Triumph of the Helix
In an epochal discovery 50 years ago, life met its own master molecule
Physicist Erwin Schrodinger had a knack for taking complex ideas and making them easy to understand. To illustrate the wacky world of quantum physics, for example, he told a story about an unfortunate feline that was both dead and alive--his famous "cat paradox." And in 1944, he helped unravel the central mystery of biology in a little book called What Is Life?
This daunting question didn't put off Schrodinger. Perhaps, he speculated, the genetic material in cells' chromosomes contains some kind of chemical Morse code. With just a few simple letters, this code could store enough information to explain the dizzying diversity of life.
Without knowing it, Schrodinger had hit on an eerily prescient description of deoxyribonucleic acid, or DNA. Scientists already knew of DNA, but most viewed it as just one more ingredient in the gunk inside cells. Less than 10 years later, however, James Watson and Francis Crick worked out the structure--the fabled double helix--that allows DNA to do just what Schrodinger envisioned. That discovery established DNA as life's master molecule and ultimately made it the master molecule of biology and medicine as well.
Now, half a century later in a world transformed by DNA, scientists are still trying to work out how this molecule became nature's record keeper. They are also wondering whether life could arise without DNA--whether some other form of the molecule, or even something completely different, could do the same job. Stanford University chemist Eric Kool says he and others are asking: "Could you just monkey with the structure a little bit and still get life? Or could you entirely redesign it from scratch and still get life?"
Fifty years ago, DNA seemed an unlikely master molecule. For one thing, it was chemically simple, even boring, compared with the complex proteins also found in the cell nucleus. But earlier experiments showing that DNA from one strain of bacteria could permanently alter another convinced Watson and Crick that it might hold the secret of heredity. They'd also seen some X-ray pictures that suggested DNA had a spiral shape. On Feb. 28, 1953, Watson cleared off his desk and began fiddling with cardboard models of four key parts of DNA--adenine, guanine, cytosine, and thymine.
Suddenly the puzzle pieces fit into place: A linked with T and C with G. The two pairs looked identical, and Watson realized they could form the steps of a spiral staircase. This double helix could duplicate itself by unzipping into two strands, each a template for building another helix with the same sequence of letters. It was just what was needed from the molecule of heredity. In wry understatement, Watson and Crick wrote that their structure had "novel features which are of considerable biological interest."
Truth and beauty. The beauty of the structure convinced some scientists right away. Leslie Orgel, now at Salk Institute for Biological Studies, remembers feeling awestruck when he saw the model in 1953. But he adds, "The world of biochemistry was extremely slow to pick up on it." Few newspapers spotlighted the discovery, and scientists had doubts about the structure. How could DNA unzip itself without getting all tangled up? And how could those few letters serve as code for all the complex proteins of life?
But Watson and Crick were proved right. DNA has achieved superstar status, and its lovely double spiral is an icon of science. DNA has cured deadly diseases and allowed labs to create animals with fantastic new features. It has freed the innocent from death row and caught a president in a tawdry lie. In this 50th-anniversary year, scientists will put the finishing touches on the full 3-billion-letter sequence of our own DNA, and in it they hope to learn what makes us human.
In reality, DNA's star turn has lasted much longer than 50 years. Somehow, this one chemical came to dominate the world at least 3.5 billion years ago, when one-celled microbes were the pinnacle of biology. Its reign has been unbroken since then. Evolution sticks with winners, and DNA is an ideal information storage facility. Its highly stable structure resists degradation but is not so unchanging that it doesn't provide a few chance errors for natural selection to work on. Weak bonds between its two strands allow them to get pulled apart easily for copying--but not too easily. "DNA might sound boring, but it's beautiful in its boringness," says chemist Ryan Mehl of Franklin and Marshall College.
DNA's structure has enough complexity that it couldn't have spontaneously assembled itself in the primordial soup. Scientists think it evolved from another long-chain molecule: RNA, which still plays myriad roles in today's cells. Like DNA, RNA has four "letters" that store information. But it has an extra oxygen unit that makes it highly reactive. That oxygen even attacks RNA itself, making it unreliable for long-term information storage.
RNA's willingness to tangle with other molecules does let it play a bigger role in life's chemistry than DNA can, which might have been an advantage when life had only a handful of molecules. As early as 1968, Orgel and Crick proposed that RNA could have done double duty, both storing genetic information and assembling proteins. Later, as biochemistry grew more elaborate, this primordial RNA would have created a DNA version of itself to keep life's code safe.
The idea of an earlier "RNA world" got a boost in 1982, when scientists found that RNA can act as an enzyme, speeding up chemical reactions like protein synthesis. Less than two years ago, David Bartel's group at the Massachusetts Institute of Technology found another hint that RNA was once the key living molecule: a small RNA enzyme that can build up other stretches of RNA, suggesting that RNA was once able to duplicate itself.
Even RNA, however, could not have emerged straight from the prehistoric muck. "Everyone seems to agree that RNA came before DNA. So what came before RNA?" asks Gerald Joyce of the Scripps Research Institute. "This is the game now." Several labs have tried to concoct simpler molecules that might serve as RNA precursors. Ultimately, they hope to piece together a plausible path from lifeless chemical parts to the DNA-centered life we know.
A different turn. NASA is a major sponsor of such work, which could show how life might begin on other worlds. Researchers are also investigating whether the story could have turned out differently, culminating in something other than the double helix. That could prepare us to recognize alien life and help explain why DNA on Earth works the way it does.
Today's DNA, for example, uses 20 different three-letter "words" to code for the building blocks of proteins, called amino acids. But why stop at 20? Last month, Mehl and Peter Schultz's group at Scripps reported that they had managed to write a new word in ordinary DNA, coding for an unnatural, 21st amino acid. They slipped the altered word into a gene for a protein called myoglobin, then inserted the modified gene into the DNA of bacteria. They also engineered the bacteria to make their own supply of this unnatural amino acid. The result: bacteria that could independently produce an unnatural form of myoglobin. The group is now pitting bacteria with this extra DNA word against bacteria without it to see which can adapt better to new conditions.
Other groups hope to expand DNA's four-letter alphabet. Floyd Romesberg's group at Scripps has created extra chemical letters and slipped them into DNA in a test tube. Now they're trying to get the altered DNA into living bacteria. Romesberg wants to see what a cell would do with an extra chemical letter in times of stress or need. His ultimate plan, he says, is to "give the bugs freedom and let them run with the ball. Give them an evolvable system and sort of let them go."
Some scientists have a far more radical fantasy: creating a completely novel chemical that could do everything needed for life. "I dream of coming up with an unnatural genetic molecule and an unnatural protein that copies it," says Stanford's Kool. "I don't think there's any question that would be life."
But he has no illusions that it will be easy to come up with a rival for the double helix. For the foreseeable future, it seems, DNA will still reign supreme--at least on the planet we call home.
Home-Brewed DNA
DNA is all around you, and you don't need a Ph.D. to extract it. You will need a source of DNA (any living matter will do, but strawberries work well), salt (the noniodized kind), shampoo, and 90 percent rubbing alcohol (chilled in the freezer).
1. Mash the DNA source. Add an equal amount of water. Throw in a couple of squirts of shampoo and a spoonful of salt. Stir gently.
2. Strain the mash through a wet paper towel or cheesecloth so you're left with a clear fluid.
3. Pour an equal amount of ice-cold alcohol into the fluid. You will see a cloud form. Take a chopstick or the handle of a spoon and twirl it inside the cloud to capture long, gooey strings of nucleic acid (DNA and RNA). -Nell Boyce
This story appears in the February 24, 2003 print edition of U.S. News & World Report.