Originally created 12/18/97

With DNA, `simple' cells perform feats of computation



WASHINGTON - Without benefit of graduate degrees or even a "For Dummies" manual, the cells of living things routinely perform complex computations. They "read" and "rewrite" vast quantities of genetic information to produce the astounding variety of creatures and plants on Earth.

But how did mere molecules get so organized? Scientists are finding it devilishly difficult to trace that vital learning curve back to its genesis billions of years ago.

Now researchers have begun to eke out new insights by intertwining two rapidly advancing but seemingly unrelated fields: computer science and molecular genetics. A computer scientist deals in a cleverly arranged logic of zeroes and ones that get processed by manipulations of the flow of electrons through circuits. A molecular biologist specializes in the natural chemical interactions that take place in the basic building blocks of life. Together they demonstrate an intriguing synergy.

In 1994, computer theorist Leonard Adleman of the University of Southern California in Los Angeles revealed he had found a way to harness the power of nature's genetic data bits - DNA - to solve a computation problem of his choosing. (He posed the "seven-city traveling salesman problem," a classic whose solution would be the mapping of a certain type of efficient route among seven departure and destination points.) In his lab, the four units of DNA (the chemical "letters" A, T, C and G, assembled in various sequences) replaced zeros and ones as computational symbols. In about a week, trillions of DNA strands reacting in a test tube produced an answer. A field was born.

Now, in a laboratory at Princeton University, evolutionary biologist Laura Landweber is approaching the issue from a different direction, studying present-day organisms that have developed bizarre approaches to genetic problem-solving.

Landweber has discovered, for example, that "simple" single-celled organisms (ciliated protozoans of genus Oxytricha or Stylonychia) have solved a much harder computing problem than the one posed by Adleman - one with nearly 50 starting points and destinations, instead of seven. "This is an astounding feat of DNA computation," Landweber said. Puzzles with this level of difficulty "are classified as hard problems in computer science."

The ciliates mastered the skill millions of years ago as an evolutionary strategy. To assemble their own "rebellious" genes, she said, these organisms learned to unscramble some, starting with smaller pieces and executing more steps along a more complicated path than any other known cell.

"The invention of the computer was fairly recent, and the invention of DNA computing is even more recent," she said in an interview. "But these ciliates ... and other remarkable single-celled organisms have really scooped the entire field by 100 million years."

Landweber's ciliates are the sort of creatures seen in pond water under a microscope. They swim and feed with the aid of a hairlike covering of fine whiplike tendrils (cilia).

As a graduate student at Harvard, she was inspired by a talk given by colleague David Prescott, of the University of Colorado at Boulder. "I shared his immediate enthusiasm for the stunning acrobatics of these unusual genes," said Landweber, 30, who described her work at a recent workshop on cutting edge research in molecular evolution held at the Marine Biological Laboratory in Woods Hole, Mass., and in interviews. "I was awestruck by the bewildering diversity of the gene arrangements that could take place."

Ciliates have the bizarre characteristic of possessing two different types of nuclei, instead of one. (The nucleus contains the genetic "recipes" that govern all the cell's structures and functions.) The ciliate cell's smaller nuclei contains all the hereditary information required for survival - but the instructions are broken into many smaller bits and sometimes even "crippled" by chunks of what appears to be gibberish. It was Prescott who, in 1988, discovered that some genes must be unscrambled in order to form the second, fatter nucleus, where the genetic instructions are reorganized so they function properly.

Every human gene also seems to consist mostly of gibberish - "junk DNA" - which scientists speculate might play a crucial role in regulation and evolution of new genes. The ciliates, however, throw out most of their junk, "popping out" only the presumably useful material for retention in the second nucleus. The ciliate, she said, "has thereby solved the riddle of junk DNA. Having had a few million years longer (to evolve), it's possible they've come up with a more clever solution than the vertebrates."

Along with microscopes, test tubes and gels, Landweber uses a conventional computer. "I've spent many hours and nights staring into a screen trying to disentangle these (gene) rearrangements," she said.

In the DNA unscrambling process, the business end of each segment of DNA code has a "word," and it must find the next word in the "sentence," perhaps thousands of units away. "When it finds its match, they line up and are knitted together by an unknown recombination process," Landweber said. Watching the process reminds her of her undergraduate days in the Princeton marching band, whose members would scatter all over the playing field and then reassemble in a prearranged order.

She is investigating questions such as how many steps it takes to reassemble a scrambled gene, how the "programs" are written and how much backtracking and error-correcting the process involves.

These oddly advanced cells might teach scientists "how to build a DNA computer in the laboratory to solve other mathematical assembly problems," Landweber said.

And, by studying various ways in which genes reorder themselves in a single cell today, researchers suspect they might find clues to how genes first began to assemble themselves, when they began to "write" the genetic code now used in virtually all living things.