It's a Bird! It's a Plane! . . . It's a Bat? by Rabiya S. Tuma Abstract A growing number of scientists are acknowledging the limits of studying model organisms - fruit flies, nematodes, mice, chicks, frogs - and are taking up with new research organisms. Researchers have invested enormous amounts of time and energy in the study of model organisms - fruit flies, nematodes, mice, chicks, frogs - and it has paid off handsomely, without a doubt. But a growing number of scientists acknowledge the limits of studying so few animals and are taking up new research organisms. For Richard Behringer, at the M.D. Anderson Cancer Center in Houston, Texas, the realization came at a meeting several years ago. Having recently met several marsupial biologists, he realized that although the meeting was advertised as being about "mammalian development," the phrase was misleading. Everyone, including himself, was presenting work on mouse development, and no matter how good or how valuable that work was, it couldn't possibly model all mammalian development. After returning home, he bought a field guide to mammals. Next to rodents, he noticed, bats are the most abundant species group. Add to this the fact that their front limbs are wings, and Behringer, who's studied limb development in mice for years, was hooked. Limb development is a basic paradigm in developmental biology. But it's a paradigm based on only two model systems, mouse and chick, points out Behringer. So he started wondering what is different between mouse development and bat development that allows the forelimbs of bats to become wings. Together with Chris Cretekos, a postdoctoral fellow in his lab, Behringer quickly found that there was a sizable bat research community already in place in North America. But most of the researchers focus on the animals' ecology. John Rasweiler, in the obstetrics and gynecology department at the Weill Medical College of Cornell University in New York, is an exception to that trend. He has been studying reproduction in a short-tailed fruit bat called Carollia perspicillata for many years, and maintains a self-perpetuating colony in his lab. Happy to have new, enthusiastic colleagues, Rasweiler has made the colony available to Behringer and Cretekos. He also helped them learn how to handle the animals and accompanied them to Trinidad several times to collect wild bats. Behringer acknowledges that one of the problems with working in a new system is that the molecular tools aren't in place. "In a new system, what usually happens is that you approach it descriptively," says Behringer. "You look at homologues from other species and then draw conclusions based on the comparisons. But that is only correlative. I'm not satisfied with correlation." So over the last two years, Cretekos and Behringer have made a BAC (bacterial artificial chromosome) library from bat DNA and have started cloning genes involved in limb development. Using these clones, the researchers have compared the sequence of both the protein coding regions and the regulatory regions of the relevant genes from bats and mice. Considering the high degree of gene conservation between even very distant organisms, such as Drosophila and humans, Behringer and others speculate that the difference between making a bat wing and making a mouse front leg will come down to gene regulation - when and where a gene is used during development - rather than to novel coding sequences. But the real experiment, which the researchers are currently doing, is to replace the mouse sequences with those from bats and ask what happens. It's not likely that they'll see a wing develop, because multiple steps are surely involved. But they might see altered expression patterns or cell behavior, which will give them clues to how the two animals develop so differently. Though Cretekos and Behringer have yet to publish any of their bat work, they have been talking about it at scientific meetings, and several other researchers have joined in the effort. For example, Lee Niswander at the Memorial Sloan-Kettering Cancer Center in New York wants to know how it is that the cells making up the webbing between digits (fingers and toes) die in mice but not in bats. At first she hypothesized that a simple downregulation of an apoptosis-promoting factor in bats allowed the webbing cells to survive. But it seems to be a little more complicated than that, says Niswander, because the apoptosis-promoting factor is expressed to the same extent in both systems. In contrast, she says, a pro-survival protein that blocks apoptosis is upregulated in bats relative to mice, which suggests that it might be a key to webbing-cell survival. But setting aside the details of Niswander's and Behringer's experiments, one might ask how important it is to be exploring development in non-model systems. In Rasweiler's case, he started working with bats because their early reproduction - implantation and placental development - closely resembles that of humans. And, like humans, they have menstrual cycles. "Menstruation is very limited in the mammals," says Rasweiler. "It occurs in elephant shrews, higher primates, and in two families of bats." But Rudy Raff, a developmental geneticist at Indiana University in Bloomington, looks at the problem in a more general manner, and for him exploring development outside model systems is essential. He points out that most model species were chosen for their ease of handling - based on criteria such as how much housing space they need and the time between generations - not because of their intrinsic scientific value or their similarity to humans. "The idea of model systems is inherently flawed," says Raff, "because each organism is its own thing. If you take a model organism point of view and are going to represent all of the species in the world with five model systems, you are going to have a lot of gaps." Now, with a growing number of developmental biologists working outside model organisms, they can begin to learn what makes one organism different from another - and how they got that way. And after being completely separate fields for the last century and a half, evolutionary and developmental biology are beginning to merge into one, affectionately called EvoDevo by insiders. Raff predicts that the combination will be much more powerful than merely the sum of its two parts. Just as the fusion of chemistry and biology led to a whole new field with new questions, approaches, and answers, he expects EvoDevo will forge a very productive new path in science. "A whole different set of questions come up with an evolutionary point of view," explains Raff. "How did it happen to be that my organism came to have four legs? Or to gastrulate the way it does? Or, more generally, how did development per se evolve? "Evolution and development are intertwined in a very important way," Raff says. In each generation, the egg gets fertilized and develops into the adult. If there is a change in a lineage over time, then something must have changed in the developmental processes that give rise to the adult. Both Behringer and Raff think EvoDevo has come of age this year: Cold Spring Harbor Laboratory in New York is sponsoring a conference on EvoDevo this spring; a National Science Foundation granting panel has put together a subcommittee to review grants on the subject; and the field now has several journals of its own. Maybe that means that next time a researcher discusses work on stickleback fish or skinks or an unusual type of sea urchin, colleagues will only look surprised, rather than skeptical. Rabiya S. Tuma is a freelance science writer based in Oregon and New York Oh dear, was this from The Scientist? Or ?? LINK/article on Animal Experimentation Issues CA Veterinary Medical Association British Medical Journal, posted here 1/07 Remember we are NOT Doctors and have NO medical training. This site is like an Encyclopedia - there are many pages, many links on many topics. Support our work with any size DONATION - see left side of any page - for how to donate. 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