Microcosm (22 page)

In
H. influenzae,
Fnr immediately switches on FrdB and FrdC. But in
E. coli
those genes also need a signal from NarL. It takes time for Fnr to drive the level of NarL high enough to give the two genes both the signals they need. A minor dip in oxygen won’t provide them with enough time to prime the pump.

As
E. coli’
s network evolved, it became impressively robust. The growth of man-made networks offers some clues to how that happened. The Internet did not suddenly appear one morning, ready to send your e-mail anywhere in the world. It began in 1969 as a crude link between computers at the University of California in Los Angeles and the Stanford Research Institute in Palo Alto, California. Other institutions joined the network over the years, and more links were added between them. The Internet became robust thanks to its overall architecture. But no one wrote down the design specifications for the entire Internet in 1969. They emerged along the way. Computer engineers focused their attention on how well each small part of the network performed. They worried about the cost of long-range connections between servers, and so they kept the links short.

E. coli’
s network grew in a similar way. As genes were accidentally duplicated, the network grew more complex. Mutations rewired some of the new genes so that they interacted with other genes. Natural selection then selected the favorable mutations and rejected the rest. As efficient small-scale components evolved, a robust network emerged as a by-product.

At the Dover intelligent design trial, creationists revealed a fondness for analogies to technology. If something in
E. coli
or some other organism looks like a machine, then it must have been designed intelligently. Yet the term
intelligent design
is ultimately an unjustified pat on the back. The fact that
E. coli
and a man-made network show some striking similarities does not mean
E. coli
was produced by intelligent design. It actually means that human design is a lot less intelligent than we like to think. Instead of some grand, forward-thinking vision, we create some of our greatest inventions through slow, myopic tinkering.

FIRST WORDS

Scrape away
E. coli’
s new genes—the arrivistes carrying resistance to penicillin and other drugs. Peel back the older genes that
E. coli
evolved after splitting off from other bacteria millions of years ago. Strip off the deeper layers, the ones that build
E. coli’
s flagella and the ones that have been destroyed beyond use. Strip away the genes for its peptidoglycan mesh, its sensors for rewards and dangers, its filters and amplifiers. Get rid of the genes that encode the proteins that were carried by the last common ancestor of all living things some 4 billion years ago.

You are not left with a clean sheet. A scattered collection of enigmatic chunks of DNA remains. These are not typical genes.
E. coli
uses them only to make RNA, and that RNA is never used to make proteins. These RNA genes are the oldest level of the palimpsest. Scientists suspect that they are vestiges of some of the earliest organisms that existed on the planet, from a time before DNA.

Life’s raw materials are no different from lifeless matter. Stars made the carbon, phosphorus, and other elements in our bodies. If you travel the solar system, you will encounter meteorites and comets with ample supplies of amino acids, formaldehyde, and other compounds found in living things. The Earth incorporated many of these molecules as it formed 4.5 billion years ago, and showers of space dust and the occasional impact of a bigger hunk of rock or ice brought in fresh supplies. The planet acted like a chemical reactor, baking, mixing, and percolating these molecules, probably producing still more molecules essential to life before life yet existed. The great mystery that attracts many scientists is how this reactor gave rise to life as we know it, complete with information-encoding DNA, its single-stranded counterpart RNA, and proteins.

As soon as the basic outlines of molecular biology became clear in the 1960s, scientists decided that DNA, RNA, and proteins did not emerge from the lifeless Earth all at once. But which came first? DNA may be a marvelous repository of information, but without the care provided by proteins and RNA it is just a peculiar string-shaped molecule. Proteins are awesomely versatile, able to snatch atoms drifting by, forge new molecules, and break old ones apart. But they are not so good at storing information for building proteins or for passing that information on to the next generation.

Francis Crick spent many hours in the mid-1960s speculating on the origin of life with his colleague at Cambridge, the chemist Leslie Orgel. They came to the same basic conclusion, one that Carl Woese came to on his own. Perhaps DNA and proteins emerged well after life began on Earth. Perhaps before life depended on DNA and protein, it was based on RNA alone.

