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 organised, 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, 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: genes accounted for only 2 per cent 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 DNA codes for individual proteins are often split and scattered throughout the genome.
A visionary physician-scientist named Leroy Hood, now at the Institute for Systems Biology in Seattle, 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.
Hood completely transformed the biomedical enterprise. DNA-writing machines give genetic engineers an unlimited capacity to create novel genes that can be studied in test tubes or added to the genomes of living organisms. And protein-writing and -reading machines provided drug firms with the ability to create a new generation of protein-based drugs. The DNA-reading machines suddenly made it conceivable to crack the 3 billion-base sequence of an entire human genome. In 1990 the U.S. government embarked on a 15-year, $3 billion project to do just that.
Eight years later, however, the project — parceled out to many US scientists — was still less than 10 percent complete. Now it was biotech entrepreneur Craig Venter who was frustrated. Convinced that government-funded workers were the problem rather than the solution, Venter enlisted private funding of $200 million to build an enormous lab filled with hundreds of automated machines, working 24/7, overseen by a handful of technicians. Within three years, the first reading of a human genome was essentially complete.
Armed with data from the genome project, scientists figured they’d surely be able to crack the really hard diseases, like cancer and heart disease. But a funny thing happened when they began to look closely at this vast storehouse of genetic information. Geneticists Andrew Fire and Craig Melo galvanised the field by discovering a key mechanism that had been completely overlooked— the cellular process of RNA interference. (They shared a Nobel Prize in 2006 for the work.)
Geneticists had taken for granted that the machinery of cells involved genes directing the production of proteins, and proteins doing the work of the cell. Here was a process that didn’t involve proteins at all. Instead, tens of thousands of hitherto mysterious regions of the human genome — part of the so-called junk DNA — directed the production of specific molecules called microRNAs (consisting of bits of RNA, a well-known component of cells). These microRNAs then oversaw a whole new process, called RNA interference (RNAi), that served to modulate the expression of DNA.
The good news was that RNAi could open up a whole new approach to biomedical therapy (more on that later). But RNAi also made it clear that the fundamental unit of heredity and genetic function is not the gene but the position of each individual DNA letter.
To make it all harder to fathom, each bit of DNA is susceptible to mutation and variation among individuals. Of the 3 billion DNA bases in the human genome, geneticists identified about one tenth of one percent (millions) that differ from one person to another. Variations in these particular letters — called “snips,” or SNPs, for single nucleotide polymorphisms — have replaced genes as the unit of heredity.
Many scientists responded to this devastating realization by going into a funk. Fortunately, another visionary scientist, Kari Stefansson of Iceland, was already blazing a trail out of this thicket. If the genome was far more complex than scientists had thought, they would need to test for many more variables, and to do that they would need more test subjects. To find the cause of diseases would now require the participation of very large groups of genetically related people.
Stefansson decided to solve this problem by taking aim at the largest well-documented extended family that he knew — his own. Nearly all the 300,000 citizens of Iceland can trace their ancestors back, through detailed, public genealogical records, to the Vikings who settled this desolate European island more than 1,000 years ago. He persuaded the Icelandic government to provide his company, decode, with exclusive access to the health records of its citizens in return for bringing investment capital and hi-tech jobs to the capital, Reykjavik. So far, more than 100,000 Icelandic volunteers have donated their DNA to deCODE.

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