Dr Julian Knight, Wellcome Trust Centre for Human Genomics, Oxford
Kat - From the moment we’re born, we’re exposed to millions of bacteria and viruses in the world around us. Most of the time they don’t make us ill, but if they do, most of us can fight off the infection. But for some people, it’s a different story, and they can become desperately sick. I spoke to Dr Julian Knight from the Wellcome Trust Centre for Human Genomics at the University of Oxford, to find out how genetic studies are helping to reveal more about these differences.
Julian - A classical approach that people have used is to look at the very rare examples of patients who have a specific genetic difference that predisposes them to a particular disease. For example, with very young children, they may be born and have genetic differences that result in severe primary immune deficiencies where they're very vulnerable to infections. The other way of thinking about the genetic contribution to immune related diseases is with common diseases which might include infections or autoimmune diseases like rheumatoid arthritis.
We now have the genetic tools to actually try and look across the whole genome and look for what are often several different genes and genetic differences that may be contributing to the same disease. That's really been driven by new technologies that have become available to us within the field of human genetics such that, rather than focusing on a single gene, we can now look at many thousands of different genes and indeed, many millions of different genetic differences.
Kat - I guess, to draw an analogy it would be a bit like the more severe diseases, you look at a car and the wheel has fallen off and you can see that whereas – I guess what you're trying to do with the population saying, well, some people are more like a Ferrari, some people are more like a Fiat Panda. How do you even go about classifying all those huge number of differences?
Julian - An approach that's been successful over the last 4 or 5 years is to take a set of patients - so, you define a particular disease phenotype, so the condition with which the patients are manifesting, and then you define a set of individuals who are controlled, who don’t have your disease, and you try and look for the genetic variants that are in one group, but not present in the other. By doing that, you can try and build up a map of where those genetic differences are lying and what particular genes they may or may not be influencing. Because it may be that the genetic difference is arising within the coding sequence of a gene and that would change the structure and the function of the protein that's encoded by the gene. And that might be something that you can very readily detect. Or it might be that it’s a genetic difference lying outside of the gene within the regulatory sequence that controls how much protein we produce. Although those are more subtle, they're perhaps more common and very much more important in these complex disease traits than we’d initially anticipated.
Kat - So, what do we know so far about the kinds of genes that are involved in regulating our immune system and some of the differences between people and their immune systems?
Julian - We’ve got some evidence that goes back a long time in terms of genetics research - we’re talking 40 or 50 years now - that we’ve understood that genes within a region on the short arm of chromosome 6 called the major histocompatibility complex. We know that genetic differences in that region are critical to encoding proteins that present foreign antigens to the immune system and that's critical in our response to infection.
Kat - So, this is like picking something up and going, “Look at this immune system. Recognise this and fight it.”
Julian - Absolutely, and that takes quite complicated machinery to break up the protein loaded on to what we call a presenting molecule that can then be taken to the surface of the cell and other cells within the immune system can recognise that and initiate what we hope is an appropriate immune response to deal with that infection. In some instances, we think that that process goes wrong, and that can lead either to an excessive immune response which might actually be harmful to us. Or indeed, it might be that the body starts to fight itself and that can lead to autoimmune diseases. But now that we can look at the rest of the genome, we know that outside of the MHC, there were also important differences between people and patients in particular that contribute to developing the risk of disease
Kat - When we discover more about these genes, not only is this helping us to understand who’s more vulnerable to certain diseases or not, would this explain why some people for example, seem to get flu all the time or some people seem to be very sickly and others are very robust?
Julian - Absolutely. So, over in the hospital, we see elderly patients who are very dependent and are coming perhaps from a nursing home with a severe infection. And despite the pessimism that they might be in some of those situations, these patients can be remarkable and they can survive. We know that people differ in how well they're able to respond to infection, how appropriately they can respond to infection, given that this is still a major killer in our society in terms of severe sepsis - the mortality rate on intensive care units is still of the order of 20%.
Understanding this very basic biology in terms of why some people are able to survive and overcome severe infection I think is potentially very important because it can lead us into potentially new therapeutic avenues, drug targets for example, or indeed, being able to better understand where and who we should be targeting therapy for. It may be that possessing particular genetic differences means you produce more or less of a particular protein, critical to an immune response. If we can understand that both at a population level and in the lab, then hopefully, we can go some way forward to understanding the genetic basis of these diseases.
Kat - The knowledge that you're gaining now about how people’s immune systems respond in different ways to diseases and to things like sepsis, how close are we seeing this genetic knowledge actually coming into the clinic and benefiting patients?
Julian - Well, I think that we’re perhaps still 2 or 3 years away from really understanding with confidence what these genetic contributors are to diseases such as severe sepsis. We have been able to identify in specific patients who have rare inherited defects or problems with their immune response particular genes and that can be very helpful in terms of making a diagnosis and guiding therapy. But it may be that if we can understand these genetic causes better and predispositions, then perhaps there are some patients who might benefit from therapies who we can target specifically to use such therapies. By only targeting those patients who are going to benefit, we can avoid the downside of these sort of therapies, which paradoxically increase your risk of infection in some cases.
So, I think that there is a hope that by using genetics, we can more rationally use existing drugs, we can identify targets, whereby we can develop new drugs or use existing drugs in new ways. We may be able to reduce what is really, still a devastating disease whereby, we’re faced with high mortality rates despite best care in terms of the intensive care units and available antibiotics and so on. I think that's what motivates a lot of people who were interested in trying to use these new genetic approaches in a whole range of different diseases.
Kat - That was Dr Julian Knight from the Wellcome Trust Centre for Human Genomics.