 These are two real patients diagnosed with the autoimmune disease lupus when they were less than three years old So their immune system has turned against their own tissues. In the case of Julia, her disease mainly It's damaging her joints and brain. In the case of Carmen, the disease is affecting the kidneys and heart So there is a range of ways in which lupus can manifest because it can be caused by many different Immune pathways that makes it very difficult for us to develop a cure or even effective therapies for lupus And the sad truth is that we do not have cures for any of the over 80 autoimmune diseases that collectively affect 5% of the population. In these cases like Julia and Carmen We are treating them with drug after drug blindly until if we are lucky one drug makes a difference These drugs are often toxic and expensive and the problem is that we do not understand the specific defects in cells or Molecules that are causing their disease. So if we could find the specific mutations in their genomes responsible for the disease It would not be that difficult to find a drug that might Specifically correct the problem. In the case of the immune system We are fortunate because there's a large number of drugs that are on the shelf And we could use if we could predict which patient would respond to which drug So what cost nearly a billion dollars and took 15 years to do? Sequencing the first human genome is now possible in just a few days Thanks to a blue sky research discovery a new and fast and cheap way of sequencing called next generation sequencing Which we have used to establish a molecular diagnosis for Carmen and Julia in the case of Julia It was pretty straightforward She had a mutation in a known protein that we understood the function So it was relatively simple for us to generate the mutated protein in the laboratory and establish and prove that the mutation made It lose its function So then we could know of a drug that would be more effective and less toxic than the combination of drugs that she's currently on The case of Carmen is more complicated. We found a mutation likely to cause her disease But we didn't really know how that protein worked So in this case in order to understand the disease and find an effective drug We need to come up with an additional highly specialized research tool a mouse model that carries the same mutation as Carmen does Again, what seemed impossibly difficult to do is now possible. Thanks to another blue sky research discovery a genome editing tool called CRISPR that allows us to cut the DNA and substitute any letter of the three billion letters that constitute the human genome and We have been able to do that. We now have a line of mice that are born with the same genetic defect as that of Carmen we now can use these mice to understand the disease and In the next few months or years We could probably understand how the mutation causes disease and identify a drug that might be effective So in the old approach, we used to start with spontaneous mouse models that developed lupus and find drugs that cured the mice Not surprisingly because the mice were not based on real mutations found in real patients These drugs have not been effective in treating humans the new approach we select severe cases identify the precise mutations and Generate bespoke mouse models of disease that we can use to understand how disease develop and how we treat them So one of our worries is that these approach is far too costly for developing countries Which generally lack the infrastructure to perform this whole genome sequencing and to analyze it another worry is that the process is long It takes my lab even several years sometimes to identify to understand how each mutation works Even after we've successfully made the personalized mouse model to complicate things further It is likely that there will be a long list of genes that will be responsible for autoimmune disease And that the disease might require more than one gene to be mutated So the likelihood that any two patients will have the same gene or combination of genes is very small So is this feasible? Well, we think it is because once we've understood a few severe cases like those of Carmen and Julia It is likely that we have we will have found unique characteristics of their disease that are shared by their mouse models for example an excess amount of proteins or Substances in the blood we call these biomarkers So then we can use these biomarkers to screen large cohorts of patients and we can then Stratify them into subgroups that have a similar cause of disease overcoming the need of making or Sequencing their genomes or making additional mouse models And then we can treat these groups of patients with drugs that we have found to be effective for each disease cause So in summary we select severe cases of disease Identify mutations that are putatively cause of disease Generate the bespoke mouse models and identify drugs that can be used to treat the patient along the way We find biomarkers that we can use to screen larger cohorts Divide them into subgroups that can then be treated with pathway targeted therapy So the process is complex. It's challenging. It's risky But we do think that it has the potential to transform some of these chronic diseases and Improve the lives of many and that's why I love doing it. Thank you