Armed with a grant from the U.S. Department of Energy, the scientists are using the rapidly developing zebrafish embryo to study the effects of low doses of radiation - the type of radiation many of us encounter daily - during the earliest and most delicate stage of life.
Ionizing radiation - which has shorter, more powerful wavelengths than visible or ultraviolet light - undoubtedly is strong enough to break apart chemical bonds in the body, including DNA, says Dr. William S. Dynan, biochemist and chief of the Program in Gene Regulation at the Medical College of Georgia Institute of Molecular Medicine and Genetics.
Dr. Dynan, principal investigator on the new $750,000, three-year grant, has been studying how cells respond to radiation that can break one or both strands of the double-stranded DNA, leading to cell death, successful cell repair or misrepair that may result in cancer.
But key issues still unexplored are whether the low levels of radiation all around us - even inside us in unstable forms of common elements such as potassium and hydrogen - cause problems and exactly what genes and proteins in the body help repair and, more importantly, prevent damage.
"The reason to do this in fish is to look at mechanisms of injury and innate mechanisms for repair and protection," Dr. Dynan says. "We want to know what goes wrong first. What is the most sensitive tissue? Is there a threshold for damage? We don't know the answer to either question. We might come up with some reassuring answers here. We could find there is a threshold. We could find that the damage is completely self-healing below a certain amount."
The researchers are exposing zebrafish embryos - which grow outside the mother and have developed, functioning organs within three days - to levels of radiation that mimic what humans routinely receive. A high-powered microscope enables them to look inside a live embryo and, as an example, mark specific brain cells with a fluorescent dye to see if the numbers change after irradiation. They also plan to document double-strand breaks and repairs within single cells.
"We want to know what bad things happen to an early embryo both at the DNA level and, on a more macroscopic level, how that affects development," says Dr. David J. Kozlowski, developmental geneticist and director of MCG's Transgenic Zebrafish Core Laboratory. "Say for example, a whole bunch of cells gets these double-strand breaks and they die. What happens to the embryo? Does it fix itself or is there irreparable damage? And, if we have a gene we think protects the embryo from radiation, if we reduce the function of that gene, does that make the embryo more sensitive to even lower doses of radiation?"
Studies of the babies of pregnant women exposed to high radiation doses from atomic bombs dropped at Hiroshima and Nagasaki in 1945 have linked higher exposures to lower IQ and smaller head size. In fact, most of the information about human cancer and other risks from radiation exposure came from the aftermath of those bombings.
"We know it must create problems for the embryo," says Dr. Catherine Bladen, postdoctoral fellow in Dr. Dynan's lab. "But what we don't really understand is what those problems actually are and how detrimental they can be to the embryo, to the development of the embryo, and if (low doses) really are a significant problem ... We have a lot of information about what radiation does to cells that live in a dish but we don't have a lot of information about the effect on a living organism, and that is something we are working to get," Dr. Bladen said, referencing work in Dr. Dynan's lab that has focused on test tube studies and is now moving into the zebrafish.
Her studies already have shown that particular organs in the embryo, including the brain, are sensitive to relatively low doses of radiation. She's also identified at least one gene that, when knocked out, results in more cell death.
"Clearly there are protective mechanisms that repair damage," says Dr. Kozlowski, a co-investigator on the DOE grant. "Imagine if you could actually ramp up one of these protective mechanisms so it doesn't miss."
"There may be some way you can genetically alter the environment in the cell that makes the cell repair damage better," echoes Dr. John T. Barrett, MCG radiation oncologist who is helping with experiment design. "From a therapeutic standpoint, there also may be a way in cancer cells that you can increase the damage or disable the repair mechanism for these double-strand breaks so that you get better cell kill."
Dr. Barrett theorizes that the repair/protective mechanisms are generally adequate since most people get regular exposure from everything from cosmic rays to some foods to naturally abundant radiation isotopes in the body. " There is radiation in my body sufficient to make a double-strand break all the time," Dr. Dynan says. Some occupations, such as Dr. Barrett's, along with aviation and nuclear plant work, routinely may involve even more exposure.
Current exposure standards for all groups err on the side of caution. For example, diagnostic use of radiation, in an X-ray or CT scan, as well as therapeutic radiation used for cancer treatment are largely avoided in pregnant women, unless there simply is no option, Dr. Barrett says.
He hopes the new study will help quantify the risk and determine subsets of people who may be more - or less - susceptible to damage.
"We'd like to find new genes that nobody knows about yet that are involved in protection from radiation" and the zebrafish is perfect for those types of gene discoveries, Dr. Dynan says. Plans for MCG's cancer research building include an expanded zebrafish facility to support the search for other genes, such as those that predispose people to colon cancer. "DNA repair mechanisms are nice, but we want to look at what provides actual protection to the organism," he says.