A PhD student tells the story behind his current scientific research at The University of Cambridge.
Josh Newman, PhD Student at the MRC Laboratory of Molecular Biology
Way back in 1902, Auguste Deter found herself in a mental institution in Frankfurt, Germany. Not that she really understood where she was, why she was there, or what she was doing. She had lost touch with the world, her surroundings, the people she knew and loved, and famously uttered the words “Ich hab mich verloren” – I have lost myself. But what had this woman lost herself to? The answer became clearer after she was visited by a man whose name would go on to identify her malady – that man was Dr. Alois Alzheimer.
Fast forward over 100 years and, whilst we understand a huge amount more about this type of dementia, we are yet to truly understand the underlying molecular mechanisms that initiate and spread the disease around the brain. Alzheimer’s disease is thought to be caused by two proteins that behave abnormally and clump together. Imagine our brains, made up of hundreds of thousands of millions of nerve cells; within these cells, these proteins start to stick together and form large aggregates, ultimately leading to disruption of brain signals and nerve cell death. To this day, we are uncertain as to which of these proteins is the primary culprit in this disease, nor are we sure as to why this happens in the first place, or how it causes cell death. It is information like this that is key to working out an effective treatment.
But what are the offending molecules in question? The first is amyloid beta – this forms clumps known as plaques outside of the cell. The second is called tau, and forms clumps of sticky proteins known as tangles. There appears to be some overlap and interplay between the two but on the whole, it is not clear which is the more important. The focus of my PhD at the moment is on tau – this molecule is particularly interesting as it has been implicated in a number of other neurodegenerative diseases, such as progressive supranuclear palsy, Pick’s disease, and corticobasal degeneration, yet we still do not really understand its role in such disorders.
Tau’s normal day job involves stabilising the microtubules, which are essentially the backbone and highway of the cell – but, as we age, tau starts being rebellious and adopts an incorrect structure, allowing it to become aggregation-prone. Under healthy conditions, the odd rebellious tau every now and again is not a problem – the cell is clever and has evolved its own molecular police service. These policing networks check that everybody is behaving as they should, and any molecules that break the rules are soon dealt with and reformed into good citizens once again. This process of ensuring that proteins are correctly folded and, if not, degrading misfolded conformations involves an elaborate network of molecules, many of which have overlapping functions to ensure that order is maintained within the cell. However, it appears that as we age this police service becomes less effective, allowing for more of these misfolded forms to remain and form aggregates. Like many criminals, these misbehaving tau proteins seem to be part of their own underworld gang and have the ability to recruit other tau proteins to the dark side - towards a misfolded conformation. This ability to convert other proteins to the incorrect structure is reminiscent of another set of illnesses known as prion diseases. In the UK, these are relatively well known due to a mass outbreak in the farming community in the 1980s causing bovine spongiform encephalopathy – otherwise infamously known as mad cow disease. But what do mad cow disease and Alzheimer’s have in common? It’s all to do with the way they spread around the brain. In prion disease, a protein known as PrP is able to misfold and induce correctly folded proteins to misfold as well. As with many diseases of this nature, these molecules then stick together and cause degeneration of the surrounding cells. Sound familiar? Well, these prion-like properties crop up in many neurodegenerative diseases and the importance of this on the spread of pathology is what I’m researching.
So that’s a brief introduction to the background of Alzheimer’s disease. But how do I actually study it? Well, I spend my days with a type of nematode known as Caenorhabditis elegans – for those of you (presumably the majority…) who are unfamiliar, these are microscopic, transparent worms. They’re cute, I swear, but I’m biased. One of the first questions I often get after explaining that I look at Alzheimer’s disease in worms is… “But how can you tell if a worm has Alzheimer’s? Do they start forgetting things?”. The answer to that is, unfortunately, no, memory deficits are not something I study. Instead, I look at how this spread occurs and the influence that the police service of the cells has on the spreading efficiency. As these worms are transparent, it is possible to tag the tau protein with a fluorescent marker and observe it within their cells. By doing this, tau can be tracked to see where it moves and what it associates with. Some of our worms also have hyperactive policing mechanisms – a kind of ‘police state’, if you will - and by doing the same in these worms, we can identify whether or not this impedes the ability of these tau gangs to recruit more members. By monitoring these tau interactions, we are becoming more aware of the criminal network of recruitment and aggregation that is taking place in the brains of many people with Alzheimer’s disease. A better understanding of this process of spreading is important to identifying ways to stop the spread in the first place.
But worms don’t get these diseases naturally – they don’t express the same set of proteins that higher organisms such as you and I do. Instead, we must induce these pathologies by genetically engineering them to express human forms of these molecules – by doing this, we can give worms human diseases and try to figure out what conserved cellular mechanisms might be in place to help or hinder their progression. That’s the beauty of using a model organism with a very basic and well understood biology – it simplifies the science and hopefully points us in directions that may be evolutionarily conserved in humans. So, from a German woman with an undiagnosed case of early onset Alzheimer’s disease in the 1900s to worms in a petri dish today, we certainly have come a long way. But we still have much further to go and many more exciting discoveries to make.