Nuclear radiation exposure from nuclear power plant accidents affects relatively few people. On the other hand, radiation treatment for cancer is widespread. It is important that we learn all we can about how radiation harms human beings, so we can find ways to repair the damage if possible. Animal models of radiation damage are not very useful in assessing radiation damage to humans but medical ethics prevent experimenting on people. Now a group of researchers have found a new way to improve our knowledge of the effects of radiation on human beings.
Researchers from the Wyss Institute for Biologically Inspired Engineering at Harvard University, Instituto Superior Técnico (IST, Portugal), Boston Children's Hospital, and Harvard Medical School (HMS) have just published a study on their use of what is called an “organ-on-a-chip” to assess radiation damage to the human gastrointestinal tract.
An organ-on-a-chip is a “multi-channel 3-D microfluidic cell culture chip that simulates the activities, mechanics and physiological response of entire organs and organ systems.” (Wikipedia) The chip used by the researchers is transparent and contains two parallel microchannels which are separated by a porous extracellular matrix membrane. One of the channels is coated with epithelial cells from the lining of a human intestine. The other channel is lined with human endothelial cells that are similar to the cells lining blood vessels. The researchers refer to this type of organ-on-a-chip as a Gut Chip
Cell cultural media is injected into each of the channels. There are side chambers located long both of the channels. A suction is periodically applied to these side chambers to stretch the cells lining the channels. This is done to imitate the motions of a human intestine as food move through it. The cells in the channels spontaneously form intestinal villus-like structures and surface microvilli that serve to expand the cell surface area for nutrient exchange.
The researchers subjected the Gut Chip to eight Grays of radiation. A Gray is a measure of radiation absorption. An eight Gray dose is known to cause damage to the gastrointestinal tract of a human being. The Gut Chip showed a variety of indicators of cellular damage. These included cell death, generation of free radicals, double stranded DNA breaks, membrane lipids damage, loss of microvilli structure, and disruption of junctions between the protective mucous lining of the intestine and the nearby cells.
The endothelial cells in the Gut Chip showed more damage from the radiation than the epithelial cells. In the endothelial cells, the peak of cell death occurred twenty-four hours from the exposure while the epithelial cells showed peak cell death after forty eight hours. The conclusion drawn from these results is that the endothelium is more sensitive to radiation than the epithelium.
A coauthor of the study said, “This finding helps explain why other models of the human gut that don't include endothelial cells generally fail to mimic the gut's response to radiation injury. More studies are needed to confirm the link between endothelial and epithelial cell responses, but we think that free radicals generated by endothelial cell damage will prove to be the driving force behind epithelial cell damage, and this could serve as a target for future anti-radiation therapeutics."
In the next stage of the research, the scientists injected dimethyloxaloylglycine (DMOG) into the Gut Chip before they exposed it to radiation. DMOG a drug known to protect animals against radiation damage in the gut by promoting the production of two proteins. The DMOG significantly reduced cell death, free radicals, lipid degredation and microvillus injury in both channels of the Gut Chip.
One of the researchers said, "Now that we have successfully tested a potential drug candidate in a human organ system, our goal is to use this chip to identify new radioprotective drugs by physiologically mimicking radiation damage in the gut.”
Another researcher said, "The grand vision for the future of this technology is to link different Organ Chips into a fully personalized body-on-chips model, where we'd be able to take cells from a patient and test which medicines will best protect all their organs from radiation, either higher doses from nuclear events or lower doses from off-target cancer treatment."
The Founding Director of the Wyss Institute said, "This research marks an important advance bringing us closer to realizing our goal of creating clinically relevant chips for each major organ system that can help predict and prevent disease, and importantly, it meets a longstanding need for more human-relevant models of radiation toxicity that can be used to develop appropriate countermeasure therapies, which was the challenge raised by the Food and Drug Administration (FDA) when they funded our work."
