Biophysics, Cell Biology
University of California, San Francisco
Dr. Mullins is a professor in the Department of Cellular and Molecular Pharmacology at the University of California, San Francisco.
Dyche Mullins studies the assembly and regulation of cytoskeletal networks—collections of molecules used by living cells to move molecular cargo, establish polarity, and propel themselves forward. Understanding how cells construct their internal molecular "skeletons" is key to understanding a wide variety of biological processes and human diseases.
As a boy in rural Appalachian Kentucky, Dyche Mullins was transfixed by the Apollo moon landings. "In kindergarten, I knew the parts of the Saturn V rocket like kids today know dinosaurs," he says. Fascinated with figuring out how things work, he earned two bachelor's degrees—in mathematics and electrical engineering—at the University of Kentucky.
Biology, on the other hand, held little interest for him.
The summer after he began his graduate studies in engineering, however, Mullins worked for a university biologist, building tiny implantable devices to stimulate nerves. After reading a few research papers related to the project, he suddenly found biology—and its connection to systems engineering—compelling. "I realized how many fascinating and fundamental unanswered questions there were in biology. I decided then that I wanted to be a biologist," he says. So he took the legendary physiology course at the Marine Biological Laboratory (MBL) in Woods Hole, Massachusetts, and became captivated by one of the central questions of biology: how does a mindless mob of molecules work together to form a living cell? In particular, he wondered how a cell creates a cytoskeleton, a complex network of filaments composed of many proteins, including one key player called actin, that's crucial to cell function. By building, cross-linking, and reshaping actin filaments, the cell constructs scaffolds, pillars, and highways that enable it to change shape, to move, to transport cargo, and to make one end of the cell different from the other, a property called polarity.
At the time of Mullins's scientific epiphany, the mechanism for building new actin filaments was still a mystery. For his postdoctoral research at the Johns Hopkins School of Medicine and the Salk Institute for Biological Studies, Mullins decided to tackle the problem. "I thought I would much rather dive into something where no one knows anything," he says.
Mullins soon made a key discovery, showing that a cluster of proteins he called the Arp2/3 complex can stimulate formation of new actin filaments. Perhaps most surprisingly, he found that the Arp2/3 complex does not just make new filaments; it makes three-dimensional, space-filling networks of filaments. The ability to make networks boils down to a very simple rule that the complex follows when creating a new filament: it will only make a new filament, called a daughter filament, on the side of a preexisting mother filament. Putting together his findings with the work of other labs, he proposed a biochemical cycle in which signals on the cell membrane activate the Arp2/3 complex, which then creates a growing three-dimensional network.
But Arp2/3 wasn't the only route to growing actin filaments, Mullins found after launching his own lab at the University of California, San Francisco in 1998. He uncovered a protein called Spire that promotes filament growth by a simpler mechanism, but one that appeared later in the course of evolution than the Arp2/3 complex. This work paved the way for discovery, a few years later, of "a very strange protein," he says—one with the unexpected and peculiar ability to promote actin filament formation by two separate mechanisms. That protein, called JMY, plays a role in cell migration and embryonic development. "In a few short years, we've gone from zero to several methods of [creating actin filaments]," Mullins says, "It's almost an embarrassment of riches."
His lab group is now exploring those riches, studying how cells move and how cytoskeletons make one end of an egg cell different from the other. His team has also studied actin-like proteins in bacteria and is trying to figure out how bacterial cytoskeletons move cargo and create order in the cytoplasm. "Bacteria still hold lots of secrets," Mullins says.
His research also extends from basic science into potential applications. His team is studying how actin-like filaments in bacteria help propagate small DNA molecules called plasmids, which often carry antibiotic-resistant genes from microbe to microbe. "That could lead to new ways to combat drug resistance," Mullins says. His group is beginning to study how the cytoskeleton is involved in cell-cell adhesion, the way cells associate to form tissues and tumors, and whether that might be linked to cancer outcomes.
Mullins has stayed connected to the physiology course at MBL, where he first became captivated by the cytoskeleton. He recently finished five years as director of the course, traveling to Woods Hole each summer to teach students how to use cutting-edge microscopy, computational analysis, and other tools to tackle their own questions about the workings of cells. And one of his pursuits outside the lab seems apt for a former engineer who studies cellular scaffolding—he welds metal sculptures. "I am one of those people who believe that art and science are the two most important ways of seeing and understanding the world," he says.