The human body is constantly shedding old or damaged cells, so that new cells may take their place. This natural process of cellular self-destruction (called “apoptosis” from an ancient Greek word meaning “falling off”) is hard-wired into cells.

The process is a cellular spring cleaning, one that turns out to be as crucial as it is constant; over the course of a year, each of us will shed a mass of self-destructed cells approximately equal to our full body weight. The body uses this natural process to rid itself of cells that are damaged, infected or mutated. Even before we’re born, apoptosis plays a vital role in the early stages of infant development in the womb.

It’s an efficient and controlled system – most of the time. But what happens when apoptosis fails, and a sick cell is unable to self-destruct?

Sometimes mutations disable the self-destruction capability of apoptosis, for instance in many cancers. Instead of self-destructing and being replaced by a healthy cell, these mutant cells continue to divide and multiply. Such resistance to apoptosis is one of the key hallmarks of cancer.

But what if we could learn to re-activate apoptosis in cancer cells? If we identified the key signals that the body uses to control apoptosis, could we trigger that process ourselves, to induce the cancer to self-destruct?

It’s a field of research that is finally yielding results – with medicines that are designed to fight cancer by helping cancer cells to destroy themselves.

One of the scientists whose discoveries paved the way for this progress is Vishva Dixit, MD, PhD, Vice President, Physiological Chemistry at Genentech. He has spent decades working to understand the signals and pathways that govern apoptosis.

“Cancer cells are clever and have found ways to resist the cell death process,” Dixit explains. “But out of this has come a huge opportunity, because we've begun to understand the molecular basis for this resistance and are starting to harness this knowledge in the fight against cancer.”

Years of painstaking basic science research have now uncovered several distinct mechanisms by which the body controls apoptosis, and identified several key proteins that regulate it. Some of these proteins promote apoptosis, while others inhibit the cell’s self-destruction. These include proteins such as MCL-1 and BCL-XL – but so far, the furthest progress has been with a protein called BCL-2 (short for B-cell lymphoma 2).

BCL-2 is one of the key proteins responsible for suppressing apoptotic cell death. Instead of allowing the tumor cell to self-destruct, as it has been programmed to do, BCL-2 blocks that pathway.

Which led researchers to wonder: what if they could block BCL-2?

“It turns out that there are certain cancers that are exquisitely dependent on BCL-2 for their survival,” explains Wayne Fairbrother, DPhil, a Director and Senior Staff Scientist, Early Discovery Biochemistry at Genentech, whose team helps develop novel technologies to explore protein targets. “And therefore, those cancers are also exquisitely sensitive to BCL-2 blockade.”

“In hindsight, targeting BCL-2 was a no-brainer,” remarks Avi Ashkenazi, PhD, Senior Staff Scientist, Cancer Immunology. Ashkenazi should know – after 30 years of research, he’s a veteran among the teams at Genentech who have pioneered work to discover and understand the signals that control apoptosis. “BCL-2 is genetically altered in some cancers: it’s mutated and amplified. That in itself provides some incriminating evidence that it’s involved in the disease. And it also provides a marker that one can look for in order to identify the types of tumors, and the individual patients, that may benefit the most from therapy.”

“But of course,” Ashkenazi says, “hindsight is 20/20.”

“There was resistance against targeting [BCL-2] initially, because it was considered too difficult,” Fairbrother says, noting that interactions between proteins are notoriously tough to target.

In fact, when BCL-2 was first identified, the feat was considered impossible. But by carefully engineering small molecules that uniquely target the BCL-2 protein, scientists have finally discovered a means to block it. The result essentially reactivates apoptosis in the cells, triggering the cancer to self-destruct.

The unique aspect of apoptosis, according to Ashkenazi, “ is that it ultimately leads to the irreversible death of the cancer cell – it eliminates it altogether. As opposed to some other targeted approaches that merely slows down the proliferation of tumor cells, this is more direct.”

This journey from raw scientific discovery to clinical reality has been an opportunity to use 21^st century scientific tools to help restore one of the body’s key natural processes And for the scientists who have dedicated their careers to studying apoptosis, no reward could be better.

“This process of discovery has taken decades and required persistence,” Dixit says. “The emergence of medicines that can restore apoptosis is an exciting discovery for the entire field of oncology, and particularly for scientists studying cell death processes. It’s incredibly gratifying.”