Make Mice Immune to
In a breakthrough that could change the lives of cancer victims, pilots and nuclear power plant workers, researchers might have found a way to protect cells from radiation damage.
In a study published in the new AAAS journal Science Translational Medicine (see video below), researchers at the University of Pittsburgh School of Medicine and the National Cancer Institute found that they could protect healthy cells from radiation injury by turning off an inhibitory pathway that regulates nitric oxide.
"[Nitric oxide] is a bio gas, produced by enzymes in cells, and flies around almost at light speed compared to other processes," Jeff Isenberg, M.D., a professor at Pitt's school of medicine, tells DOTmed News.
While nitric oxide mostly works to prevent clotting of arteries, it also appears to help animals survive stress conditions.
But Dr. Isenberg and his team made the discovery that by switching off a related inhibitory pathway that controls nitric oxide, they could give animals "near immunity to record levels of radiation," he says.
In mice, when Dr. Isenberg and his team introduced a drug that prevented a protein, thrombospondin-1, from binding to a surface cell receptor called CD47, the animals could endure almost unheard-of doses of radiation with virtually no ill effects.
In cellular studies, cells could withstand up to the tested amount: 60 Gy. And in whole animal studies, mice could endure the limit they were given: 40 Gy.
"Primarily, [on mice] people are using 5-10 Gy. This is off the scale from what they've published," he says.
Shockingly, the irradiated rodents were almost completely unharmed. Other than some mild hair loss at the site of dosage, there was almost no cell death or damage when histological samples were checked.
"There was no skin laceration or muscle loss," Dr. Isenberg says. "When we stained for cell death, we didn't even see significant loss of bone marrow, which is exquisitely sensitive...to radiation damage."
In comparison, control mice -- who didn't get the pathway-blocking treatment -- were eaten away with tissue loss and "frank necrosis of the limbs."
In fact, one reason Dr. Isenberg doesn't know the upper-limits of protection the drug confers to a whole animal is that ethics boards refuse to give permission to expose mice to much more than 40 Gy. (Whatever he gives to the treated mice -- who will be fine -- he has to give to the untreated mice, who will not.)
However, he says at some point radiation would damage tissue through thermal energy, which this process might not be able to stop.
Perhaps equally exciting, Dr. Isenberg and his team found that while his technique protected healthy cells from damage, it actually increased the effectiveness of radiation treatments on cancer cells.
The reason, Dr. Isenberg suspects, is that while the tumors were not protected by inhibitory-pathway blocking actions, the immune cells surrounding them were, and are thus able to attack the weakened tumor following radiotherapy exposure.
The potential applications of this technique are manifold, from protecting patients getting CT or X-ray exams to helping certain workers, such as commercial airline pilots and engineers at nuclear power plants, from higher-than-normal radiation exposure in their job. Because of the diverse ways that the pathway can be blocked, sunscreens could even be developed to help protect skin cells from UV rays.
Dr. Isenberg believes that in addition to radiation, this pathway has profound implications for heart disease and other disorders "perhaps on a scale not yet appreciated," he says.
Currently, his lab is working toward getting funds for toxicology tests so at some point drugs could be developed for humans. He also plans studies to see how long an effective dose lasts -- would someone get one-month, or one-year immunity following a dose?
Also, a bigger mystery is figuring out how, by blocking this pathway, cells are able to fix the damaged DNA within. Dr. Isenberg says they know that following radiation exposure, the DNA is scrambled, but somehow, with this treatment, the cells are able to get themselves right.
"It's not that we're blocking radiation from hitting the tissue," he says. "Somehow...they repair themselves, and go about their business."
And finally, research may reveal why we aren't born with the inhibitory pathway already blocked. Dr. Isenberg says the process probably evolved when deep sea fishes emerged on land, and somehow was used to regulate changes in internal pressure. So would turning it off create other, unwanted effects? Although none were seen in the studies, nitric oxide is a powerful vasodilator, he says, and maybe the body needs some way to control it.
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