‘Heavy Mouse’, Fed On a Diet Of Isotopes May Be the Key To Generating Tissues In Lab

By Shweta Iyer on May 16, 2014 5:07 PM EDT

mouse
Scientists have developed the world's first 'heavy mouse'. (Photo: Photo courtesy of Shutterstock)

Scientists have developed the world's first 'heavy mouse'. This is not a super-sized rodent, but it's so called because it has been fed with a diet containing heavy but non-radioactive isotopes. By analysing the magnetism inherent in these isotopes the scientists can map precise details of natural tissues, which will help them to create artificial tissues in the lab.

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This method will help scientists develop artificial tissues which are similar to natural ones down to the last atom, and hence will have a greater chance of being accepted by the body. This will be a giant leap in medical innovations as artificial tissues can be used to replace defective heart valves and such.The research was funded by the Biotechnology and Biological Sciences Research Council and British Heart Foundation and led by Dr. Melinda Duer from Cambridge's Department of Chemistry. The research paper has been published today in the journal Science, according to a news release.

Using this new technique, the team has already made an interesting discovery. that poly(ADP ribose) (PAR) - a molecule believed to only exist inside a cell for the purpose of repairing DNA - not only travels outside cells but may trigger bone mineralisation.

"It was crazy to see PAR behaving in this way; it took six months of detailed analysis and many more experiments to convince ourselves," said Dr. Duer."I think this is just the first of many discoveries that will stem from the heavy mouse. Isotope-enriched proteins and cells are fairly commonplace now, but the leap to a whole animal is a big one.The heavier nuclei in the carbon isotopes changes the rate of chemical reactions, and many people - myself initially included - didn't believe you could enrich a whole animal with them. But it worked beautifully," she said.

The technique used for this is called Nuclear Magnetic Resonance spectroscopy (NMR) that uses the magnetic properties of certain isotopes, such as carbon-13, which has a neutron more than most carbon. Carbon-13 NMR allows the identification of carbon atoms in an organic molecule but its natural abundance in the body in only 1 percent. So, the scientists overcame this problem by isotopic enrichment that is feeding the mouse with feed rich in carbon-13, which increased the carbon levels in it by 20 percent.

They then conducted NMR analysis of the mouse tissue to map the distance between the carbon atoms and reveal atomic structures. This gave them a reliable reference to grow artificial tissues in the laboratory, which would be as close to the real ones as possible. In fact the artificial ones were so close to the original that Duer says she has yet to find a biologist who can tell the difference. "We found that once you get it right at a molecular level, the rest looks after itself," she said.

Tissues developed earlier were nanoscopic in structure and the chances of them being rejected by the immune system were quite high. But the new method goes to the atomic level to develop tissues.

"We could see signals in the NMR data for our lab-grown tissue, extra intensities that - when matched with the heavy mouse data - revealed where proteins hadn't folded up properly," said Brooks. Things like misfolded proteins trigger the rejection. But says Brooks, "through a process of repeat NMR comparisons we were able to modify the lab tissue until it looked near identical with NMR and under the microscope."

Along with growing tissues the scientists also identified a molecule when they were trying to develop bones out of soft tissues. The find of this molecule, they say was completely unexpected.The molecule they found was poly(ADP ribose) or PAR, thought to be found only inside cells and whose chief role is repair of damaged DNA.

"Not only is PAR there, and leaving the cells entirely, but once it's in the surrounding matrix it's perfectly designed to start pulling together the calcium and phosphate that make up bone crystals," explained Duer.

This is happening at the exact same time the cells start laying down the organic matrix to house the mineral crystals that form bone, says Duer. The team then developed a staining test to check the presence of PAR in bone tissue taken from the animal. "When the results came back, even I couldn't believe it! The bone tissue was stained everywhere," said Duer. Which means that PAR also plays a crucial role in generating bone.

"The fact that we are already making such remarkable discoveries using the techniques that have been developed as a result of the heavy mouse is hugely exciting, and shows the enormous potential of this approach," said Duer."We're now looking at blood vessels to see if lab-grown tissue could be used for replacement arteries and heart valves - and to see if we can find the molecules that trigger calcification of the arteries, as well as calcification of bone."

"One mouse on a specific diet might end up rewriting the textbooks", she concludes.

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