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Testing Ground

A native of South Africa who spent five years under house arrest for actively opposing apartheid, Aderem grows animated as he leads a tour of the institute’s 6,000-square-meter lab complex, thrilling as much to the scientists themselves as to the facility’s wealth of new equipment. In his baggy shorts, he looks like a safari guide as he points out a man and woman together at a microscope. “She’s a cardiologist working with a physicist,” he says. Aderem’s lab also includes a mathematician and an engineer, in addition to the more usual assortment of biology and medical specialists. “My job is to integrate everybody,” he says.

This integration of different scientific perspectives and different types of data is key to puzzling out the complexity of a network like the immune system, which is responsible for the body’s exquisitely orchestrated response to microbial attack. And even with a diverse team in place, Aderem is starting with a small part of the puzzle: the various cells that make up the so-called innate immune system, the body’s first line of defense. Innate immune cells are somewhat dimwitted; they have no memory and have trouble making fine distinctions between microbes. (In contrast, the acquired immune system, which includes antibodies and more troops of cells, remembers how to recognize and destroy every invader it meets.) But the innate system plays an essential role in keeping people healthy by destroying some intruders and by shuttling others to the acquired immune system.

Because it is a relatively simple network, innate immunity makes an excellent testing ground for systems biology. In January 2003, the National Institute of Allergy and Infectious Diseases awarded a $24 million grant to the Institute for Systems Biology, Rockefeller University, and the Scripps Research Institute in La Jolla, CA, to create an “encyclopedia” of the innate immune system. Using the tools of systems biology, the researchers have started to catalogue precisely how the network reacts to microbial attack, exploring specific biochemical pathways and behaviors of genes and proteins. Compared to acquired immunity, “the players are much more well defined in innate immunity. And it will be possible to ask how important they are in the various pathways,” says Richard Ulevitch, chair of immunology at the Scripps Research Institute and head of the encyclopedia project. Aderem, for instance, has long focused on one particular innate immune player, a type of white blood cell called a macrophage. “The macrophage really opens up a whole window” on systems biology, Hood says.

An early test of the macrophage-centric approach came after an unlikely event: death at a Dutch flower show. In February 1999, an annual flower show in the Netherlands attracted 77,061 visitors. Of these, 178 developed Legionnaire’s disease, as did 10 exhibitors. Caused by a bacterium, Legionnaire’s disease leads to severe pneumonia, which in this outbreak killed 21 people. Dutch scientists quickly identified the likely source of the infection: a contaminated whirlpool spa on exhibit. But the outbreak raised a question that Aderem and his team thought they could help answer: why had these 188 people developed severe cases of Legionnaire’s disease, while others who paused at the whirlpool exhibit had not? Aderem was certain it was not simply bad luck.

When a bug like Legionella pneumophila infects a person, the cellular sentinels of the innate immune system sample it and carry off pieces of it to alert the acquired immune system. That sounds simple enough, but it’s actually an intricate, tangled drama that cries out for a systems biology approach. It turns out, for instance, that innate immune cells aren’t quite as mindless as was once thought. Proteins called toll-like receptors, which stud the surfaces of macrophages, allow them to detect, at least on a crude level, differences between microbes. Since the discovery of the first toll-like receptor in 1997, Aderem’s group has played a major role in describing how macrophages use the molecules to distinguish a virus from, say, a bacterium. “There’s a bar code on the membranes of microbes that the toll-like receptors can read,” says Aderem. Thanks to these bar codes, different microbes prod different toll-like receptors into action, which in turn triggers different biochemical cascades that can activate or suppress genes, cause or prevent inflammation, and steer the eventual response by the acquired immune system. If that seems complex, factor in that researchers have so far found 10 different toll-like receptors, and that the proteins work in concert. For example, three different receptors together recognize the category of bacteria that includes Legionella pneumophila.

Aderem’s lab at the institute began its study of the Legionnaire’s outbreak by hunting through thousands of blood samples to find mutated versions of one of the receptors. The task required sorting through millions of blood cells to pluck out minute variations in the billions of DNA letters that make up each person’s genome. To aid in this search, the team turned to a myriad of souped-up lab machines, many modified in-house to more quickly collect the massive amounts of data that a systems-level approach requires. Cell-sorting machines, for example, typically deposit cells on plastic plates that have 96 wells each. But the institute’s sorter operates so quickly that the researchers devised a new contraption to collect the cells: a long strip of wells that spools continuously off of a reel and through the sorter.

In all, the researchers found four mutations of the targeted receptor. They then studied the DNA of people who had stopped at the contaminated whirlpool-both those who got sick and those who did not. “This was a blessed study, because we had the controls,” says Aderem. Using more high-throughput tools, they hunted through the DNA samples for the mutations they had earlier identified. By comparing the gene patterns of the people who developed Legionnaire’s disease and the healthy controls, they discovered that a mutant version of the receptor tripled a person’s risk of getting sick. The speed with which the researchers were able to make the discovery illustrates the power of the Institute for Systems Biology’s strategy. “If I had been in a genetics lab where everything was set up, I assume it would have taken many months, if not years,” says Aderem. “Here, it took not more than one week.” And in uncovering the mutation and linking it to a heightened risk of contracting Legionnaire’s disease, they had taken a small but important step toward understanding how individual receptors and other molecules interact within the innate immune system to dramatically affect human health.

Working with pediatrician David Speert of the University of British Columbia in Vancouver, Aderem and his team hope to expand that understanding. Speert is investigating several more “experiments of nature” similar to the Netherlands flower show, with the aim of explaining how innate immunity can determine whether children get sick from infections such as tuberculosis and E. coli. “With every infectious disease, most people who are exposed do not become sick,” says Speert. “We’re trying to figure out what’s different about the small percentage who get sick.” Young children provide an interesting study population, he notes, because they often have not seen a particular infectious agent before and have no acquired immunity to confuse analyses of the innate system. For similar reasons, the young have the most to gain from new therapies, and unraveling how harmful microbes interact with the innate immune system could speed the development of new antimicrobial drugs and vaccines.

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