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Sunlight and Systems Biology in Seattle

By John Russell

Nov. 13, 2007 |  SEATTLE — On this Monday in July it is not raining in Seattle. Apparently this is typical in summer and contrary to the region’s dreary image. A record-setting heat wave had bikers and joggers out in force under bright sun. Inside the Institute for Systems Biology (ISB),  thirty or so “students” gathered for the first day of ISB’s intensive week-long introduction to systems biology course and I was one of them.

It was a diverse group, drawn heavily from academia. About half had Ph.D.s (or soon will) in something and their experience ranges from newbies and post-doc (several) to experienced researchers (somewhat fewer). The rest had varying backgrounds. Gautam Venkatesan, a Stanford University-trained economist with experience at Hewlett-Packard and a software startup, ended up asking many of the week’s most interesting questions. There was a high school biology teacher from Tacoma, a medical lab worker from Dubai, and, of course, a science journalist (someone has to drag down the curve).

It was also a decidedly international group. There were attendees from institutions in Sweden, Italy, Switzerland, Spain, Qatar, and the United States. For five days, we were immersed in the concepts and tools that comprise systems biology (SB). We tackled a lab experiment designed to put SB ideas and tools into practice — measuring, analyzing, developing a hypothesis, and then testing the hypothesis. By the end of the course, “Each student should be able to develop a research outline that could form the core of a systems-based grant application,” say course materials.

That seemed like a stretch for me, but not for more advanced participants. In fact, one attendee, Scott Berceli, has already done just that. Berceli is a vascular surgeon affiliated with the University of Florida who also has Ph.D. in chemical engineering.

“I attended the course with a specific purpose,” he said, “to realign some of my multidisciplinary research activities with some of latest concepts in systems biology. In particular, the discussion of gene regulatory networks, and mathematical approaches for solution of these complex systems, provided me an important step forward in re-tooling my ongoing research efforts.”

Systems Projects
No stranger to molecular biology, the course proved broadly useful to Berceli but perhaps more valuable were independent meetings with ISB founder Leroy Hood and other investigators at the ISB, which provided a cornerstone for an NIH/ NHLBI systems biology proposal Berceli submitted in September 2007.

Berceli’s ambitious proposal, “examines vascular remodeling through a multi-scale approach, conceptualizing the process of vascular adaptation as two parallel, but interconnected, processes. The global remodeling response is mediated through variations in the gene regulatory network, while the focality of lesion development is modulated through the dynamics of monocyte homing to regions of altered flow.”

My goal was more modest: to have a hands-on experience (lecture, lab, and informatics tools) that crystallized the ideas, goals, and future directions of systems biology. Berceli was part of my lab group, and his guidance helped ensure my unpracticed lab skill didn’t muck up our piece of the class experiment. Indeed one of the cornerstones of systems biology is multidisciplinary collaboration and the 3- and four-person lab groups we divided into delivered a bit of that experience.

No doubt ISB has many goals in offering the course. Planting SB project seeds was certainly one, and that’s happening to some degree as exemplified by Berceli’s grant proposal. A few attendees said they had “job interviews” lined up inside ISB during the week so clearly recruiting is also going on. Identifying possible collaborators is another objective. And, of course, just getting the systems biology word out is important. The cost is fairly modest, $2000 for corporate attendees and $750 for students and postdocs. (ISB waived tuition for me.)

The opportunity to directly interact with Hood and prominent ISB staff was clearly a big attraction. Hood kicked off the week with an hour-long discussion of systems medicine and offered his definition of systems biology (see ISB Is a Sure Cure, Bio•IT World, Aug. 2007). Hood’s vision is powerful and his track record impressive. He takes aim at biology’s past dependence on rote memorization and cites his early training as an undergraduate at CalTech. He had Richard Feynman for freshman physics and Linus Pauling for freshman chemistry. Nice lineage! Both emphasized conceptual clarity and quantitative approaches, says Hood, and that’s stuck with him — the essence of systems biology.

Hood along with Reudi Aebersold and Alan Aderem founded ISB in 2000 to help chart systems biology future. Since that time ISB has broken a good deal of new ground in systems biology (particularly in technology development), championed the cause of multi-disciplinary teams and approaches to solving biological questions, assembled a faculty of 12, grown to about 200 staff, and spun a few companies out to commercialize technologies developed there. Indeed, Hood’s often-repeated belief that new technology (instrumentation) is necessary to advance all sciences is a dominant theme at ISB.

Buoyed by Hood’s opening salvo, the real work of the course began. Most days had two components, class and lab (wet and informatics). We started promptly at 8:30 AM and finished around 4:30 PM. ISB staff provided lectures on all things SB, including proteomics, functional genomics, network analysis, modeling techniques, systems genetics, hypothesis generation and testing, etc. Much of the material is readily accessible, but instructors often dig deep and are generally willing to have follow-up discussions later.

SB in the Lab
The lab exercise is designed to demonstrate an SB approach. We attempted to learn how a salt-loving bacterium, Halobacterium NRC-1, responds to copper stress. We did some cell culturing, took samples at different times, extracted RNA, determined its quality, labeled it, ran the microarrays, processed the raw data, used informatics tools to store, visualize and analyze results, imported appropriate pathway data from public sources, developed a hypothesis, and tested the hypothesis. In other words, quite a bit.

Some of us (me) hadn’t pipetted since the days of mouth pipetting! One of us (not me) cleaned a slide before the sample was applied, wiping off the probes! Our slides, prepared by ISB, had the full set of the bacterium’s 2400 genes. Fortunately, we were repeating portions of an experiment ISB has previously published. And the ISB staff was well prepared for most contingencies. Perhaps most surprising was that most of our data turned out to be quite useable.

A fair amount of time and effort throughout the course was devoted to introducing basic informatics tools and, again, the range of familiarity with those tools varied widely among attendees. Each student was provided with a laptop in class, and ISB personnel were generally able to keep students on track though it was occasionally challenging.

ISB primarily uses open source tools, many of which have been developed by ISB. The institute uses a home-grown software framework called Gaggle Boss, into which individual software tools called — you guessed it — Geese are plugged. A researcher can move data fairly easily from one tool to another using Gaggle. A few of the tools we used included Cytoscape; R statistical environment; Data Matrix Viewer; and we imported data from the KEGG database.

The class tentatively identified two responses to stress including gene networks for a chelating agent and a membrane transport mechanism; we then confirmed the findings.

Course director John Aitchison emphasizes, “[The course] provides an overview of systems biology, including sufficient background to understand the strengths and limitations. Systems biology can do a lot of things, but it does not work miracles. Students [will] understand its possibilities, get a sense of the promise, get excited about it and, where possible, incorporate systems thinking and systems biology into their projects.”

Venkatesan was sufficiently inspired to subsequently enroll in a genomics and proteomics course at the University of Washington, Department of Genome Sciences. “I hope to work in industry,” he says. “The people at ISB are truly distinguished pioneers. It is difficult to overestimate the complexity of the data and methods that we are undertaking.” It’s not hard to imagine this ‘02 Stanford grad running a SB company and, of course, Berceli has high hopes for his grant.

On the final day, Hood again addressed the class. His broad opening and closing presentations served as bookends for our time at ISB. This time he also took considerable time to answer the class’s many questions — the crowning event on what was a very worthwhile week.
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