How a tiny mutant worm is helping find a cure for a rare form of cancer
The Williamson worm
The defective gene in the Williamson family altered the structure of a protein calledSDHB. SDHB has a very unusual function that needs an introductory explanation from science fiction. In theBack to the Futurefilms, Doc Brown’s time-travelling DeLorean sports car is powered by a water-fueled “flux-capacitor” that can generate vast power. Now imagine that human life itself depends on the biological equivalent of such a device that fuels our internal power generation system. In biology, SDHB is like a flux capacitor that splits apart the sugar we eat into its constituent hydrogen and electricity.
So in the Williamsons, the puzzle lay in finding out how a tiny malfunction in one DNA instruction (mutant SDHB) could cause recurrent cancer in the family. In the past attempts by researchers to make a mouse phaeo model failed to yield insight because the mice looked healthy.
A new approach was needed. By genetic manipulation of DNA, our international group created a worm model of SDHB malfunction that has yielded some new data. We chose to model phaeo using worms because the worm equivalent of SDHB has remained substantially unchanged over hundreds of thousands of years.
So, despite the vast gulf of time that separates worms from modern humans, nature had not changed the DNA blueprint for this essential “flux-capacitor” that permits the energy generation needed for life. This power generator was perfected over 400 million years ago and still works unchanged in animal cells today.
The results
The results are revealing because it was immediately obvious that the Williamson mutant worms are sick, sterile, small and sickle shaped. Importantly, the changed appearance can be further investigated by mating them with other mutant worms with other cancer-causing genetic defects. This is underway. In the meantime, a few conclusions can be drawn.
First, the Williamson family mutation does not delete the whole SDHB gene in the affected DNA. This family has a differently folded three-dimensional “origami” structure to their SDHB protein driven by the wrong instructions from their mutant SDHB gene. The Williamson SDHB protein is misshapen, exactly where fuel metabolism occurs. These worms also make so much less of this mutant misshapen SDHB protein. So Williamson worms have contributed something new to nature.
Second, Williamson worm power stations – ormitochondria, the part of the cell that transforms what we eat (proteins, sugars, fats) into energy – use a very different fuel mix. Normal SDHB runs like a car that can seamlessly switch fuel sources when one fuel runs low. Williamson worms cannot do this and they can only partially burn fuels to releaselactic acidas a “frustrated” end product ofglucose metabolism.
So when pushed to perform at their collective personal best, and despite plentiful oxygen trapped inside a tiny molecular cage or cavity made of iron and protein found inside all mitochondria, the Williamson mitochondria cannot effectively maximize their energy output.
Third, and rather excitingly, it is possible to kill Williamson worms with drugs that leave normal worms unscathed. This is where new hope arises because at the moment there is no cure for the Williamson cancer. The search is now on for useful drugs to test in animals, and the findings of this research mean they could now be developed.
Finally, SDHB has just been found to be abnormally controlled across a wide variety of common cancers which adds to the potential of this worm research. Which means that rare and common may well be different manifestations of the cancer process.
This article byAnil Mehta, Honorary Reader in Experimental Medicine,University of DundeeandGordon Stewart, Emeritus Professor of Experimental Medicine,UCL, is republished fromThe Conversationunder a Creative Commons license. Read theoriginal article.
Story byThe Conversation
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