Exploring the Genome in 3D

Since 2008, Leonid Mirny, Professor of Medical Engineering and Science, and Physics, has worked to understand the human genome in 3D with his team at MIT in collaboration with the Dekker Lab at UMass Medical School. Using new data uncovered via Chromosome Conformation Capture (Hi-C) technology and computer simulations, they explore how the genome is organized inside a cell.

“It’s a totally different level of genome understanding,” says Mirny. “Obtaining Hi-C data about genomic interaction is like getting information on who’s contacting whom in a city without knowing the map of the city. And then trying to infer how it’s all organized in space.”

In October 2015, Mirny and UMass Professor Job Dekker became co-directors of the new Center for 3D Structure and Physics of the Genome at UMass Medical School and MIT, funded by the National Institutes of Health’s 4D Nucleome Program. The program, initiated by Director of the NIH Francis Collins, is a focused, interdisciplinary directive, funding more than 25 labs to map not only the 3D architecture of the human genome, but also how this organization changes over time — the fourth dimension.

“The total length of all the chromosomes in a single cell in our bodies is two meters and they are all packed inside five microns of a cell nucleus,” says Mirny. “The question is: what aspects of this spatial organization are functionally important?”

Three years ago, the Mirny and Dekker labs published the first 3D model of the condensed (mitotic) human chromosome (“Solving Chromosomes’ Structure,” MIT News: Science, 2013). Now they are focused on how this structure changes during the cell cycle.

The Genome Folding Problem

“We are roughly at the beginning of the structural biology of the genome,” says Mirny. “Take a look at any textbook picture of a double helix of DNA. One turn in 10 base-pairs. Our genome is 300 million such turns. How are 300 million turns of the helix folded? Hi-C data and computer simulations help us learn.”

He points out that many theories in textbooks, museums of natural history and scientific papers are just guesses of how human chromosomes are folded during cell division.

“In 2013, when working on the model of the human condensed chromosome, we developed detailed computer simulations of the many popular folding models. When we compared these with the Hi-C data, we found they don’t entirely work. They’re not consistent with the Hi-C data.

“We know about the first level of organization: the double helix is turned around protein barrels called nucleosomes, forming “beads-on-a-string” fiber. But how this fiber is folded in space to give rise to a functional genome, and how it is packed for cell division, are mysteries,” he says. “During cell division, the process of chromosome condensation starts. At the end of it, we get compact chromosomes that are passed to two daughter cells. After cell division is over, chromosomes get unpacked and all the essential features of 3D folding come back in a couple hours. It’s an absolutely fundamental process. Kind of like unpacking a suitcase into a very well-organized, functional closet.”

This “unpacking” could illuminate molecular biology in unfathomable ways.

“Generally, scientists believe that for things to work in a cell, all molecular players and genetic information should be super well-organized and orchestrated. But fundamentally, this is all driven by stochastic molecular process,” says Mirny. “What fascinates me as a physicist is how stochastic motion of molecules gives rise to reliable biological processes – growth, development, cellular physiology.”

Mirny’s work fascinates the scientific community, as well. His lab’s recent papers published in Cell Reports, eLife, and Biophysical Journal, dig deeper into these core explorations.

“Our new idea is that the genome is folded and unfolded in 3D by molecular machines, similar to molecular motors that allow our cells to move and muscles to contract,” says Mirny (“Study: Molecular motors shape chromosome structure,” MIT News, 2016).

Cancer’s driver mutations

Stochastic processes and the nature of randomness are also central to Mirny Lab’s work in cancer research, particularly the role of mutations.

“Cancer needs certain driver mutations in specific genes to fully develop. But these mutations come with baggage of other random passenger mutations appearing in cancer cells. Nobody really paid attention to these passengers, because they aren’t helpful to cancer,” says Mirny, also an Associate Member of both Dana-Farber/Harvard Cancer Center and the Broad Institute of MIT and Harvard. “Our theory is they can be deleterious to cancer. Can we use this load of passenger mutations to bring cancer down or slow down cancer’s evolutionary process?”

Mirny Lab has published on this idea (“Some cancer mutations slow tumor growth,” MIT News: Proceedings of the National Academy of Sciences 2013) — one that could result in new therapies.

“Drugs that are used in chemotherapy attack all dividing cells, and since cancer cells divide more, they are affected more,” he says. “One could try to develop drugs — or use available ones — to increase the load of passenger mutations, or to make existing mutations more damaging to cancer. These approaches could target cancer cells more specifically.”

Working on such complex problems with MIT and Harvard students is the “biggest thrill,” Mirny says. “I want them to feel ownership of their projects and be excited about them. And I think we’re at a moment where we can make a big difference.”

In fact, it’s exactly what Mirny always wanted to do.

“My father worked as a biomedical engineer in Russia. I remember playing with artificial heart valves he brought home from his lab,” he says. “I’ve always wanted to combine fundamental research with helping to treat diseases. So I’m very excited I can combine my love of physics with biomedical research.”