"This method takes a process that would normally require two days of hands-on effort and compresses it into less than half an hour," says developer Charles Keller, a researcher at the University of Texas Health Science Center at San Antonio. And it can be nearly six times faster and more than tenfold cheaper than the other computerized histology technique, magnetic resonance microscopy (MRM). However, he notes, MRM can yield anatomical information that microCT cannot, such as the finest details of tissue fiber direction.

Keller and his colleagues, including HHMI investigator Mario Capecchi, reported the new technique as the cover story in the April 2006 issue of the Public Library of Science Genetics.

According to Capecchi, in whose University of Utah lab Keller was inspired to develop the technique, automated virtual histology will enable far more precise measurements of anatomical structures—particularly when trying to detect subtle changes caused by genetic alteration. "No matter how much or how hard you try, when you know you're looking at the mutant versus the control, there is always some inherent bias in your evaluation," he says. "The computer doesn't have any such bias; it doesn't care what animal it's measuring."

Keller suggests that virtual histology would most likely serve as a highly effective initial screening technique, giving scientists an overview of a sample's anatomy and potentially revealing specific features—the effects, perhaps, of a chemical contaminant on a developing fetus—that can be examined in greater detail using follow-on techniques such as biochemical analyses or light microscopy.

Similarly, virtual histology could be used to precisely map the arrangement and extent of blood vessels in tumors. Such measurement would enable tracking of the ability of anti-angiogenesis therapies to halt blood vessel growth and starve the tumors.

Capecchi says his laboratory plans extensive use of virtual histology for basic studies. "For example," he says, "we are now developing a program to automatically scan an entire skeleton, no matter what position a mutant mouse is in, and directly compare the lengths and widths to that of a control. Otherwise, you'd have to photograph and measure each bone by hand."

Capecchi points out that the new whole-skeleton analysis will enable his group to explore how modulation of genes controls mammalian formation of the body plan. "Mammals range from mice to elephants to humans in their body plan, yet we all use essentially the same set of genes. One of the great questions is how this extraordinary variation arises," he says.

While virtual histology is available, without restriction, to the scientific community through the detailed description of the technique in the journal, Keller and colleague Michael Beeuwsaert have sought to encourage its use by founding Numira Biosciences, which will provide commercial laboratory materials and imaging services. For academic laboratories that do not wish to handle the very toxic osmium stain or do not have access to the specialized microCT scanners, academic pricing and low-cost pilot studies are available.

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