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Out of Control

Artificial evolution is not merely confined to silicon, however. Evolution will be imported wherever engineering balks. Synthetic evolution technology is already employed in the frontier formerly called bioengineering.

Here's a real-world problem. You need a drug to combat a disease whose mechanism has just been isolated. Think of the mechanism as a lock. All you need is the right key molecule -- a drug -- that triggers the active binding sites of the lock.

Organic molecules are immensely complex. They consist of thousands of atoms that can be arranged in billions of ways. Simply knowing the chemical ingredients of a protein does not tell us much about its structure. Extremely long chains of amino acids are folded up into a compact bundle so that the hot spots -- the active sites of the protein -- are held on the outside at just the right position. Folding a protein is similar to the task of pushing a mile-long stretch of string marked in blue at six points, and trying to fold the string up into a bundle so that the six points of blue all land on different outside faces of the bundle. There are uncountable ways you could proceed, of which only a very few would work. And usually you wouldn't know which sequence was even close until you had completed most of it. There is not enough time in the universe to try all of the variations.

Drug makers have had two traditional manners for dealing with this complexity. In the past, pharmacists relied on hit or miss. They tried all existing chemicals found in nature to see if any might work on a given lock. Often, one or two natural compounds activated a couple of sites -- a sort of partial key. But now in the era of engineering, biochemists try to decipher the pathways between gene code and protein folding to see if they can engineer the sequence of steps needed to create a molecular shape. Although there has been some limited success, protein folding and genetic pathways are still far too complex to control. Thus this logical approach, called "rational drug design," has bumped the ceiling of how much complexity we can engineer.

Beginning in the late 1980s, though, bioengineering labs around the world began perfecting a new procedure that employs the only other tool we have for creating complex entities: evolution.

In brief, the evolutionary system generates billions of random molecules which are tested against the lock. Out of the billion humdrum candidates, one molecule contains a single site that matches one of, say, six sites on the lock. That partial "warm" key sticks to the lock and is retained. The rest are washed down the drain. Then, a billion new variations of that surviving warm key are made (retaining the trait that works) and tested against the lock. Perhaps another warm key is found that now has two sites correct. That key is kept as a survivor while the rest die. A billion variations are made of it, and the most fit of that generation will survive to the next. In less than ten generations of repeating the wash/mutate/bind sequence, this molecular breeding program will find a drug -- perhaps a lifesaving drug -- that keys all the sites of the lock.

Almost any kind of molecule might be evolved. An evolutionary biotechnician could evolve an improved version of insulin, say, by injecting insulin into a rabbit and harvesting the antibodies that the rabbit's immune system produced in reaction to this "toxin." (Antibodies are the complementary shape to a toxin.) The biotechnician then puts the extracted insulin antibodies into an evolutionary system where the antibodies serve as a lock against which new keys are tested. After several generations of evolution, he would have a complementary shape to the antibody, or in effect, an alternative working shape to the insulin shape. In short, he'd have another version of insulin. Such an alternative insulin would be extremely valuable. Alternative versions of natural drugs can offer many advantages: they might be smaller; more easily delivered in the body; produce fewer side effects; be easier to manufacture; or be more specific in their targets.

Of course, the bioevolutionists could also harvest an antibody against, say, a hepatitis virus and then evolve an imitation hepatitis virus to match the antibody. Instead of a perfect match, the biochemist would select for a surrogate molecule that lacked certain activation sites that cause the disease's fatal symptoms. We call this imperfect, impotent surrogate a vaccine. So vaccines could also be evolved rather than engineered.

All the usual reasons for creating drugs lend themselves to the evolutionary method. The resulting molecule is indistinguishable from rationally designed drugs. The only difference is that while an evolved drug works, we have no idea of how or why it does so. All we know is that we gave it a thorough test and it passed. Cloaked from our understanding, these invented drugs are "irrationally designed."

