Microcosm (23 page)

I have met some scientists, however, who simply hate Monod’s quip. It tramples over some fundamental differences between the elephant and
E. coli.
Elephants—and humans and lichens and all other eukaryotes—have vastly larger genomes than
E. coli.
Our own genome, for example, has about five times as many genes. It’s also padded with a lot of DNA that does not encode proteins. Another major difference can be found in the proteins we use to replicate DNA. They do not show any clear relationship to the proteins used by
E. coli
or other bacteria. Eukaryotes do swap a few genes, but much more rarely than
E. coli
does. We do not shake hands with friends and take up their genes for blue eyes. As animals, we have a way of reproducing that couldn’t be more different from
E. coli’
s. Only a tiny fraction of the cells in our bodies have the potential to carry our genes successfully to the next generation, and our genomes carry the information necessary for the stately development of a new trillion-celled body complete with 200 cell types and dozens of organs.

These differences are indeed great and genuine, and yet scientists have surprisingly little idea of how they came to be. Why we’re not more like
E. coli
is, in some ways, an open question. The answer must be lurking in the early history of life on Earth. Scientists are agreed that life split into three branches very early on, and the differences among them—particularly those that divide eukaryotes from bacteria and archaea—are profound. Yet at the moment, experts are contemplating some radically different explanations for how those divisions emerged. Some have claimed that eukaryotes originated from archaea that swallowed oxygen-breathing bacteria. Others claim that the split occurred long before that, before life crossed into the DNA world.

I find one explanation particularly intriguing. It comes from Patrick Forterre, an evolutionary biologist at Monod’s Pasteur Institute. He proposes that the profound split between us and
E. coli
is the work of viruses.

Forterre’s scenario begins in the RNA world, before the three great divisions of life had yet emerged. RNA-based organisms were promiscuously swapping genes. Some of these genes began to specialize, becoming parasites. They no longer built their own gene-replicating machinery but invaded other organisms to use theirs. These were the first viruses, and they are still around us today, in the form of RNA viruses, such as influenza, HIV, and the common cold.

It was these RNA viruses, Forterre argues, that invented DNA. For viruses, DNA might have offered a powerful, immediate benefit. It would have allowed them to ward off attacks by their hosts by combining pairs of single-stranded RNA into double-stranded DNA. The vulnerable bases carrying the virus’s genetic information were now nestled on the inside of the double helix while a strong backbone faced outward.

Early DNA viruses probably evolved a range of relationships with their hosts.
E. coli’
s viruses are good to keep in mind here: the lethal ones that make the microbe explode with hundreds of viral offspring, the quiet ones that cause trouble only in times of stress, and the beneficial ones that have become fused seamlessly to their hosts. Forterre argues that on several occasions, DNA viruses became permanently established in their RNA hosts. As they became domesticated, they lost the genes they had used to escape and make protein shells. They became nothing more than naked DNA, encoding genes for their own replication.

Only at that point, Forterre argues, could RNA-based life have made the transition to DNA. From time to time, mutations caused genes from the RNA chromosome to be pasted on the virus’s DNA chromosome. The transferred genes could then enjoy all the benefits of DNA-based replication. They were more stable and less prone to devastating mutations. Natural selection favored organisms that carried more genes in DNA than in RNA. Over time, the RNA chromosome shriveled while the DNA chromosome grew. Eventually the organism became completely DNA based. Even the genes for riboswitches and other relics of the RNA world were converted to DNA. Forterre proposes that this viral takeover occurred three times. Each infection gave rise to one of the three domains of life.

Forterre argues that his scenario can account for the deep discord between the genes that all three domains share and the ones that are different. Forterre started his scientific career studying the enzymes
E. coli
uses to build DNA. Related versions of those enzymes exist in other species of bacteria, but they are nowhere to be found in archaea or eukaryotes. The difference, Forterre argues, lies in the fact that the ancestors of
E. coli
and other bacteria got their DNA-building enzymes from one strain of virus and the eukaryotes and archaea didn’t.

