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Bootstrapping Biology


Harmit Malik
Title: Associate Member, Fred Hutchinson Cancer Research Center
Education: PhD, University of Rochester, 1999
Recommended by: Steve Henikoff

Harmit Malik began his training in chemical engineering, and his shift to biology came through sheer force of will. Following a bachelor's degree at the Indian Institute of Technology where he informally learned the basic principles of biology, Malik headed to the University of Rochester to work in Tom Eickbush's lab. While there, he took every biology class he could find — so many, in fact, that he had to get special permission for his course load because it was over the school's recommended limit for students. "It was kind of like being in a candy store," Malik says. As a member of the Eickbush lab, Malik discovered that his interest lay in evolutionary biology and genetics. Upon completion of his PhD, he signed on for a postdoc with Steve Henikoff at the Fred Hutchinson Cancer Research Center, where his work focused on centomeric histones.

Today, Malik runs his own lab there, where he investigates genetic conflict and its role in evolution. Half of his lab focuses on conflict in chromosome segregation and how chromosomes compete with each other. For instance, during egg creation, there are four meiotic products — but only one will ultimately be transmitted into the egg, Malik says. The same doesn't hold for male meiosis, so his team is trying to understand how this mechanism evolved and what it means. The other half of Malik's lab is looking at evolution designed to maintain status quo — a genome that evolves to outpace a virus, for instance. They research host-virus interactions, with a particular eye toward cases where the virus mimics a host protein to outwit the immune system.

Looking ahead

Genetic conflict will continue to be a prime focus for the Malik lab going forward. "We feel like we've only just scratched the surface of what genetic conflicts can do," he says. He and his team will use case studies to advance their understanding of these phenomena, with examples including host-virus interactions when the virus has started to mimic host proteins. That mechanism has a tremendous impact on the evolution of the host genome, which in turn affects the virus evolution as well. "What we're trying to understand is, what are the rules?" Malik says.

In addition, his lab members will pursue their studies of centromeric DNA, which has historically been largely ignored due to its repetitiveness. Figuring out the ins and outs of centromeres and how they function would offer "unprecedented insight into the biology that shapes these eukaryotic genomes," Malik adds.

Publications of note

A good example of his recent work was published in early 2009 in Nature. Malik was senior author on the paper, entitled "Protein kinase R reveals an evolutionary model for defeating viral mimicry," which demonstrated the evolution of a protein kinase involved in innate vertebrate immunity and how the host protein evolved to outsmart virus mimicry. "The ability of PKR to evade viral mimics is partly due to positive selection at sites most intimately involved in eIF2-alpha recognition," the authors write. "Although it can seem that pathogens gain insurmountable advantages by mimicking cellular components, host factors such as PKR can compete in molecular 'arms races' with mimics because of evolutionary flexibility at protein interaction interfaces challenged by mimicry."

Another paper, this one called "Positive selection of primate TRIM5alpha identifies a critical species-specific retroviral restriction domain" and published in the Proceedings of the National Academy of Sciences in 2005, looks at genetic conflict and retroviruses. "By analyzing its evolutionary history, we find strong evidence for ancient positive selection in the primate TRIM5alpha gene," the abstract says. "This history suggests that TRIM5-alpha evolution has been driven by antagonistic interactions with a wide variety of viruses and endogenous retroviruses that predate the origin of primate lentiviruses."

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