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Reviving extinct DNA

In a first for science, a snippet of genetic code from long-gone species is inserted in mice and shown to work

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6:59pm, May 19, 2008
Magazine issue: Vol. 173 #18, June 7, 2008
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Tasmanian tigers are back. Sort of. A small bit of the extinct marsupial’s DNA is alive and well in the cells of some genetically engineered mice.

Scientists have produced proteins from mammoth and Neandertal genes in cells, but the new study, appearing in the May 19 PLoS ONE, is the first to examine the activity of an extinct piece of DNA in a whole animal.

Scientists from the University of Melbourne in Australia and the University of Texas M. D. Anderson Cancer Center in Houston extracted DNA from alcohol-preserved specimens of the Tasmanian tiger, also known as the thylacine. The researchers then inserted into mice a piece of thylacine DNA that controls production of a collagen gene. The thylacine DNA worked, switching on a marker gene in cartilage-producing cells in a mouse embryo, essentially resurrecting a bit of the extinct animal.

But don’t expect mice to transform into the doglike marsupials, or for scientists to reanimate thylacines through cloning.

“This technology can tell us interesting things about thylacines bit by bit,” says Robin Lovell-Badge, a developmental geneticist at the Medical Research Council’s National Institute for Medical Research in Mill Hill, England. “As far as bringing back thylacines, this is not going to be able to do that.”

“I love the idea,” Lovell-Badge says of somehow engineering mice into thylacines, “but no, not like this.”

As for the cloning the extinct animal, it’s not likely to happen, says Carles Lalueza-Fox, a paleogeneticist at the University of Barcelona in Spain.

“It’s impossible to clone extinct animals like some people claim they will do with frozen mammoths. That’s fantasy, not science,” Lalueza-Fox says.

But the researchers involved in the new study never intended to bring back the thylacine, just to learn something more about its biology and perhaps add to the evolutionary history books. This type of study could teach biologists how species use their genes to create the tremendous diversity in body shapes and sizes.

“We were very interested in finding out a little bit more about this iconic Australian carnivore, especially since we humans were responsible for its extinction,” says Marilyn Renfree, a reproductive and developmental biologist at the University of Melbourne and one of the authors of the new study. “This study has given us proof that one can ask these sorts of questions and get answers.”

To prove that DNA from an extinct species can still work, the team chose a regulatory element, called an enhancer, which regulates the Col2a1 gene and has been conserved throughout evolution in animals with backbones, says Andrew Pask, a molecular biologist at the University of Melbourne.

Enhancers serve as landing pads for proteins that turn genes on. Only specific proteins are granted landing privileges and only at prescribed times of development in particular types of cells. The Col2a1 enhancer turns the gene on only in chondrocytes — cartilage-producing cells— in mouse embryos. The enhancer works similarly in birds and mammals, so the researchers hoped that the thylacine DNA would also produce a familiar pattern of gene activity.

That hope was fulfilled. Mouse embryos engineered with the thylacine enhancer turned on production of a marker that the researchers use to track gene activity. The enhancer worked only in chondrocytes.

The new study is the first using extinct DNA that does not encode a protein but controls how genes are turned on and off. In previous studies, mammoth and Neandertal genes were used to produce proteins in cell culture, not in living animals.

“This is the next logical step to try to bring ancient DNA into an animal or biological system,” says Stephen Schuster, a genomicist at PennsylvaniaStateUniversity in University Park. Researchers might use the technique to find enhancers and other regulatory elements that could make a chicken look like a dinosaur or an elephant look like a mammoth, he said. But such methods, even if they could achieve such dramatic results, would not bring back dodos, dinosaurs and mammoths.

“If you had a very hairy African elephant, that would be a first step to looking like a mammoth, but of course it wouldn’t be a mammoth. It would just be a weird-looking elephant,” Schuster says.

Even though the thylacine enhancer seems to work the same way as the mouse enhancer does, that’s no guarantee that the researchers have the correct answer to how thylacine DNA functions. Mice and marsupials are so different that sometimes enhancers might misbehave when placed in a mouse, giving researchers the wrong impression about how such bits of DNA worked in extinct animals, says Lalueza-Fox.

“To use an animal model is always difficult, but to use an eutherian [placental] animal model for a marsupial is really quite risky,” he says.

Other researchers concede that genetically engineered mice might sometimes yield misleading data, but see no alternative way to study gene function from extinct species.

“The problem with extinct animals is that they’re extinct,” says Michael Hofreiter, an evolutionary biologist at the Max Planck Institute for Evolutionary Anthropology in Leipzig, Germany. “Cell cultures or the mouse models are the only possibility we have of learning how non-coding DNA worked in extinct animals. The question is not whether this is the best way forward — it’s the only way forward.”

These kinds of studies are necessary to understand where and when genes are turned on and off in the bodies of extinct animals. That information may be encoded in the DNA of the animals, but predicting how variations between two species changes gene function is not well understood. Such studies could show how the thylacine got its stripes or what made mammoths so woolly.

Even armed with information about how thylacine genes worked, the technology used in the study is unlikely to bring back the Tasmanian tiger, Hofreiter says. In order to re-create the thylacine from a mouse using this technique, researchers would have to replace the mouse genome bit by bit, using about 10 million short pieces of DNA. That would take years and be would be extremely costly, not to mention that at some point, a chimeric animal (part-mouse, part-thylacine) would be unlikely to survive, he says.

Schuster favors a bigger, bolder approach to re-creating extinct animals, one that admittedly is still science fiction. He would stitch together entire chromosomes from an extinct animal and replace a host animal’s chromosomes with the synthetic creations. In that way, an elephant’s genetic material might be replaced with mammoth DNA, essentially reincarnating the Ice Age icon.

Scientists are only just beginning to learn how to create whole chromosomes.

“With DNA we’re very good at reading information, but we’re not good at writing. It’s like we’ve got a computer, but we don’t have a printer,” Schuster says.

Thylacines have no living counterpart. Their closest living relatives are Tasmanian devils, but no one has ever genetically engineered a Tasmanian devil, making it an unlikely host should the technology to clone extinct animals become available.

Re-creating extinct organisms captures the imagination, Schuster says, but it is far easier and less expensive to protect the endangered animals still living on Earth.

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