At the time the suggestion seemed a little bizarre. RNA’s main role in cells appeared to be as a messenger, delivering information from genes to the ribosomes where proteins were made. But Crick, Orgel, and Woese all pointed out that experiments on
E. coli
showed that RNA molecules also have other jobs. The ribosome, for example, is itself made up of dozens of proteins and a few molecules of RNA. Another kind of RNA, called transfer RNA, helps weld amino acids onto the end of a growing protein. Perhaps, the scientists suggested, RNA has a hidden capacity for the sort of chemical acrobatics proteins are so good at. Perhaps RNA was the first molecule to emerge from the lifeless Earth, with different versions of the molecule playing the roles of DNA and protein. Perhaps DNA and proteins evolved later, proving superior at storing information and carrying out chemical reactions, respectively.

Years later Crick and Orgel freely admitted that the idea of primordial RNA went nowhere after they published it in 1968. Fifteen years would pass before people began to take it seriously. A year after Crick proposed an RNA origin for life, a young Canadian biochemist named Sydney Altman arrived at Cambridge to work with him on transfer RNA. Altman discovered that when
E. coli
makes its transfer RNA molecules, it must snip off an extra bit of RNA before they can work properly. Altman named
E. coli’
s snipping enzyme ribonuclease P (RNase P for short). At Cambridge and then at Yale, Altman slowly teased apart RNase P and was surprised to find that it is a chimera: part protein, part RNA. Altman and his colleagues found that the blade that snips the transfer RNA is itself RNA, not protein. Altman had discovered an RNA molecule behaving like an enzyme—something that had never been reported before.

Altman would share a Nobel Prize in 1989 with Thomas Cech, a biochemist now at the University of Colorado. Cech found similarly strange RNA in a single-celled eukaryote known as
Tetrahymena thermophila,
which lives in ponds. Unlike prokaryotes, eukaryotes must edit out large chunks of RNA interspersed in a gene before they can use it for building proteins. Proteins that build the messenger RNA generally edit out these chunks. But Cech discovered that in
Tetrahymena,
some RNA molecules can splice themselves without any help from a protein. They simply fold precisely back on themselves and cut out their useless parts.

Cech’s and Altman’s discoveries showed that RNA is far more versatile than anyone had thought. Many biologists turned back to the visionary ideas of Crick, Orgel, and Woese. Perhaps before DNA or proteins evolved, there had existed what Walter Gilbert of Harvard called “the RNA world.”

If RNA-based life did once swim the seas, its RNA molecules would have had to be a lot more powerful than the ones discovered by Altman and Cech. Some would have had to serve as genes, able to store information and pass it down to new generations. Others would have had to extract the information in those genes and use it to build other RNA molecules that could act like enzymes. These ribozymes, as they were known, had to capture energy and food and replicate genes.

The possibility of an RNA world spurred a number of scientists to explore the evolutionary potential of this intriguing molecule. In the 1990s, Ronald Breaker, a biochemist at Yale, set out to make RNA-based sensors. He reasoned they would work like the signal detectors found in
E. coli.
They would have to be able to grab particular molecules or atoms, change their shape in response, and then react with other molecules in the microbe.

Breaker didn’t design these sensors, though. Instead, he took advantage of the creative powers of evolution. He dumped an assortment of RNA molecules into a flask and then added a particular chemical he wanted his sensor to detect. A few of the RNA molecules bonded clumsily to the chemical while the rest ignored it. Breaker fished out those few good RNA molecules and made new copies of them. He made them sloppily, so that he randomly introduced a few changes to their sequences. In other words, the RNA mutated. When Breaker exposed the mutated RNA molecules to the same chemical again, some of them did an even better job of binding to it. Breaker repeated this cycle of mutation and selection for many rounds, until the RNA molecules could swiftly seize the chemical.

Eventually Breaker and his colleagues were making RNA molecules that could not only grab the chemical but change their shape. These RNA molecules could act like an enzyme, able to cut other RNA molecules in half. Breaker had created an RNA molecule that could sense something in its environment and use the information to do something to other RNA molecules. He dubbed it a riboswitch.

