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2009

New Technologies Allow Scientists to Watch Cells in Motion
The New York Times, June 9, 2009
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It’s easy to imagine the cells in our bodies like bricks in a house, all cemented into place. But we are actually seething with cells that creep, crawl, and squirm. They start wandering soon after conception, and, throughout our lives, our bodies continue to hum with cellular traffic.

Some cells burrow into old bone so that new bone can be laid down in their wake. The tips of new blood vessels snake forward, dragging the cells behind along with them. White blood cells race along on flickering lobes to chase down bacteria before they can make us sick.

The fact that cells can move is old news. How they move is just now being understood. In the mid-1600s, Antonie van Leeuwenhoek built one of the first microscopes and observed single-cell organisms making what he called “pleasing and nimble” movements. But he had no idea what was going on inside those cells, and three centuries later, scientists were still baffled.

Thomas Pollard, a biochemist at Yale, started studying crawling cells in the 1960s, when, he said, “Exactly zero was known.” Today Dr. Pollard and his colleagues have identified many of the key proteins that work together to let cells navigate through our bodies. Scientists can even see some of these proteins at work in living cells and measure their forces.

“My dream was always to be a little gremlin, to get inside the cell and watch all this stuff,” Dr. Pollard said. “This is almost like being a little gremlin.

“We’ve gone from a black box to chemistry and physics.”

One of the chief reasons for these advances is the technology that scientists can now use to watch cells in motion. When developmental biologists first began to study how embryos grow, for example, they could only look at different stages under a microscope.

Today, they make high-resolution videos of embryos and track the movement of thousands of cells -- videos that overturn some traditional ideas.

“There’s tremendously more migration than we thought,” said Scott Fraser, the director of the Biological Imaging Institute at Caltech.

To undertake the migrations that form an organism from an embryo, cells need to know where to go. An embryo is awash in signals that can guide them. Different kinds of cells respond to different signals. Cells that will give rise to skin, blood vessel walls and other linings of the body -- epithelial cells -- are attracted to a signaling protein called epidermal growth factor. Released by white blood cells in the embryo, this protein draws the cells crawling toward their source.

Eventually they stop traveling and form organs. But decades later they can still be roused to move again. As white blood cells wander through the skin, they may encounter a cut. They respond by releasing epidermal growth factor, summoning epithelial cells to help heal the wound. “They’re like traffic cops,” said John Condeelis, a biologist at Albert Einstein College of Medicine.

When a cell starts to move, it has to reorganize its interior. The inside of a cell is not a simple sack of jelly; it is stiffened by a network of wirelike molecules. At the core of the cell is a cluster of pipes called microtubules. Around the edges of the cell are thin filaments made of a molecule called actin.

In the late 1990s, Clare Waterman, a cell biologist, and her colleagues developed a way to capture this skeleton in motion. They would put glowing actin molecules in a cell, which would sometimes add them to its filaments. “It’s as if you were a bricklayer, and 99 percent of your bricks were gray and one percent were red,” said Dr. Waterman, who is now at the National Heart, Lung and Blood Institute at the National Institutes of Health.

Dr. Waterman and her colleagues at the University of North Carolina then took pictures of cells every few seconds to track the glowing molecules. They discovered that the filaments are in constant flux, even when the cell is not moving.

A stationary cell adds hundreds of new actin molecules each second to the outer end of each filament. At the same time, contracting proteins called myosins pull on the actin filament at the other end, as other proteins cut up the actin molecules. All of those reactions cause the actin molecules in a filament to move from the outer edge of the cell inward, as if they are on a treadmill.

A cell has to use a lot of energy to build and destroy the filaments. But its treadmilling is valuable because it allows a cell to respond quickly to signals by moving into motion. “It’s like a car,” Dr. Waterman said. “When you come to a stop light, you keep the engine running.”

To start crawling, a cell starts to build the leading edge of filaments faster than they tear down the back end. Other proteins help the actin filaments join into a branching network. The surface of the cell bulges out into a lobe. As the lobe stretches out from a cell, it grabs onto the underlying surface with molecular clamps. The clamps become joined to the growing actin filaments and drag the cell forward.

