October 2, 2020 | David F. Coppedge

Seeing Cells Is Seeing Complex Organization

Darwin and Haeckel would never have dreamed of the complex specified information to be found in “protoplasm.”

Inner Workings: Researchers peek into chromosomes’ 3D structure in unprecedented detail (PNAS). Science writer Amber Dance described what it was like to see closer into the cell.

Clodagh O’Shea will never forget the moment in early 2015 when she peered at the cell’s nucleus in a way no one had ever done before. Using a new technique to visualize three-dimensional (3D) chromosomes as they exist in the active, unadulterated nucleus, O’Shea was able to zoom in on individual nucleosomes where DNA wrapped around organizing proteins, then zoom out to see the entire scraggly mass. “It was just like seeing another planet, this whole new world,” recalls O’Shea, a molecular biologist at the Salk Institute in La Jolla, CA. “You get lost in it.”

As her initial euphoria faded, O’Shea realized the shapes she saw were wholly unexpected. Based on widely accepted notions about how genetic material organizes in vitro, researchers had anticipated that the DNA strands would be neatly wound into regular fibers of 30, 120, and 300–700 nanometers in diameter. Instead, in the intact nucleus, chromosomes appeared as an amorphous tangle—at least at first glance. “Oh my god, how do we make sense of this?” she wondered. Further analysis revealed that chromatin formed chains of 5–24 nanometers across, winding throughout the nucleus; the chains packed tightly in some spots and more loosely in others. That doesn’t mean the standard fibers don’t exist, says O’Shea, but “there are probably more structural possibilities.”

Since the 2001 publication of the human genome, researchers have navigated DNA mainly as digital strings of As, Ts, Gs, and Cs. Related research has led to intriguing advances, such as testing for genetic risk factors for disease and precision medicine. But the work hasn’t met expectations when it comes to disease cures, notes Cliff Brangwynne, a chemical and biological engineer at Princeton University in Princeton, NJ. Brangwynne says that may be, in part, because researchers lack an understanding of how all those strings of nucleotides physically fit together in the microscopic bowl of spaghetti that is the nucleus. “That’s been wholly underappreciated,” he says. “There’s a lot of excitement now in that space.” Recent insights have started to piece together that puzzle…..

Follow up this paper by watching Illustra Media’s new short film, “18 Trillion Feet of You.

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