May 1999

MicroCAT Made to Order

Mouse researcher’s ‘make a wish’ response inspired one of ORNL’s best new technologies

A rendering of the surface and skeleton of a normal mouse using MicroCAT X-ray CT data. Both images were obtained with the same data set.
One of ORNL’s most promising new developments grew from one Lab division’s response to the needs of another. Collaboration across organizations and some modest Laboratory-Directed R&D support have produced MicroCAT, which may be the "make-a-wish" analytical tool genetics researchers have been seeking.

MicroCAT is essentially a small X-ray CT scanner, very similar to the medical imaging devices physicians increasingly rely on to diagnose maladies in humans. MicroCAT, however, is applied to mice instead of people.

Researchers at ORNL’s Mouse House find phenotypes, or expressed mutations, in about one in every 500 mice they examine. There are probably more phenotypes, but finding them often requires manual and time-consuming physical observation of the mouse, especially when internal organs are involved. And that often means destroying the mouse.

"We asked Life Sciences Division’s Dabney Johnson, who leads the Mammalian Genetics section, if she could have anything in the world, what would it be," says the Instrumentation and Controls Division’s Mike Paulus.

"Dabney’s answer was a medical imaging device that could scan a mouse a minute."

I&C’s Paulus, Hamed Sari-Sarraf and Shaun Gleason set out to adapt the CT technology to one of the Human Genome Project’s most pressing needs: faster ways to process knowledge and data about the millions of genes that make up the genome, or in the field’s inverted terminology, "greater throughput."

The device they’ve come up with, while not quite a mouse-a-minute, can drastically reduce the time and effort involved in analyzing a mutant mouse. As a bonus, the mouse comes through it unscathed. The mice think MicroCAT is great. So does Johnson.

"This means we can survey many offspring of mutagenized mice for organ or skeletal abnormalities and for changes that occur as a mouse ages or is exposed to different environmental conditions—and then still breed the mouse for genetic analysis."

MicroCAT produces a three-dimensional image with more than 10 times the resolution of conventional imaging systems. By setting thresholds on the system, researchers can image individual bones and organs. All the while the mouse perches on a balsa-wood bed, which doesn’t stop X-rays.

"There are different methods used today for medical imaging—CT, MRI, PET scanners," says Paulus, whose background is in medical imaging. "If you want high resolution and high speed, X-ray CT scanners are your best option."

One version of MicroCAT uses a digital mammography detector. The I&C team started with a goal of 50-micron image resolution. "We’re getting that," Paulus says.

A second version uses a detector that measures the position and energy of each X-ray. The energy data give the MicroCAT greater sensitivity to small variations in tissue density and provide X-ray data for structural information and nuclear medicine data on the mouse’s metabolic activity.

Currently a mouse can be screened with MicroCAT in about seven minutes. Paulus believes they can cut the time in half, which would approach the "mouse-a-minute" dream. Eventually, MicroCAT may lead to automated and computerized mouse screening, a valuable tool in the vast and repetitious task of identifying gene function.

MicroCAT could also be applied to precision screening in industry and for breast cancer screening. Sari-Sarraf, who shared the principle investigator role with Paulus, has already developed a computerized system for screening mammograms.

Gleason developed the system’s image processing, a user-friendly, graphical user interface system that runs on Windows. Other contributors to the project span a number of divisions: Mike Simpson, Chuck Britton, Steve Hicks, Miljko Bobrek and Jim Mullens of I&C, Doug Lowndes of Solid State and Russ Knapp of Life Sciences’ Nuclear Medicine group.

Mike Paulus (right) and grad student Kevin Behel observe an attentive rodent. This photo has appeared in a number of publications.

"That’s something you can do at a national laboratory, with its diversity of disciplines and organizations, that is not easily accomplished in a university setting, where researchers are often more isolated from each other," Paulus says.

MicroCAT has been a hit in the scientific media. Interest has been high, and a photo of Paulus and graduate student Kevin Behel peering at an obliging rodent subject has already graced a couple of magazine covers.

Paulus expects the Mouse House to have a working MicroCAT unit sometime in the fall. A product could be on the market in a couple of years.   —B.C.