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COMMANDING THE EMBRYO Hedgehog Molecules |
In 1992, scientists working with fruit flies (drosophila) discovered that a single gene was critical in signaling the flies' development. Fly embryos without the gene not only died but, more significantly, underwent a visible change in form first. Their unusual, bristly appearance suggested a name for the missing molecule: hedgehog. Hedgehogs are one of five major families of "inducing molecules," which encode genetic information that triggers apparently undifferentiated cells--those of an embryo, for instance--to form complex structures like wings, eyes, or legs. Inducing molecules are messengers carrying marching orders for the legions of cells that make up many living organisms. The discovery of such a messenger--a controlling, signaling protein--in flies raised the question of whether similar proteins existed in vertebrates.
To today's molecular biologists, this seems like an obvious line of inquiry, "but at the time it wasn't clear how similar the regulation of development in different organisms would turn out to be," says Cliff Tabin, professor of genetics at Harvard Medical School. The discovery in 1993 that a molecule similar to that controlling aspects of embryogenesis in flies also controlled major developmental processes in vertebrates was a big surprise.
Tabin's is one of three collaborating labs that were the first to discover and clone the vertebrate homologues to the drosophila hedgehog molecule. The others were those of professor of molecular and cellular biology Andrew McMahon and of Philip Ingham, then at the Imperial Cancer Research Fund and now at the University of Sheffield. The three scientists, each of whom brought different interests and areas of expertise to the search for the vertebrate hedgehog, decided to team up after meeting at a conference in Germany.
Ingham, one of the key people studying the genetics of hedgehog signaling in flies, had recently switched to working with fish. Tabin's lab had developed considerable skill working with chick embryos. And McMahon's background in the rigorous and precise genetic manipulations possible in mice, the model mammalian system, was a perfect complement to the work of the other two.
First McMahon found the molecule, now dubbed desert hedgehog, which turned out to regulate sperm production. Then Tabin's lab, using a technique that compared the DNA sequence of desert hedgehog with that of drosophila hedgehog and searched for related sequences, found two other such molecules. Ingham, working with zebrafish (which are transparent when young), discovered that one of these two molecules, now known as sonic hedgehog, expressed itself along the fish's midline--down the neural tube, in other words--in a stripe. "That's exactly what we were looking for," says Tabin, "an important signaling molecule that might control how the embryo forms." Tabin and McMahon immediately diverted their attention to sonic hedgehog, which turns out to regulate limb development, skeletal growth, branching of the lungs, and the development of the nervous system (including the brain), among other things. They had found one of the key molecules that organize whole embryos from a mass of seemingly identical cells.
"Pattern is how form and structure happen in embryogenesis," explains Tabin. "My arm and my leg have all the same cell types in them, but they've got a different pattern. The same is true of the thumb and the little finger." Says McMahon, "Much of the control of cell differentiation--the process of forming different cell types like nerves, muscles, cartilage, and bone--is exerted by inducing molecules." Indian hedgehog, the third of the vertebrate hedgehog molecules, controls cartilage and bone development, for example.
Tabin and McMahon continue their basic research at Harvard, posing yet more questions. "What are hedgehogs' targets?" Tabin wants to learn. Says McMahon, "We want to know not only where they are taking effect, but how they work. How do you receive a hedgehog signal? What does that do to a cell?" Ultimately they are aiming for complete understanding of how embryonic growth processes work.
Meanwhile, the enormous potential that hedgehog molecules have for curing disease in adults has not been lost on the biotechnology industry. Harvard has a patent on the hedgehog molecules that are licensed to a Cambridge-based firm called Ontogeny.
"Understanding how the body plan is put together in a rational way might allow doctors to tackle diseases where there is a deficiency in cells," notes McMahon. The same inductive signals that regulate growth in an embryo might be made to regenerate cells in adults, or help grow cells in culture for transplant to adults. Degenerative diseases of the nervous system like Parkinson's or Alzheimer's, in other words, might some day be treated with the fruits of a fly.
~ Jonathan Shaw