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The Land of Lincoln

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They say that necessity is the mother of invention, and in the case of Lincoln Stein, necessity inadvertently gave birth to one of the most influential bioinformaticists to date. It may be hard to believe, but Stein, now a professor at Cold Spring Harbor Laboratory, happened upon bioinformatics as a graduate student when he could not afford the $15 monthly fee charged by Harvard's biology department to analyze a nematode gene sequence. The young Stein was so short on cash that instead of coughing up the $15 to the department's VAX system, he instead went home and proceeded to write his own sequence assembly program using the now ancient 6800 Assembly Language on his equally antique Macintosh computer.

During his graduate days in the late 1980s, Stein was strictly focused on cell biology — although he does acknowledge that a longtime interest in computers, having taken a class at IBM's Watson Research Lab during high school.

Stein is respected for the many contributions to both computer science and biology he has made over the course of his nearly 20-year career. For example, in an effort to publish genome maps to the Web in the early days of the Internet, Stein developed CGI.pm, a Perl module that became an integral tool in the transformation of the World Wide Web's initial incarnation as a sea of one-dimensional directory pages to more interactive, database-supported websites. Stein is also a core member of the Bioperl project, an international effort to develop Perl-based bioinformatics applications. He helped launch the online resource Wormbase for the C. elegans community, and is a major contributor to the HapMap project as director of the International HapMap Project Data Coordinating Center.

His current area of focus centers on the integration of biological information to understanding the effects of genetic variation on phenotype, as well as reanalyzing whole-genome association studies via HapMap data sets using biological pathways in the Reactome database, another Stein-led Web resource.

Beyond his bioinformatics contributions, Stein says his best bit of work was a study in which he led a large group of colleagues and students to do the full analysis of the C. briggsae genome and compared it to that of C. elegans. The study covered everything from very low-level gene prediction and functional annotation to the analysis of repetitive and conserved elements. "It was kind of neat to look at how the two gene families have evolved, and one of the unexpected things we found was that C. briggsae has many more olfactory receptors than C. elegans," Stein says. "This has raised the questions of what in the microenvironment that the two nematodes live in is different that one needs more olfactory receptors than the other. We still haven't solved that."

Early in his career, Stein was able to parlay his postdoc position in Nathan Goodman's lab at the Whitehead Institute into a full-time job. After Goodman left in 1994, Stein took his place as director of the informatics core at the Whitehead. It was during this time that he began his apprenticeship with Eric Lander, who Stein says was a huge influence on the way he conducts himself now as a principal investigator. "The way he worked with me was to set out the problems, send me off to find the solutions, and then to come back and present them to him where he would then systematically tear them apart," he says. "I learned a lot better by working independently and trying to find my own solutions and getting the feedback rather than [having him] micromanaging me."

Because his research lies at the junction of biology and computer science, Stein looks for postdocs and graduate students who have experience with both disciplines. "I really try to find people who have both background in biology and a background in quantitative systems or who have stats training," he says. "It is difficult for somebody to get into it if they don't have exposure to a little bit of both." Beyond that, Stein looks for students who have a real passion for research and are motivated by a driving curiosity.

More than anything, Stein wants his students to leave his lab with the ability to critique their own work. "I like people to be very skeptical of their results," he says. "I really insist, although I'm not always very successful, that they be their own worst critics and really explore all the alternatives for something that they've found, rather than try and gloss over inconsistencies and deficiencies in the data." More than just being good investigators, having the ability to express themselves in written form and in scientific visualization forms using quantitative display of information is also very important for Stein's students. And although he considers himself to be a pretty hands-off advisor, he does jump in during the paper-writing phase to make sure that the young investigators' findings are conveyed accurately.

Ravi Sachidanandam joined Stein's lab after completing his postdoc at Tel Aviv University and a short stint at an Israeli biotech startup. "I had seen references to Lincoln's work on … Internet security and setting up websites, so when I saw that he was working at Cold Spring Harbor doing bioinformatics, I decided to apply there," Sachidanandam says. "So certainly his early Internet fame attracted me, and it still amazes me that he still does a lot of work with Perl and development of modules that are useful to the software community."

Sachidanandam worked closely with Stein during the early days of the HapMap project, when it was still known as the SNP Consortium. "We built everything from the ground up, and it was very exciting for me — and every day I learned something new about programming and biology," he says. "That magical time of building a new lab and setting up new operations is rare to find, and I cherish those memories."

The informal atmosphere of Stein's lab has also guided the way Sachidanandam runs and interacts with his own students today. "We never had lab meetings or weekly reports or things of that sort, and I really enjoyed this," he says. "I follow this practice in my own lab, by not having lab meetings or formal reporting, but instead having more individual interactions and expecting people in the lab to talk to each other, thereby making everyone aware of the work the lab is doing.""

Naming Names

Lincoln Stein's lab has hosted a number of students, including these:

Tristan Fiedler
Fiedler helped lead the software development group at WormBook, the online text companion to Wormbase. He is currently the assistant vice president for university advancement and an assistant professor at the Florida Institute of Technology.

Christopher Maher
During his graduate studies with Stein, Maher was tasked with identifying plant microRNAs that were later found to play a pivotal role in plant biology. Currently, Maher is a research fellow at the University of Michigan in the department of pathology, where he works to uncover the role of microRNAs in cancer.

Doreen Ware
During her time in Stein's lab, Ware collaborated o several research projects focusing plant genomics, including the development of the Plant Ontology Database, an annotated resource for plant development and structure. She is now a research scientist at USDA Agricultural Research Service and an adjunct assistant professor at Cold Spring Harbor.

Jack Chen
Chen took part in many efforts related to WormBase during his stint with Stein, including navigation, visualization, and data mining improvements. He has gone on from Stein's lab to become a mentor to his own students as an associate professor of molecular biology and biochemistry at Simon Fraser University.

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