Evolving drugs allows a researcher to be stupid, while evolution slowly accumulates the smartness. Andrew Ellington, an evolutionary biochemist at Indiana University, told Science that in evolving systems "you let the molecule tell you about itself, because it knows more about itself than you do."

Breeding drugs would be a medical boon. But if we can breed software and then later turn the system upon itself so that software breeds itself, leading to who knows what, can we set molecules too upon the path of open-ended evolution?

Yes, but it's a difficult job. Tom Ray's electric-powered evolution machine is heavy on the heritable information but light on bodies. Molecular evolution programs are heavy on bodies but skimpy on heritable information. Naked information is hard to kill, and without death there is no evolution. Flesh and blood greatly assist the cause of evolution because a body provides a handy way for information to die. Any system that can incorporate the two threads of heritable information and mortal bodies has the ingredients for an evolutionary system.

Gerald Joyce, a biochemist at San Diego whose background is the chemistry of very early life, devised a simple way to incorporate the dual nature of information and bodies into one robust artificial evolutionary system. He accomplished this by recreating a probable earlier stage of life on Earth -- "RNA world" -- in a test tube.

RNA is a very sophisticated molecular system. It was not the very first living system, but life on Earth at some stage almost certainly became RNA life. Says Joyce, "Everything in biology points to the fact that 3.9 billion years ago, RNA was running the show."

RNA has a unique advantage that no other system we know about can boast. It acts at once as both body and info, phenotype and genotype, messenger and message. An RNA molecule is at once the flesh that must interact in the world and the information that must inherit the world, or at least be transmitted to the next generation. Though limited by this uniqueness, RNA is a wonderfully compact system in which to begin open-ended artificial evolution.

Gerald Joyce runs a modest group of graduates and postdocs at Scripps Institute, a sleek modern lab along the California coast near San Diego. His experimental RNA worlds are tiny drops that pool in the bottom of plastic micro-test tubes hardly the volume of thimbles. At any one time dozens of these pastel-colored tubes, packed in ice in styrofoam buckets, await being warmed up to body temperature to start evolving. Once warmed, RNA will produce a billion copies in one hour.

"What we have here," Joyce says pointing to one of the tiny tubes, "is a huge parallel processor. One of the reasons I went into biology instead of doing computer simulations of evolution is that no computer on the face of the Earth, at least for the near future, can give me 1015 microprocessors in parallel." The drops in the bottom of the tubes are about the size of the smart part of computer chips. Joyce polishes the image: "Actually, our artificial system is even better than playing with natural evolution because there aren't too many natural systems that come close to letting us turn over 1015 individuals in a hour, either."

In addition to the intellectual revolution a self-sustaining life system would launch, Joyce sees evolution as a commercially profitable way to create useful chemicals and drugs. He imagines molecular evolution systems that run 24 hours, 365 days a year: "You give it a task, and say don't come out of your closet until you've figured out how to convert molecule A to molecule B."

Joyce rattles off a list of biotech companies that are today dedicated solely to research in directed molecular evolution (Gilead, Ixsys, Nexagen, Osiris, Selectide, and Darwin Molecule). His list does not include established biotech companies, such as Genentech, which are doing advanced research into directed evolutionary techniques, but which also practice rational drug design. Darwin Molecule, whose principal patent holder is complexity researcher Stuart Kauffman, raised several million dollars to exploit evolution's power to design drugs. Manfred Eigen, Nobel Prize-winning biochemist, calls directed evolution "the future of biotechnology."

But is this really evolution? Is this the same vital spirit that brought us insulin, eyelashes, and raccoons in the first place? It is. "We approach evolution with a capital D for Darwin," Joyce told me. "But since the selection pressure is determined by us, rather than nature, we call this directed evolution."

Directed evolution is another name for supervised learning, another name for the Method of traversing the Library, another name for breeding. Instead of letting the selection emerge, the breeder directs the choice of varieties of dogs, pigeons, pharmaceuticals, or graphic images.