The Year of Miracles

Why is all this happening now? What has changed between this year and last? To answer these questions, we need to trace the story of how mainstream biomedical scientists tried to link the cause of diseases to single genes and, despite early success, hit a brick wall. Meanwhile, a handful of renegade scientists, pursuing their own pet projects, happened to develop exactly the intellectual tools needed to break through that wall. These biologists are now the leaders of the new revolution in biomedical science.

The seeds of our new understanding were first sown in the 1960s, when molecular biologists figured out how genetic information is organized, regulated and reproduced inside single-cell bacteria. In bacteria, a gene is a discrete segment of DNA that contains the "code" that tells the cell how to make a particular type of protein. Bacterial genes are arranged along a single DNA molecule, one after the other, with only tiny gaps in between. Since all organisms have DNA and work by essentially the same biochemistry, scientists assumed that a human genome would look like a larger version of a bacterium's.

Clues that something was amiss came quickly with the development of DNA-sequencing methods in the 1970s. The first surprising result was that genes accounted for only 2 percent of the human genome—the rest of the DNA didn't seem to have any purpose at all. Biologists Phillip Sharp and Richard Roberts made things worse with a discovery that won them a Nobel Prize in 1993. If the gene were the basic unit of heredity, the DNA required to make any particular protein should be contained in its corresponding gene. But Sharp and Roberts found that DNA that codes for individual proteins is often split and scattered throughout the genome.

Scientists could ignore these signs largely because they seemed to be making progress. By combining new DNA-sequencing tools with studies of inherited diseases in large families, medical geneticists identified the genetic culprits responsible for cystic fibrosis, Huntington's disease, Duchenne muscular dystrophy and a host of other diseases. Each of these "all or none" diseases is caused by a mutation in a single protein-coding region of the DNA. Few diseases, unfortunately, work so neatly. In particular, the search for genetic bases of common diseases that affect large numbers of aging people came up empty.

During this lull, a visionary physician-scientist named Leroy Hood, now at the Institute for Systems Biology in Seattle, was growing impatient. Genetics, he recognized, was still a cottage industry of government-funded university professors, who each directed a small group of students and technicians to study an isolated gene. At the pace research was progressing, it would have required 100,000 worker-years of concerted effort to decipher just one complete human genome.

Hood thought it was absurd that genetic scientists spent nearly all their lab time performing tedious and repetitive mechanical and chemical procedures. At the same time, he grasped the far-reaching implications of a fundamental fact: while even the simplest organism is immensely complicated, the primary structures of its most complicated parts—DNA and proteins—are very simple. The alphabet of DNA contains only the four chemical letters (or bases) A, C, G and T, and proteins are made from just 21 amino acids. Hood saw that this simplicity would make it possible for robots and computers to read and write DNA and proteins more quickly, accurately and cheaply than human beings.