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Rockville’s Born-Again Californian

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In 1991, while finishing up a postdoc in a branch of theoretical physics called phenomenology at UCLA, John Quackenbush embarked on a search for his first real job. He sent out 350 applications for various teaching and postdoc positions, but with the Cold War over and funding support for physics on the wane, he didn’t have much luck.

It just so happened that Quackenbush’s girlfriend at the time was a biologist, and through her he picked up a bit about how hormones regulate genes in cockroaches (she dissected the critters for her experiments).

Later, while helping a biology graduate student employ a transformation matrix to model a biological system, he realized that he could easily apply his problem-solving skills to biology. Over the course of a Saturday afternoon, Quackenbush listened while the biologist explained her attempts to model DNA substitution rates as part of her research into evolutionary biology. Quackenbush attempted to explain how she might use a transformation matrix to compute the eigenvalues and eigenvectors she needed to model the substitution rates.

“I tried to explain the mathematics to her,” he says, “but her eyes would just glaze over. I’d get to the end of what I thought was a beautiful explanation, and she’d say, ‘Well, OK, but how do I solve my problem?’ So I realized there really was a good opportunity for somebody who had a good quantitative background, but understood some biology.” Once word got out that Quackenbush had a knack for applying math to biology, others in the biology department began requesting his help too.

Function Follows Sequence

Quackenbush follows a line of physicists who have successfully crossed over into genomics and bioinformatics, and he has been particularly successful in his adopted field. After winning a fellowship from the National Center for Human Genome Research designed to attract physical scientists to genomics, Quackenbush set off for the Salk Institute in San Diego, where he worked for Glen Evans on constructing an EST map of chromosome 11. There, in an effort to prove that a physicist could pipette with the best of them, Quackenbush jumped hands-first into the lab. Soon he found himself in charge of the mapping project.

When Evans moved to the University of Texas Southwestern Medical Center in 1994, Quackenbush found himself surveying the genomics landscape for his next gig. He decided to join Rick Myers and David Cox at Stanford University because theirs was “a mapping group that was serious about building a sequencing capacity,” he says.

At Stanford, Quackenbush wrote software and designed databases to analyze and store the human genome data flitting off Stanford’s sequencers. “Without building the infrastructure for managing the data, collecting the data was going to be pretty useless,” he says.

But after two years with Myers and Cox, Quackenbush realized that Stanford had entered the sequencing game too late to be a major player, and in any case, he believed the real challenge was to assign functions to all the human genes. Once again searching for a new position, this time in functional genomics, the long-haired, “born-again Californian,” as he describes himself, felt drawn to the East Coast. The magnet: TIGR.

“I talked to a lot of people, got a number of job offers, but the one that intrigued me the most was the possibility of coming to TIGR and starting a program in functional genomics,” says the Pennsylvania native.

The Domestic Life

He certainly wasn’t attracted to TIGR’s Rockville, Md., home because of the food and weather. There were other adjustments as well. While in LA and San Diego, Quackenbush socialized with other single, 30-something coworkers, but in “suburban hell” he found he was hanging with 22-year-old TIGR colleagues “because they were the only ones who still did anything.” His foray for a social life outside of the lab forced him to adapt. Nowadays, he spends what little free time he has at home with his wife Mary, who works as an editor for National Academies Press, in their house in nearby Gaithersburg where they tend after a cat, a parrot, two rabbits, and two gerbils.

At TIGR, Quackenbush immersed himself in the world of DNA microarrays. When he started in 1997, he was the lone functional genomics researcher in a sea of sequencing and bioinformatics experts, but during his six years at TIGR he has built a group of 30-odd devotees to the microarray cause.

His projects include a study of gene expression in rats with Norman Lee and Renae Malek at TIGR and gene expression in malaria parasite Plasmodium falciparum with Dan Carucci at the Naval Medical Research Center in Silver Spring, Md. In addition, Quackenbush has continued an ongoing initiative at TIGR, known as the Gene Index databases, to assemble existing EST data for more than 60 species and produce a representation of the transcribed sequences within their genomes. “John is one of the most productive investigators I know,” says Claire Fraser, TIGR’s president.

Quackenbush is perhaps best known for his software for analyzing microarray data. His tools include Resourcer, which allows researchers to compare data collected with one microarray platform to those from another, such as between human gene expression data collected with Affymetrix arrays and mouse cDNA expression data, and to link data from differential expression studies to annotated genome sequences. “His freeware is what it should be,” says Vivian Cheung, a microarray researcher at the University of Pennsylvania Medical School. “The software is held to a high standard, and he really supports it.”

Around the lab, Quackenbush is known for his hands-off approach to guiding his postdocs and lab personnel, says Priti Hegde, one of his first postdocs at TIGR, who met Quackenbush when he was dressed as a French maid for a TIGR Halloween party. The next year he came as a Spice Girl, although his cross dressing ended after that because “it lost its ability to shock people here,” says Quackenbush.

Far from a micromanager, he is a scientist with “absolutely no ego” whom his group members have no qualms about calling any time of day or night with a problem — scientific or personal, Hegde adds. He keeps his office ornamented with curios, including a collection of Jesus fish with slogans such as “Evolve,” “Darwin,” “Alien,” and “Gefilte” (he’s seen but not yet acquired “Buddha” and “Holy Mackerel”).

Assessing his own approach to running a lab, Quackenbush returns to his roots in the physical sciences, stressing that his problem-solving background allows his group to straddle the fence between biology and the software required to make sense of biological data. “What’s odd about biology is the dichotomy between those who do software and those who do experiments,” he says. Just as Quackenbush had to scramble to learn the fundamental biology, he likewise requires all his postdocs with backgrounds in biology to take programming classes. “Those who are successful stand on both sides of the dividing line,” he says.

The Scan

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Preprints OK to Mention Again

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Hundreds of Millions More to Share

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