Chapter 2: Building Blocks
34 - Evolution Inc.
In the flood of information conveyed to us each day about sex, it’s easy to forget that sex is itself a way of transmitting information. The data that sex transmits is then stored in the genes of our DNA. Since all organisms unfold from DNA, it’s through changes there—in the merger of two parents, or via mutation—that new varieties spring forth to try their luck in the outside world. Those that succeed get leading roles in life’s evolutionary drama. But life takes its time; species tend to change very little over millions of years. In view of that, impatient humans have developed a much speedier form. It’s called “directed evolution,” and new generations of its rapidly evolving progeny are now springing forth in labs around the world.
The method is simple in theory. Start by picking some eligible DNA. Use any of a number of available techniques to reproduce them and encourage mutations. Load each mutation into its own bacterium or yeast cell. Then grow the cells into populations. Out of those select the ones that are best at doing whatever it is you want done. Then repeat the process as many times as needed to evolve the final product. In principle it’s a lot like breeding cats or horses. But directed evolution will bring changes far beyond those imagined by traditional breeders.
It all began with RNA, the molecule that usually serves as the cell’s information processor. In the early 1980s, Thomas Cech and Sidney Altman independently discovered that a rare RNA molecule could also behave like an enzyme. (An enzyme is a molecule that usually either merges or “cleaves” other molecules—as when our digestive enzymes cut up the proteins in food, separating them back into their amino acid building blocks.) A decade later, in 1992, Gerald Joyce and his colleague Amber Beaudry took up that discovery in their lab at the Scripps Research Institute in La Jolla, California. They were curious about what else RNA might do. Specifically, they wanted to see if they could breed it to cleave DNA. Being able to cleave DNA at a precise location—in order to remove a damaging mutation, for instance, and patch in a healthy replacement—is a crucial step in genetic therapies.
RNA is not alive. The Scripps team couldn’t just mate various RNA strands and wait for nature to take its course. So they used standard recombining techniques to get a population with something like ten trillion variants, then turned them loose on a DNA target. To their amazement, a vanishingly small number of them, something like one in one billion, did split the DNA.
The team quickly used those successful RNA as the basis for a new generation, and so the process moved forward as they tested each new cycle to see which variants were more effective, then discarded the rest and started again. By the tenth generation, they had evolved individuals that were sixty times more efficient than their ancestors. After a few dozen cycles the artificially selected cleavers could do in five minutes what had taken those rare members of the first generation an hour.
Joyce saw something else he found interesting while watching this process: the mutations seemed to be competing with one another. A kind of survival-of-the-fittest contest was going on between parts of the molecules themselves as they evolved. It began when he noticed two different mutations that were ineffective at DNA slicing on their own. If they occurred together, though—within the same RNA molecule—they were highly effective. When he graphed their accumulation, it looked like two spires, so he called them the “twin towers.” Next he discovered another promising mutation, located right next to the site of the towers. It worked only in those versions where the towers had fallen away. In RNA with the twin towers, the neighbor was suppressed; then, when the neighbor occurred, the towers were suppressed. “They were mutually exclusive,” he said. Joyce came to see this as a horse race between competing factions. Generation after generation, he watched as one or the other pulled ahead. For a while the twin towers surged. Then, by the eighteenth cycle, things reversed: the towers were down and the neighbor was up. By the twenty-seventh generation it reversed again but with a twist—one tower came up with its own fresh mutation.
“Today’s loser may turn out to be tomorrow’s winner,” Joyce joked at the time, adding, “That’s evolution.” But he went on to make a more serious point. We are, he said, “beginning to see that evolutionary traits are highly dependent on each other. You can’t simply say, ‘Here’s a gene, it does this. Here’s another gene, it does that.’ It’s more how they interplay with each other—synergistic effects, mutually exclusive effects.” By that he meant to sound a note of caution for the practice of gene-splicing. “It’s not known what adding or removing one gene in a whole system of genes will do. It all depends on how its effect plays out in a network of interactions.”
With what we know today about gene networks, Joyce’s thoughtful early warning was well advised. But it’s being lost in the shuffle of a present-day race in which some outsize players jockey for position. A first generation of commercial operations is now looking to evolve genes, too. With names like Applied Molecular Evolution, Celltech Chiroscience (formerly Darwin Molecular), and Maxygen, they are flush with venture capital and looking for new markets. As those companies emerged from the labs, one front-page story trumpeted: “Mother Nature at Warp Speed.”
Does that sound like a good idea? A number of serious people are persuaded that it is, and are taking pains to show why. They cite numerous potential benefits to industry and health, and point to such feats of traditional genetic engineering as the bacteria that now produce human insulin.
The first “evolved” product to actually make it to market was a new stain-fighting enzyme for laundry detergents, which was launched by the Danish industrial-enzyme giant Novo Nordisk in 1998. Since then, the field has expanded in a number of other directions. Maxygen, one of the largest and most assertive of the new directed-evolution firms, is using what it calls “gene shuffling” to develop a complete product line ranging from crops to medicines. Diversa, a San Diego biotech, has evolved new human antibodies to fight cancer and infectious and autoimmune diseases. Applied Molecular Evolution, another San Diego company, has evolved a drug called Vitaxin, which blocks the growth of blood vessels in tumors. According to the company’s CEO, “Initial human trials showed actual decrease in the size of some tumors.” The drug is currently licensed to the Gaithersburg, Maryland–based biotech MedImmune, which has advanced it to Phase 2 clinical trials for the treatment of prostate cancer, melanoma, psoriasis, and rheumatoid arthritis.
Directed evolution is itself now evolving at a rapid pace. Caltech’s Frances Arnold, a pioneer in the field, remarks on how quickly a once-obscure area of research has been transformed into a billion-dollar industry. Says Arnold, “Now it’s the standard paradigm—it’s not science fiction anymore.”
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