Bijal Trivedi, award-winning journalist and senior science writer for the National Geographic, has stunned with her debut novel, Breath from Salt: A Deadly Genetic Disease, a New Era in Science, and the Patients and Families Who Changed Medicine Forever. In this expansive chronology spanning over 80 years, Trivedi unravels the comprehensive historical review of the discoveries which led to the current understanding of and treatment for cystic fibrosis.
Soon after Dr. Dorothy Hansine Andersen, one of the few practicing female physicians in 1935, entered the field of pathology, she was met with a confounding autopsy that had been classified under the umbrella of celiac disease despite a number of uncharacteristic findings. While searching for other similar cases, she uncovered a long history of deceased children with fibrous pancreatic cysts; dense, mucus-filled lungs; and scar tissue-filled pancreases being classified as celiac-related deaths. Dr. Andersen compiled a report of dozens of case studies, naming this celiac-resembling disease “cystic fibrosis” and defining its typical symptoms as vitamin A deficiency, visual deficits, and lung infections. The recognition of cystic fibrosis as its own clinical entity led to the creation of diagnostic tests to identify the laboratory findings characteristic of cystic fibrosis, namely high chloride levels of sweat. Twenty two years after the diagnosis was recognized, Wynne Sharples, the mother of two children with the disease, launched what would soon be called the National Cystic Fibrosis Research Foundation in order to advance research efforts and advocate for this little-known disease.
With the knowledge that sweat glands appeared to be dysfunctional in CF patients, scientists hypothesized that a gene involved in proper sweat gland function might be the responsible mutation. Beginning the hunt for the mutated CF gene in 1984, scientists began searching for genetic markers -- landmark pieces of nucleotide differences inherited with the mutant gene, lying near this gene and signifying the general location of the mutated DNA. The ultimate goal was to discover a marker only present in CF patients, one inseparable from the disease, and within a year, their hunt for markers concluded that the mutant gene lies within the seventh chromosome. By 1989, a mutation within the amino acid phenylalanine at position 508 was demonstrated to occur within 70% of CF patients and be nonexistent in those without the disease. Moreover, it turned on within the relevant organs, and was carried by both affected parents and children.
This mutation was part of an amino acid group coding for a transporter protein, prompting the hypothesis that the protein leads to the faulty chloride transfer within patients and the naming of the protein as the Cystic Fibrosis Transmembrane Conductance Regulator (CFTR). Aside from the mutation within phenylalanine at position 508, also known as the F508del mutation, scientists found over 2,000 other cystic fibrosis-causing mutations within the CFTR gene. Although gene therapy, the insertion of an unmutated gene into the patient’s body to allow formation of the correct protein, was attempted as a cure for CF, it soon became evident that such treatment was ineffective. At best, the gene therapy had no impact on the patient and the inserted CFTR gene disappeared within 4 days; and at worst, it triggered flu-like symptoms and extreme inflammation.
Concurrent with the above CF trials, gene therapy trials were being conducted on other hereditary disorders including ornithine transcarbamylase deficiency (OTC) in which the body cannot produce an enzyme responsible for the removal of nitrogen. Trial volunteer Jesse Gelsinger was randomized to the highest dose arm of the trial. Not long after the treatment, his red blood cells exploded and leaked proteins into his blood -- a catastrophe for Gelsinger, whose body could not process proteins, and within 24 hours he entered a coma. His lungs stiffened, his kidneys failed, his body swelled with fluid, and he died within four days of receiving the therapy. The field of gene therapy crumbled, essentially brought to a halt for a decade under the weight of such tragedy, and the world was left to question the ethics behind the treatment. Scientists were accused of being overly confident, cutting corners, and rushing the development of clinical trials. The impact of the crisis was felt throughout the gamut of clinical research trials. The FDA not only shut down the OTC trial, but ended the university’s Human Gene Editing program, triggered scrutiny of 69 other national gene therapy trials, and prompted two patient protection plans -- the Gene Therapy Clinical Trial Monitoring Plan and the Gene Transfer Safety Symposia.
The field withered under scrutiny for over twenty years, yet eventually rebounded, driven by the potential financial and medical promise offered by gene therapy. The concept of a daily pill that would restore chloride flow was developed, and the National Cystic Fibrosis Research Foundation partnered with private industries in order to begin high-throughput screening for CFTR-repairing candidate molecules.
In order to repair the chloride channel function in mutations such as F508del, one corrector drug is needed to refold the protein and allow it to reach the surface; then a “doorman” drug is required to open and close the channel. As proof of principle that the channel could be restored, it was decided that the first drug to be developed would be the doorman molecule drug which would be effective by itself in only 4% of the CF patients (those with mutations which could be repaired with only the doorman drug). In 2004, after screening hundreds of thousands of possible doorway molecules, the 770th molecule within the notebook of one of the contributing scientists, labeled VX-770, was observed to enable chloride transport within both rat and human cells. Breezing through phase I, II, and III trials, the drug dropped patients’ chloride levels dramatically and was soon FDA approved for patients who had the G551D mutation in 2012 under the brand name Kalydeco.
The next step was to develop the corrector molecule in order to treat those whose channels could not be restored by Kalydeco alone. In late 2004, a corrector molecule named VX-809 was developed; however, although it was the most promising candidate, it only raised the protein function by 14%. It was soon discovered that the F508del mutation causes two distinct incorrect folds, therefore multiple drugs would be required to create a strong corrector. The author chronicles in detail the stepwise pathway leading to more effective combination drugs which gained FDA approval. The FDA also approved drugs that were demonstrated to be effective in cell models but could not be tested in humans due to the rarity of the mutations. Since many extremely infrequent CF mutations would never be able to have their own clinical trials, this allowed additional groups of patients hope of effective therapies.
Please see the post titled 'Book Review: Breath From Salt by Bijal Trivedi (Part 2 - Reflections)' for the second half of this review.
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