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Big ideas sometimes require the simplest questions. "It's almost a childlike innocence --you ask questions that adults might never ask, because they have a background where the question is no longer appropriate," says Harmit Singh Malik, an assistant member of the Seattle-based Fred Hutchinson Cancer Research Center's basic science division.

Malik should know. His career has just begun, but already he has a broader background than most scientists will acquire in a lifetime. That background has helped him make a swift impact in the field of molecular evolution. His research has unveiled rapidly evolving genes in processes crucial to cellular reproduction, where one would expect to find stability. His findings could have implications ranging from cancer to the origin of new species.

From Engineering to Biology

As a 16-year old in India, Malik took the all-India Joint Entrance Exam, and his rankings suggested chemical engineering would be an attractive option. He went on to major in the field at the Indian Institute of Technology, Mumbai, but even then he was drawn to biology. "I was thinking more of biochemical engineering, with large-scale fermenters, manufacturing, and so on," he recalls. But the more he looked into biology, the more interested he became. "I definitely wanted to do biology more than engineering. What started out as a subspecialty of the bachelor's degree motivated me" to take up biology, he says.

Another defining moment came following an introductory molecular biology course. He sat down with the instructor the following summer to discuss the field, and put together a reading list. That conversation, and the subsequent reading, motivated him to learn about the rogue genetic elements--transposons--that duplicate themselves within host genomes. "That's what got the ball rolling in my Ph.D. career," he says.

When he searched for graduate schools, he was surprised to find that it was easier to get into a school in the U.S. than in India, because biology departments in his native land wanted him to have a biology background. "(U.S. schools) were more open to the idea of accepting someone trained as an engineer."

He landed at the University of Rochester, in New York, intent on studying molecular biology. He was one of six students in his class entering the graduate program in biology, but the only one without a biology background. He found the classes relatively easy, but one experience stands out. He was asked to be a teaching assistant for a genetics class. "I asked the instructor, 'are you sure I shouldn't take the course first?' But he told me that teaching it would be the best way to learn. Being forced to do sessions in front of students involves you getting really well prepared, and I still consider genetics to be my strongest suit," Malik says. Despite having never taken the class himself, Malik won a University-wide teaching award for his contributions to this class, based on evaluations by his students.

Invasive Elements

Malik joined the lab of Tom Eickbush, who studies genetic elements called R1 and R2 retrotransposons. In the Eickbush lab, he began a study of the evolutionary relationships among non-long-terminal-repeat (non-LTR) retrotransposons, which are abundant in the genomes of animals, plants, and fungi. These elements insert themselves into the host genome using two enzymes that they encode for themselves: an endonuclease that cleaves the host chromosome in a specified location, and a reverse transcriptase that copies the retrotransposon's DNA back into the host genome.

Malik and Eickbush compared the reverse transcriptase sequences among non-LTR retrotransposons to determine how closely related they were. They found 11 genetically related subgroups (clades) of retrotransposons, but were surprised to find no evidence of interspecies transfer. Their analysis suggested that all 11 clades date back to at least the Precambrian era. "They don't benefit the host in any way, yet they have this remarkable (ability) to hitchhike on a host's genome for a billion years," says Malik.

A Surprising Arms Race

After finishing his Ph.D., Malik searched for a postdoc position. He met with Steven Henikoff of the Fred Hutchinson Cancer Research Center, and a dinner conversation decided his fate. Henikoff told Malik about his work with proteins--histones--that attach to the central regions of chromosomes--centromeres--during cell division, maintaining adhesion between chromosomes most of the time, but also playing a role when the chromosomes are pulled apart to prepare them for duplication. "I was convinced that they would be interesting to look into," he recalls.

In 1999, Malik moved to Henikoff's lab, where his investigations revealed a surprising process in the centromeres: portions of the region were undergoing rapid evolution. A histone (CenH3) showed a similar variability. Conventional wisdom has it that genes vital to the life or reproduction of a cell are likely to be highly conserved, yet these crucial regions appear to be diverging rapidly.

By way of explanation, Malik and Henikoff proposed an evolutionary arms race, not unlike that which occurs between a virus and a host's immune system. Centromeres, in this view, constantly jockey for position during egg formation. During that process, chromosomes pairs get drawn apart and duplicated, but only one of the four resulting chromosomes will make it into the egg cell; the others are destroyed. That applies tremendous selection pressure, specifically for mutations in the centromeres that maximize the chances that one of the chromosomes will make it into the egg, Malik and Henikoff argue. Any change that bolster's a chromosome's odds will quickly become dominant.

The rapid changes in CenH3 could represent the host's response to mutations in the centromeres. Mismatched centromeres can cause problems for the organism during cell division, possibly even leading to sterility in males. Changes in CenH3--which binds to centromeres--may be the host's response, countering centromere mutations and once more leveling the playing field between chromosomes.

Malik and Henikoff believe that a mismatched combination of centromeres and CenH3 could even account for the sterility of interspecies hybrids. Once two genetically similar populations begin to produce sterile offspring, divergence into new species cannot be far behind.

After completing his postdoctoral work, Malik applied for academic positions and received a number of offers, including from two separate departments at Harvard. But he liked where he was, Fred Hutchinson hired him from within, and he joined the basic sciences division in August of 2003. Since then, he has continued to do groundbreaking work. Recently, Malik and his colleagues recently discovered that a primate gene, TRIM5alpha, appears to be locked in an evolutionary arms race with HIV1.

Persistence of Vision

Malik continues to straddle disciplines, asking big questions. He attributes some of his success to closely watching his colleagues in other fields. He goes to seminars to learn not just what they're doing, but how they're approaching questions. "It's really exciting to see how this person went about developing the story and making these connections . . . It's really useful to see how a scientific mind thinks about a particular problem."

Still, moving between disciplines can be difficult, even emotionally taxing. When he was in graduate school learning bioinformatics, others in the department would approach him and ask for his assistance on a problem. He would read up on the issue and approach them with a potential solution. "Sometimes they were excited, but sometimes they had moved on," he recalls. The disappointment was difficult for him at first. "As a student, you're eager to please. I don't think I had the emotional maturity to deal with that [rejection]."

But like most lessons Malik has been offered over the years, he learned this one well. With support from Eickbush he persevered, and he was rewarded with longstanding, fruitful collaborations. Now, as PI, he knows to save taking chances for the science; when it comes to forming scientific collaborations, he prefers to play it safe. Some who inquire might only be curious, or not really convinced that another discipline could be useful. "Now, as a PI, I need to make sure they are as intellectually vested as we are. There's no point in it otherwise," Malik says.

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