On the northwest corner of the Salk Institute campus, the history of cancer research has just been altered. There’s no magic pill or vaccine yet, but a major assumption about the disease — which kills around 9 million people a year worldwide — has just been proven false.
Salk’s Molecular and Cell Biology Lab is a maze of hallways lined with shelves of gadgets, beakers and busy workers. In a small corner office, a 50-year-old man with a thick Austrian accent greeted the Light a week after his potentially history-changing discovery was published in the journal Nature.
Jan Karlseder was asked to explain the implications of his findings. First, though, Karlseder — who grew up in a small village outside Innsbruck and moved to San Diego in 2002 — reported the results of a less-scientific survey. He conducted this one among his colleagues.
“The number of times I’ve been asked to say I’ll be back is very high,” Karlseder said, breaking the ice with an Arnold Schwarzenegger reference. “I’ve been told our accents are very similar.”
Karlseder’s lab studies telomeres, which protect the ends of chromosomes when a cell divides — not unlike plastic tips protect the ends of shoelaces.
“Sometimes I don’t like the analogy,” Karlseder said, “but it works.”
How cancer happens
Each time an animal cell divides, according to Karlseder, its telomeres shorten slightly — a process similar to copy-machine degradation. Once the telomeres become too short to protect exposed chromosomes, the cell receives a signal to stop dividing permanently. However, due to viruses or other cancer-causing conditions, some cells don’t get the message and keep dividing.
Firing up his Echo Laboratories digital microscope to illustrate, Karlseder pointed to a plate of human fibroblast (connective-tissue) cells with short and missing telomeres. The damage automatically places them in a scientific state called crisis, in which their unprotected chromosomes can fuse and become dysfunctional. Cancerous tumors grow when these cells keep dividing.
What Karlseder’s team discovered is that autophagy — a recycling process in which a cell eats itself — is the main way that cells in crisis normally die before becoming a cancer danger. By shutting down this process in human fibroblast and epithelial (surface) cells forced into crisis mode, the team watched all grow almost immediately into cancer.
“These results were a complete surprise,” Karlseder said. “There are many checkpoints that prevent cells from dividing out of control and becoming cancerous, but we did not expect autophagy to be one of them.”
The a-ha moment was actually experienced by Joe Nassour, Karlseder’s postdoctoral fellow and the paper's first author.
“I remember seeing the first few western blots that I got and thinking that this was something very interesting,” said Nassour, who joined the lab three years ago and sits at a station right outside Karlseder’s office.
Karlseder’s team quickly realized that switching autophagy back on, for cells that are in crisis, would be a novel way to prevent cancer in the first place. But the more immediate implication was that currently prescribed autophagy-inhibiting cancer drugs may actually promote cancer in the earliest stages of the disease.
Previously, autophagy was thought to be a mechanism that only fueled cancer, helping it cannibalize healthy cells and recycle their raw materials. Indeed, some cancer cells are dependent upon autophagy — in later stages of their existence.
“It is an interesting conundrum,” Karlseder said. “I think it points at an interesting future research direction for us, where we try to understand why autophagy is first required to prevent cells from becoming cancer cells, and then it becomes a life-support mechanism.”
Previously, animal cells in crisis were thought to die exclusively from a process called apoptosis (basically, shriveling up and dying). Karlseder knows this incorrect theory well. He published a paper describing it in 1999, while he worked at New York’s Rockefeller University.
“It was actually correct at the time,” Karlseder said, “because autophagy was not known then.”
Karlseder’s team is now working diligently to discover how autophagy can switch from a tumor-suppressive mechanism to a tumor-promoting one.
“The more we understand the intricacies of different pathways, the better we can target only specific cancer cells,” Karlseder said. “The problem with most chemotherapies is that they simply kill every cell that divides. Therefore, they have horrible side effects.”
It’s impossible to force a time frame on a cancer target that incorporates this new breakthrough, Karlseder said. But researchers are now one major step closer. And, if Karlseder has his way, his lab will have an even bigger hand in developing such a target than it already has.
In other words, he’ll be back.