Ok ok the click-bait was a joke, but this really was a super surprising result. It’s a really interesting story that has come out of our lab in the past few weeks and I just wanted to write a quick blog about it because it just shows how the unexpected result can open up a whole new area of science we had never thought about. I think this kind of thing is what makes working in science so great, the more you look the more questions you find. It also gives a really interesting aspect on failure in science. I’ll give a tiny bit of backstory…
We do a lot of work on a group of cellular complexes called inflammasomes (see previous post). In summary these are little machines which sense patterns either on microbes or things released from our own cells when they die. When activated by these patterns, inflammasomes start to produce pro-inflammatory molecules which aim to neutralise the threat. The problem is they often just end up making things worse. There are a number of different types of inflammasomes but one in particular, catchily coined “NLRP3”, has been implicated in an array of what we called ‘non-communicable diseases’ (basically those that aren’t caused by an infection by some kind of microbe). These include but are not limited to gout, atherosclerosis, cancer and Alzheimer’s disease. A role has also been proposed in stroke although previous work has been unclear, the lab therefore decided to properly look into the NLRP3 inflammasome in a mouse model of stroke.
Early work showed that genetic knock-out of NLRP3 in mice had absolutely no effect on the outcome after stroke. The study was a failure. Now failure is a word that means different things to different people, and to some people it simply means you’ve got yourself another battery questions to answer. How you take what some will perceive as a failure makes a huge difference to what you can achieve. The lab thought they had failed, but they kept searching and what they next found was hugely surprising and was something no-one has described before. Although the NLRP3 inflammasome had no effect, deletion of another inflammasome, NLRC4 (yet another super catchy name!) was significantly protective.
I know what you’re thinking – “Wow no way! Not NLRC4!? You’re pulling my leg!” But this is seriously a really interesting discovery. You see, the NLRC4 inflammasome has only ever been shown to be activated by bacteria, something that just isn’t there in the case of a stroke. This complete mystery opens up a whole new set of questions. What is activating this usually infection-only inflammasome? Are its wires crossed somewhere? Is it our own gut bacteria? How long have we been ignoring NLRC4 in diseases like atherosclerosis or Alzheimer’s thinking it could not possibly be involved?
There are some possible ideas to answer these questions but it will take a lot of work, as does everything in the world of science. In biology things are never as simple as they appear (as a colleague recently put it, Occam wasn’t a biologist); and what I believe this story shows us is that with every failure comes a new set of questions to answer and ideas to explore (contradictory disclaimer – you also have to know when to call it quits). This is a great example of why it can be both spine-tinglingly exciting and excruciatingly frustrating to work in science and why I just can’t get enough of it. Remind me to read this back when I’m on a two year nothing-is-working bottomless pit of sorrow and despair in the future, I’m sure I’ll hate me.