Once the three domains split, they followed different trajectories. Our own ancestors, the early eukaryotes, may have acquired their nucleus and other traits from other viruses. Eukaryotes grew to be larger than bacteria or archaea, and as a result their populations grew smaller. In small populations it’s easier for slightly harmful mutations to spread, thanks merely to chance. It may have been only then that the eukaryote genome began to expand. Interspersing noncoding DNA within genes may have been harmful at first, but over time it may have given eukaryotes the ability to shuffle segments of their genes to encode different proteins. We humans have 18,000 genes, but we can make 100,000 proteins out of them.

Forterre’s proposal is as radical as the suggestion in 1968 that life was once based on RNA. It will demand just as much research to test. In the meantime, it is intriguing to think about what it would mean if Forterre is right. The differences between the elephant and
E. coli
would actually be the sign of yet another fundamental similarity: we—all living things—are different only because we got sick from different viruses.

Ten

PLAYING NATURE

PORTRAIT IN PROTOPLASM

         
IN CHRISTOPHER VOIGT’S LABORATORY
at the University of California, San Francisco, you can have your picture taken by
E. coli.
Voigt will place a photograph of you before a hooded contraption. The reflected light from the picture strikes a tray covered with a thin, gummy layer of
E. coli.
It’s a special strain that Voigt and his colleagues created in 2005. They inserted genes into the bacteria, some of which let the bacteria detect light and some of which cause them to produce a dark pigment. The genes are wired so that if a microbe detects light—such as the light reflected from a photograph—it shuts down the genes for making pigment. The bacteria that catch photons from light parts of the picture remain clear. The ones that don’t churn out pigment and turn sepia. A picture emerges, soft, fuzzy, but recognizably you.

Voigt is an assistant professor with a long list of scientific papers on his résumé. But he is also a child of the biotechnological age. He had not yet been born when scientists first learned how to insert genes in
E. coli
in the 1970s. That breakthrough was one of the most important in the history of biology. Genetic engineering allowed scientists to decipher some of the genome’s most baffling features. They turned
E. coli
into an industrial workhorse and created a $75 billion industry. Once scientists had mastered the art of inserting genes into
E. coli,
they began putting them in other microbes and then in animals and plants. Now goats produce drugs in their milk. Now 250 million acres of farmland are covered in crops carrying genes that make them resistant to pesticides and herbicides.

But as genetic engineering spreads to other species,
E. coli
has not faded into the background. It remains the species of choice for scientists who want to develop new tools for manipulating life. Voigt’s work, for example, is part of a new kind of genetic engineering called synthetic biology. Instead of simply moving a single gene from one species to another, synthetic biologists seek to create entire circuits of genes. They wire together genes from various species and fine-tune them to carry out new functions. For now synthetic biologists have learned enough only to create eye-catching proofs of principle, like Voigt’s microbial camera. But these lessons could lead to microbes that act as solar-power generators, or that can produce drugs when the conditions are right—call them thinking drugs. Some synthetic biologists are even trying to dismantle
E. coli
and use its parts to rebuild life from scratch.

This new research tingles with controversy. A debate is raging over the risk sposed by synthetic biology and other advances in biotechnology—the accidental release of dangerous new creatures, for example, or even intentional engineering of biological weapons. Thinking drugs could become thinking plagues. Synthetic biologists have also given a fresh spur to the debate over the morality of biotechnology in general. Today the world faces a huge, confusing surge of scientific research, with mice growing human neurons in their brains and deadly viruses being built from the ground up. In order to resolve these debates, we must think seriously about what it means to be alive and how biotechnology changes that meaning. And
E. coli,
the germ of our biotechnological age, has much to tell us. The face looks back, less a portrait than a mirror.

NEOLITHIC BIOTECH

Biotechnology was born many times, and each time it was born blind.

