Coming up against such attitudes, Davis had trouble finding a journal willing to publish his early papers. Editors feared they would be opening the doors to ridicule about the MTV generation taking over scientific research. “The convention was that videos were more about entertainment than information,” he says. “It was almost impossible to persuade people that video can have much more information than a still image.” Soon, though, as new knowledge began emerging from video microscopy, the same editors were clamoring for him to submit more video-based papers.

Now, those dramatic images have shown that the immune system is far more dynamic and actively choreographed than previous static-image studies had led scientists to believe. Davis and others are zooming in on that activity in molecular detail. Until moving images showed them otherwise, most biologists thought that the signaling process leading to an immune response required hours or even days of continuous communication between T lymphocytes and antigen-presenting cells (the cells that engulf cells infected with viruses and, through communication with T cells, initiate the process that will kill the virus).

		View Full Image T CELLS In a recent finding, researchers in Mark Davis's lab learned that a T cell can detect a single molecule of a foreign antigen ligand on another cell. In this captured still frame, a single ligand molecule (red) is visible at the interface of a T cell (blue and green) and an antigen-presenting B cell. Image: Courtesy of Darrell Irvine/Davis lab

Video microscopy revealed, instead, that these two fundamental immune-system components engage in a day-long minuet beginning with multiple short contacts. Each lasts only a few minutes, yet these fleeting encounters prove sufficient to activate the T cells. “Few people anticipated the enormous rapidity with which cells move,” says Ulrich H. von Andrian, an immunologist at the CBR Institute for Biomedical Research, an affiliate of Harvard Medical School, and a leader in the use of video microscopy.

Many unstable cellular structures collapse when they are prepared for static observation. As a result, says von Andrian, static studies may have given scientists a false conception of living immune system mechanics. Studying the immune system in its natural state, he says, “provides an essential reality check for determining which phenomena are different in living animals and not faithfully reproducible” statically. Davis agrees: “It's like seeing an animal in its natural environment, rather than in a zoo. It's really important to see where they are and how they behave in different stages of their lives in their native habitat.”

Nearly all real-time knowledge of the immune system comes from studying T cells circulating in the blood. Yet, while a T cell typically spends only about 30 minutes in the bloodstream, it might spend hours or even days migrating through other organs, querying cells for antigens. Because “there is no evidence out there for what goes on inside an organ,” says Dan R. Littman, an HHMI investigator at the New York University (NYU) Medical Center, only a small fraction of the life of the lymphocyte has ever been observed. He and others have begun to open up that hidden life.

In his laboratory, Littman, in collaboration with Michael Dustin at the Skirball Institute of NYU, uses IVM in mice to observe the living immune system within organs that are accessible by surgical procedures. He started with the liver, where natural killer T (NKT) cells, the immune system's sentinels against virus-infected cells, have long been known to concentrate. Scientists had observed NKT cells in the bloodstream, but little was known about how they functioned within the complex stew of nutrients, toxins, lipids, and other chemicals trapped in the labyrinth of microscopic vesicles that pervade the liver. By opening a flap in the membrane covering the organ, the researchers could deploy IVM to observe and record fluorescently labeled NKT cells going about their business.

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