In yet another collision of nature versus nurture, a team of scientists at the University of Arizona says the genetic research community must control for the environment when conducting experiments, because it may well affect the results.

The Study: The group specifically targets studies that utilize knockout mice, a technique developed in the late 1980s in which strains of mice are bred with specific genes turned off. The methodology is used to try to determine whether disorders ranging from sickle cell anemia to alcoholism have a genetic component. According to the new study—published in the current issue of PLoS ONE—environmental differences can mask or exaggerate phenotypes or behaviors even if a gene's function has been disabled.

The Arizona researchers studied whether cage conditions affect mice with one copy of a gene called fibulin-4, a member of a family of genes believed to code for proteins that stabilize the connective tissue found between cells in arteries and other blood vessels. If both copies of the gene are deleted from developing mouse fetuses, they terminate before birth due to arterial rupture and hemorrhaging. The mice seem to develop normally when only one copy of the gene is removed, but microscopic inspection reveals a number of small "gaps," or disorganized regions of tissue (on the scale of a few nanometers) on their aortas, the largest artery in their bodies.

In an effort to determine the environmental impact, scientists housed the knockout mice differently. In some cases, they placed groups of four in small cages containing only bedding; in other cases, they put pairs in sprawling cages that were twice as large and furnished with an exercise wheel, a ladder and a plastic tube that the mice could crawl through.

Scientists found that the mice in the luxury accommodations spent an average of 40 percent of their time on their in-home exercise wheel and had significantly less fat tissue around their aortas and weighed up to 40 percent less than their compeers from the cramped quarters. When researchers viewed their aortas under microscopes, they found that they had nearly 80 percent fewer gaps than their packed-in pals.

Implications: Senior author Ann Baldwin, a psychologist and physiologist at the University of Arizona College of Medicine, says she cannot explain why the mice in the enriched environment were significantly healthier than their counterparts. "All I can say is that it was a different environment," she says. "Further experiments would be needed to just test the exercise or just test the cage size or just test having a tunnel in the cage."

The authors do state in the paper that their work indicates that environment may change the expected outcome of a genetic deficiency—a warning to all those using knockout mice that they must factor it into study results. In addition, Baldwin suggests that future mice studies should test subjects under standard and enriched environments to get more accurate readings of the genetic effects.

Experts Weigh In: "My body is in better health when I exercise. I haven't changed my genetic makeup when I exercise," says Mario Capecchi, co-chair of the Department of Human Genetics at the University of Utah School of Medicine and a pioneer in working with knockout mice. "This paper has little to do with knockout mice," he continues. "It simply states that mice and their physiology, too, can respond to their environment."

John Crabbe, a behavioral neuroscientist at Oregon Health & Science University in Portland, says that the paper shows biological effects but that it does not offer evidence of a genetic impact. "It's clear that the environmental enrichment had a biological effect," he notes. "They are performing a clear manipulation of the environment, so the manipulation is physical. ... So, what's the story [with] genes?"

"The one thing that I think that is useful is maybe when people write knockout papers they might describe the housing conditions in more detail," says Chris Paszty, scientific director at the biotech company Amgen, Inc., headquartered in Thousand Oaks, Calif., who as a postdoctoral researcher at Lawrence Berkeley National Laboratory developed a mouse model for the study of sickle cell anemia. "There's nothing wrong with any of the knockout studies that people have ever done. It's just that for some of those phenotypes, there might have been an influence on the way that they handled the animals or housed them that's just an unknown variable."