IN 1995, WHILE he was a graduate student at McGill University in Montreal, the biomedical scientist Peter Friedlsaw something so startling it kept him awake for several nights. Coordinated groups of cancer cells he was growing in his adviser’s lab started moving through a network of fibers meant to mimic the spaces between cells in the human body.
For more than a century, scientists had known that individual cancer cells can metastasize, leaving a tumor and migrating through the bloodstream and lymph system to distant parts of the body. But no one had seen what Friedl had caught in his microscope: a phalanx of cancer cells moving as one. It was so new and strange that at first he had trouble getting it published. “It was rejected because the relevance [to metastasis] wasn’t clear,” he said. Friedl and his co-authors eventuallypublished a short paper in the journalCancer Research.
Two decades later, biologists have become increasingly convinced that mobile clusters of tumor cells, though rarer than individual circulating cells, are seeding many—perhaps most—of the deadly metastatic invasions that cause 90 percent of all cancer deaths. But it wasn’t until 2013 that Friedl, now at Radboud University in the Netherlands, really felt that he understood what he and his colleagues were seeing. Things finally fell into place for him when he read a paper byJeffrey Fredberg, a professor of bioengineering and physiology at Harvard University, which proposed that cells could be “jammed”—packed together so tightly that they become a unit, like coffee beans stuck in a hopper.
Fredberg’s research focused on lung cells, but Friedl thought his own migrating cancer cells might also be jammed. “I realized we had exactly the same thing, in 3-D and in motion,” he said. “That got me very excited, because it was an available concept that we could directly put onto our finding.” He soon published one of the first papers applying the concept of jamming to experimental measurements of cancer cells.
Physicists have long provided doctors with tumor-fighting tools such as radiation and proton beams. But only recently has anyone seriously considered the notion that purely physical concepts might help us understand the basic biology of one of the world’s deadliest phenomena. In the past few years, physicists studying metastasis have generated surprisingly precise predictions of cell behavior. Though it’s early days, proponents are optimistic that phase transitions such as jamming will play an increasingly important role in the fight against cancer. “Certainly in the physics community there’s momentum,” Fredberg said. “If the physicists are on board with it, the biologists are going to have to. Cells obey the rules of physics—there’s no choice.”
The Jam Index
In the broadest sense, physical principles have been applied to cancer since long before physics existed as a discipline. The ancient Greek physician Hippocrates gave cancer its name when he referred to it as a “crab,” comparing the shape of a tumor and its surrounding veins to a carapace and legs.
But those solid tumors do not kill more than 8 million peopleannually. Once tumor cells strike out on their own and metastasize to new sites in the body, drugs and other therapies rarely do more than prolong a patient’s life for a few years.
Biologists often view cancer primarily as a genetic program gone wrong, with mutations and epigenetic changes producing cells that don’t behave the way they should: Genes associated with cell division and growth may be turned up, and genes for programmed cell death may be turned down. To a small but growing number of physicists, however, the shape-shifting and behavior changes in cancer cells evoke not an errant genetic program but a phase transition.
The phase transition—a change in a material’s internal organization between ordered and disordered states—is a bedrock concept in physics. Anyone who has watched ice melt or water boil has witnessed a phase transition. Physicists have also identified such transitions in magnets, crystals, flocking birds and even cells (and cellular components) placed in artificial environments.
But compared to a homogeneous material like water or a magnet—or even a collection of identical cells in a dish—cancer is a hot mess. Cancers vary widely depending on the individual and the organ they develop in. Even a single tumor comprises a mind-boggling jumble of cells with different shapes, sizes and protein compositions. Such complexities can make biologists wary of a general theoretical framework. But they don’t daunt physicists. “Biologists are more trained to look at complexity and differences,” said the physicist Krastan Blagoev, who directs a National Science Foundation program that funds work on theoretical physics in living systems. “Physicists try to look at what’s common and extract behaviors from the commonness.”
In a demonstration of this approach, the physicists Andrea Liu, now of the University of Pennsylvania, and Sidney Nagelof the University of Chicago published a brief commentary inNature in 1998 about the process of jamming. They described familiar examples: traffic jams, piles of sand, and coffee beans stuck together in a grocery-store hopper. These are all individual items held together by an external force so that they resemble a solid. Liu and Nagel put forward the provocative suggestion that jamming could be a previously unrecognized phase transition, a notion that physicists, after more than a decade of debate, have now accepted.
Though not the first mention of jamming in the scientific literature, Liu and Nagel’s paper set off what Fredberg calls “a deluge” among physicists. (The paper has been cited more than 1,400 times.) Fredberg realized that cells in lung tissue, which he had spent much of his career studying, are closely packed in a similar way to coffee beans and sand. In 2009 he and colleagues published the first paper suggesting that jamming could hold cells in tissues in place, and that an unjamming transition could mobilize some of those cells, a possibility that could have implications for asthma and other diseases.
source: wired.com by