This is a question that has vexed scientific investigators for centuries, and for the last century, our belief was predicated upon physical observation that cancer reflected altered cell growth. After all, to the untrained eye, or even to the rather sophisticated eye, the mass in the pelvis or the lymph node under the arm, or the abnormality on a chest x-ray, continued to expand upon serial observation. This was “growth” (at least since the time of Rudolph Virchow); and growth it was reasoned represented cell division.
Based upon the cell growth model, cancer therapists devised drugs and treatments that would stanch cellular proliferation. If cells were growing, then cells needed to reproduce the genetic elements found in chromosomes leading to the duplication of the cell through mitosis. If chromosomes were made of DNA, then DNA would be the target of therapy. From radiation to cytotoxic chemotherapy, one mantra rang through the halls of academia, “Stop cancer cells from dividing and you stop cancer.”
As in many scientific disciplines, nothing spoils a lovely theory more than a little fact. And, the fact turned out to be that cancer does not grow too much, it dies too little. Cancer doesn’t “grow” its way into becoming a measurable tumor, it “accumulates” its way to that end.
In 1972, we realized that the most basic understanding of cancer biology up to that point was absolutely, positively wrong.
Working in a laboratory during my fellowships, I began to realize that something was wrong with the principles that guided cancer therapeutics. My first inkling came from the rather poor outcomes that many of my patients experienced despite high-dose, aggressive drug combinations.
Then, it was the failure of the clonogenic assay to predict clinical outcomes that further raised my suspicions. I began to ponder cell growth – cell death, cell growth – cell death. With each passing day the laboratory analysis that I conducted identified active treatments that worked. Using short-term measures of cell death (not cell growth),. I could predict which of my patients would get better. All of the complicated and inefficient clonogenic assay investigations could not. Cell growth – cell death – what was I missing?
It would be years before I would attend a special symposium on the topic of cell death that it all became abundantly clear.
My “eureka” moment is captured in Chapter 6 of my soon-to-be-released book, Outliving Cancer.