Using non-radioactive isotopes, scientists have created the first atomically “heavy-weight” mice whose tissues can be mapped with atomic-scale precision. The creation of heavy-weight organisms is not only a scientific “first”, but is already leading to surprising discoveries about how seemingly familiar molecules in a person’s body may act in ways scientists had never previously expected.
The heavy-weight mice were fed a special diet containing isotopes—atoms that contain more neutrons than the number typically found in the most abundant forms of elements. Specifically, the mice were fed foods containing carbon-13 and nitrogen-15. After three weeks of this “heavy” diet about 20 percent of the nitrogen and carbon in the rodent’s tissues were composed of the isotopes. By contrast, in normally fed animals, the levels of isotopic carbon are about one percent. While heavy isotope labeling has been used in biology since the famous Hershey-Chase experiments in 1952, this is the first experiment in which isotopes were integrated into a whole, living animal.
Neither carbon-13 nor nitrogen-15 are radioactive, but they can still be detected because they act like tiny magnets that can be sensed using nuclear magnetic resonance (NMR) spectroscopy. Using NMR spectroscopy, researchers were able to map the exact details of how carbon and nitrogen are integrated into the molecules that make up the tissues of an organism.
Mapping tissues in detail as fine as individual atoms is an incredible advancement for science. Aside from questions of applied research such as developing cures for a disease, basic research in fields as far afield as embryology, botany, or marine biology could also make great strides forward by utilizing these new methodologies.
The field of regenerative medicine in particular stands to greatly benefit from these atomically-precise maps of living tissues. The researchers reasoned that perhaps the high levels of rejection from implanted, artificial organs and tissues were due to imperfections in how certain molecules fold or aggregate. Examining tissue samples at the atomic level may seem like splitting hairs, but to the immune system it can make all the difference. Even a few mis-folded proteins are enough to set the immune system on red-alert and result in a host-rejection of the foreign tissue.
Using the same heavy isotopes that were fed to the heavy mice, the investigators engineered synthetic tissues to mimic those that had been grown in the heavy mice. By comparing the isotope maps of the heavy mouse tissues and those of the artificial tissues, they were able to identify tiny molecular imperfections. Subsequent modifications produced artificial replicas that would fool both trained scientists and the immune system into believing that it they were the genuine article.
Already, scientists are uncovering surprising insights through the study of heavy mice. One particularly surprising result was the discovery that poly-ADP ribose—a molecule previously thought to be confined to matters of flagging damaged DNA for repair—is actually also essential for the development of healthy bone. Perhaps even more intriguing is the question as to whether or not poly-ADP ribose is involved with excess accumulation of calcium salts in other tissues besides bone.
The stumbled-upon finding of the body’s use for poly-ADP ribose is surely just one of many discoveries that will be made using tissue maps from isotopically-enriched heavy-weight organisms. Already, the innovative researchers who invented this technique are developing replacement heart valves and arteries that match their natural counter-parts atom-for-atom. In addition, they are following-up on the roles of poly-ADP ribose in bone calcification and potential associated pathologies.
By Sarah Takushi