16th century and later spread to western Europe, North America, and eastern Europe”(Bates). And in the
18th century this “white plague” was the cause of 25% of all deaths in Europe (Bloom). If this were the case, it offers a logical explanation as to how carriers of the advantageous allele would quickly increase in frequency among the population for generations to come. Although this hypotheses are under debate today, it offer insight on the importance in balancing selection, which is the maintenance of varying deleterious mutations among populations to ensure the survival of the human race via the heterozygote advantage ( Cyr).
In the early 1930’s, CF was identified by a Swiss pediatrician, Guido Fanconi, and his associates
(Wailoo, 68). Their paper described two children with “cystic pancreas fibromatosis and bronchiectasis”
(Fanconi, Uehlinger, Knauer) which meant that the disease was a metabolic disorder as well as effecting the lungs. The diagnosis of CF in the 1930’s meant with almost complete certainty that the patient would not reach his or her third birthday and there was no preventative paths offered to the families. But the use of antibiotics, lung drainage, and other therapeutic technics proved to be invaluable and by the 1980’s most patients could expect to live until their 30’s, but patients, advocators, and researchers a like were waiting for the next step.
In 1985 the promise of gene therapy was in full swing, and feeding the excitement was the media publishing articles such as one from Business Week grasping readers with terminology such as “Gene Doctors”,
“erasing natures mistakes”, and “curing life’s cruelest diseases”( Shulman). Sensationalism was having its effect on the scientific community. Leading the way to the cure was the Cystic Fibrosis Foundation (CFF) and the
National Institute of Health (NIH). Anyone associated with CF, directly or indirectly, started dreaming of a treatment that would fix the underlying causes. Researchers also were aiming high with the intent to make gene therapy with CF the base model for subsequent gene therapy treatments for other diseases. Gene therapy was the next big thing and was predicted to change the way the world thought of genetic disease as not something permanently determined at birth, but modifiable . In the mid 1980’s investors, pharmaceutical companies, universities and entrepreneurs were putting a huge effort to get into the business and anything with research objectives, including the glamorous subject of gene therapy, rather than a drug therapy approach, was the equivalent to getting triple funding from both private and federal grants. The U.S. congress, with the encouraging of the CFF and NIH, put more than $50 million into the CF gene therapy research (Beall). In 1988,

before the gene responsible for CF had yet to be identified, the CFF was busy promoting gene therapy and the
NIH was working on stimulating interest in the field (Lindee, Mueller 319). Francis Collins and his collaborators identified the gene as CFTR the following year, 1999 (Rommens). The race to come up with the gene therapy technique had begun.
In 1992, three years after the gene had been discovered, proposals to start research trials were presented by three separate researchers; Michael Welsh (U. of Iowa), James Wilson (U. Penn), and Ronald Crystal
(Cornell). Around the same time both Wilson and Crystal founded their own biotech companies to benefit from their research in gene therapy (Lindee, Mueller 320). Their proposals were simple; expose the lungs to an adenoviral vector that would swap out the CFTR mutation for a functional one. This posed another fault in the pursuit of gene therapy. As previously described, CF does not only affect the lungs but also encompasses pancreatic, reproductive, and metabolic malfunctions. From the beginning of the trials, researchers and critics knew that gene therapy was not going to be a cure-all. Using a more humble note, they did not know if it was going to work at all, contradicting all of the press and enthusiastic talk from the researchers. The two major hurdles that shaped gene therapy was how to test the effectiveness of the adenoviral vector and how to ensure that the vector went to the targeted cell type. In other words there was no clear test for success and even when a potential test was proposed, they still questioned if that was even applicable to testing for the presence of the newly swapped, healthy CFTR gene(Lindee, Mueller 321). As for the target cell type, researchers could not ensure that it would affect the airway epithelia while a variety of lung cells express CFTR proteins and could also be exposed. Regardless of not having a clear way to measure success, or identify a target cell through a specific method, “all three protocols were approved with minor changes” (Lindee, Mueller 321).
The drug trials proved to be no different in revealing skewed promises instead of the likely reality.
Despite unresolved questions regarding the fundamental aspects of the procedure, reports of Ron Crystal’s phase
1 trial “described the subject as a “patient” and was replete with references to “breakthroughs,” “firsts,” and
“milestones” ”(Wailoo, 97). This only encouraged the cystic fibrosis community in believing that a rapid cure was on the way, and as long as this was the belief, the funds for research grew exponentially as research in drug therapy was ignored. In 1993 Crystal hit a setback; his third “patient” had severe side effects including lung

