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The Biological Art of Organ Sculpture

Andy Ewald studies the cellular teamwork that fashions the mammary gland

March 2009 -- A kidney is not a bladder is not a breast. But how do kidney cells form a bean-shaped organ while bladder cells build a balloon-like structure and breast cells sculpt a lobe? What governs the architectural process that molds tissues out of cells, and organs out of tissues?

Biologists have pondered such questions for centuries, says Andy Ewald, an assistant professor who joined the Department of Cell Biology and the Center for Cell Dynamics in August 2008. But only in the past decade or so have they had the tools to observe these events as they occur—literally to watch a tissue form or an organ take shape. “What’s exciting right now,” says Ewald, “is that we have imaging and molecular tools to watch and tease apart how different cell types, in response to different molecules, build a tissue.”

Ewald is using such tools to study the morphology of the mammary gland, using the mouse as a model system. He chose that organ because much of its development occurs after birth, specifically in puberty, when hormones induce a rudimentary network of ducts to grow and elaborate into branches, a process called branching morphogenesis.

His ultimate goal is to understand the abnormal morphology and molecular biology that drive cancerous growth in mammary tissue. First, however, says Ewald, “we need a detailed understanding of what is normal.”

“I think the impact of Andy’s work is going to be really enormous,” says Denise Montell, director of the IBBS Center for Cell Dynamics. “He is right at the interface of basic and translational research. This is a really exciting opportunity to build a bridge between the two, and Andy is the perfect person to do this.”

Ewald grows mouse mammary epithelium in organotypic culture, which preserves the tissue’s three-dimensional structure. He then records the tissue’s morphology using a CCD camera and a bright-field microscope or a spinning disk confocal microscope.

One day in his office, Ewald calls up on his computer screen a movie of mammary morphogenesis, a film he recorded while completing a postdoc in Zena Werb’s lab at UCSF. An oblong gray blob appears; it is a segment of cultured epithelial tissue called an organoid. As the film continues, small budlike structures sprout from the organoid and grow outward like branches on a tree. The entire process took 115 hours to record; thankfully for time-lapse cinematography, the film races by in less than a minute.

That’s a large-scale view of branching morphogenesis, says Ewald. Most of his films peer even closer. “We want to get a cell’s eye-view,” he says, specifically, to see what different cells do at each stage of morphogenesis. “As in NFL football, there’s not just one player on the field. It's a team effort, so we’re trying to break it down into a discrete series of steps.”

One question Ewald has explored is what causes duct elongation. A prominent hypothesis holds that cells at the front edge of the emerging duct use actin fibers, or protrusions, to pull toward the direction of growth, the way a climber uses a rope and grappling hook. Scientists have recorded many instances of cells using such a mechanism, says Ewald, and he fully expected to see it in his cultures. However, much to his surprise, he saw no evidence of actin protrusions.

Instead, he explains, the action takes place within the elongating duct. Just before elongation, cells proliferate rapidly, and the epithelium changes from a bilayered to a multilayered structure. Then, a duct begins to emerge.

Ewald calls up another movie to show what happens next. The film zooms in on the tips of extending ducts. Fluorescent staining distinguishes two types of epithelial cells: Red fluorescence marks the luminal cells, which initially border the inner hollow cavity of the organoid; and green fluorescence identifies a second cell type, myoepithelial cells.

As the movie rolls, the red and green cells careen around like bumper cars. They appear to move in a wild frenzy. But Ewald hypothesizes that there is order to this chaos. He suspects that the myoepithelial cells are programmed to constrain the otherwise unbridled growth of the luminal cells. Imagine squeezing a semi-inflated balloon with your hand, suggests Ewald. Portions of the balloon squish out from the spaces between your fingers. In this analogy, the balloon represents proliferating luminal cells, and your fingers represent the restraining myoepithelial cells. The system illustrates a balance of growth and constraint.

Cancer, of course, involves unfettered growth. As he continues these studies, Ewald plans to test the hypothesis that cancer occurs when a normal phase of growth occurs at the wrong time or in the wrong place. 

–Melissa Hendricks

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