The Lazarus Mice

By Pat Ohlendorf-Moffat|Wednesday, July 01, 1992
RELATED TAGS: CANCER
Right now, the only way to find out whether a substance causes cancer is to expose animals to a lot of it. By forcing mice or rats to consume the equivalent of millions of cigarettes or hamburgers over a short period, researchers try to deduce what a pack or a Big Mac a day might do to a human over a lifetime. It is a dubious procedure, and cancer researchers know it. But it is the only one they’ve got.

Two researchers at a weapons laboratory, of all places, are developing a new tool that may offer a way around this problem. Physicist John Vogel and toxicologist Ken Turteltaub of the Lawrence Livermore Laboratory in California are using a particle accelerator to follow actual molecules of a carcinogen through the tissues and organs of some very unusual lab mice. We can see exactly what happens, says Vogel, when the mice are exposed to the equivalent of the heterocyclic amines in one hamburger or the benzene in a paint factory or the hydrocarbons in traffic fumes.

The idea behind their method is clever and simple: Most carcinogens contain carbon. The rarest of carbon’s three main isotopes, carbon 14, is radioactive. If you could get rid of the natural carbon 14 in a mouse, you could feed it any carbon 14-containing substance; then, with the right detection tool, you could track the molecules of that substance through the mouse as if they were meteors on a dark night. Getting rid of the mouse’s own carbon 14 would be like turning off the glare of the moon.

That’s not so easy to do. Carbon 14, though not abundant, is ubiquitous; it is made in the atmosphere by cosmic rays, is absorbed by plants like any other carbon isotope, and passes from plants into animals. But being radioactive, it decays, and at a constant rate, with a half-life of 5,730 years. Archeologists and paleontologists exploit that fact to determine how long ago an organism died and stopped absorbing carbon 14. Turteltaub exploited the same fact to raise mice containing so little carbon 14 that, according to the carbon clock, they are 11,000 years old. He and Vogel call their work the Lazarus project.

Turteltaub’s trick was to feed his mice brewer’s yeast that had been grown in natural gas, which comes from organic matter that died and lost its radioactive carbon millions of years ago. On a diet of 70 percent yeast, Turteltaub’s mice have only 20 percent as much carbon 14 as normal mice do. That makes them a fine background for tracking carcinogens.

Last year Turteltaub fed the mice phenylimidazopyridine (PhIP), a supposedly potent carcinogen in cooked meat. Usually in such tests mice ingest the equivalent of 100 million hamburgers, but Turteltaub fed each mouse the amount of PhIP in just one Big Mac. Then he took samples of the mice’s urine, feces, blood, and virtually every organ and tissue, at intervals from a few minutes to 96 hours after they’d eaten the PhIP. We sampled everything but the squeak, he says.

Next Vogel extracted the carbon from the pinhead-size samples and ran it through an accelerator. That device separated the carbon atoms by mass, which allowed them to be counted one by one. The number of carbon 14 atoms revealed how many PhIP molecules were in each sample, and thus how PhIP was traveling through the mice’s bodies.

After digestion, it turns out, the PhIP first went to the liver. But it wasn’t stored there, or in fat cells, as some other carcinogens are, or anywhere else in the mice’s bodies. The researchers found that the mice excreted 70 percent of the PhIP within 48 hours, mostly in their urine; after 96 hours not a single PhIP molecule was left. The result suggests that, in realistic doses, PhIP may not be much of a carcinogen at all. If it does trigger cancer-causing mutations, says Turteltaub, it must work surprisingly fast.

He and Vogel plan to test other carcinogens. And since the Lazarus method can track any carbon-containing molecule, its widest application may be for studying how nutrients are distributed in the body. Eventually, Vogel and Turteltaub hope, they will move beyond mice and follow molecules through the human body. But for that they’ll need to raise a human Lazarus.
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