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2008

The More We Know About Genes, the Less We Understand
Wired.com Dissection column, April 18, 2008
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In life, one mystery gives way, revealing a new one underneath, waiting to be solved.

An early mystery was genes. Scientists did not know what hidden factor lurked inside living things, giving rise to their traits and traveling from parent to child to recreate those traits anew.

The answer, of course, turned out to be DNA: Segments of the molecule encode the proteins and RNA molecules that carry out the work of life, send signals, capture energy and build biomass.

But it quickly became clear that just having genes was not the full secret of life. The genes need to become active at the right time and place. Think about it: Each one of your cells contains genes that can produce hair and toenails, and can crank out neurotransmitters and digestive enzymes. If all your genes did churn away, your body would become a hideous, useless jumble. Our life depends on the courteous restraint of our genes.

In the late 1950s, French scientists discovered how genes are restrained. They wanted to know why the microbe E. coli sometimes made enzymes for feeding on lactose (the sugar in milk), and why sometimes it didn't. The scientists demonstrated that E. coli uses three genes to feed on lactose, and all three are lined up next to each other in the microbe's DNA. They also discovered that the three genes can all be shut down at once. A special protein latches onto a distinctive bit of DNA near the genes, blocking the molecules that would read their genetic recipes. If the repressing protein is pried away, the genes switch on.

All living things, ourselves included, turn genes on and off in a similar way, by making switch-like proteins called transcription factors. And as scientists have identified more of these, they've discovered something remarkable: They form a chain of command. The job of some transcription factors is to switch others on and off, and they in turn are controlled by other transcription factors. Even a seemingly simple microbe like E. coli has an impressive hierarchy. Just nine genes rule over about half of the 4,000-odd genes in E. coli.

E. coli's network allows it to respond quickly to the challenges it meets, from starvation to heat to the loss of oxygen. It can rapidly reorganize itself, switching on hundreds of genes and switching off hundreds of others. What makes this network all the more impressive are the feedback loops that keep it from spinning out of control. When one gene switches on, for example, it may make a protein that shuts down the gene that switched it on in the first place.

Yet even as scientists uncover this network, they discover yet another mystery. In the latest issue of Nature, scientists reported an experiment in which they wreaked havoc with E. coli's network. They randomly added new links between the transcription factors at the top of the microbe's hierarchy. Now a transcription factor could turn on another one that it never had before. The scientists randomly rewired the network in 598 different ways and then stepped back to see what happened to the bacteria.

You might expect that they all died. After all, if you were to pop open the back of an iPod and start linking its components together in random ways, you'd expect it to crash. But that's not what happened.

About 95 percent of the rewired bacteria did just fine with their new networks. They went on with their lives, feeding, growing and dividing. Some even performed better than microbes with the original wiring, under some conditions.

The tolerance these bacteria showed reveals something important about how evolution works. Humans can randomly rewire cells, and so can mutations. There's something about gene networks that allow them to thrive despite these mutations, and, in some cases, to even gain an edge in the evolutionary race.

But scientists don't quite know why a network like the one in E. coli can handle this rewiring so well. The source of their strength lies not in a single molecule -- DNA -- but in a complicated web of relationships. The network itself is the mystery for biologists in the 21st century.

Copyright 2008 Carl Zimmer
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