Finding health in fragility

A unifying principle for protein networks' weaknesses could aid development of new drugs

Normal 0 false false false MicrosoftInternetExplorer4 GOTHENBURG, Sweden —Woody Allen might have coined it: the law of conservation of fragility. If part of a biological network gets stronger, some other part is bound to get weaker, new research shows. Its total fragility never gets better or worse, it just stays the same.

Rather than being a statement of pessimism, this new law of conservation offers hope for finding better drug targets to treat diseases such as diabetes, heart disease and cancer, according to research presented by Hans V. Westerhoff, systems biologist at the Manchester Centre for Integrative Systems Biology at the University of Manchester, England, and at the Netherlands Institute for Systems Biology in Amsterdam. He presented the work August 24 during the International Conference on Systems Biology in Gothenburg, Sweden.

“The system may be robust in some places, but it must also be fragile in some other places,” Westerhoff says. “If you’re developing a drug, you might want to target these fragile places.”

Westerhoff’s team found that, when all the fragility measurements for the proteins in a network are added, the total always equals one. The team’s novel measure of fragility is based on the amount of change in a protein’s activity necessary to reduce the network’s overall output by exactly 1 percent. A network’s output could be a converted form of a sugar or a signaling molecule, for example.

If a small change in a protein is able to cause this much disturbance, the protein is considered a fragile spot in the network.  On the other hand, the activity of a robust protein could change to a much larger degree without upsetting the network.

Since these measures of fragility always add to one, whenever part of a network becomes more robust and stable, some other protein must become more fragile to compensate.

“You could consider this a law of networks, a law of systems biology,” comments Barbara Bakker, a systems biologist at VrijeUniversity in Amsterdam who has collaborated with Westerhoff on related research. “To apply it to drug development is definitely a new idea.”

This tradeoff leads to some surprising results. Westerhoff and his colleagues analyzed the fragility of proteins in a signaling network called the MAP kinase pathway. Mutations that trigger overactivity of RAF, a protein in this pathway, are common in a wide variety of human cancers. Because extra activity of RAF contributes to cancer, common sense might suggest that scientists should design drugs to inhibit RAF.

“It’s the wrong thing to do,” Westerhoff says. In cancerous cells, RAF is actually less fragile than it is in cells that are healthy, Westerhoff’s team showed. That means cancer cells would be less vulnerable to a drug targeting RAF than healthy cells would be, the research suggests. In other words, the drug would cause greater damage to healthy tissues than to the tumor. Westerhoff suggested that such unintended effects could help explain why many drug candidates fail during clinical trials, often because of unexpected toxicity.

But conservation of fragility predicts that, if RAF is less fragile in cancer cells, some other protein must be more fragile. Westerhoff and his colleagues showed that a protein adjacent to RAF in the signaling cascade becomes more fragile in cancerous cells. A drug targeting this neighboring protein would disrupt tumor cells more than healthy ones.

Scientists have previously used other methods to measure the opposite trait, a protein’s robustness. But these efforts led to the conclusion that the total robustness of a network of proteins is always conserved — an idea that Westerhoff’s research overturns.

“We’ve proved that robustness is not conserved, but that fragility is,” Westerhoff says.

He adds that looking at fragility within a network, rather than just considering individual proteins, could be fruitful for finding new drug targets for a number of hard-to-treat conditions such as obesity, arthritis and even aging. “Humanity’s been able to find treatments for a lot of other, simpler diseases,” he says. “These harder diseases remain unsolved because they aren’t caused by individual proteins. They’re diseases of the network.”

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