We are delighted to say that the GenOMICC study is now supported by the Fiona Elizabeth Agnew Trust (FEAT).
Our genes (or DNA) determine how vulnerable we are to sepsis and other forms of critical illness. By comparing DNA between critically-ill patients and members of the general population, we aim to discover specific genes that might control the processes that lead to life-threatening illness.
Sepsis is a life-threatening condition in which immune processes are triggered by a severe infection, and cause the heart, lungs, kidneys and other organs to fail. It causes hundreds of thousands of deaths every year. Because surviving infection has been a major force driving our evolution1, and because the bugs that cause infection directly interfere with our immune responses, the biological processes that cause death in sepsis have evolved to become extremely complex. This complexity makes the effect of new treatments very difficult to predict.2
Perhaps the best way to test our knowledge of the biological processes that cause death in sepsis is to look at how well we have been able to predict the effect of new treatments. There is no shortage of evidence here. Since the first trial of a treatment for sepsis in 19763, more than 100 large-scale clinical trials of treatments for sepsis have been conducted,4 each costing millions of dollars (current estimates of Phase II/III trial costs range from $7-$50 million5). For each of these treatments, a wealth of supporting evidence existed from our existing knowledge of sepsis. No-one starts a clinical trial without good reason to believe that the treatment might work.
Not one of these trials has produced an effective new treatment for sepsis. I have proposed two explanations for this. Firstly, we don’t understand the biological processes that cause death in sepsis - we are choosing the wrong drug targets2. Secondly, we don’t understand the syndrome itself. We are lumping together patients with different underlying problems, such that even if our treatments are targeting the right biological processes, we are trying them in the wrong patients so we can’t see the effect6.
Susceptibility to infection is very strongly genetically determined. Adopted children whose biological parents died young from infection are 6 times more likely to die of infection themselves. In contrast, if their adoptive parent - who brought them up but is not genetically related to them - died young of an infection, then the child is no more likely than anyone else to die of an infection themselves.7
Once a patient has sepsis, a complex cascade of immune signals leads to failure of critical organ systems and death. These events are not specific to a particular type of infection - they can happen to any patient with a severe infection. Although we know that susceptibility to a particular bug, such as the influenza virus, or a bacteria like Staphylococcus aureus, is genetic, it is harder to tell if there are specific genes that alter a patient’s chance of survival once they are already desperately sick with sepsis. However, we know that the immune system plays a key role in causing organ failure, and we know that immune diseases, including infectious diseases, are very strongly genetic.
If we find a gene that changes a patient’s chance of dying from sepsis, then we have found something that has so far eluded us: a “lever” that changes the intractably complex cascade of biological events to promote survival in humans.2 Understanding the biological effect of disease-associated genetic variation requires computational work and experimentation in model systems. More information on the approaches we have developed to this problem can be found elsewhere on this site.
The choice of patient population to study will wholly determine the nature of the genes that we find. Ideally we need people who are previously healthy, and don’t have other risk factors for death from sepsis. We need to compare people who survive, with people who do not, on a level playing field. The characteristics of the infection that initiates their sepsis must be as similar as possible - they should have similar quantities the same pathogen, in the same organ system. Finding these people is very difficult.
There are millions of DNA sequence differences between any pair of humans. Any of these could be important in determining the outcome in sepsis. Finding the ones that matter requires us to recruit large numbers of patients. Typically, we need to find thousands of patients in order to find genetic associations with disease. Because the patients we need to study are rare, we need to recruit over a large area, and for a long time, in order to acquire the DNA we’ll need. This requires global collaboration among critical care doctors, openness and sharing of data between researchers, and an innovative approach to funding.
1.Grossman, S.R., Shlyakhter, I., Shylakhter, I., Karlsson, E.K., Byrne, E.H., Morales, S., Frieden, G., Hostetter, E., Angelino, E., Garber, M., Zuk, O., Lander, E.S., Schaffner, S.F. & Sabeti, P.C. A composite of multiple signals distinguishes causal variants in regions of positive selection. Science (New York, N.Y.) 327, 883–6(2010).
2.Baillie, J.K. Targeting the host immune response to fight infection. Science 344, 807–808(2014).
3.Schumer, W. Steroids in the treatment of clinical septic shock. Annals of Surgery 184, 333–341(1976).
4.Marshall, J.C. Why Have Clinical Trials in Sepsis Failed? Trends in Molecular Medicine 20, 195–203(2014).
5.Sertkaya, A., Wong, H.-H., Jessup, A. & Beleche, T. Key cost drivers of pharmaceutical clinical trials in the United States. Clinical Trials (London, England) 13, 117–126(2016).
6.Scicluna, B.P. & Baillie, J.K. The Search for Efficacious New Therapies in Sepsis Needs to Embrace Heterogeneity. American Journal of Respiratory and Critical Care Medicine (2018).doi:10/gfsvvr
7.Sørensen, T.I., Nielsen, G.G., Andersen, P.K. & Teasdale, T.W. Genetic and environmental influences on premature death in adult adoptees. The New England journal of medicine 318, 727–32(1988).
We are proud to say that
Achieving this requires ongoing funding - fundraising for FEAT will help us to get as many samples as possible stored so that we can get to the stage where we can find important differences in the genomes of patients with sepsis.
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