Peter Schultz Tinkering with nature

Tim Appenzeller / US News and World Report 25dec00

Gulls wheel in a brilliant sky, pines cloak nearby bluffs, and gray whales play a few miles offshore. Who could chafe at the finiteness of nature in such a setting? Yet at the Scripps Research Institute, a collection of sleek laboratories overlooking the Pacific near San Diego, chemist Peter Schultz sees a profound limitation.

Every living thing, from microbes on up to pine trees, whales, and scientists, shares the same kit of basic parts–just 20 different amino acids. That's less variety than you might find in a child's Lego kit. The acids serve as building blocks, snapping together in myriad different combinations to create proteins–the complex molecules that do all the hard work of life, from tensing muscles to transforming sunlight into sugar. "Proteins are amazing," says Schultz, "but there's a huge chemical limitation in the number of building blocks." Schultz, a professor at Scripps and director of a new industry-funded genomics institute, thinks he can do better.

The key is a bigger kit of parts. Schultz says his group is tantalizingly close to designing a cell that can create entirely new proteins, never found in nature. Trying to revamp the molecular intricacies of living cells is audacious, and not everyone who points that out means it as a compliment. "I'll wait to see it in print," says University of Florida chemist Steven Benner.

If Schultz does succeed, the universe of molecules made by living things could vastly expand, opening the way to new drugs and enzymes. Although the altered life-form will be no more than a sludge of E. coli bacteria, it would offer a glimpse of a new chemistry of life. "If God had worked on Sunday," Schultz asks rhetorically, "what would life look like?"

Schultz has always loved molecule making. "It's the world's most interesting Tinkertoy set," he says. And for most of his career, nature has been his mentor. "Chemists aren't even in the same league." The immune system is his favorite case in point. To react to an infection, for example, the body generates millions of differently shaped antibody molecules by mixing and matching a few pieces of protein. It then tests them all at once, launching them into the bloodstream to find the one antibody with just the right shape to latch on to the invading microbe and destroy it.

In one research effort starting more than a decade ago, Schultz and other chemists re-created the immune system's mix-and-match strategy in the laboratory. They developed clever techniques for linking simple artificial molecules in different combinations. The result: a varied crowd of compounds–any one of which might be the next wonder drug or material. The approach, called combinatorial chemistry, spawned a litter of companies that generate and screen compounds by the millions for potential cancer drugs, new catalysts and electronic materials, and other prizes.

For the past year and a half, Schultz has headed the Genomics Institute of the Novartis Research Foundation, a 150-person effort that is analyzing the tens of thousands of proteins encoded in the newly deciphered human genome. Just across the road from Scripps, GNF is exploiting the same rapid-fire approach Schultz admires in the immune system. Room-size robots run thousands of tests at a time to learn what the newly discovered proteins do and how they might be turned on or off to treat disease.

Hijacked. But Schultz, who speaks with a lazy cadence that masks his intensity, isn't content to focus on nature's handiwork. Ten years ago, he began building on work by other chemists to add extra amino acids–some of them natural molecules, some lab-made–to proteins in the test tube. It took painstaking chemistry to create even tiny quantities of these exotic new proteins in the test tube, so Schultz and his student David Liu–now a professor at Harvard University–decided to try to hijack living cells to do the job. Five years ago, they set out to engineer an E. coli that would feed on an unnatural building block and spin it into a brand-new protein.

They have been slogging since then and are just getting close. "We've had hundreds of problems," Schultz admits. "You have to convince the [cell's protein-making] machinery to take the new building blocks, but you can't have any scrambling–any cross-talk–with the natural ones." And then there's the problem of rewriting the cell's DNA instructions, so that the cell knows how to make new molecules. Schultz and his Scripps colleague Floyd Romesberg are now working on new forms of DNA, able to spell out protein recipes more elaborate than those in nature.

If it all works, "it's potentially a very powerful technology," says chemist Sidney Hecht of the University of Virginia, a pioneer in making proteins with unnatural amino acids. But could organisms that make new wonder molecules turn out to be a threat? No, says Romesberg. The altered cells could survive only in the laboratory, fed a steady diet of synthetic building blocks. Wild microbes will remain the real killers, Romesberg says. "Nature doesn't need any help being nasty."

Schultz will soon know whether he and his colleagues can remake nature for more-benign purposes. "We need only one more data point," he said in November. But he added with uncharacteristic humility, "Sometimes God makes it tough." It could be there's simply no monkeying with the fine-tuned chemistry that fashions gulls, pine trees, and scientists who dream of remaking life.