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Scientists' work: of mice and men and vitamin C

Carolina scientists have successfully developed the world's first mice incapable of synthesizing vitamin C, a nutrient essential for growth and healthy bones, teeth, gums, ligaments and blood vessels. The genetically engineered research mice should become a valuable tool in determining vitamin C's role in health and illness, the scientists say.

Nobuyo Maeda, professor of pathology and laboratory medicine at the School of Medicine, and her colleagues have previously generated mutant mice that showed high cholesterol and atherosclerotic lesions like those found in humans. Such mice now are used widely in research laboratories throughout the world.

"By inactivating a gene that is a key enzyme in ascorbic acid synthesis, we have generated mice that, like humans, depend on dietary vitamin C," Maeda said. "If they don't receive supplementary ascorbic acid, which is another name for vitamin C, within five weeks they become anemic, begin to lose weight and die."

As levels of vitamin C in the mice's blood drop, small but significant increases in their total cholesterol can be measured along with decreases in high-density lipoproteins, the so-called "good cholesterol," she said. But the most striking effects of insufficient vitamin C in the mice are abnormal changes in the wall of the aorta, the main artery channeling blood from the heart to the body.

"Marginal vitamin C deficiency affects the vascular integrity of mice unable to synthesize ascorbic acid, with potentially profound effects on their susceptibility to vascular diseases," Maeda said.

A current, controversial theory about important common illnesses affecting many people such as heart disease and cancer is that oxidative stress may be an important risk factor for disease development, said Oliver Smithies, excellence professor of pathology and laboratory medicine at Carolina and Maeda's colleague. That is the basis for the opinion that antioxidants such as vitamin C or vitamin E have preventive benefits.

"However, the scientific evidence for this opinion is rather weak, partly because there has not been a good animal model system in which to evaluate it," Smithies said. "Breeding the vitamin C-dependent mice with mice carrying defined genetic mutations will provide numerous opportunities for systematic studies of the role of antioxidants in health and disease."

A report on the continuing research appeared recently in the Proceedings of the National Academy of Sciences.

"Most animals with the exception of humans, some of the higher apes and guinea pigs, can make vitamin C on their own, and so they don't need to eat it," Smithies said. "The value of the mice Dr. Maeda has made is that they are now in a sense `humanized.' That means experiments with them can combine the dietary things that have long been possible with guinea pigs with the marvelous genetic experiments that are possible only with mice."

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