In his original profile in The Scientist back in 2011, Harmit Malik told the story of how he went from a chemical engineering undergraduate with no background in the biological sciences to earning a PhD in evolutionary biology. After early research on the evolution of retrotransposable elements and centromeres, he started his own lab at the Fred Hutchinson Cancer Research Center (Fred Hutch). There, he began studying a subject that would capture his imagination for years to come: the evolutionary arms race between viruses and their hosts.
Since then, Malik’s research has spanned the gamut of basic to translational research—from mutating human proteins to prevent viruses from escaping the immune system to studying speciation in Drosophila. For The Scientist’s 40th Anniversary, Malik spoke with us about his major projects, using his discoveries to develop therapeutics for respiratory illnesses, and why viruses are such fascinating subjects for evolutionary research. “It's all driven by curiosity,” he said.
Exploring Viral Fossils and Manipulating Human Immune Proteins
One of Malik’s early projects involved paleovirology: the study of ancient viral ‘fossils’ that sit in the human genome. Specifically, he became intrigued by the concept of indirect paleovirology.
“[In indirect paleovirology] we don't actually have the viruses themselves, but they leave a pretty unmistakable signature in the genome by virtue of the evolution they drove and the immune genes required to suppress them,” Malik said. “By tracing this evolutionary history, we not only learn a little bit about the types of viruses that probably drove this evolution, but [it] actually gives us a really good evolutionary playbook of how immunity might evolve to [prevent] these viruses from becoming zoonoses in the human population.”
Malik and his team investigate these signatures of rapid evolution in human immune proteins, figuring out which corresponding viral domains are rapidly evolving at that interface between virus and host. More recently, Malik said, they don’t wait for evolution to occur but take matters into their own hands, mutating human immune proteins, such as antiviral restriction factors.1 “We actually introduce a bunch more changes at these critical positions that evolution has told us are important,” he explained. “We can actually introduce many combinations, millions of combinations in theory, and ask in the lab if we can actually evolve versions of human innate immune proteins that are much better able to defeat viruses that we currently have a hard time defeating.”
Postdocs take their projects with them when they leave Harmit Malik’s lab, allowing them to launch their own research groups. For Malik, this means he is constantly reinventing himself and asking new research questions.
Robert Hood
Some of those include strains of influenza that have escaped immunity and have strong potential to prompt future pandemics.2 “What we've shown through work is that just with a couple of mutations in the correctly located places, we can essentially re-engage the human immune system to recognize and then defeat these strains of influenza,” he added.
To translate these discoveries into potential therapeutics, Malik and his team aim to partner with other research groups who are focused on delivery methods to develop, for example, an mRNA-based nasal spray for respiratory viruses. “You can imagine taking a spray which is full of these slightly modified mRNAs that'll go to your lungs, and your lung cells will now start producing this more protective [immune protein] variant,” Malik said.
Genomic Thievery, Speciation, and Asking Stupid Questions
Malik and his lab also explore a range of other evolutionary puzzles. For example, one project focuses on the tendency of viruses to be genomic thieves, stealing pieces of host DNA and incorporating them into their own genome—particularly host immune genes. “It turns out that by taking the right piece, the virus can actually gum up the works of immunity by blocking a particular immune protein,” Malik said. “So, viruses have actually learned that mimicry or mimicking host immune proteins to block them is a very effective strategy.” Inspired by viral evolution, Malik and his team are exploring whether they can reverse this, taking pieces of viral genomes and creating antivirals from them.
Outside of the world of viruses, Malik is similarly fascinated by the rapid evolution of other species and the conundrum of speciation, using Drosophila as a model organism. “Think about the gears of a Swiss watch mechanism,” he explained. “The gears really need to work well together, but in one species, one gear revolves a certain way, and the other gear revolves a different way. Now, when you try to make a watch made of these composite gears, they don't work well together, and that's kind of like how we think speciation occurs.” Unsurprisingly though, Malik said, it's more common for students to want to study viruses, purely because of the speed at which they can get results: “It's evolution on steroids.”
Underpinning Malik’s passion for the study of rapid evolution is some rapid evolution of his own. Unlike what is the norm for most laboratories, the postdoctoral researchers in his group take their projects with them when they leave, allowing them to launch labs of their own. The frequent departures of his postdoctoral researchers with their respective projects—Malik has just fledged his 18th—mean he is constantly reinventing his research and formulating new questions.
It isn’t always easy. “We are [always worried that] there is something fundamental that we are missing,” he said. “I always had that fear at the back of my head. I was like, ‘I think this is really cool, but maybe this is already in textbooks, and we're just rediscovering something that is like 50 years old.’” However, Malik said that this challenge keeps him fresh and prevents him from getting into the type of rut caused by confidence and success in a particular area. “The smartest people I know are unafraid to ask a stupid question,” he remarked.
- Mitchell PS, et al. Evolution-guided identification of antiviral specificity determinants in the broadly acting interferon-induced innate immunity factor MxA. Cell Host Microbe. 2012;12(4):598-604.
- Colón-Thillet R, et al. Combinatorial mutagenesis of rapidly evolving residues yields super-restrictor antiviral proteins. PLOS Biol. 2019;17(10):e3000181.