inflammation, low oxygen in his blood, and lung damage (Wailoo, 99). Crystal quickly defended this by stating that they were results pertaining to the specific patient, but no other success was followed by any three research teams. In 1994, all researchers gave predictions of success within the next year and reports contained overall enthusiasm about their studies when in reality all of their trials yielded results that showed no success, even in the primary tests to demonstrate the effectiveness of delivering the adenoviral vector. By 1995, all researchers admitted that they had falsely judged the complexity of CF, and James Wilson went on to study
, claiming it to be much less complex.
So the question stands; why were all signs of confusion, uncertainty, and complexity ignored in the early stages of gene therapy of CF and replaced with sensationalism, glamour, and false enthusiasm? There seems to be not one answer, but many, all of which lead to a race for a “rapid” cure and in the end, no finish line. Genetic therapy became the dream of science and everyone involved (NIH approval members, legislators, parents, and patients) believed and wanted to see its success. The problem was that only a select few would be willing to fund research of fundamental techniques that needed to be addressed in order to engineer an effective treatment to be tested. The disease as a whole seemed to be manipulated into an oversimplified problem and as Keith Wailoo stated in his book, “the scientific community’s focus on…underlying mechanisms seemed far removed from the practical concerns of families and patients.” (76). They wanted a cure for CF, not a test to successfully demonstrate the path of electrolytes like chloride. As a side note, to this day, measuring effectiveness of CFTR gene has undergone no major improvements (“Methods to Study Ion Channels”). Another factor that played an integral part was conflict of interest which ultimately led to the overly optimistic updates of the results. Two of the head researchers founded their own biomedical companies and they all had support from biotech companies, which lead to the use of marketing tactics rather than the pursuit for scientific advancement. The researchers were directly involved in the success of their companies and were the best source of PR; naturally they would be pressured to release positive and successful updates that pleased the company's investors. Of course, the researchers were not the only ones with exaggerated optimism; the media took off with gene therapy as if it were a superman comic strip. Readers loved the fascinating, almost science-fiction-like, tales that the “gene doctor” embarked on. Overall this led to an imbalanced view of the expectations for cystic fibrosis treatment. The year

1995 marked the end of the rapid race to cure CF with gene therapy. On December 7, 1995, a NIH committee admitted that, contradictory to widespread beliefs, none of the tested protocols had led to any success and their report of recommendations found that:
“Significant problems remain in all basic aspects of gene therapy…Overselling of the results of laboratory and clinical studies by investigators and their sponsors has led to …the perception that gene therapy is further developed and more successful than it actually is.”(Orkin, Motulsky)
Researchers should not be put in a position where they are rewarded with money for giving enthusiastic press conferences but for carrying out the most ethical and sound techniques and procedures. As of today, December,
17th, 2013, eighteen years after the report was released, there is not a single gene therapy drug in the U.S. market.
Where would the scientific progress of gene therapy be today if researchers had pursued an effective test to measure success of the adenoviral vector instead of just grabbing a promising vector and performing trials?
The scientific community must not overlook the effect that hope and faith, turned into unbridled enthusiasm, has in the effort to secure funding and approval while brushing aside prudent testing protocols. This is not just a scientific problem, but can also be applied to private entities, academic institutions, federal research facilities, as well as industry. With this knowledge, we must make a strong effort into rigorously investigating exactly what we are allowing to be immersed in enthusiasm for the sake of promoting research.

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