Erez Lieberman Aiden’s research isn’t easy to classify, and that’s what he had in mind from a young age.
“I never really considered doing anything other than research,” said Aiden, a longtime senior scientist at Rice’s Center for Theoretical Biological Physics, who joined the faculty in Biosciences this fall. “It really flowed from curiosity. At a certain point around my late teens, I just became incredibly interested in the nature of everything. Much of my aim was actually trying to avoid specialization, because there’s just a lot of different things to be curious about.”
He studied mathematics, physics, philosophy and history before pursuing his Ph.D. at Harvard and MIT. His thesis spanned multiple fields, from using topology to explore the evolution of populations to collaborating with Google to create a tool for the study of large language datasets. He is best known for his groundbreaking research in 3D genomics.
“A DNA sequencer can tell you the sequence of letters in DNA, but DNA is a magnificent and complex three-dimensional machine,” Aiden said. “When you just look at the letters, you don’t see the machine at work.”
Every cell in our bodies contains the same genetic code, a six-foot-long strand of DNA containing some 3 billion genetic letters grouped into 23 chromosomes. In cells, these strands are compacted into knot-less balls about one-hundredth of a millimeter wide.
“The sequence of letters is the same in all cells. Understanding what makes a heart cell beat, what makes a brain cell think, what makes immune cells fight disease, all of that has to do with how DNA is structured in three dimensions,” said Aiden, who splits time between Rice and the University of Texas Medical Branch at Galveston, where he is Chair of the Department of Biochemistry and Molecular Biology.
“Early in my career, I came up with an approach — together with collaborators, and building on many decades of work — to turn a DNA sequencer into a DNA scope that can capture both the sequence of letters and how they’re shaped,” he said. That approach, known as Hi-C, is useful for studying any form of life.
“If you’re interested in studying primates, it’s useful. If you’re interested in studying Japanese Killifish or extinct species, it’s useful,” Aiden said. “If you’re interested in rescuing endangered species like the Pacific Pocket Mouse, it’s useful. We just published a paper about that.”
It’s also produced surprising results. In 2014, Aiden’s lab created the first reliable catalog of DNA loops spanning the entire human genome. The work, and a 2015 followup, showed loops form — and genes become activated — when DNA is extruded through a protein called CTCF that joins distant regions of DNA on chromosomes.
“The smoking gun for this was a very arresting result about certain DNA sequences always pointing towards one another,” Aiden said. “It was like flipping two coins, and finding that they both land on heads every time.”
He recalled telling his team, “Look, you have to think! It doesn’t make any physical sense. It’s completely impossible.” They spent weeks searching for bugs in their code.
“They couldn’t find the bug, and in fact we’ve never found one. The explanation for these correlated states turns out to be this remarkable secret about how DNA, across the entire tree of life, forms the physical connections that help turn genes on and off.”