Ibrahim Cissé, MIT assistant professor of physics, is devising new ways to look inside a living cell to see how DNA is read and written out as messenger RNA, the instructions used by the cell to make the molecular machines that do the cell’s work. An understanding of how cells perform this essential task of transcribing DNA has obvious practical implications. Many pharmaceuticals aim to control gene expression, and finding new ways to regulate genes is a priority for drug developers and bioengineers.

But Cissé is a physicist who happened to get excited by the idea of visualizing these subtle molecular interactions in cells and seeing what might come of them. “What are we missing?” he asks. “What can a closer look at this process teach us about how nature works?”

Cissé recently won a National Institutes of Health New Innovator Award to develop new microscopy techniques to answer these questions. His approach builds on three chemists’ 2014 Nobel Prize–winning super-resolution microscopy technology, which allows for finely detailed visualization of individual molecules, typically in a non-living cell fixed on a slide.

But Cissé isn’t looking for a clearer snapshot of the compounds that read and transcribe DNA. He wants to know how these wildly complex machines, which are made on the fly from a multitude of parts, can come together fast enough to allow the cell to quickly activate genes in response to environmental cues. “From what we know about biochemistry, this assembly should be a very inefficient process, but we know that genes can be turned on very efficiently and rapidly,” says Cissé. “How is it that cells can do that?”

The answer, he believes, lies in an area of biochemistry that isn’t yet well understood: that of weak and transient interactions between biomolecules. The strong bonds between molecules inside cells are fairly well understood. They build complex, long-lasting machines that are relatively easy to study because they hold together even when they are removed from a cell. In contrast, weak and transient molecular interactions are much harder to study because they are so fleeting and also because they tend to happen only in the tightly packed confines of a living cell.

In fact, weak interactions between molecules are so subtle that, taken individually, they may seem insignificant. But when they happen en masse, special things happen. A group of molecules following similar cues can start to work together, taking on what physicists call “emergent” properties.

Emergent properties can be seen elsewhere in nature, such as in schools of fish that self-assemble into an efficient feeding-cloud through slight but collectively significant interactions between individual fish following one another’s leads. “It turns out that nature has a way in complex systems for things to come together and exhibit properties where the whole is more than just the sum of the individuals,” Cissé says. “We think this is also how gene expression regulation happens.”

Existing methods to visualize single molecules miss these weak and transient interactions, but Cissé has found new and clever ways to apply a form of super-resolution microscopy called photo-activated localization microscopy (PALM) to capture the movements of molecules in a living cell. He has found that RNA polymerase II, the molecule that initiates the reading and writing of DNA, clusters around genes that are about to be transcribed. He has also shown that these clusters appear to regulate gene expression, tuning the level of gene activation. “Now,” he says, “we’re trying to figure out how the clusters self-assemble in the first place.”


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