Diligent work yields the first branching diagram of the developing lung, a model that sets the stage for studying other branched organs.

The thick scroll is made of 29 pieces of paper taped end to end. As HHMI investigator Mark Krasnow unrolls it in his office at Stanford University, an elaborate diagram looking something like a family tree reveals itself. But instead of chronicling births and deaths, marriages and children, it traces the lineage of thousands of branches of the mouse lung during its early development.

This scroll—“our Torah of the lung,” he calls it—represents the culmination of nearly a decade of painstaking work by Ross Metzger, a faculty fellow at the University of California, San Francisco, and a former student of Krasnow's. Armed with a fluorescence dissecting microscope and a lot of patience, Metzger examined hundreds of mouse embryo lungs at different stages of development to place them on a timeline.

“This is the first time anybody has constructed a branch lineage diagram of any organ in any animal,” Krasnow says. The branching turned out to be stereotyped—that is, it follows a consistent, reproducible pattern. The model sets the stage for studying the development of other branched organs—the vascular system, kidneys, mammary glands—to learn if they also develop in a stereotyped way.

The finding settles a question that has perplexed scientists for at least a century. The branching in the lung seemed so complicated that some argued that it is a random process. Others believed that it follows mathematical rules, with branches simply splitting off from earlier ones in a repeated fashion, into ever smaller airways, creating geometrical patterns. The end of the process produces millions of tiny pockets called alveoli that allow gases to be exchanged with the blood.

Krasnow, whose lab had mapped the fruit fly tracheal system in detail over a decade ago, decided that the best way to answer the question was to map the mouse lung. Metzger might appear to have been an unusual pick for this daunting task: a philosophy major in college, he had no science background when he started working in Krasnow's lab nine years ago. He had enrolled at Stanford Medical School intending to pursue a career in psychiatry and approached Krasnow about gaining some lab experience.

Illustration: Jacob Magraw-Mickelson

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