You could say that my research is all about worms – though not the kind of worms you might have had at primary school! Mine are transparent worms, a millimetre long, that live in soil when they aren’t under a microscope in the lab. They became vital for Molecular Biology in the 1970s after Sydney Brenner selected them as a model system for molecular research. He probably couldn’t have predicted that by now there would be hundreds of labs across the world working on Caenorhabditis elegans (C. elegans) and even a biennial international conference for C. elegans researchers – held in LA, no less – with its own worm comedy show.
C. elegans turned out to be an excellent choice for a number of reasons. In the first place, surprising as it sounds, it turns out that there isn’t a huge difference between C. elegans and humans at the level of the genome (the hereditary information that’s encoded in DNA). Which means that my worms are excellent for exploring processes and problems with which we are all familiar – like development or ageing. Second, because C. elegans is tiny and transparent, and made up of a mere 959 cells, we can observe biological processes at the level of individual cells in a way that would be impossible in a more complex organism. Finally, because C. elegans takes just three days to develop from egg to maturity, because it has a life span of three weeks, during which it feeds only on bacteria, and because it can produce large numbers of offspring by self-fertilisation (a large proportion are hermaphrodite), it is easy to observe the same biological process repeatedly within a short time span.
The first strand of my research on C. elegans focuses on the process of development and how individual cells come to take on their various roles. In particular, I’m interested in how stem cells maintain a balance between self-renewal – i.e. the generation of further stem cells, and the generation of cells that will ‘differentiate’ – that is, cells that will develop to serve a particular function (e.g. as muscle or skin cells). If we can understand in detail how a cell manages to maintain this balance, we will be much closer to understanding how certain cells get out of balance and generate the wrong sort of cells – as happens with certain sorts of cancer. And with that in mind, I’m looking closely at the development, in my worms, of certain stem cells called ‘seam’ cells that are comparable to the stem cells that generate blood cells in humans. Because where the seam cells’ development goes wrong, the consequences in my worms are similar to what we find in humans who suffer from acute myeloid leukaemia (known as AML1), a cancer of the blood. And because two of the genes involved in what happens to my worms are equivalent (‘homologous’) to genes that have been shown to play a critical role in AML1, the worms could be the key to understanding and controlling this particular form of cancer.
As well as using normal development as a way of understanding where and how molecular biological processes go wrong, I’m also looking at what C. elegans has to teach us about the other end of life. This developed from a project I supervised for one of my undergraduate students, which led her on to a PhD, and me into a collaboration with Dr Lynne Cox, a colleague who works in Biochemistry. Together we’ve been experimenting with speeding up or slowing down the ageing process in C. elegans so that we can understand more about how lifespan is determined genetically, again using the worm as a model organism. We know that Werner’s Syndrome – a disease that causes premature ageing and early death in humans – is caused by a mutation in just one single gene, therefore this gene (the WRN gene) must be absolutely crucial for regulating the ageing process. We’ve discovered that if we take out the homologous gene in my worms, we can recapitulate the premature ageing. Then we can look for other genes, or even drugs, that prevent this premature ageing. These factors could, in the future, represent novel anti-ageing factors. The real goal of ageing research is not to make us live forever, but rather to increase our “healthspan” – to alleviate some of the diseases and discomforts associated with old age.
This is more than enough to be getting on with, but if you were to ask me to predict the future of research in my field, I’d say that, as well as the rich veins of biological investigation still to be mined in the worm, there are huge opportunities in relation to drug development. We are increasingly moving away from testing drugs for humans on vertebrates and recognising the advantages of using invertebrates (like C. elegans) to screen for ‘targets’ – points in molecular biological processes at which key regulators can be stimulated or disrupted – switched on or off, if you like. Once these key regulators are identified, we can begin to work on what we can do to activate or inhibit processes we want either to promote or to prevent. So there’s plenty still to be done as long as you aren’t squeamish about working with worms. And why would you be? They are not called C. elegans for nothing…..