Modelling Traumatic Brain Injury
Every year thousands of people are victims of traumatic brain injuries, or concussion. The causes range from sporting incidents to car crashes, but the outcomes and the best way to manage head injured patients are very hard to study because no two injuries are alike. Now, David Wassarman and Barry Ganetzky have solved the problem by coming up with what can only be described as, well, a high-tech fly swatter.
David - We think that this complexity that is part of traumatic brain injury can be studied in a simpler animal system, and we have been doing this in fruit flies. The brain in the fly is encapsulated in a structure that's very similar to the human skull. A mechanical injury to the outside of the fly head will cause that brain to ricochet around inside this capsule, causing injury to those brain cells which are very similar to the cells in the human brain.
Chris - So, how did you create an objective way of doing this - a standardized injury to a fly then?
Barry - We created an instrument that we called a HIT device, which stands for High Impact Trauma device. We take the flies and we put them in a container and then we uniformly strike that container against a solid surface so that all of the flies in the container receive equivalent injury.
Chris - And Barry, when the flies are traumatized in this way what happens to them? What do they look like?
Barry - We've made high-speed movies so we can watch the flies subjected to this treatment. There isn't any noticeable physical external damage to the flies but a proportion of the flies become, I think it's fair to say, knocked out. They become immobilized, they might show what one would think of as a seizure - some twitching of the legs and wings - but they will remain paralyzed for about 5 minutes or so. Then they will eventually recover. They will be somewhat uncoordinated and woozy, which is very similar to what humans who have suffered a concussion would exhibit.
Chris - And David, what happens to them once they've recovered in this way? Do they then go back to being normal?
David - Yeah. So, we think that all of the flies have deleterious outcomes to various extents. The major thing that we see within a very short period of time is that a large fraction of them do die, and that's one of the things that we measure. And then we can take the surviving flies and study their behavior, as well as the molecular events that occur inside organs of that fly.
Chris - And Barry, when you ask those questions - what happens to the internal organs? - what do you see? Do you see consistent features emerging following traumatic brain injury?
Barry - One of the first things that we did when we were subjecting flies to traumatic brain injury is to ask whether there are genetic differences among different strains of fruit flies that made them more or less sensitive to traumatic brain injury. There were differences. We tracked down some of the genes that were responsible for those differences that led us to being able to detect particular secondary injuries that were consistent and reproducible, the most remarkable of which was a breakdown of the barrier that separates the contents of the intestine from the circulatory system.
Chris - So, you're saying that a brain injury has a subsequent consequence for the intestinal system. This is not an injury sustained at the time of the trauma. There's something going on downstream of the brain injury that does this.
David - Yeah. So, we can feed the flies a blue dye. We can see how long it takes for that blue dye to leak out of the intestines. We see significant breakdown at about two hours after the initial injury.
Chris - What are the consequences of this enhanced intestinal leakiness downstream of the brain injury? What does it do Barry?
Barry - There are two consequences. When the barrier breaks down, there's a leakage of material out of the gut, for example, bacteria. We could ask whether some of the chemicals, in particular certain sugars, out of the intestine into the circulatory system were resulting in bad consequences. And we could test that as well by taking flies after they had been subjected to traumatic brain injury and putting them on a water diet as opposed to their normal food source that was rich in sugars. Surprisingly, it turned out that when flies were fed on water after traumatic brain injury, those flies in fact survived better. So, there's some negative consequence of the elevation in sugar leaking out of the intestine into the circulatory system after a traumatic brain injury.
Chris - And David, do you think it's just glucose, or do you think that glucose may be a proxy marker for the fact that other "stuff" is coming across from the intestine? And perhaps coupled when you have injury to the brain, you also get a dismantling, albeit temporarily, of the blood-brain barrier. Perhaps that increased permeability enables something from the blood, not necessarily just sugar, but something to go into the brain that then has a deleterious effect on that organ.
David - I think that's definitely a possibility, that something else could be playing a role. But our data in flies actually show that if we lower the levels of glucose through feeding flies water instead of food that contains high levels of sugar; that did reduce the poor outcomes in flies. So, what we think is that the high levels of glucose are producing some kind of signal. And we need to understand what that signal is, what's occurring downstream of that after that.