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Seattle Biomed pioneering ‘rational’ approach to vaccines

Seattle Biomed's Alan Aderem, left, and Dan Zak examine results of a systems biology analysis of young people with TB.
Early anti-vaccine hysteria. Cartoon of Edward Jenner administering cowpox vaccine to frightened young women, and cows emerging from different parts of people's bodies.
Early anti-vaccine hysteria. Cartoon of Edward Jenner administering cowpox vaccine to frightened young women, and cows emerging from different parts of people’s bodies.
Wikipedia, James Gilray

Vaccines are widely, legitimately, hailed as one of medicine’s most powerful weapons in the fight against infectious disease. Millions of lives are saved, deaths prevented, every year using this simple tool that can cost as little as a handful of pennies.

Holy bang for the buck, batman!

So it’s unfortunate we know so little about how vaccines actually work. Not knowing has spawned a persistent anti-vaccine movement by those who fear, based on little hard evidence, the potential for harm caused by tweaking our immune system.

But not knowing is also causing some problems for the biomedical community.

“I don’t see how we’re going to ever develop effective vaccines against AIDS, TB or malaria without first gaining a lot more insight into how the immune system works – and how vaccines promote immunity,” said Alan Aderem, president of Seattle Biomed, a research organization that has been working on matters of global health since Bill Gates was a teenager.

Aderem and his colleagues are proponents of a relatively new approach to studying disease, and especially for doing vaccine research and discovery.

Arguably, the science of vaccine discovery hasn’t changed much since the days of Edward Jenner, the 18th Century British physician who (unethically, by today’s standards) injected a boy with pus taken from a milkmaid infected with cowpox. Jenner had noticed milkmaids don’t get smallpox. He theorized that if you injected someone else with whatever it was in the milkmaid’s reaction to cowpox, you could also protect against smallpox.

Jenner was right and the first vaccine, against smallpox, was created (to much hysteria and fear back then as well). Since Jenner’s day, the methods of developing and testing experimental vaccines have become vastly more sophisticated – using recombinant DNA techniques, testing only pieces of killed viruses (as opposed to whole, live bugs like Jenner did) and so on.

But, behind all the sophisticated new methods of developing and refining experimental vaccines, the final test in humans doesn’t look that different from Jenner’s day. Inject and see what happens.

“That approach isn’t working any more for some of our biggest problems in global health,” Aderem said. The scientific community has failed to find effective vaccines against HIV, TB and malaria, he said, largely because Jenner’s ‘hit and miss’ strategy doesn’t reveal why vaccines may not work.

The approach Aderem and his colleagues are advocating is known as systems biology and, until recently, most other scientists thought it would be about as useful as waving your hands at the stars to convince God to cure a person’s disease. Some still think that. I, too, had my doubts when I first heard about the scheme from Leroy Hood – the celebrated father of automated DNA sequencing machines and Aderem’s former boss at Seattle’s Institute for Systems Biology.

Okay, there’s no question Seattle is at the epicenter of systems biology. But what the hell is it exactly?

Systems biology is, very simply, about making use of powerful computers to sift through and explore massive amounts of biological data – be it genes, proteins, gene-protein interactions or immune system cells  – to identify otherwise hidden goings-on in the body. Rather than start with a hypothesis and test it using the typical reductionist methods of science, systems biologists like Aderem just sort of set things in motion to see what emerges.

That’s basically why some scientists think systems biology is bunk. If you don’t design an experiment to test a theory or hypothesis, critics say all you will end up with is some elegantly crafted, computer-generated meaningless ‘patterns’ and pointless emergent data points.

Aderem and one of his lead scientists at Seattle Biomed, Dan Zak, say the critics are stuck in a rut. The whole point of using systems biology is to avoid the obstacle of having to propose a starting hypothesis. That mindset has stalled progress in vaccine research, they contend, because we lack the knowledge needed to come up with new hypotheses. What they think we need is a ‘rational design’ strategy, a systems approach, to crafting new vaccines.

Seattle Biomed's Alan Aderem, left, and Dan Zak examine results of a systems biology analysis of young people with TB.
Seattle Biomed’s Alan Aderem, left, and Dan Zak examine results of a systems biology analysis of young people with TB.

As an example of why they think their approach holds promise, Zak and Aderem have been working with scientists at the University of Cape Town in South Africa studying some 6,000 adolescents at risk for tuberculosis. The world desperately needs a better vaccine for TB, a big problem in South Africa and worldwide due to growing drug resistance.

TB is a bizarre disease, a bacterium that doesn’t really act like most infectious agents – sealing itself off in capsules in the body and remaining dormant (latent) for decades only to emerge as a disease later, triggered by a decline in a person’s immunity (due to HIV or some other affliction). It also evolves very slowly, which should make it less likely to be resistant and easier to treat with drugs. But it isn’t.

“There’s an awful lot we still don’t know about the basic biology of TB in the human body,” Zak said.

Zak, Aderem and the South Africans hope to use systems analysis techniques to identify changes in gene expression and protein activity within the cells of these adolescents. They don’t really know what they are looking for, Zak acknowledged, but patterns are emerging that hold tantalizing clues.

“We can see which genes are turned on in the blood of people who progressed to active disease,” Zak said. They aren’t necessarily looking for a single indicator but for pattern or ‘networks’ of change.

“We are seeing predictive changes,” says Zak, adding that the research is not yet published. He believes their findings will identify new players in the immune response that will then lead to better drugs or a better TB vaccine. It would be impossible to find these cellular ‘needles in the haystack’ through traditional, reductionist science, he said.

“The problem with drugs is they usually have a single target,” Aderem says. “If we can hit an entire network, or critical nodes in a network, it’s much harder for the bug to get around the treatment.”

The systems biology approach appears to be winning over the critics, Aderem said. Tonight, at Seattle Biomed’s annual Passport to Global Health celebration, he and others will talk about the progress they’ve been making on this front and some of the new big projects in the works. Some of that progress includes multi-million dollar grants for systems biology studies.

“It wasn’t that long ago we couldn’t get a single grant for systems biology work,” Aderem said. “The change in the last few years, toward accepting this new approach, has been quite amazing.”

For you scientists, or nerds, here’s a more detailed news report I wrote for Nature on the promise and controversial aspects of using systems biology for vaccine research and development.


About Author

Tom Paulson

Tom Paulson is founder and lead journalist at Humanosphere. Prior to operating this online news site, he reported on science,  medicine, health policy, aid and development for the Seattle Post-Intelligencer. Contact him at tom[at] or follow him on Twitter @tompaulson.