Cells act like tiny computers, and finally, scientists are figuring out what makes their genetic circuits blink on and off.

Like ENIAC troubleshooters of old, biologists reverse-engineered the way that an immune cell's genetic network recognizes invading diseases by turning off its circuits one by one.

"It's the cell as computer. You tweak the things inside, tweak them outside, and see what happens," said Nir Hacohen, an immunologist at Massachusetts General Hospital and co-author of the new study, published Thursday in Science. "In a computer, if you came with a voltage meter and there were 17 parts to a circuit, you'd cut the parts one by one, and see how the others lit up."

The network could help researchers better understand how the immune system functions, but the approach could be used to investigate the workings of any set of genes working in concert.

Researchers have long had difficulty making sense of the complicated choreography of genetic activity in living cells. One gene might call for a protein that triggers two other genes to call for proteins, which in turn trigger even more genes — and on and on, for hundreds or thousands of genes.

Thousands of such networks guide every cellular function, but have been largely impenetrable in complex mammalian cells. Researchers have been left with lists of genes relevant to disease or development, but little idea of what they actually do.

"At the level we're trying to understand them, almost no network is understood," said Aviv Regev, a Broad Institute cell biologist and co-author of the Science paper.

To make sense of their network, Regev and her colleagues used a pair of biotechnological tricks. The first was RNA interference, in which single-stranded DNA snippets are used to turn genes on and off. The other was fluorescent DNA probes that change color when exposed to the protein products of active genes.

After exposing immune system-calibrating cells, called dendritic cells, to E. coli bacteria and viruses, the researchers identified several hundred genes that appeared central to immune function. Then they used RNA interference to turn the genes off one by one, at each step measuring the effect on other genes as the cells were exposed to pathogens.

In the new study, the researchers describe how different parts of the network are involved in recognizing different pathogens. About 100 genes appear to be "central regulators," modulating the activity of dozens of other genes. Some of these were not previously implicated in immune function. One gene, called Timeless and known almost entirely for its role in circadian rhythm maintenance, affected 200 other genes.

"It's an excellent example of using systematic perturbation to reveal an underlying regulatory network," said Trey Ideker, a University of California, San Diego geneticist who was not involved in the study. "Mammals are the ultimate target from a human health standpoint, but systematic network mapping approaches have been more difficult to implement" in their cells.

In future experiments, the researchers plan to turn off more than one gene at once, and to measure activities in cell cultures that contain more than one type of immune cell. Ultimately they hope this will provide drug developers with better targets, or even lead to diagnostic tests of a patient's cell networks.

But the researchers say the study's most important part isn't the immune system findings, but the approach they used.

"We've been able to measure the expression of each gene in a cell for more than a decade now, but figuring out what contols that expression has proved much more challenging," said Hacohen. "You can do this for any biological process."

Citation: "Unbiased reconstruction of a mammalian transcriptional network mediating the differential response to pathogens." By Ido Amit, Manuel Garber, Nicolas Chevrier, Ana Paula Leite, Yoni Donner,Thomas Eisenhaure, Mitchell Guttman, Jennifer K. Grenier, Weibo Li, Or Zuk, Lisa A. Schubert, Brian Birditt, Tal Shay, Alon Goren, Xiaolan Zhang, Zachary Smith, Raquel Deering, Rebecca C. McDonald, Moran Cabili, Bradley E Bernstein, John L. Rinn, Alex Meissner, David E. Root, Nir Hacohen, Aviv Regev. Science, Vol. 325 No. 5945, September 3, 2009.

Image: Science

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