Radiation bystander effects

Los Alamos National Laboratory biologist Bruce Lehnert's study of the effects of extracellular mediators, including proteins, from irradiated human cells on non-irradiated cells has confirmed the existence of the so-called "bystander effect," which essentially refers to radiation- induced effects in unirradiated cells.

The effect induces a response that could hold the key to the causes of gene instability that underly cancer, as well as other phenomena such as increases in cell growth that have been observed with low doses of ionizing radiation, radio-adaptive responses to low doses of radiation provide protection against the killing effects of subsequent high-dose exposure.

"We are studying cancer mechanisms at their most basic level, looking for pathways that may underlie genomic instability," Lehnert said. "Finding those pathways may show us how we can deal therapeuti- cally with the health effects of radiation exposure."

According to Lehnert, mounting evidence suggests that many impor- tant effects of radiation can occur in the absence of direct irradiation of cell nuclei. Results from recent experiments show that at least some cancer-associated effects of ionizing radiation, including the induction of genetic mutations, can occur in cells that have not been directly exposed to radiation.These results have profound implications for assessing cancer risk and other collateral effects of environmental, diagnostic or therapeutic exposure to ionizing radiation.

When Lehnert first came to Los Alamos nearly 20 years ago, he worked on the effects of toxic gases on the lungs and lung defense mechanisms. On the lookout for interesting problems in radiation biology, Lehnert was intrigued by papers on genomic instability that suggested a far-reaching phenomenon activates something in cells making them susceptible to damage even when their nuclei are not directly irradiated.

Recent advances in charged-particle micro-beam technology have provided a means to directly assess the consequences of irradiating cell nuclei as opposed to irradiating extranuclear regions. With these approaches, the nucleus and the cell's body, or cytoplasm, are differen- tially stained with compounds that fluoresce with different emission spectra when illuminated by ultraviolet light. This allows visualization of the subcellular regions so that the subcompartments can be prefer- entially targeted for irradiation by charged particles and the results observed. Such studies have confirmed that the irradiation of parts of cells aside from their nuclei can cause numerous effects.

Lehnert and his group obtained evidence that alpha particles like those emitted by radon, radon progeny and plutonium 238 can cause increases in sister chromatid exchanges – an indicator of DNA damage that involves symmetrical transfers of DNA fragments between two chromatids of the same chromosome – in normal human cells without direct nuclear traversals. They also found that these increases were maximally induced over a low-dose range in an "all or none " manner. They concluded that the excessive chromatid exchange response could have been induced by an effect of alpha particles in some region outside the nucleus and theoretically even outside the cell itself.

In further investigations, Lehnert's group found unequivocal evidence that this and several other cellular effects are mediated by the production of extracellular factors that transmit signals that produce responses in unirradiated cells to the same extent as those observed when cells are directly irradiated to low doses of radiation.

Definitively demonstrating that radiation can produce bystander effects on neighboring cells has introduced a new variable in risk assessment. Under some experimental conditions, DNA, or even whole cells, can no longer be viewed as the only relevant target for the actions of ionizing radiation, or even necessarily the most important target for eliciting at least some of the detrimental effects of ionizing radiation.

The Department of Energy has long been interested in individualized risk assessment for radiation exposure. Scientists are seeking to identify genes that play crucial roles in determining an individual's susceptibility to the effects of ionizing radiation and are looking for the mechanism that causes genes to become unstable. What is clear from Lehnert's work is that one important bystander effect is an increase in intracellular reactive oxygen species, which potentially can cause several types of DNA damage. A second important bystander effect is that the growth of cells is enhanced, and cells showing this response fail to stop growing when subsequently exposed to radiation.

"All of these features of bystander responses readily fit into current models of carcinogenesis," Lehnert said. "This makes this new area of radiobiological research so interesting and important. The bystander effect may or may not contribute to cancer, as yet we simply don't know its full health implications. The confirmation of its existence and newly available information about its causes, at least in cell culture systems, are already changing how we think about risk assessment."