The Gene: An Intimate History - Siddhartha Mukherjee Page 0,44

genes; he had linked two disciplines—cell biology and genetics. The gene was not a “purely theoretical unit.” It was a material thing that lived in a particular location, and a particular form, within a cell. “Now that we locate them [genes] on chromosomes,” Morgan reasoned, “are we justified in regarding them as material units; as chemical bodies of a higher order than molecules?”

The establishment of linkage between genes prompted a second, and third, discovery. Let us return to linkage: Morgan’s experiments had established that genes that were physically linked to each other on the same chromosome were inherited together. If the gene that produces blue eyes (call it B) is linked to a gene that produces blond hair (Bl), then children with blond hair will inevitably tend to inherit blue eyes (the example is hypothetical, but the principle that it illustrates is true).

But there was an exception to linkage: occasionally, very occasionally, a gene could unlink itself from its partner genes and swap places from the paternal chromosome to the maternal chromosome, resulting in a fleetingly rare blue-eyed, dark-haired child, or, conversely, a dark-eyed, blond-haired child. Morgan called this phenomenon “crossing over.” In time, as we shall see, the crossing over of genes would launch a revolution in biology, establishing the principle that genetic information could be mixed, matched, and swapped—not just between sister chromosomes, but between organisms and across species.

The final discovery prompted by Morgan’s work was also the result of a methodical study of “crossing over.” Some genes were so tightly linked that they never crossed over. These genes, Morgan’s students hypothesized, were physically closest to each other on the chromosome. Other genes, although linked, were more prone to splitting apart. These genes had to be positioned farther apart on the chromosome. Genes that had no linkage whatsoever had to be present on entirely different chromosomes. The tightness of genetic linkage, in short, was a surrogate for the physical proximity of genes on chromosomes: by measuring how often two features—blond-hairedness and blue-eyedness—were linked or unlinked, you could measure the distance between their genes on the chromosome.

On a winter evening in 1911, Sturtevant, then a twenty-year-old undergraduate student in Morgan’s lab, brought the available experimental data on the linkage of Drosophila (fruit fly) genes to his room and—neglecting his mathematics homework—spent the night constructing the first map of genes in flies. If A was tightly linked to B, and very loosely linked to C, Sturtevant reasoned, then the three genes must be positioned on the chromosome in that order and with proportional distance from each other:

A . B . . . . . . . . . . C .

If an allele that created notched wings (N) tended to be co-inherited with an allele that made short bristles (SB), then the two genes, N and SB, must be on the same chromosome, while the unlinked gene for eye color must be on a different chromosome. By the end of the evening, Sturtevant had sketched the first linear genetic map of half a dozen genes along a Drosophila chromosome.

Sturtevant’s rudimentary genetic map would foreshadow the vast and elaborate efforts to map genes along the human genome in the 1990s. By using linkage to establish the relative positions of genes on chromosomes, Sturtevant would also lay the groundwork for the future cloning of genes tied to complex familial diseases, such as breast cancer, schizophrenia, and Alzheimer’s disease. In about twelve hours, in an undergraduate dorm room in New York, he had poured the foundation for the Human Genome Project.

Between 1905 and 1925, the Fly Room at Columbia was the epicenter of genetics, a catalytic chamber for the new science. Ideas ricocheted off ideas, like atoms splitting atoms. The chain reaction of discoveries—linkage, crossing over, the linearity of genetic maps, the distance between genes—burst forth with such ferocity that it seemed, at times, that genetics was not born but zippered into existence. Over the next decades, a spray of Nobel Prizes would be showered on the occupants of the room: Morgan, his students, his student’s students, and even their students would all win the prize for their discoveries.

But beyond linkage and gene maps, even Morgan had a difficult time imagining or describing genes in a material form: What chemical could possibly carry information in “threads” and “maps”? It is a testament to the ability of scientists to accept abstractions as truths that fifty years after the publication of Mendel’s paper—from 1865 to 1915—biologists knew genes only through the properties they produced: genes