Humans began to manipulate other life-forms to make useful things, such as food and clothing, at least 10,000 years ago. In places such as Southeast Asia, Turkey, West Africa, and Mexico, people began to domesticate animals and plants. They probably did so unwittingly at first. Gathering plants, they picked some kinds over others, accidentally spreading the seeds on the ground. The wild ancestors of dogs that lingered near campfires might have fed on scraps and passed on their sociable genes to their pups. These species adapted to life with humans through natural selection. Once humans began to farm and raise livestock, natural selection gave way to artificial selection as they consciously chose the individuals with the traits they wanted to breed. Evolution accelerated as humans assembled a parade of grotesque creations, from flat-faced pugs to boulder-sized pumpkins.

The first Neolithic biotechnologists were manipulating microbes as well. They learned how to make beer and wine or, rather, how to allow yeast to make beer and wine. The job of humans was simply to create the best conditions in which the yeast could transform sugar to alcohol. Yeast also lifted bread with its puffs of carbon dioxide. Domesticated microbes evolved just as weedy teosinte evolved into corn and scrawny jungle fowls evolved into chickens. The yeast of winemakers became distinct from its wild cousins that still lived on tree bark.

With the invention of yogurt an entire ecosystem of bacteria evolved. Yogurt was first developed by nomadic herders in the Near East about five thousand years ago. They probably happened to notice one day that some milk had turned thick and tangy, and that it also proved slow to turn rancid. Plant-feeding bacteria had fallen into the milk and had altered its chemistry as they fed on it. The herders found that adding some of the yogurt to normal milk transformed it into yogurt as well. The bacteria in those cultures became trapped in a new ecosystem, and they adapted to it, evolving into better milk feeders and jettisoning many of the genes they no longer needed.

For thousands of years, humans continued to tinker with animals, plants, and microbes in this same semiconscious way. But as the microbial world unfolded beginning in the nineteenth century, scientists discovered new ways to manipulate nature. The first attempts were simple yet powerful. Louis Pasteur demonstrated that bacteria turned wine sour and contaminated milk. Heat killed off these harmful microbes, leaving children healthier and oenophiles happier.

As microbiologists discovered microbial alchemy, they searched for species that could carry out new kinds of useful chemistry. Chaim Weizmann, the first president of Israel, originally came to fame through his work in biotechnology. Living in Britain during World War I, he discovered bacteria that could manufacture acetone, an ingredient in explosives. Winston Churchill quickly took advantage of it by building a string of factories to breed the bacteria in order to make cheap acetone for the Royal Navy. The next generation of microbiologists began manipulating genes to make them even more efficient. By bombarding the mold that makes penicillin, scientists created mutants with extra copies of penicillin genes, allowing the mold to make more of the drug.

As scientists discovered how to manipulate life, they wondered what sort of world they were creating. In a 1923 essay, the British biologist J.B.S. Haldane indulged in some science fiction. He pretended to be a historian of the future looking back on the 1940 creation of a new strain of algae that could pull nitrogen from the air. Strewn on crops, it fertilized them so effectively that it doubled the yield of wheat. But some of the algae escaped to the sea, where it turned the Atlantic to jelly. Eventually it triggered an explosion in the population of fish, enough to feed all humanity.

“It was of course as a result of its invasion by
Porphyrococcus
that the sea assumed the intense purple colour which seems so natural to us, but which so distressed the more aesthetically minded of our great grandparents who witnessed the change,” Haldane wrote. “It is certainly curious to us to read of the sea as having been green or blue.”

For the next fifty years, hope and dread continued to tug scientists in opposite directions. Some hoped that biotechnology would offer an alternative to a polluted nuclear-powered modern world, a utopia in which poor nations could find food and health without destroying their natural resources. Yet the notion of rewriting the recipe for life sometimes inspired disgust rather than wonder. It might well be possible to create an edible strain of yeast that could feed on oil. But who would want to eat it?

