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By John Russell

February 18, 2004 | What’s really up with systems biology?

Biologists can’t agree on a definition. Pharma is happy to let others do systems biology. Doctors and medical schools largely ignore it. Starry-eyed venture capitalists gush about the opportunity, but the few systems biology companies to actually venture forth have suffered the slings and arrows of disappointed investors decrying a lack of fortune.

True enough, but not terribly important, said Leroy Hood at last month’s Symposium in Systems Biology, hosted by MIT’s Computational and Systems Biology Initiative (CSBi)*. 

“My prediction is we will have predictive medicine in the next 10 to 15 years,” said Hood, co-founder and president of the Institute for Systems Biology (ISB). “There are really two dimensions to this. First, if we can do your genome, we’ll look at your genes and write up your probabilistic health history.

 “Second, the blood is a wonderful window that gives you a view of how environmental perturbations interacted upon the individual. I think in 7 to 10 years, we’ll be able to use microfluidic approaches and have a little handheld device that takes a small droplet of blood from your thumb and analyzes 10,000 elements in it, and then be able to distinguish between health and disease.”

If there is a muse for systems biology, Hood is it.

For two frigid days in Cambridge, Mass., leading bioscience figures discussed and debated what constitutes systems biology, how best to teach it, and what its payoff is likely to look like. David Botstein (Princeton University), George Poste (Arizona State University), Marc Kirschner (Harvard Medical School), Matthew Scott (Stanford University), Huntington Willard (Duke University), and Peter Sorger (MIT) were among the high-profile presenters.

The opening day focused on specific research programs at MIT, while day two tackled trends in the systems biology field and various approaches that institutions are taking to teach it.

In the Eye of the Beholder
Hood, while conceding “systems biology is still in the eye of the beholder,” defended his prediction with a glimpse into ISB research. “[ISB co-founder] Ruedi Aebersold has developed a wonderful new blood proteomics diagnostic technique. The problem with proteomics diagnostics is that six proteins constitute 80 or 85 percent of the serum. So they bury all of the lowly expressed proteins.”

Aebersold has found a way “to make those six proteins invisible by looking only at proteins that have N-glycosylated residues, and in fact only looking at tryptic peptides from those proteins.”

Briefly, the technique involves getting the N-glycosylated sites to “bead,” cleaving the proteins with the enzyme trypsin, thereby throwing out 98 percent of the serum proteins. The remaining proteins are labeled, purified, and put through a MALDI mass spectrometer. Aebersold has performed this with proteins from normal mice and mice with skin cancer induced by chemical carcinogens.

According to Hood, “The results really were spectacular … He got 3,000 unique peptides, which came from roughly 1,000 proteins, and he found that 100 of these peptides really were quite diagnostic … You see how clean the proteomics profile is of this kind of thing.

“The blood is going to be a fascinating window that lets you predict before you have any phenotypic example of disease. We’ve done similar experiments in mice that get type I diabetes, and we can say that the answer to that question is yes, very beautifully.”

Hood said that improving assay technology -- particularly microfluidics and nanotechnology -- along with better data integration and new visualization tools are the keys that will unlock the power of this kind of systems biology. Indeed, so-called “nanostrings” used for single-molecule identification were important in Aebersold’s research. ISB recently created a for-profit “accelerator” to spin out companies focusing on pivotal systems biology technologies, including one based on Aebersold’s research. 

Training Day
When discussion turned to training the next crop of systems biologists, the need for cross-discipline education -- physics, mathematics, computer science -- was taken as a given. But strategies differ widely.

MIT’s approach is decidedly universitywide, drawing on expertise and teaching assistance from various departments.

Princeton’s newly formed Lewis-Sigler Institute for Integrative Genomics (see “Learning the Language of Systems Biology,” Dec. 2003 Bio-IT World, page 22) has created an undergraduate program designed to infuse rigorous quantitative methods into all its courses. After two years, students can transfer to any other major -- physics, for example -- and be deemed ready for all advanced courses without having to backtrack.

Harvard Medical School has created a new Department of Systems Biology -- the university’s first completely new department in more than two decades. Hood complained that he is often invited to speak at medical schools, but no one listens, even though doctors will presumably be the ones running predictive models.

“Why create a systems biology department at Harvard Medical school?” department founder and chairperson Kirschner asked rhetorically. “I stay awake at night sometimes, wondering whether they made the right investment, but I’m confident it makes sense at this point. Whether it succeeds is another question.”

“We’re a full academic department with four faculty [who] come out of the cell biology department who I don’t think represent the center of systems biology, but it’s what we’ve got to go with. They’re people who [have] reasonable quantitative backgrounds and interest in the kinds of problems we’ve talked about,” Kirschner said.

Harvard plans to add another 20 or so full-time positions in the next 10 years, all backed by endowment. Kirschner said: “Our two major research priorities are to understand the stability of the living state, really go back to the problem of homeostasis, and then -- and this gets to the medical side -- to be able to predict the impact of perturbing systems, to understand what mechanisms bring it back into balance, what happens when these mechanisms fail, understand the root causes of disease, and understand the genetic basis and pharmacological intervention.”

But Kirschner cautioned the audience not to get “overwhelmed with enthusiasm for mathematical biology” because of its checkered history, noting there have been few great accomplishments. “I would maintain that the subculture of mathematical biology has had little influence on biology or other physical sciences,” he said.

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*CSBi 2004 Symposium in Systems Biology (MIT): Cambridge, Mass., Jan. 8-9.





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