There's good news and bad news for rats. The good news is that common rats with a genetic mutation can develop a resistance to rat poison, also known as warfarin. The bad news? The mutation leaves them vulnerable to arterial calcification and, down the road, osteoporosis.
The mutated gene could be the solution to the so-called calcification paradox, the puzzling connection between metabolic bone disease and vascular calcification. Part of the answer lies in the vitamin K cycle, which regulates blood clotting and is thought to keep calcium out of the body's bones and vessels.
Warfarin, which humans have long used in a medicine called Coumadin, interferes with the vitamin K cycle by thinning blood and reducing its ability to clot; it is often used in the treatment of heart attacks, strokes, and blood clots. In larger doses, Coumadin was once used as a rat poison that caused overbleeding in rodents, until a gene mutation effectively blocked it.
Now, Kohn, an assistant professor of ecology and evolutionary biology, hopes the equivalent gene in people turns out to play a similarly key role.
"As you look at humans, this calcification of arteries is, I suspect, a very important precondition to thrombosis and stroke," Kohn said in a press release announcing the findings. "So to find such a strong effect was shocking to us. We had a tough time publishing the paper because people might have thought it was too good to be true, that you can explain the effect to such a degree by looking at just one gene."
Kohn also noted that Alzheimer's patients tend to be vitamin K-deficient. "Could there be one mutation that explains osteoporosis, arteriosclerosis and Alzheimer's? That would be huge," said Kohn.
The findings helped Kohn land a grant of $900,000 from the National Heart Lung Blood Institute at the National Institutes of Health; Kohn will now use mutant and normal rats to pinpoint additional genes that respond to warfarin.
There are two thrusts to the study: First, to see if rats have additional genes to battle poisons that are more potent, and second, to fine-tune doses of Coumadin for humans.