Aside from scientists, few people took these speculations very seriously. For all the progress biotechnology made up until 1970, there was no sign that life would change anytime soon. And then, quite suddenly, scientists realized they had the power to tinker with the genetic code. They could create a chimera with genes from different species. And they began their transformation of life with
E. coli.
Monod’s motto took on yet another meaning: if scientists could genetically engineer
E. coli,
there was every reason to believe they would someday engineer elephants.

CUT AND PASTE

Before 1970,
E. coli
had no role in biotechnology. It does not naturally produce penicillin or any other precious molecule. It does not turn barley into beer. Most scientists who studied
E. coli
before 1970 did so to understand how life works, not to learn how to make a profit. They learned a great deal about how
E. coli
uses genes to build proteins, how those genes are switched on and off, how its proteins help make its life possible. But in order to learn how
E. coli
lives, they had to build tools to manipulate it. And those tools would eventually be used to manipulate
E. coli
not simply to learn about life but to make fortunes.

The potential for genetic engineering took
E. coli’
s biologists almost by surprise. In the late 1960s, a Harvard biologist named Jonathan Beckwith was studying the
lac
operon, the set of genes that
E. coli
switches on to feed on lactose. To understand the nature of its switch, Beckwith decided to snip the operon out of
E. coli’
s chromosome. He took advantage of the fact that some viruses that infect the bacteria can accidentally copy the
lac
operon along with their own genes. Beckwith and his colleagues separated the twin strands of the DNA from two different viruses. The strands containing the
lac
operon had matching sequences, so they were able to rejoin themselves. Beckwith and his colleagues added chemicals to the viruses that destroyed single-strand DNA, leaving behind only the double-strand operon. For the first time in history someone had isolated genes.

On November 22, 1969, Beckwith met the press to announce the discovery. He let the world know he was deeply disturbed by what he had just done. If he could isolate genes from
E. coli,
how long would it take for someone else to figure out a sinister twist on his methods—a way to create a new plague or to engineer new kinds of human beings? “The steps do not exist now,” he said, “but it is not inconceivable that within not too long it could be used, and it becomes more and more frightening—especially when we see work in biology used by our Government in Vietnam and in devising chemical and biological weapons.”

Beckwith flashed across the front page of
The New York Times
and other newspapers, and then he was gone. The debate over the dangers of genetic engineering disappeared. Other scientists went on searching for new ways to manipulate genes without giving much thought to the danger. Scientists who studied human biology looked jealously at the tools Beckwith and others could use on
E. coli.
To study a single mouse gene, a scientist might need the DNA from hundreds of thousands of mice. As a result, they knew very little about how animal cells translated genes into proteins. They knew even less about the genes themselves—how many genes humans carry, for example, or the function of each one.

Paul Berg, a scientist at Stanford University, spent many years studying how
E. coli
builds molecules, and in the late 1960s he wondered if he could study animal cells in the same way. At the time, scientists were learning about a new kind of virus that permanently inserts itself into the chromosomes of animals. The virus was medically important because it could cause its host cells to replicate uncontrollably and form tumors. Berg recognized a similarity between these animal viruses and some of the viruses that infect
E. coli.
In the 1950s, scientists had learned how to turn
E. coli’
s viruses into ferries to carry genes from one host to another. Berg wanted to know whether animal viruses could be ferries as well.

Berg began to experiment with a cancer-causing monkey virus called SV40. He pondered how he might insert another gene into it. Eventually he decided he would need to cut open the circular chromosome of SV40 at a specific point. But he had no molecular knife that could make that particular cut.

As it happened, other scientists had just found the knife. In the 1960s, scientists had discovered
E. coli’
s restriction enzymes, which slice up foreign DNA by grabbing on to certain short sequences. One of those scientists was Herbert Boyer, a microbiologist at the University of California, San Francisco. Boyer gave Berg a supply of a restriction enzyme he had recently discovered, called EcoR1.