Professor Hans Westerhoff's hypothesis of fragility in biological networks is gradually picking up steam. Science News covered it today and I described it as part of a feature on systems biology at the start of the month for the IET's Engineering & Technology.
Westerhoff's approach is deceptively simple. If you look at all the chemical kinetics model for a cell, you can calculate how robust each reaction by analysing the change in production of a target compound based on how much you reduce the amount of enzyme that supports that step. If you cut enzyme concentration by 1 per cent and the production of chemical barely budges, it's robust.
There is no principle of conservation of robustness in a cell: some simply are better at producing material than others. However, if you invert the numbers and call them the fragility of the step, they always add up to one. In a sense, fragility is always conserved. That provides drug designers with a new set of non-obvious targets. In cancers, for example, many drugs try to hit the effects of an oncogene. But the pathways controlled by those genes are often strengthened in a cancer, so they are actually poor targets. Better to look at a precursor that may have a weak link.
The idea picked up support from Professor Kwang-Hyun Cho of Korea's KAIST who has been researching into the way that genetic networks form complex interlocking feedback loops in mice. He noticed that as the number of loops increase, the more fragile they can become to certain steps being knocked out. Often these are "lethal nodes" because the networks that evolve more slowly tend to be those that are essential and they have acquired many feedback loops. "That has important implications for finding drug targets," Cho claimed. "By blocking feedback you can disturb the whole dynamic function of a network."
It does not mean you can go around knocking out all the weak steps and expect the cell to die - the calculations only work for one perturbation. A second intervention may alter the shape of the shape entirely, as Westerhoff pointed out when I talked to him at a Royal Society meeting in June.
Barbara Bakker of Vrije University points out that organisms will generally try to resist changes and use backup pathways if they have one. "We have to find the most fragile steps. But there is a risk, if we are focusing on the most fragile steps then the network as a whole will adapt more. Many will invoke gene expression network to make more of the drug enzyme," she said at the International Conference on Systems Biology in Gothenburg on Sunday.
Things can go the other way, which may be bad news for the trypanosome parasite that causes sleeping sickness. It turns out that the weakest link in trypanosome brucei is a glucose conversion. Hitting that had a surprising effect on the organism, however, leading to what Bakker called a domino effect. It turns out that if the parasite thinks it is low on sugar, which it will if it's not converting glucose, it starts to think it's back in the insect. And, instead of producing a constanly changing antibody-fooling coat, it puts on its insect coat, which is far easier to attack. So, thanks to fragility analysis and its odd lifecycle, the trypanosome turns out to be a lot more fragile than expected.
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