To further understand the process scientists at Yale have invented a new technique. “We basically play a tug of war,” said Eric Dufresne, a physicist. Dr. Dufresne and his colleagues implant beads on the tip of a neuron. The cell links the beads to filaments, and the beads move down the actin treadmills.

Dr. Dufresne and his colleagues then train lasers on the beads and use the energy of the beams to trap them. As the cells pull on the beads, the lasers pull back. The pull of the lasers lets the scientists measure the forces generated by many filaments at once.

A cell will tug at each bead, the scientists have found, for ten seconds or so before releasing it. A few minutes later, it will try to tug again. Dr. Dufresne suspects that the cells are continually testing their surroundings for good places to lay an anchor. As an advancing lobe drags a cell forward, the same signals trigger drastic changes in the rest of the cell. “It’s like squeezing a tube of toothpaste -- everything get pushed to the front,” said Alan Hall, chair of the cell biology program at Memorial Sloan-Kettering Cancer Center.

The timing of these changes is carefully choreographed, as Dr. Waterman and her colleagues demonstrate in a paper to be published in Molecular Biology of the Cell. They found that skin cells called keratinocytes respond in several ways to epidermal growth factor. It causes keratinocytes to push out a lobe and make the lobe’s clamps stronger. At the same time, the pulse of growth factor also starts chemical reactions that loosen the same clamps after about 10 minutes. That’s amount of time it takes for the slow-moving keratinoctyes to roll over them. This intricate choreography is essential to our well-being. Immune cells have to chase down pathogens, for example. To form a brain, neurons sprout over a million miles of branches, and every time we learn new things, they sprout new ones.

But there are also times when cells move when they shouldn’t. When cancers become metastatic, some cells creep out of a tumor and make their way to other parts of the body.

To understand how cancer cells move, Dr. Condeelis and his colleagues have developed a microscope through which they can peer at tumors in living mice. The mice can be genetically engineered so that the cancer cells glow, allowing Dr. Condeelis and his colleagues to watch the cells creep out of their tumors.

In studies on mammary gland tumors, Dr. Condeelis and his colleagues have discovered that metastatic cancer cells are guided by the familiar signaling protein, epidermal growth factor, or E.G.F., produced by immune cells in nearby blood vessels.

Dr. Condeelis took advantage of this discovery to build a trap for cancer cells. He coated a plastic tube with E.G.F. and inserted it in a mouse mammary gland. The crawling cancer cells were drawn to the tube like flies to honey, and Dr. Condeelis and his colleagues removed the tube with the mobile cancer cells inside. They could then identify the genes that became active when cancer cells start crawling. The scientists found nothing peculiar about the cells. They were using the same genes to move as epithelial cells use in an embryo.

These results and others have led Dr. Condeelis to a surprising hypothesis about metatstatic breast cancer. “The cancer cells think they’re making another breast,” he said.

Dr. Condeelis argues that the peculiar environment inside a tumor fools some of the cells into thinking they’re inside an embryo. The cells release signals that attract white blood cells, which, in turn, release the growth factor that causes the cells to start moving.

But the cues that work in an embryo send cancer cells astray in an adult breast, and they end up in blood vessels, where they are carried away to other parts of the body.

Scientists have found that they can treat some diseases by interfering with the ability of cells to move when they shouldn’t. An eye disease called macular degeneration causes blood vessels to spread out too much over the retina. Drugs are now available that can block the cells in the blood vessels from getting the signals that trigger them to start crawling.

As scientists probe the inner workings of crawling cells, they’re looking for other ways to fight diseases. “The biggest thing is cancer therapy,” said Dr. Waterman.

It’s easy enough to imagine treating cancer by stopping cancer cells in their tracks, but many experts say it will be challenging to zero in on them without interfering with the crawling of normal cells. And without cells that can move, we cannot survive.

“We’re dealing with fundamental, universal stuff,” Dr. Pollard said.

Copyright 2009 The New York Times Company. Reprinted with permission.
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