Evolutionary biologist receives LRI grant for lupus research

Evolutionary biologist Harmit Singh Malik, Ph.D., of Fred Hutchinson Cancer Research Center, has received a $300,000 grant from the Lupus Research Institute to study the potential role of "genetic conflicts" in the development of lupus, an autoimmune disease.

Malik and colleagues want to find out whether a lost evolutionary arms race causes lupus autoimmunity.

"We want to determine whether autoimmunity - when the body's immune system turns against itself - results from an evolutionary arms race between ancient parasitic genes and the defense mechanisms that control them, which could provide a new model for understanding what causes lupus," said Malik, a member of the Hutchinson Center's Basic Sciences Division.

More than half of the human genome consists of parasitic "jumping genes," or endogenous retroelements, which can replicate and re-insert themselves into DNA. During millions of years of evolution, most of these genes have lost their ability to jump, but a tiny fraction are still capable of becoming active. Recently it has been discovered that some people with lupus carry a mutation in the TREX1 gene, which inhibits their body's ability recognize and attack these jumping genes when they become active. This led Malik and collaborator Richard McLaughlin, Ph.D., a research associate in Malik's lab, to theorize that autoimmunity may arise when cells can no longer recognize these jumping genes, or retroelements.

"The Lupus Research Institute grant will allow us to test this theory for the first time by analyzing genetic variation in the TREX1 gene and active retroelements, and look for evidence that each has influenced the evolution of the other," Malik said.

A native of India, Malik joined the Hutchinson Center faculty in 2003. He is also an affiliate assistant professor of genome sciences at the University of Washington School of Medicine and is a Howard Hughes Medical Institute Early Career Scientist.

As a researcher of genetic conflict, Malik sees battles raging within a cell's nucleus as genes jockey for evolutionary dominance. These clashes can have a long-term impact on organisms, as they sometimes alter the function of essential genes. Malik uses biochemistry and genomics to study the causes and consequences of these genetic conflicts in yeast, fruit flies and other model organisms. His work has offered novel explanations in two disciplines: host-pathogen interactions and the evolution of structural DNA elements (centromeres) that are critical for proper cell division.

Malik was among 12 researchers to receive Lupus Research Institute grants totaling $3.6 million to accelerate discovery in lupus by supporting original, highly promising ideas from some of the country's most creative scientists.

"What distinguishes the Lupus Research Institute is our insistence on funding only novel ideas rather than furthering established concepts," said Margaret Dowd, LRI president and CEO. "Our success in delivering pivotal discoveries proves that openness to inventive science works. As one advisor eloquently noted, 'great science cannot be managed; it must be imagined.'"