Life's Complexities Just Begin with the Genome

If a person's genes are his destiny, why do Sunney Xie's twin daughters have different personalities, and even different fingerprints? The girls share identical genes and nearly identical upbringings, and yet somehow, as they developed through toddlerhood, their biological paths diverged. Biologists have been pondering the relative influence of nature and nurture since long before Crick and Watson discovered the basic structure of DNA in 1953, but is it possible, after all these years, that they've been missing a third influence? Xie, a biologist at Harvard, has for the past three years performed experiments in his Cambridge, Massachusetts, lab aimed squarely at this question, and he thinks he's found the overlooked factor. It is pure chance.

The idea that randomness may play a role in the life of the cell is still largely conjectural, but it is typical of the kind of intellectual ferment in the life sciences of late. It's been nine years since Craig Venter and others decoded the human genome, the panoply of genes that govern the workings of each and every human cell, and declared that the "book of life" had been revealed. Since then, biologists have found that the genome is only the beginning to life's complexities. Only slightly more than 1 percent of the genome consists of genes that produce proteins, which do the day-to-day job of running the cell's operations. Scientists are pretty sure the other 99 percent plays a big role, but what that might be is still being sorted out. Although biologists have known since the 1980s that only a few diseases are caused by a single gene, some are now thought to arise from varying subsets of tens of thousands of genes. And as if the genome weren't complex enough, the way these genes are packaged in the cell may have as much to do with development and disease than the genes themselves. This phenomenon, called "epigenetics," may even account for traits that are passed down from one generation to the next—in other words, inheritance without DNA.

These developments mean that the full bounty of the genomics revolution is going to take longer than most people thought 10 years ago. But there's reason to believe that the route out of the present confusion will lead to deeper and wider insights, as the stories in this special report on the life sciences show. For one thing, significant practical breakthroughs are already brewing in the labs. Epigenetics has already led to some startling leads in the war on cancer and other diseases, and drugs for some forms of leukemia, for instance, are already in the pipeline. Scientists have figured out how to take adult stem cells from the skin and other organs and reprogram them genetically, the first step toward turning them into replacement tissue tailor-made to the patient's immune system. The realization that the cell is a complex entity that is greater than the sum of its parts has forced doctors on the forefront of medical research to consider their patients as biological "systems." This awareness is now transforming the way medicine is practiced and taught, as Dr. Leroy Hood points out in an essay.

Medicine isn't the only field that's set to benefit from the new genomics, as our report shows. A better understanding of the biological underpinnings of plants is giving scientists ways of improving the yields and nutritional content of crops without having to tinker directly with the genetic makeup of plants. It's also opened the door to the possibility of meddling with the biosphere itself by introducing genetically modified creatures, such as mosquitoes with immunity to the malaria parasite, into the wild. Research along these lines is causing something of a furor in environment circles, as health officials look to technology to improve global health.

Randomness hasn't yet emerged into the mainstream of biology, but its recent appearance in scholarly journals adds a certain symmetry to science. Probabilities played a role in the huge upheaval in physics in the early 20th century. In 1926 Erwin Schrödinger declared that an atom isn't anything like a tiny solar system, and that electrons, unlike planets, are best described in terms of the likelihood of their appearing at any one place and time. The idea raised Albert Einstein's hackles: "God doesn't play dice with the universe," he objected. But it made the equations come out better, and equations are hard to argue with, especially when they produce nuclear weapons and iPods. If it turns out that God also rolls the dice each time a stretch of DNA does its work, it could mean that biology needs a new mathematics that takes probabilities into account, just as physics did after Schrödinger. To say that biology stands today where physics stood in 1926—on the verge of rewriting its equations—is pure conjecture, but it's got the feel of truth.

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