POSTED 18 OCTOBER 2007
Genetically manipulated mice go to head of med-research
class
The process of gene-targeting that bagged the 2007 Nobel Prize for Medicine
or Physiology has become a bedrock technique for research in biology and
health. We scrounged around for some greatest gene-targeting hits from
the past two years, and found that gene-targeted mice have produced advances
related to heart disease, Alzheimer's disease, obesity, cancer, even itching!
The fat mouse (right) lacks a gene for the protein
SH2B1. Restoring SH2B1 in the brain reversed the tendency to gain weight,
even among mice that ate a high-fat diet. Photo
by Liangyou Rui, University
of Michigan Medical School
Heart
disease: Gene-targeted mice are helping investigate fibrosis,
a stiffening of the tissues that can damage or destroy the heart or other
organs. Fibrosis may originate in over-active fibroblasts, which are cells
that make a fiber called collagen to help heal wounds. "Heart disease
is the number-one cause of death in the Western world," explains study
author Elisabeth Zeisberg of Beth Israel Deaconess Medical Center in Boston.
"And most people who suffer from heart disease have developed scarring
of the heart tissue, known as fibrosis." Researchers suspected that fibrosis
results when epithelial cells -- a type of cell lining the skin and other
surfaces -- convert to fibroblasts. Zeisberg's group created gene-targeted
mice with special labels on their epithelial cells and saw that same label
on fibroblasts at the end of the experiment, confirming the conversion
hypothesis. The researchers
also identified a protein that blocked the production of excess fibroblasts,
and improved heart function in the gene-altered mice.
Alzheimer's disease: In 1906, German doctor Alois Alzheimer noticed tangles and plaques in the brains of people who had the incurable, memory-destroying disease that acquired his name. Plaques and tangles remain the hallmarks of Alzheimer's disease, which is wreaking havoc among four million older Americans. Microscopic studies have shown that an enzyme called Pin1 could untangle tangles, and other research has linked Alzheimer's to changes in the Pin1 gene. To look further, researchers at Beth Israel Deaconess Medical Center in Boston created mice with the Pin1 gene knocked out, and saw an increase in both plaques and tangles. Kun Ping Lu of Beth Israel explained that although many researchers had explored the link between plaques and tangles, "the exact relationship between the two has remained controversial and elusive... These new results suggest that lack of sufficient Pin1 enzyme may be a key culprit in the onset of Alzheimer's disease."
Fat
cells from mice without SH2-B (right) are four times larger than fat cells
from normal mice (left). Photo by Liangyou
Rui, University
of Michigan Medical School
Obesity: Researchers at the University of Michigan have targeted a knockout that works only in the mouse brain, and found that a protein called SH2B1 helps regulate body weight and the response to two key metabolic signals, the hormones leptin and insulin. Animals lacking SH2B1 get sluggish and obese, and cannot stop eating. SH2B1 affects the hypothalamus, a part of the brain already known to regulate eating and metabolizing food. Although SH2B1 may play a role in developing obesity drugs, patients are unlikely to benefit for several years.
Cancer: Gene targeting can affect more than one gene. An experiment in Boston showed that three "FoxO" genes are critical to the health of blood stem cells -- the cells in the bone marrow that make new blood cells. "If we didn't have these FoxO proteins to keep stem cells healthy, it is likely that we wouldn't be able to live for more than a few months," said Gary Gilliland of the Dana Farber Cancer Institute. The three FoxO proteins also suppress tumors in cells that are threatening to turn cancerous, and so the FoxO system could become new targets for cancer drugs.
The "itch" gene (dark spots) is expressed in a few neurons in the spinal
cord. Photo: Washinton
University
Itching(!): As we scratch the surface of mouse research that used gene-targeting, we pause to exalt the discovery of the itching gene, GBPR. Chronic itching, often due to disorders of the skin, kidney or liver, can interfere with sleep and obsessive scratching can cause painful wounds, but "...itch research has lived in the shadow of pain research," says Yan-Gang Chen, associate professor of anesthesiology and psychiatry at Washington University, "and no one knew which gene was responsible for itching ... until now." Chen began looking at the role of GRPR in pain, but noticed that mice with the gene knocked out responded normally to painful stimuli. When those little rodents were exposed to something itchy, however, they scratched less than expected. The link between GRPR and itching might seem a mere curiosity, but GRPR also seems to be a factor in cancer, Chen says, and so "a lot of substances have been made that block the activity of GRPR. So now researchers can study the effect of these agents on the itch sensation and possibly move that research to clinical applications fairly soon." We'll scratch to that!
These days, gene targeting can do a lot more than just knock genes out...
