Grant: Operating Grant

Why do patients respond differently to the same drug? Why do two people that inherit the same mutation develop such different diseases? These are critical problems in modern health care -- solving them opens new areas for personalised medicine. At present we are far from understanding this variability between people, and cannot predict it at all. At the heart of this problem is the way that genes interact. If two people inherit the same mutated copy of a particular gene, one reason they develop such different diseases is that the rest of their genes are not identical. People have millions of genetic differences and these combine to change the effect of a drug or a mutated gene. We propose to take a systematic view of how natural variation between individuals affects the outcome of a single treatment and thus to learn the rules for how the changes in each of our genomes combine. We cannot do direct experiments in humans, so we turn to the nematode worm, C. elegans. This simple animal shares half its 20,000 genes with humans including many pathways mutated in genetic diseases. Critically, in the worm we can turn off any gene using a technique called RNAi and examine the effect. We have already looked at the effect of removing each gene in the worm and found ~1500 genes that strongly affect the animal. However, when we now repeat exactly the same experiments in a different naturally occurring worm strain, we often obtain strikingly different effects. This is like examining the differences between people in response to the same drug, and the question is the same -- why do these individuals respond differently? We will answer this in worms by first examining the effect of removing each gene on a whole series of naturally occurring worms, then using genetics to map down the exact changes that cause these differences. We will thus get insight into how genetic variation affects our responses to drug treatments or genetic mutations.