Of mice and men

  Human element needed
In reporting the recent success in treating cancers in mice, scientists have stressed that mouse results may not apply to people. Yet we've just read about the value of mice to cancer research. Why so much doubt? It turns out there are many reasons to be cautious when interpreting animal tests:

Checkered history. Most obviously, mouse experiments have been proven wrong in the past. "Many times we are disappointed going from mice to people," says Robert Auerbach, a University of Wisconsin-Madison zoology professor who has worked with angiogenesis factors in cancer for more than 20 years. There's a long history of miracle cancer cures -- interferon, interleukins and cytokines all come to mind -- that worked much better in mice than in people.

How similar? Much of the rationale for testing drugs on animals rests on the similarities among organisms. Basic cellular enzymes -- and the DNA code that governs life's chemistry and structure -- are similar in widely divergent organisms. Many times we are disappointed going from mice to peopleAnd yet similar does not mean identical, notes Daniel Masys, an associate professor of medicine at the University of California, San Diego. Masys, who specializes in the biological processing of information, says genes with the same function in mice and men contain, on average, 85 percent similarity in the actual sequence of DNA sub-units.

Even a single change in the order of DNA bases can make a huge difference, Masys adds. Sickle-cell anemia is a painful disease caused by one erroneous atom in the hemoglobin molecule that carries oxygen in red-blood cells. This mistake, Masys notes, results from a single erroneous sub-unit among the thousands that comprise the hemoglobin gene. "Even a very tiny difference between the normal and abnormal gene can make all the difference between a molecule that works and one that's defective," he observes. "Biological control molecules are exquisitely sensitive to differences in the geography of the molecules they link up with."

And even though it's true that similar enzymes and structures are found across many kinds of animals, Masys contends that, "Mother nature finds different ways to fill the same need. At the molecular level, there are certain functions that living organisms need that have evolved over the years of evolution, and there have been an astonishing variety of different solutions to the same problem."

How toxic? And then there is the toxicity issue. Interleukin-2 is a blood-borne signaling molecule that produced remarkable results against cancer in animals a decade ago. But in people, it caused leaks in blood vessels, and could never be used at the dosages that worked so well in animals. Instead of becoming the magic bullet some had predicted, IL-2 is now a small member of the overall anti-cancer tool kit.

Stickin' around. Even if an anti-angiogenesis molecule would work in mice and men (and angiostatin has been detected in the blood of healthy members of both species), other problems could arise. "You have to look at how long it stays in circulation," says Auerbach. Perhaps an enzyme would break the drug down too quickly in people. Conversely, if it's actually a breakdown product that inhibits the blood vessels, the breakdown enzyme might not be present in humans.

The right cancer? Even beyond these issues, Auerbach points to a "more serious concern" -- the nature of the experimental tumors. The mouse experiments used tumors that grow well in laboratories, but human tumors arise spontaneously and could have quite different genetics and properties. "The biology of the tumor may be different, not because it's a human tumor growing on a mouse, but just because its spontaneous and not grown in a lab," Auerbach says

Masys says these points have clear relevance to the present discussion of cancer "cures." "You can't predict across species how some function like blood vessel formation will be controlled." (For more on the debate over using animals in medical research, see "Neglected Benefits of Animal Research" and "Is Your Experiment Really Necessary?" in the bibliography.)

Although he agrees that targeting new blood vessels is a promising approach, Masys doubts that angiogenesis inhibitors will beat cancer by themselves. "History would predict that anti-angiogenesis factors will earn their spurs and will get a place in the armamentarium against cancer. Almost certainly history would predict that they will not be a magic bullet for all cancer."

What's next in the angiogenesis story?

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