Of cells that creep and crawl

Cellular Biology

It’s easy to imagine the cells in our bodies like bricks in a house, cemented into place. But we are actually seething with cells that creep, crawl, and squirm. They start wandering soon after conception, and 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.

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.

Thomas Pollard, a biochemist at Yale, started studying crawling cells in the 1960s. Today, he and his colleagues have identified many of the key proteins that work together to let cells navigate through our bodies.

“My dream was always to be a little gremlin,  to get inside the cell and watch all this stuff,” Pollard said. “This is almost like being a little gremlin. We’ve gone from a black box to chemistry and physics.”

High-res videos to observe embryos

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 travelling 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 reorganise its interior. The inside of a cell is not a simple sack of jelly; it is stiffened by a network of wire-like 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 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 per cent of your bricks were gray and one percent were red,” said Waterman, who is at the National Heart, Lung and Blood Institute at the National Institutes of Health.

Waterman and her colleagues 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 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.

How does the cell start moving?

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 join the growing actin filaments and drag the cell forward.

“We basically play a tug of war,” said Eric Dufresne, a physicist. 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.

They 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 lets the scientists measure the forces generated by many filaments at once.

A cell will tug at each bead for ten seconds or so before releasing it. A few minutes later, it will try to tug again. Dufresne suspects that the cells are continually testing their surroundings for good places to lay an anchor. The timing of these changes is choreographed, as 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 the amount of time it takes for the slow-moving keratinoctyes to roll over them.

Vital for our well-being

This 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.

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 Waterman.