Does that mean that there’s absolutely no possible risk from swallowing bacteria loaded with human immune signal genes? No. We might guess that these genes would put these bacteria at a competitive disadvantage against the other bacteria struggling to survive in our guts. But that’s a hypothesis. Judging the risks of these kinds of organisms is a lot harder than judging the risks of a cigarette or an asbestos factory. The microbes can evolve and they can pass their genes on to other microbes. Their effects may depend on the other species around them. This is true both for engineered microbes inside of us and for engineered crops and other free-living creatures in the wild. In both cases, we’re introducing new players into ecosystems, and ecosystems are horrendously complex things. I’ve been looking over a new report from the National Academies of Sciences on the risks of genetically engineered organisms, and it deals mostly in experiments that still need to be done, not insights from past experiments. Are we really just getting started thinking about this stuff?

This may sound like a futuristic nightmare, the kind that we will only experience if we neglect our moral compass and let science go berserk. But it is actually happening right now. Today millions of people with diabetes will inject themselves with insulin that was produced by E. coli.

The fact that no one is disturbed by this state of affairs says a lot. It’s like the curious incident of the dog in the night-time Sherlock Holmes notes in the story “Silver Blaze.” When a Scotland Yard detective replies, “The dog did nothing in the night-time,” Holmes replies, “that was the curious incident.” But thirty years ago the dog was barking loudly.

In the early 1970s, a handful of scientists realized that they might be able to insert genes from other species into E. coli. They chose E. coli because, as I explain in my book Microcosm, it was the organism they knew best. With that knowledge came the power to manipulate it. Scientists figured out how to use some enzymes made by E. coli to snip segments of DNA out of the cells of animals. Then they loaded the segments onto tiny rings of DNA called plasmids, and injected the plasmids into E. coli. In 1973 Herbert Boyer, a biologist at the University of California, San Francisco, announced that he and his colleagues had endowed E. coli with DNA from an African clawed frog.

Boyer and others wondered if engineered E. coli might not just be able to carry alien DNA. Maybe it could read those new genes and make proteins from them. The bacteria could become biochemical factories.

A race began. Boyer and colleagues in California vied with a team of Harvard scientists headed by Walter Gilbert to be the first to engineer E. coli carrying the human insulin gene. At the time, diabetics could only get their insulin from the pancreases of pigs. E. coli might be able to create it in vast amounts from little more than sugar. By 1980 the race was won: Boyer’s team had created an insulin-spewing E. coli. Their start-up company, Genentech, passed on the bugs to the pharmaceutical giant Eli Lilly, which breeding it in gigantic fermentation tanks.

In those few frenzied years of scientific research, the world shuddered at the thought of E. coli carrying alien genes. It could trigger unspeakable disasters, they thought. Insulin-producing E. coli might escape from their tanks, take up residence in people’s guts, and cause epidemics of diabetic comas. They might spread cancer viruses, or some other unnatural plague. Erwin Chargaff, an eminent Columbia University biologist, called genetic engineering “an irreversible attack on the biosphere.”

“The world is given to us on loan,” he warned. “We come and we go; and after a time we leave earth and air and water to others who come after us. My generation, or perhaps the one preceding mine, has been the first to engage, under the leadership of the exact sciences,in a destructive colonial warfare against nature. The future will curse us for it.”

At the same time, people warned that we were doing the unnatural, something that humans were not meant to do. “We can now transform that evolutionary tree into a network,” declared Robert Sinsheimer, a biologist at the University of California, Santa Cruz. “We can merge genes of most diverse origin–from plant or insect, from fungus or man as we wish.”

It was not a power that Sinsheimer thought we could handle. “We are becoming creators–makers of new forms of life–creations that we cannot undo, that will live on long after us, that will evolve according to their own destiny. What are the responsibilities of creators–for our creations and for all the living world into which we bring our inventions?”

Engineering E. coli came to be known as the Frankenstein project. The protests sometimes took on almost religious tones. Tampering with DNA, the MIT biologist Jonathan King declared, was “sacrilegious.” Two political activists, Ted Howard and Jeremy Rifkin, condemned genetic engineering in a book called Who Should Play God?

