ORNL Review Vol. 34, No. 1, 2001

MicroCAT "Sees" Hidden Mouse Defects

The white mouse sleeps on a narrow wooden trough outside a new high-resolution X-ray computed tomography (CT) system at ORNL called a MicroCAT scanner. The anesthetized mouse is gently inserted into the instrument, where it is scanned for about 20 minutes. Mike Paulus and Shaun Gleason, researchers in ORNL's Instrumentation and Controls Division who developed the MicroCAT scanner, note that the scans show spots indicating the locations of lung tumors of 1 to 2 millimeters in diameter. The mouse is then returned to its cage. The mouse is scanned several times over the next few days to get a profile of tumor growth in its lungs.

ImTek's first customer prepares a mouse for mapping internal defects in a commercial version of the ORNL MicroCAT scanner

ImTek's first customer, Henry Lopez of Parke Davis Research Laboratories in Alameda, California, prepares a mouse for mapping internal defects in a commercial version of the ORNL MicroCAT scanner. Photo courtesy of ImTek, Inc. (Enhanced by Gail Sweeden.)

The mouse has tumors because it has been injected with lung cancer cells. Steve Kennel, a researcher in ORNL's Life Sciences Division (LSD), creates mice with lung tumors to test how well they respond to a special kind of radioimmunotherapy. When Kennel decides it is time to treat the white mouse, he injects it with a monoclonal antibody tagged with radioactive bismuth-213 (a decay product from ORNL's stockpile of uranium-233). This monoclonal antibody is like a smart bomb because it homes in on the tumor's blood vessels, where the radioactive bismuth-213 parks. The alpha radiation from the radioisotope destroys the nearby tumor tissue.

The mouse is scanned repeatedly over a period of days both during and after treatment. The MicroCAT pictures reveal that the tumors are progressively disappearing, indicating that the treatment works. (See Curing Cancer in Mice.)

Image of a tumor in the lung of a mouse injected with lung cancer cells. This MicroCAT image correlates reasonably well with histology data. The results were published by ORNL's Steve Kennel in the May 2000 issue of Medical Physics.

The MicroCAT scanner, which was developed using internal funding from ORNL's Laboratory Directed Research and Development Program, has been used to provide three-dimensional images for other small-animal studies:

Measurement of the size, weight, and distribution of fat deposits in mice found to have an obesity-related gene on chromosome 7 (in collaboration with Madhu Dhar, as described in Obesity-related Gene in Mouse Discovered at ORNL);

Imaging of tumors on the prostate glands of mice produced by researchers at Baylor University;

Imaging of rat bones to measure their resistance to the passage of X rays and their bone wall thickness as an indication of bone mass and amount of calcium in bone, as part of a study of osteoporosis in animals;

Imaging the uterus of a pregnant mouse repeatedly over time to determine the number and time of death of individual fetuses (as a result of genetic disorders);

Validation of ORNL veterinarian Charmaine Foltz's body condition scoring system, in which she presses her thumb against the body of each mouse to rank the animal's health.

A second-generation MicroCAT instrument is be-ing used for high-throughput screening of mutant mice for internal defects in ORNL's Laboratory for Comparative and Functional Genomics (Mouse House). The device saves time and money because biologists can screen mice individually for internal mutations in 7 to 20 minutes, without sacrificing and dissecting the animals.

To improve accuracy and speed in assessing mouse organs for defects and damage, Gleason has developed an automatic organ-recognition algorithm for CT images of the mouse. Gleason has shown that in the CT scan, the software can zero in on the mouse's kidneys and analyze differences in kidney texture that would show up in mice with polycystic kidney disease. He has also used the algorithm to calculate the approximate size of the lung and heart and evaluate the lung's level of fluid or amount of scar tissue, as an indication of its health or disease state.

Paulus has also used the MicroCAT scanner for research collaborations that do not involve small animals. For example, he has worked with plant geneticist Gerald Tuskan of ORNL's Environmental Sciences Division to image three-dimensional details of wood cells and cell wall thicknesses in samples of loblolly pine (see Controlling Carbon in Hybrid Poplar Trees). Paulus is writing an algorithm that will enable automatic measurement of the size and shape of wood cells.

Paulus and Gleason have developed a new instrument that combines X-ray imaging with single-photon-emission-computed tomography (SPECT). This MicroCAT SPECT scanning instrument could be used to image lung tumors in mice and detect radioactivity from the treated tumors, to map their precise location.

With support from UT-Battelle, Paulus and Gleason are on entrepreneurial leave two days a week to run their new company, which manufactures MicroCAT scanners. The company—ImTek, Inc. (www.imtekinc.com)—has sold and delivered five MicroCAT scanners and is filling orders for three more for 2001. Purchasers include drug discovery companies, universities, and biotechnology firms.

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