The Gene: An Intimate History - Siddhartha Mukherjee Page 0,136

cholera (this can be demonstrated using genetically engineered mice). Here too a mutation in a gene can have a dual and circumstantial effect—potentially beneficial in one copy, and lethal in two copies. Humans with one copy of the mutant CF gene may thus have survived cholera epidemics in Europe. When two such people reproduced, they had a one-in-four chance of creating a child with two mutant genes—i.e., a child with CF—but the selective advantage was strong enough to maintain the mutant CF gene in the population.

“To Get the Genome”

A-hunting we will go, a-hunting we will go!

We’ll catch a fox and put him in a box,

And then we’ll let him go.

—Children’s rhyme from the eighteenth century

Our ability to read out this sequence of our own genome has the makings of a philosophical paradox. Can an intelligent being comprehend the instructions to make itself?

—John Sulston

Scholars of Renaissance shipbuilding have often debated the nature of the technology that spurred the explosive growth of transoceanic navigation in the late 1400s and 1500s, ultimately leading to the discovery of the New World. Was it the capacity to build larger ships—galleons, carracks, and fluyts—as one camp insists? Or was it the invention of new navigation technologies—a superior astrolabe, the navigator’s compass, and the early sextant?

In the history of science and technology too, breakthroughs seem to come in two fundamental forms. There are scale shifts—where the crucial advance emerges as a result of an alteration of size or scale alone (the moon rocket, as one engineer famously pointed out, was just a massive jet plane pointed vertically at the moon). And there are conceptual shifts—in which the advance arises because of the emergence of a radical new concept or idea. In truth, the two modes are not mutually exclusive, but reinforcing. Scale shifts enable conceptual shifts, and new concepts, in turn, demand new scales. The microscope opened a door to a subvisual world. Cells and intracellular organelles were revealed, raising questions about the inner anatomy and physiology of a cell, and demanding yet more powerful microscopes to understand the structures and functions of these subcellular compartments.

Between the mid-1970s and the mid-1980s, genetics had witnessed many conceptual shifts—gene cloning, gene mapping, split genes, genetic engineering, and new modes of gene regulation—but no radical shifts in scale. Over the decade, hundreds of individual genes had been isolated, sequenced, and cloned by virtue of functional characteristics—but no comprehensive catalog of all genes of a cellular organism existed. In principle, the technology to sequence an entire organismal genome had been invented, but the sheer size of the effort had made scientists balk. In 1977, when Fred Sanger had sequenced the genome of the phiX virus, with 5,386 bases of DNA, that number represented the outer limit of gene-sequencing capability. The human genome contains 3,095,677,412 base pairs—representing a scale shift of 574,000-fold.

The potential benefit of a comprehensive sequencing effort was particularly highlighted by the isolation of disease-linked genes in humans. Even as the mapping and identification of crucial human genes was being celebrated in the popular press in the early 1990s, geneticists—and patients—were privately voicing concerns about the inefficiency and laboriousness of the process. For Huntington’s disease, it had taken no less than twenty-five years to move from one patient (Nancy Wexler’s mother) to the gene (one hundred and twenty-one years, if you count Huntington’s original case history of the disease). Hereditary forms of breast cancer had been known since antiquity, yet the most common breast-cancer-associated gene, BRCA1, was only identified in 1994. Even with new technologies, such as chromosome jumping, that had been used to isolate the cystic fibrosis gene, finding and mapping genes was frustratingly slow. “There was no shortage of exceptionally clever people trying to find genes in the human,” John Sulston, the worm biologist, noted, “but they were wasting their time theorizing about the bits of the sequence that might be necessary.” The gene-by-gene approach, Sulston feared, would eventually come to a standstill.

James Watson echoed the frustration with the pace of “single-gene” genetics. “But even with the immense power of recombinant DNA methodologies,” he argued, “the eventual isolation of most disease genes still seemed in the mid 1980s beyond human capability.” What Watson sought was the sequence of the entire human genome—all 3 billion base pairs of it, starting with the first nucleotide and ending with the last. Every known human gene, including all of its genetic code, all the regulatory sequences, every intron and exon, and all the long stretches of DNA between genes and all protein-coding