When Scientists Published The First

genome of E. coli in 1997, they titled it "The Complete Genome Sequence of E. coli K-12." Strictly speaking, the title was a piece of false advertising. Nowhere in the paper can you find the raw sequence of 4,639,221 bases. The omission was simply a matter of space: E. coli K-12's genome would fill about a thousand journal pages. Those who crave a direct confrontation with its genetic code must visit the Internet.

One of the sites that houses its code is the Encyclopedia of Escherichia coli K-12 Genes and Metabolism, EcoCyc for short. EcoCyc displays the K-12 genome as a horizontal line stretching across the screen, scored with a hash mark every 50,000 bases. If you click on the mark labeled "1,000,000," you will zoom in on the 20,000 bases that straddle that point in the genome. Bars run above the line to show the location of individual genes. Click on the bar for the gene pyrD and you can read its sequence. If you seek something more meaningful, you can also read about pyrD's function (creating some of the building blocks of RNA). On EcoCyc you can learn about the network of genes that controls when pyrD switches on and off.

If you browse EcoCyc for very long, you may fall under a peculiar spell. You may begin to imagine its genome as an instruction manual for an exquisite piece of nanotechnology crafted by some alien civilization. Its genome holds all the information required to assemble and run a sophisticated machine that can break down sugar like a miniature chemical factory, swim with proton-driven motors, and rewire its networks to withstand stomach acids and cold Minnesota winters.

Let that delusion pass.

If you look long enough at E. coli's genome, you will come across hundreds of pseudogenes, instructions with catastrophic typographical errors. You will encounter the genes of viruses that respond to stress by making new viruses and killing their host. Other instructions are mysteriously clumsy, redundant, and roundabout. Still others are cases of outright plagiarism.

Where the metaphor of an instruction manual collapses, other metaphors can take its place. My favorite is an old battered book that sits today in a museum in Baltimore. It was created in Constantinople in the tenth century. A Byzantine scribe copied the original Greek text of two treatises by the ancient mathematician Archimedes onto pages of sheepskin. In 1229, a priest named Johannes Myronas dismantled the book. He washed the old Greek text from the pages with juice or milk, removed the wooden boards, and cut the binding strings on the spine. Myronas then used the sheepskin to write a Christian prayer book. This sort of recycled book is known as a palimpsest.

Despite its new incarnation, the Archimedes palimpsest carried traces of the original text. The prayer book was passed from church to church, scorched in a fire, splashed with candle wax, freshened up with new illuminations, and colonized by purple fungus. In 1907, a Danish scholar named Johan Heiburg discovered that the battered prayer book was in fact the only surviving copy of Archimedes' treatises in their original Greek. But with only a magnifying glass to help him, Heilburg could make out very little of the ancient text. A century later conservationists are making more progress. They are illuminating Archimedes' works with beams of X-rays that light up atoms of iron in the original ink, resurrecting a glowing text of Greek. The palimpsest reveals new depths to the genius of Archimedes, who turns out to have been contemplating calculus and infinity and other concepts that would not be rediscovered for centuries.

E. coli's genome is not so much a manual as a living palimpsest. E. coli K-12, O157:H7, and all the other strains evolved from a common ancestor that lived dozens of millions of years ago. And that common ancestor itself descended from still older microbes, stretching back over billions of years. The genetic history of E. coli is masked by mutations, duplications, deletions, and insertions. Yet traces of those older layers of text survive in E. coli's genome, like vestiges of Archimedes.

Until recently, scientists had only crude tools for reading those hidden layers. They struggled like Heiberg with his magnifying glass. They are now getting a much better look at the palimpsest. Like Archimedes' ancient treatise, they're finding, E. coli's genome is a book of wisdom. It offers hints about how life has evolved over billions of years—how complex networks of genes emerge, how evolution can act like an engineer without an engineer's brain. Nested within E. coli's genome are clues to the earliest stages of life on Earth, including the world before DNA. Those clues may someday help guide scientists to the origins of life itself.

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