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.
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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.
Untangled code
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.
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Form and function
Just how much structure—and changes in structure—determines cellular action, however, remains unclear. "I think few people doubt whether, in some sense, this form-function connection exists," says William Noble, a geneticist and computer scientist at the University of Washington, who helped to create a 3-D map of a yeast genome last year. "The questions, though, are precisely how the two are related and in what direction the causality flows."
Figuring out whether form follows function—or vice-versa—will help answer some other big questions, such as whether "defects in genome architecture lead to disease" and whether environmental or developmental cues can prompt a genome "to change its architecture to achieve corresponding genomic functions," notes Zhijun Duan, of Washington's Institute for Stem Cell and Regenerative Medicine, and a co-author of the 2010 yeast genome paper.
Aiden and his colleagues are currently working to improve the resolution of the maps and to speed up the sequencing in hopes of answering some of these questions. Noble, however, remains skeptical that Aiden's approach can ever "hope to give us detailed insights into, for example, individual interactions that mediate specific gene regulatory events," he says. "For that, we must await new technologies."
We might not have to wait too long, however. As Duan notes, "the field has attracted enormous efforts of investigation and is advancing very quickly."