In the years that followed, Breaker created a library of riboswitches. Some can respond precisely to cobalt, others to antibiotics, others to ultraviolet light. RNA’s ability to evolve such a range of riboswitches brought more weight to the RNA-world theory. Breaker then had a thought. If the RNA-world theory was right, then RNA-based life had shifted many of the jobs once carried out by RNA to DNA and proteins. But perhaps RNA had not surrendered all those jobs. Perhaps riboswitches still survive in DNA-based organisms. In some cases, an RNA-based sensor might be superior to one made of protein. Riboswitches are easier to make, Breaker noted, since all a cell needs to do is read a gene and make an RNA copy.

Breaker and his students set out on a search for natural riboswitches. In a few months they had found one in
E. coli,
which uses this particular riboswitch to sense vitamin B
₁₂
.
E. coli
makes its own vitamin B
₁₂
, which it needs to survive. But above a certain concentration extra B
₁₂
is just a waste.
E. coli’
s riboswitch, Breaker found, binds vitamin B
₁₂
. The binding causes it to bend into a shape in which it can shut down the protein that makes the vitamin. Breaker couldn’t have fashioned a more elegant riboswitch himself.

Breaker went on to find more riboswitches in
E. coli,
and then he found more in other species. Most of them keep levels of chemicals in balance by swiftly shutting down genes. Since Breaker discovered riboswitches, other scientists have found RNA doing many other things in
E. coli.
Some shut genes off, and others switch them on. Some prevent RNA from being turned into proteins, while others keep its iron in balance. Some RNA molecules allow
E. coli
to communicate with other microbes, and others help it withstand starvation. These RNA molecules form a hidden control network that’s only now emerging from the shadows. Their discovery has helped make the RNA world even more persuasive.

Still, the question of exactly how RNA-based life emerged and then gave rise to DNA-based life gives scientists a lot to argue about. Some believe that RNA could have emerged directly from a lifeless Earth. Its ribose backbone, for example, might have been able to form in desert lakes, where borate can keep the fragile sugar stable for decades. Some argue that other replicating molecules came first and that the RNA world was merely one phase of history.

Like any living thing, RNA life needed some kind of boundary. Some scientists argue that RNA organisms did not make their own membranes but, rather, existed in tiny pores of ocean rocks. As RNA molecules replicated, the new copies spread from chamber to chamber. Other scientists see RNA life packaged in more familiar cells. They are trying to create these organisms from scratch, crafting oily bubbles that can trap RNA molecules. Proof by invention is their strategy.

There’s probably little to fear from the creation of RNA-based life. Most experts suspect it would survive only in the confines of the laboratory. DNA-based life is far superior in the evolutionary arena. But that doesn’t mean DNA-based life has abandoned all the ways of its ancestor. RNA may still work best for certain tasks, and that superiority is why it continues to exert control over
E. coli
and other species. In some ways the RNA world never ended. We still live in it today.

AU REVOIR, MON ÉLÉPHANT

In many ways, Jacques Monod was far more right than he realized when he uttered his famous words about
E. coli
and the elephant. We share with
E. coli
a basic genetic code and many proteins essential for getting energy from food.
E. coli
and our own cells face many of the same challenges. They both need to keep a boundary with the outside world intact yet not too rigid.
E. coli
has to keep its DNA neatly folded and yet accessible for speed-reading. It has to keep track of its inner geography. It needs to organize its thousands of genes into a network that can respond in a coordinated way to changes in the outside world. Its network has to remain rugged and robust despite the fact that it is swamped with noise.
E. coli
communicates with other members of its species, allies with some, fights with others, gives up its life. Like us, it grows old.

Some of these similarities are the result of a common heritage reaching back to the earliest stages of life on Earth. Others are the result of two evolutionary paths that converged on the same solution. Yet even the cases of convergence strengthen Monod’s insight. They are evidence that despite 4 billion years of separate history, we and
E. coli
are still deeply sculpted by the same evolutionary forces.