Save the Mice

"Save the mice" may sound like an animal rights slogan, but it is smart science to researchers in the Comparative Mouse Genomics Center at the University of Washington in Seattle. A major drawback of working with laboratory mice is having to kill the animals to measure endpoints such as tumor development and bone loss. Director Warren Ladiges, a veterinarian, and his colleagues are trying to save mice--and the cost of replacing them--by developing noninvasive techniques for whole-body imaging. Photo Courtesy of Robert Miyaoka VET PET POWER: A micro-crystal element (MICE) detector module for the PET system. This array, comprised of 22 x 22 crystals, each 0.8 mm x 0.8 mm, is inserted into a grid made of a highly reflective polymer film. Radiochemist Kenneth Krohn created a mouse-sized positron emission tomography (PET) scanner. The project also uses equipment designed for humans: a Lorad MII X-ray mammography unit and a Norland dual-energy X-ray absorptio-metry (DEXA) system. Less than a minute of anesthesia gets the mice to stay still for their X-rays. For the PET scanning, which takes about an hour, Krohn says he uses the "lightest amount of inhaled anesthesia that you can possibly give them." The mice wake up in their own cages, he adds; the scanner is wheeled on a cart to the mouse colonies. Feasibility was tested on 51 transgenic mice from two studies on aging. Despite the small size of the animals' organs, the investigators detected functional and anatomic changes in 23 mice aged 12 to 24 months. They tried the PET scanner with F-18 fluorodeoxyglucose and F-18 fluorothymidine kinase tracers, but have about 15 tracers available, according to Krohn. In a last-minute "hot poster" at the Gerontological Society of America's annual meeting in November,1 Ladiges showed images from a mouse bred to develop lung tumors. An X-ray revealed increased density at the tumor site, and a PET scan done with the glucose tracer showed high cellular activity in the same location. "When we superimpose those two, we can get a very good picture of the tumor and the activity of tumor," says Ladiges, who expects to produce even clearer images in a few months. Also on view were DEXA scans from a four-month-old mouse and a 22-month-old. Commonly used for diagnosing osteoporosis in women, the DEXA images were less bright in spots for the older animal, indicating loss of bone density. The investigators are excited about their new capability to do longitudinal studies in mice. Ladiges says that keeping the animals alive until they die "naturally" will benefit studies of the aging process and the progression of ailments such as cancer, heart disease, neurologic conditions, and osteoporosis. "We need to follow these mice just like human patients," he says. Money is another motivator. According to Ladiges, the price of a laboratory mouse ranges from several dollars to several hundred dollars for one that is genetically engineered or aged. Add in the cost of sustaining animals, and the investment can be considerable. Photo Courtesy of Robert Miyaoka PET CAROUSEL: A six-detector module evaluation system. Complete data sets are collected by placing the animal on a rotating stage. Vertical stages are used to allow additional images. The mouse-sized PET scanner did not come cheaply, however. Developing the prototype took about two years, and Krohn estimates the cost at half a million dollars--including the purchase of about 30,000 crystals that serve as radiation detectors. "The mouse is so much smaller than the human, but in order to make an image you need to have the same number of detected events," he says. The scanning system, says Krohn, is composed of an inch-thick ring of detectors, each of which is less than a millimeter in two axes and almost a centimeter in the third--"just awfully, awfully tiny," in Krohn's estimation. "That's the big obstacle putting them together," he says. "They have to be matched and polished, and they're fragile. Frankly if I had to polish and stick all those together, I'd go crazy. Fortunately I have graduate students who do a wonderful job." --Jane Salodof MacNeil 1. W. Ladiges et al., "Imaging of noninvasive endpoints in mouse aging studies," 55th Annual Scientific Meeting, the Gerontological Society of America, Boston, Nov 22-26, 2002.

Save the Mice

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Photo Courtesy of Robert Miyaoka
VET PET POWER: A micro-crystal element (MICE) detector module for the PET system. This array, comprised of 22 x 22 crystals, each 0.8 mm x 0.8 mm, is inserted into a grid made of a highly reflective polymer film.