The Tale of the Philadelphia Chromosome

Chronic Myeloid Leukaemia (CML) is a blood cancer that affects millions of people across the globe. Patients suffer from uncontrolled cell divisions of white blood cells resulting in abnormal clotting and uncontrolled bleeding. Most of us probably have not heard of any ‘miracle therapy’ that rids the body of cancer and would be astounded if someone told us that they could treat blood cancer with a couple of pills per day. However, the little-known story of the Philadelphia chromosome stands as a model for how innovative research and genome specific therapies can save thousands of lives.

In 1959 CML was universally fatal. With no cure or effective treatment available, doctors prescribed heavy chemotherapy to try and rid the body of its cancer. However, within a few years of diagnosis and having been given ineffective chemotherapy, patients faced an early death.

Hungerford was hunting for any abnormality linking chromosomal structure and the symptoms of CML.

In this same year, David Hungerford, who was pursuing a PhD, compared the DNA of the stem cells of CML patients with healthy stem cells. Under his microscope he analysed chromosomes – DNA wrapped up into short worm-like structures found in all dividing cells. Only four years previously it had been discovered that most humans carried 46 chromosomes in all their cells. Hungerford was hunting for any abnormality linking chromosomal structure and the symptoms of CML.

Part of Chromosome 22 appeared to be missing…

Through his studies he was fascinated to find that one of the 46 chromosomes found in his CML samples was substantially smaller compared to that of the same chromosome found in healthy tissue. Part of Chromosome 22 appeared to be missing and thus was shorter than usual. Working with Peter Nowell, they postulated that this loss of genetic material could have been due to a ‘translocation’. A segment of DNA from Chromosome 22 had swapped with a segment from another chromosome. Fascinated by the shortened chromosome, the pair of scientists baptised it “the Philadelphia Chromosome” after the city in which it was discovered. 19 years later Janet Rowely confirmed that this indeed was a translocation between Chromosome 22 and Chromosome 9.

…the translocation between Chromosome 22 and Chromosome 9 was producing the abnormal, uncontrolled protein kinase…

Fast forward to 1984 when Owen Witte, who was conducting research at the University of California, found that cells from CML patients contained a protein called a “kinase” which in healthy tissue is an on/off switch controlling cell division. However, in CML patients this protein was stuck in the ‘on’ position causing uncontrolled cell divisions – a major characteristic of cancer. Further investigation showed that the translocation between Chromosome 22 and Chromosome 9 was producing the abnormal, uncontrolled protein kinase that Owen Witte had discovered. This protein seemed to be responsible for the unregulated cell divisions that resulted in the over-production of white blood cells characteristic of CML patients.

Nick Lydon, a chemist working in Ciba–Geigy pharmaceuticals, began work to develop a ‘kinase inhibitor’ a drug that would bind to the mutated protein and stop its uncontrolled activation of cell division. He perfected a designed compound that in laboratory tests disabled the overactive protein kinase.

During the trial, patient after patient found that their abnormally high white blood cell count dropped substantially to normal levels.

Excited by the potential that he saw in this new therapy Dr Druker, working with CML patients in Oregon, campaigned with Lydon to start clinical trials as soon as possible. In 1998, Bud Romine, a CML sufferer and trial participant swallowed a 25 mg pill of the new kinase inhibiting drug named “Gleevec”. During the trial, patient after patient found that their abnormally high white blood cell count dropped substantially to normal levels. By taking one pill in the morning and evening, the symptoms of leukaemia weakened. News spread of this ‘miracle cure’ and soon Dr Druker’s phone was ringing continuously with CML sufferers throughout the world wanting to join the trial. In 1998, one year after the start of the clinical trial, Dr Druker reported that 100% of the clinical trial CML patients with the Philadelphia chromosome witnessed a remarkable decrease in their white blood cell count. In 45% of his patients, cells with the Philadelphia chromosome seemed to disappear entirely, converting a fatal cancer into a manageable chronic disease.

…Gleevec set the record for the fastest drug to be approved by the Food and Drug Administration…

On May 10th 2001, Gleevec set the record for the fastest drug to be approved by the Food and Drug Administration due to its acceleration through clinical trials. This medicine is revolutionary, not only because of the fascinating tale of discovery or the rationality behind its design but due to its beneficial effect on the prognosis of CML. Before Gleevec, fewer than half of patients survived 7 years after diagnosis. The tale of the Philadelphia chromosome shows that examining the molecular and genetic pathways of disease can aid the development of rational medications benefitting the prognosis for thousands of patients. By simply taking two pills a day, 90% of CML patients are alive 7 years after diagnosis and are able to lead relatively normal lives.

No longer do CML patients have to undergo chemotherapy and its horrific side effects. Gleevec is an example of a rational approach to medicine using a detailed background of molecular biology and genetics. The molecular pathways of disease are becoming clearer day by day and it is important that we turn this knowledge into practice. The tale of the Philadelphia chromosome is a tale worth learning from.

For more information on the Philadelphia Chromosome why not check out “The Philadelphia Chromosome” by Jessica Wapner?

Featured image of blood cells by Dr Graham Beards (CC BY-SA 3.0) at Wikimedia Commons.

Tags: Biology, cancer, Chromosome, DNA, Drugs, Leukaemia, Medicine, Treatment