The power of animal models

Bill Snyder
Published: August, 2008

The skeleton of a 9-day-old zebrafish embryo glows with calcein, a green fluorescent dye. The bone-staining dye, which the embryo ingested, also was taken up by the eye and intestines.
Image courtesy of Charles Hong, M.D., Ph.D., Vanderbilt University
The march of biomedical science during the past century owes much to a handful of humble creatures, notably the fruit fly, the frog, the worm, the mouse – and recently the zebrafish.

The common fruit fly, Drosophila melanogaster, is one of the most-studied organisms on earth, largely because it matures from fertilized egg to adult in a matter of days and is easy to grow and manipulate.

Studies of Drosophila and other cold-blooded organisms, including the African clawed frog, Xenopus laevis, and the microscopic roundworm, Caenorhabditis elegans (C. elegans), have revealed much about the mechanics of inheritance and development, while the mouse is the most widely used mammalian organism to model many aspects of human disease.

In 1983, in one of the biggest breakthroughs in developmental biology, scientists working independently at the University of Basel and at Indiana University discovered the “homeobox,” a stretch of DNA shared by regulatory-switch “Hox” genes in Drosophila that control development of the body segments.

The most surprising discovery about Hox genes is evolutionary. All animals have Hox genes, and nearly all animals use them to determine which appendage should go where along the axis that runs from head to tail. Given that the major animal groups were in place at the start of the Cambrian period, Hox genes must be at least half a billion years old, lending support to Charles Darwin’s idea that we all evolved from a common ancestor.

For example, a fruit fly gene called eyeless, which is critical for proper eye formation, is almost identical to a human gene that, when mutated, can result in an eyeless baby. Defects in the hedgehog gene signaling pathway, named for the short and prickly “hedgehog-like” fly embryos they generate, also have been linked to several types of cancer in humans.

The difference between us and flies is all in the regulation – more akin to writing new software than to building a whole new computer, or like editing an instruction manual instead of starting over with new instructions.

One of today’s up-and-coming animal models is the tiny zebrafish, Danio rerio. Its embryo is transparent and develops rapidly: within 24 hours of fertilization, it has a beating heart.

Lilianna Solnica-Krezel, Ph.D., and her colleagues at Vanderbilt University have helped establish the importance of prostaglandin and bone morphogenetic protein (BMP) signaling pathways in zebrafish development.

Prostaglandins are fat-derived compounds that in humans have been linked to pain, inflammation and cancer. BMPs induce formation of bone and cartilage, but disruption of BMP signaling also can affect development of the body plan.

While mice and rats remain important in early drug development and testing, scientists have begun to use zebrafish embryos in screens for new compounds with drug-like activity.

In a recent “chemical genetics” study, Charles Hong, M.D., Ph.D., and his colleagues at Harvard Medical School exposed developing zebrafish to thousands of chemicals to see which might disrupt the dorsoventral (back-to-front) body pattern.

One compound, which they called “dorsomorphin,” turned out to be the first selective inhibitor of BMP signaling to be discovered.

In mice, inhibiting BMP signaling increases iron levels in the blood, suggesting that dorsomorphin might be useful in treating forms of anemia.

“This work demonstrates the power of chemical genetics,” says Hong, currently a Vanderbilt faculty member in Cardiovascular Medicine. .

 

Gary Kuhlmann, a freelance science writer based in Elgin, S.C., contributed to this story.

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