In 1953, James Watson and Francis Crick made their famous groundbreaking discovery of the helical structure of DNA. The genetic root of Down syndrome has also been found the same year, kick-starting the search for associations between DNA and unexplainable diseases.

In 1956, laboratories around the world began exploring the different technologies that was needed to explore genetic matter. Peter Nowell, a doctor in his early thirties was researching cancer at the University of Pennsylvania and pioneered a new method for seeing chromosomes inside cells: rinsing cells and staining them with a bluish-purple dye.

At that point, how disease could possibly be linked to DNA was entirely unknown. Phrases such as "genetic mutation" or "chromosomal abnormality" were not coined yet.

But in 1959, David Hungerford, a then young scientist spotted something. He hovered over a microscope, recalibrated the lenses but it was absolutely certain: one of the chromosomes in a single cell, was too short.

Hungerford knew what chromosomes looked like as he had spent countless hours looking at the chromosomes of drosophila flies at the Philadelphia cancer research centre, constantly training his eyes to see the fine banding patterns within.

The photograph of serendipity


Peter C. Nowell (left) and David A. Hungerford, 1961. Photo credit: Fox Chase Centre Forward
Peter C. Nowell (left) and David A. Hungerford, 1961. Photo credit: Fox Chase Centre Forward

As fate would have it, he ended up working with Nowell after hearing about his method to see chromosomes under the microscope. Together they perfected the hypotonic solution and figured out how to air-dry slides to help cells spread out more.

For the next three years, the routine of Nowell preparing slides for Hungerford to view under the microscope continued. Then in 1959, they made a discovery: an abnormally small arm of a worm-shaped chromosome inside a cell of a person with chronic myeloid leukaemia (CML). But what was more interesting was that the same abnormality occurred in the blood samples of six other CML patients.

Hungerford snapped the camera shutter. Little did he know, the photo would have a significant effect on the lives of countless patients and on the future of cancer treatment.

"Until we stumbled over this Philadelphia chromosome, there was really no evidence that cancer might be due to genetic change," Nowell said in 2013.

But it wasn't until the 1970s did researchers learn how the Philadelphia chromosome was formed.

Forty years of understanding the link between genes and cancer

Janet Rowley from the University of Chicago discovered that chromosome 22 and chromosome 9 had exchanged part of DNA - a process called chromosomal translocation. Translocation would later prove to play a key role in other forms of cancer as well.

In the 1980s, Nora Heisterkamp and her colleagues at the National Cancer Institute discovered that the translocation resulted in the fusion of two genes, creating a new gene known as BCR-ABL.

Later on, Owen Witte and his colleagues at the University of California, Los Angeles, discovered that the fused gene coded for an abnormally active form of an enzyme known as tyrosine kinase that stimulated uncontrolled cell growth in white blood cells.

After a whirlwind of discoveries within forty years, researchers finally had a target for treatment: the highly active enzyme.

The start of precision medicine


The photograph that started it all. The Philadelphia chromosome is seen at chromosome 22.  Photo credit: The Cancer Textbook
The photograph that started it all. The Philadelphia chromosome is seen at chromosome 22. Photo credit: The Cancer Textbook

Brian Druker from Oregon Health and Science University was studying tyrosine kinases as possible targets for precise treatment and was focusing on CML as a promising disease to study as the cause was simple: the result of one translocation in a singular mutation.

Finally in 1993, Nicholas Lydon who led a drug discovery group at the pharmaceutical company Ciba-Geigy (now Novartis) approached Druker to develop a drug that turns off cancer-causing enzymes.

CML was the best candidate and Druker's research was absorbed into the company. Druker found one compound called STI571, which was eventually named imatinib. It was highly effective as it would kill every CML cell in a petri dish, every time.

The first human trial produced such dramatic results and later trials showed blood counts returned to normal in about 95% of patients in initial stages of CML when the cancer grew slowly.

Fast forward to 2011, a study concluded that CML patients whose disease was in remission after two years of consuming imatinib, have the same life expectancy as those who never had the disease.

Imatinib was the start of precision medicine, putting an end to treatments with serious side effects and limited success such as some forms of immunotherapy, chemotherapy or radiotherapy. Essentially, imatinib stops patients from dying from CML, Druker says.

To think, that it all began with a photograph of an abnormal chromosome. MIMS

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