It is striking to look back at this controversy from 2008. We suffered no epidemic of diabetic comas, no cancer viruses spread by E. coli from host to host. None of the dire warnings about engineered E. coli, in fact, came to pass. It appears that the safeguards put in place were good enough, and that engineered E. coli could not compete with its wild cousins. Scientists continued to engineer E. coli, and today it can make all manner of substances, from blood-thinners to jet fuel.

Despite all these bacteria suffering the indignity of being violated with human genes, no one seems to care. No one thinks the dignity of E. coli has been compromised. I have not heard of anyone refusing blood-thinners or insulin because it was produced from human genes put inside another species. In Europe, where protests over genetically modified plants and animals rage today, few seem to be bothered by the fact that a lot of cheese is produced with a cow’s enzyme, chymosin, made by E. coli rather than cows. In fact, this cheese is labeled organic, because it’s produced with “real” chymosin, rather than “artificial” chemicals.

I think that the story of engineered E. coli is an important one to bear in mind these days. Today we are faced with intense debates about whether it’s right to create chimeras–a mouse that carries human neurons, for example. Headlines assault us with the danger that scientists will be playing God by creating life from scratch. We are revisiting old ground.

There’s no question that scientists must think carefully about the potential risks of engineered organisms. And we must beware that we don’t try to use genetic engineering to fix problems it can’t fix. Diabetes can be controlled with insulin from E. coli, but it can’t be cured with biotechnology. In fact, diabetes has exploded since Lilly started producing the stuff from bacteria.

But it’s also important to bear in mind how easy it is to be terrified by a science-fiction caricature of what’s really going on in synthetic biology labs. We have a profound distrust of what seems unnatural, such as crossing species boundaries. Yet a casual glance at E. coli’s genome demonstrates that nature has been inserting foreign genes into it by the hundreds for millions of years. Our own genome is not immune from these violations. We carry the remains of thousands of viruses in our DNA, and most people on Earth may even carry genes inherited from another species of human–Neanderthals. We may be disgusted by the thought of violating species boundaries because of deeply ingrained instincts. But that disgust is an unreliable guide to the realities of biology, whether that biology is in E. coli or in ourselves.

[Picture: "The Young Family," by Patrician Piccini (2002-3). Wikipedia]

We all have a sense that we know what’s alive and what’s not, but I think that sense is really just an intuition. We use different circuits in our brains for recognizing biological motion, for example, as opposed to the motion of rocks or cars or other dead things. But the trouble comes when we try to turn that intuition into definition. We can see that things that look alive to us–tigers, roses, lobsters–share some things in common. And when we get tools to let us see new things, such as bacteria, we wonder, are they like us–in other words, are they alive? I find it interesting that in the nineteenth century, bacteria seemed to be at the hazy border of life and non-life. They seemed to be featureless bags of protoplasm. That was why the research on E. coli I write about in Microcosm was so astonishing. Down to many fine details, E. coli is a lot like us. Their genes are made of DNA. So are ours. They use a genetic code to read those genes and build corresponding proteins out of amino acids. So do we. There are actually dozens and dozens of different amino acids in nature, but E. coli only uses 20 of them to build proteins. We use a nearly identical set. Nobody would claim that E. coli is not alive anymore, because it is so much like us.

But just making a list of traits shared by us and E. coli is not a good definition of life. All known living things use the same set of amino acids. Or at least they did till some scientists engineered E. coli to use “unnatural” amino acids a few years ago. Are they no longer alive? Perhaps there are just a few basic things that qualify somehting as alive. A lot of people like to put metabolism on that short list–the ability to take in food and turn it into living matter. Some would say viruses are not alive, because they don’t have their own metabolism. The classic picture of a virus is a package of genes that uses a host’s cells to make more packages of genes. Yet some viruses appear to grow and undergo other changes outside their hosts, making this a dubious standard.

I also think it’s a mistake to try to cordon off viruses in some non-living quarantine because they evolve, and their evolution is intertwined with the evolution of their hosts. A sizeable chunk of E. coli’s genome is made up of genes delivered by viruses–many of which are essential to the microbe’s survival. The same goes for all the microbes in the ocean, the soil, and in our bodies. I think now of life as a global matrix of genes, shuttling from node to node and changing over time.

So viruses may or may not be alive, but they are definitely a part of life.

