eLife episode 19: Herpes vaccine, and flies with brain damage

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.

Unlike their divaesque human equivalents, animal models have contributed enormously to biological research over the past few decades. But how does life in the lab compare to life in the wild? And what can researchers gain from knowing much more about the natural history of the organisms that they use in their research? eLife are exploring these questions with a new series of articles called, The Natural History of Model Organisms. Ian Baldwin is the series editor.

Ian - There is very little communication between people who know how to use the incredible, powerful, molecular tools that been developed in the last three decades, and the people who know how to figure out natural histories of organisms and identify them and characterize them in their natural environment. That's a particularly sad situation because right now is one of the first times in the history of biology it's possible to actually utilize all the amazing things that have evolved, to actually analyze them at a molecular level and even be able to use them, because you can take out traits from one organism and put them into another organism. So the reason for this set of articles here is to take the particular organisms that have become the supermodels for the molecular biologists, the ones who've been able to really understand fundamental biological principles by developing an organism and putting all the tools so that you can actually get to the genetic basis of particular traits, and to explore where those organisms came from.

Chris - Why do you think this will solve the problem? Why will having the Claudia Schiffer of the C. elegans world, how is that going to help to solve this problem?

Ian - I think it's going to help solve the problem because amongst model system biologists, they're beginning to run out of things to work on. They're beginning to get a bit bored with the types of questions that you can study when you're only studying Claudia Schiffer. And it turns out that the nearest relatives of Claudia Schiffer actually have other much more interesting traits. I think that we are at a stage when both the ecologists who want to learn and use these molecular tools, as well as the molecular biologists who have been using particular model organisms, want to start to branch out and look at other organisms. So, I think it's a time that's ripe for that, and also it's a time that's right because of the advent of cheap sequencing that's allowing everybody to sequence the genome of every organism that they can, at a reasonable cost. And with the development of these genome editing tools that are coming online, it means that the whole business of being a model organism and a non-model organism is a divide that is becoming blurred, and pretty soon most of biology is going to be able to be accessed in the same way that the handful of models are currently.

Chris - So, a person who comes and picks up these reviews or this sequence of reviews - what are they physically going to experience? How have you approached this?

Ian - We've approached it by asking people who are this sort of this new generation of biologists. Usually, these are biologists who were trained on the molecular side of the divide and are beginning to go out into the field and find the wild relatives of these models. Figuring out where they live and what they do, and how they defend themselves, and what sort of other traits they have, and also to start looking at their nearest relatives. And as we mentioned in the article series here, the ones that were domesticated for laboratory life all seemed to share a particular suite of traits that allow them to be easily domesticated. They're boom and bust type of organisms, they reproduce easily, have very fast growth rates, they're not very finicky about the type of culturing techniques that you have to keep them under. Those are not traits that are shared by the nearest relatives in almost every single one of these model organisms. Those sorts of natural history details are what you're going to find out when you delve into the individual articles.

Chris - When will the items be coming out? What's the sort of style or format of them? What will a person get out of each individual article? How will it help them in their biology?

Ian - There's going to be an introduction that Jane Alfred and I have written to the series. And then, there's going to be a brief exposé on Zebra fish, on maize arabidopsis, on C. elegans - the nematode, and then a couple of microorganisms - E. coli and budding yeast. In each one, an expert will tell a very intriguing vignette about the life history of this model that so many scientists only consider as a reagent-grade organism, not something that lives outside the lab. And I think it's going to enrich their understanding of that organism as they go to the lab and work with it. And also the fact that some of these models all come together in various places. For example, you know, on rotting apples you find not only sometimes yeast but also C. elegans loves rotting apples. And Drosophila of course visits rotting apples, and even C. elegans hitchhikes on Drosophila occasionally in order to catch a ride onto the next rotting apple. So, there's some convergence of these model organisms in the real world with each other the specialists may not have realized.