Experimental Evolutionary Biology, Genetics
Fred Hutchinson Cancer Research Center
Dr. Malik is also a member of the Basic Sciences Division at the Fred Hutchinson Cancer Research Center, Seattle, and an affiliate professor in the Department of Genome Sciences at the University of Washington. Dr. Malik was an HHMI early career scientist from 2009 to 2013.
Investigations of Genetic Conflicts
In almost every scientist's story, says Harmit Malik, there is a moment when you realize you can actually entertain the idea of doing science for a living. For Malik, that moment came while he was studying chemical engineering in India. He'd gone into the program because he was three days too young to accept a slot in a top medical school without deferring admission for a year. He wasn't inspired by chemical engineering, but an engineering mentor steered him into a private tutorial in molecular biology with a biotechnology professor. "It was extremely unusual—and fantastic for me. I essentially received a self-designed course on molecular biology," he says.
Reading evolutionary biologist Richard Dawkins and other pioneers, he became captivated by the idea of "selfish" genes competing with each other. So for his PhD degree, he chose a lab at the University of Rochester that specialized in mobile DNA elements—bits of DNA that move around in the genome. The cell, he realized, isn't like a Swiss watch with all the gears humming smoothly. Instead, evolution and invasions by viruses and mobile genetic elements keep producing new gears that fight for survival, forcing the cell to constantly adjust just to maintain the status quo, he says. Written in our genes, Malik realized, are the tales of those battles, ancient and modern. And much like a modern-day Homer, he began to tell those stories, first as a graduate student at Rochester and then as a postdoc in HHMI Investigator Steven Henikoff's lab at the Fred Hutchinson Cancer Research Center in Seattle.
Malik's first major discovery revealed that chromosome structures called centromeres compete with each other. Centromeres help separate chromosomes during cell division. Most of the time, cell division produces two identical daughter cells. The two-step process of meiosis, however, produces four daughter cells, only one of which will become the egg. "That sets up a battleground among proteins and DNA where chromosomes have to be selfish to ensure their transmission," Malik explains.
In a second major advance, Malik and his colleague Michael Emerman realized that the genome is like a living fossil—and that adaptations in genes that fight off viral invaders offer a record of virus evolution. That insight created a whole new field, indirect paleovirology, in which scientists used reconstruct ancient viruses based on the imprints they've made in the genetic tapestry.
The approach has profound implications for medicine as well as for science, Malik says. For instance, he discovered that 40 million years ago, our primate ancestors faced a deadly virus similar to HIV. He was able to reconstruct the gene that those ancient primates evolved to fight the threat and showed that it codes for a protein complex that's very effective at binding to—and neutralizing—the virus. "Our ancestors are bequeathing to us a way to defeat these viruses," Malik says. Other labs are already using these findings to create designer antiviral drugs.
Now Malik, who became an HHMI early career scientist in 2009, is tackling the question that bedeviled Charles Darwin—how does one species split into two? The answer may lie in these genetic conflicts, he suggests. To extend the Swiss watch metaphor, "a gear from one watch company may not work in a watch from a related company," he says. "That might be the beginning of the process of speciation." It's an exciting prospect, he says. "With this new model of how conflicts arise, we hope we will get detailed insights into one of the most fascinating problems in biology," he says.