I think it’s better to think about life not in terms of hard definitions, but in terms of rules–ways in which species tend to work, no matter how different they seem superficially. The fact that all living things use 20 amino acids is not part of the definition of life, but it certainly is a rule that applies to all life on Earth outside of laboratories. Some scientists think this rule probably the result of some sort of frozen accident early in the evolution of life, or perhaps natural selection zeroing in on the most efficient or reliable system for building proteins.

In the book I also point out other surprisingly widespread rules of life. Life, for example, is robust. In other words, the ways in which genes interact allows living things to stay stable in a world full of change. E. coli copes with rising and falling temperatures, times of feast and famine–all sorts of change–while maintaining an even keel. Its robustness, like our own, is the result of how its genes are organized, like the parts of an airplane. (That’s why engineers are now helping make sense of E. coli’s genes, using the same tools they might use to build autopilot systems.) But that doesn’t necessarily mean that life started out robust to begin with. In each lineage, robustness was a good long-term strategy.

When I imagine the day when we discover alien life, I wonder about whether aliens will be robust too. I also wonder if they will also obey the rules of Earthly life. E. coli and other microbes are surprisingly social, for example, communicating, cooperating, and sometimes even killing themselves for their fellow microbe. Perhaps to be alive is to be social? And the fact that E. coli ages like we do–as an evolutionary strategy to cope with the inescapable decay of biological molecules–makes me wonder if aliens get old too.

I came to write Microcosm after having worked on several articles and blog posts that swarmed around the same fundamental question: What does it mean to be alive? This is obviously a very old puzzle, but today scientists are attacking it with a fresh passion.

Astrobiologists hoping to find life on other planets, for example, want to know what they should be looking for. Life on Earth is incredibly uniform, based on DNA, RNA, and proteins. Does that mean life on other worlds also have to be made of these ingredients? Synthetic biologists are helping astrobiologists answer that question by tinkering with Earth-bound organisms to see just how far they can alter life as we know it without killing it.

Meanwhile, other biologists are asking fundamental questions about life as they compare the genomes of hundreds of species. Some rules are emerging about how genes must be organized so that their entire network can run smoothly and stably. Engineers are turning themselves into biologists, applying what they learned from building flight controllers to understanding how living things remain stable in a changing world.

By studying genomes, scientists are also learning some surprising lessons about how life evolves. Along with the flow of genes from ancestors to descendants, they’re also finding evidence of a sideways flow–in other words, organisms can slurp up genes from other species. Darwin’s tree of life is morphing into something more like a world-wide web. To understand what it means to be alive, we may have to look away from individual creatures and turn our attention to entire ecosystems, entire planets.

As I learned more about all this work, I knew there was a book to be written. But I also knew that unless I found a way to narrow the scope, I would need a trillion pages to finish the job. So I started thinking about how I could find a manageable path through all this science. It was not until I was driving down a desolate stretch of the New Jersey Turnpike, somewhere around Penns Grove, that the solution came to me. (If you ever have writer’s block, I suggest taking a trip down that way.)

I would write a biography of E. coli.

For seventy years, this resident of our guts has been poked and prodded by scientists, who have won a dozen or so Nobel Prizes for their efforts. By studying E. coli, scientists figured out some of the most fundamental questions about life–what genes are made of, how they give rise to living matter, how genes change over the course of evolution. When scientists then turned to other species, they found time and again that other organisms followed E. coli’s rules. “What is true for E. coli is true for the elephant,” the French Nobelist Jacques Monod once famously said.

Today scientists also study many other species, but E. coli remains at the core of research into what it means to be alive. One reason for its popularity is that it was also the first organism scientists discovered how to genetically engineer–in other words, to insert genes from other species into it for fun and profit. Now they’re altering E. coli in far more radical ways, turning into, among other things, a living camera.

Some of the rules of life that E. coli can reveal are not rules that some people want to hear about. If you think that every species has some impenetrable integrity that must never be violated, E. coli is going to make you very unhappy. Creationists tried to use E. coli as evidence that life could not have evolved complex traits, but it’s got the marks of evolution all over it (including microbial versions of ostrich wings).

So you can see (I hope) why a couple years spent pondering E. coli can be a couple years very well spent. I’m very excited that Scienceblogs has picked Microcosm for its first selection in its book club. I’m a loyal reader of all three of my fellow club members, and I’m very curious to see what they think of the book–which parts spoke to them the most. Of course, I’ll also be looking forward to comments people leave here, some of which I’m sure will spur us to new discussions.