AN ELEGANT MESS: A new essay explains the inspiration and concepts behind some of the recent efforts to map the human genome in three dimensions. Image: Miriam Huntley/Rob Scharein/Erez Lieberman Aiden
Erez Lieberman Aiden was an undergraduate at Princeton University in 2000 when scientists announced with great fanfare that they had sequenced the first human genome, yielding a trove of information about what happens inside every human cell. But Aiden wondered what it would be like to see what was happening inside a human cell. How does this gigantic genome—which would stretch 2 meters if you unwound it from its 5-micron-wide coil in the nucleus—actually go about its work?
To get to the bottom of this central question, he parlayed his mathematics major into applied math and health sciences and technology Ph.D. work at the Massachusetts Institute of Technology and at Harvard University, where he is currently a Harvard Fellow. Today in the journal Science, he explains the fruit of this work: a technique for mapping the genome that has already shed light on the human genome in all its 3-D glory. The essay won this year’s GE & Science Prize for Young Life Scientists.
The mapping technique that Aiden and his colleagues have come up with bridges a crucial gap in knowledge—between what goes on at the smallest levels of genetics (the double helix of DNA and the base pairs) and the largest levels (the way DNA is gathered up into the 23 chromosomes that contain much of the human genome). The intermediate level, on the order of thousands or millions of base pairs, has remained murky.
As the genome is so closely wound, base pairs in one end can be close to others at another end in ways that are not obvious merely by knowing the sequence of base pairs. Borrowing from work that was started in the 1990s, Aiden and others have been able to figure out which base pairs have wound up next to one another. From there, they can begin to reconstruct the genome—in three dimensions.
Even as the multi-dimensional mapping techniques remain in their early stages, their importance in basic biological research is becoming ever more apparent. "The three-dimensional genome is a powerful thing to know," Aiden says. "A central mystery of biology is the question of how different cells perform different functions—despite the fact that they share the same genome." How does a liver cell, for example, "know" to perform its liver duties when it contains the same genome as a cell in the eye? As Aiden and others reconstruct the trail of letters into a three-dimensional entity, they have begun to see that "the way the genome is folded determines which genes were on and off," he says.
One hypothesis that Aiden and his colleagues are pursuing is that the configuration of genetic information within any given cell has been arranged in essence like a newspaper. All the information is contained inside, but certain headlines have been chosen for the proverbial front page. So a liver cell's genome would have made the most important and relevant information the most accessible, whereas a cell in the cornea would be folded differently.
Through their research over the past few years, Aiden and his colleagues have discovered that at the level of a megabase—1 million base pairs—the human genome has wrapped itself into a structure known as a fractal globule. Although the spherical globule might look like a mess, the researcher discovered that by analyzing proximity data it is in fact an elegantly organized structure, which can be unfurled without getting tangled.
"Though it may sound abstract," Aiden wrote in his new Science essay, "the fractal globule is easy to explain to graduate students because it closely resembles the only food we can afford: Ramen." Uncooked, 30 meters of noodles fit neatly into a small package, woven together without being tangled.