Lake Union lab suddenly a force

Seattle is home to well-known scientific powerhouses such as the University of Washington and Fred Hutchinson Cancer Research Center.

But most locals would be hard-pressed to name the upstart that bested all U.S. research labs in a recent ranking of scientific clout: the Institute for Systems Biology (ISB).

"For an institution that's only 10 years old, this is nothing short of remarkable," said Dr. Leroy Hood, the maverick biologist and entrepreneur who split from the UW to form ISB.

Hood's ambitious goal is nothing short of a revolution in medicine.

At the institute's complex on the north side of Lake Union, biologists, engineers and computer wizards are working to unravel the intricate web of genes, proteins and biochemical signals underlying human disease.

Hood is convinced the work will lead to better drugs, earlier diagnoses and "personalized medicine" — the ability to more precisely tailor medical treatments to individuals.

Landing on a list ahead of Harvard University, the Massachusetts Institute of Technology and other elite research centers shows ISB's approach is paying off, said co-founder Alan Aderem.

"There were a lot of naysayers when we started."

ISB made national headlines last month for its full-genome analysis of a family of four from Utah. The work pinpointed the mutation responsible for a disfiguring disease that affects the family's two children.

The institute also scored a surprising coup when the tiny European nation of Luxembourg decided to invest more than $100 million to pioneer personalized medicine. ISB scientists will sequence the genomes of 100 Luxembourgers to identify genetic variations linked with disease and drug response.

But one of the main reasons ISB isn't a household name in its hometown is that much of its research has focused on far humbler creatures: yeast, sea urchins and the type of bacteria that thrives in the Great Salt Lake.

That's because systems biology is so mind-bogglingly complex it would have been impossible to start with human studies, Aderem said.

Even Hood struggles to explain the endeavor in simple terms. At its core, he said, it looks at living things holistically, rather than focusing on single genes or pathways.

In the past, Hood has offered analogies to automobiles and football to make the point that the whole is greater than the sum of its parts. These days, he favors the radio.

If engineers wanted to figure out how a radio works, first they would break the machine into its components, he said. Decades of research on the building blocks of life and the sequencing of the human genome have provided an equivalent parts list for biology.

To understand how a radio functions, though, it's necessary to assemble the parts in circuits and see how they interact. In humans, the circuits can include thousands of proteins, scores of genes and multiple environmental factors that interact to cause a disease like diabetes.

Daunting complexity

Until recently, there was no way to sort out such tangled networks. The best scientists could do was to focus on individual genes or the workings of a particular enzyme — an approach that has proved disappointing in terms of medical breakthroughs.

Now, a new generation of lightning-fast machines coupled with unprecedented computing power is providing a big-picture view.

Hood kick-started the era with his development of automated DNA sequencing machines that made the Human Genome Project possible. ISB scientists spend a lot of time designing similar tools to identify and measure the mélange of molecules that are crucial to the way cells function.

One of the institute's most influential projects described a method to identify and measure hundreds of proteins in a drop of blood.

That ability is crucial to one of Hood's objectives: pinprick tests that diagnose disease in its earliest stages by detecting minute changes in a person's blood.

A big chunk of ISB's floor space and energy is devoted to computer processors and the programmers who interpret the blizzard of data churned out by systems biology. To identify "biomarkers" that show up in the blood before the onset of a mad-cow-like disease in mice, ISB scientists analyzed 30 million biological measurements.

"The human mind itself is not capable of integrating that amount of information," Aderem said.

Skeptics of systems biology said it wouldn't be possible to sort through haystacks that big and pick out useful information. Those who remain skeptical note that the field hasn't delivered blockbuster drugs or diagnostic tests.

Systems biology is still in its infancy, Hood admits.

In the early days, he put up $5 million of his money to keep the institute afloat until it could attract funding. ISB still hasn't scored the major endowment Hood sought, but its budget hovers around $50 million a year, mostly from federal grants. At least 100 other systems-biology programs have sprung up around the world in the past decade.

Influential studies

The scientific-clout ranking from SCImago Research Group, based in Spain, is a testament to the way systems biology is shaping medical research, Hood said.

SCImago examined citation rates, the scientific equivalent of baseball players' batting averages. How often other researchers reference a study reflects its influence. A turn-of-the-screw journal report might get a handful of citations. A game-changer can garner a few hundred.

Several ISB studies have been cited more than 500 times. Some have racked up more than 2,000.

SCImago concluded that ISB's scientific impact between 2003 and 2007 was more than triple the worldwide average. Only two institutions out of 2,000 ranked higher: one in Britain and one in France.

"Maybe 1 percent of papers really have a dramatic impact in terms of changing how people think about science," Hood said. "This says that in the United States, ISB has more of those papers, per capita, than any other institution."

Scientists at other institutions are less impressed by the ranking. As with livability indexes that put Portland on top one year, and Pittsburgh the next, there's room for disagreement on the yardsticks and how they're used.

But few deny that ISB has turned out groundbreaking research.

"ISB is a great place that has accomplished a lot in a short time," said Peter Sorger, of Harvard Medical School's Department of Systems Biology.

But the field is fraught with hype, he cautioned. "The notion that suddenly there's this powerful tool that's going to change the world is not realistic."

Human applications

Much of ISB's work is shifting to projects with more direct relevance to people. Aderem and his colleagues are working on computer models of the immune system, which will allow them to predict whether a vaccine is likely to work and the possible side effects of new drugs.

Cardiologist Dr. Elizabeth Gold is working to understand the cascade of events that leads to the formation of artery-clogging plaque — and how to short-circuit it.

Gold has been aided by advice from one of her office-mates: an acclaimed astrophysicist who helped her learn how to deal with massive amounts of data.

Unusual collaborations are one of ISB's hallmarks. The staff includes engineers, oceanographers, experts in stem cells and database designers. "It's a fantastic sandbox," Aderem said.

As a nonprofit, ISB has shucked off the bureaucratic constraints of a university while maintaining the freedom to pursue research for its own sake. The institute also can react quickly to opportunities — such as the offer from Luxembourg.

When it comes to recognition among the general public, however, Aderem admits the "systems biology" tag is a handicap. Consultants repeatedly have advised a name change.

But that's not likely — unless a wealthy donor steps forward with a lot of cash and a desire to see his or her moniker on the door.

"I suspect we might be open to that," Aderem said with a laugh. "If we found the right benefactor."

Sandi Doughton: 206-464-2491 or sdoughton@seattletimes.com

A previous version of this story ("Fremont lab suddenly a force"), published April 5, 2010, and corrected April 7, 2010, incorrectly stated the location of the Institute for Systems Biology complex. The complex is in Lake Union.