Ikerbasque News

Part of your work is on the study of Multiple Sclerosis. Are their any genetic factors that determine one’s predisposition to the disease?

MS carries a significant genetic component. The disease tends to cluster in families, and twin studies have revealed the degree of genetic involvement. The consensus right now is that susceptibility to MS is driven by multiple genes with modest effects, but complex gene-environment interactions do play a role, too. One locus, the so-called HLA locus on chromosome 6, was known for a long time to be involved in predisposition, but it has been excruciatingly difficult to identify the other susceptibility genes; as a matter of fact, we are not yet at the end of the story. Only in 2007, after at least 15 years of intense genetic research, did the first piece of evidence emerge to indicate precisely which the non-HLA MS susceptibility genes were. That was possible as a consequence of two important developments. Firstly, the technology was available to perform very dense whole-genome screens, and advanced data bioinformatics tools had been developed to manage and analyse the enormous datasets arising from such screens. Secondly, it had become increasingly clear that huge numbers of patients were needed in order to find the modest susceptibility genes with sufficient statistical power. Emergence of international consortia that share patient DNA samples was therefore a conditio sine qua non for successful identification of such genes. In one study, in which our group participated, we analysed more than 20,000 patients and control subjects! One of the lines of research is on cytokine secretion inhibitors. What role do they play in neurodegenerative diseases?Cytokines are small secreted proteins that are central to the development of immune reactions.

Most of the time, the effects of cytokines tend to be beneficial, for instance, where they guide protective immune responses against infections or against cancerous cells. However, this scenario is not true in autoimmune diseases. Here, a misguided immune system tends to attack harmless tissue components. In MS, the target of this attack is the CNS, in rheumatoid arthritis it is the synovial membrane, and in Type 1 diabetes the insulin-producing beta cells of the islets of Langerhans in the pancreas. It is generally thought that specific cytokines play a central role in this misguidance. Our group is particularly interested in cytokines belonging to the IL-12 family (IL-12, IL23 and IL-27). Of these, IL-12 induces a particular branch of white blood cells: Th1 cells, which are known to be capable of driving inflammation in the CNS, as seen in MS. IL-23 is an even more important mediator that induces another branch of T cells, Th17 cells, and all current evidence points to the IL-23/Th17-axis as acting as a “master regulator” in CNS inflammation. Our group is studying the specific mechanism by which these cytokines are “folded” in a cell organelle –known as the endoplasmic reticulum– prior to their secretion. We have identified several small molecule drugs that can interfere with this process. We are performing preclinical trials to assess the activity of our compounds in animal models of MS. Importantly, one of our compounds is capable of blocking disease progression in this model, making it an interesting candidate on which to base a future new drug for treatment for MS.

Few resources are devoted to research into rare diseases, because they are not very common. Is it not difficult to propose personalised treatments, which are presumably more expensive, for a small number of cases?

In terms of prevalence, MS is clearly a significantly smaller health burden than, say, cardiovascular diseases or cancer. While MS does feature on the list of rare diseases issued by the National Organization for Rare Disorders (NORD), it is important to remember that it is the leading cause of disability and death among young adults between the ages of 20 and 40, and especially so in women, who are 2-3 times more likely to contract the disease than men. One solution is to consider this problem supra-nationally. As indicated earlier in this interview, the budget for MS medication on a European level is considerable, and in the context of this budget, there should be more room for personalized medicine. What is of even greater importance is that you have to factor in the indirect costs arising from the fact that it is mainly young people at the economic peak of their lives who are struck down by this disease. If personalized medicine enabled MS patients to have, to a certain degree, a more normal productive professional life (something current drug and patient management strategies largely fail to achieve), the extra costs related to personalized medicine could be indirectly recovered through this increased economic performance.

Finally, the escalating cost of drug development and testing can be offset via cheaper clinical trials. While classical clinical trials can involve thousands of patients, it is thought that pharmacogenomics-guided clinical trials could be much more cost-effective due to a more simple and faster design relying on lower numbers of participants. In such new-generation trials, pre-screening of participants for biomarkers of response, and selecting only those likely to respond, would decrease the number of trial subjects but also increase the therapeutic index of the drug tested, and hence, the chance that the drug could make it onto the market. As a consequence, the drug consumer would benefit from significantly reduced drug costs. Such considerations are relevant in all sorts of diseases, but in the case of rarer diseases they could tip the balance for drug development from infeasibility to a realistic and economically viable perspective.

What has accepting Ikerbasque’s offer meant with respect to your career as a research scientist?

Before I arrived here, I was Chair in Applied Genomics at Queen’s University of Belfast. A few years ago I spent one sabbatical year of research at CIC bioGUNE. This experience, as well as the fact that my wife is from the Basque Country, triggered a desire to move to Spain. Just when I heard about the call for applications from Ikerbasque, I had been offered the position of Director of the Department of Rare Diseases by the Instituto Carlos III and was involved in negotiations with respect to it. After comparing both options, I decided that the position offered by Ikerbasque coincided more with what I wanted to do professionally. I arrived in December 2007, and I can honestly say that I’ve never looked back! I was one of the first scientists to be appointed by Ikerbasque. Ikerbasque fills a very important niche for senior scientists. While it is relatively easy for a PhD student or post-doc to move around Europe, as long as you are happy with temporary contracts, this is not the case on a more senior level when your professional expectations have matured. Finding a place in the Spanish university system is very difficult due to linguistic and other barriers. Ikerbasque takes a shortcut in this protracted administrative system by appointing academic scientists directly. The Ikerbasque workshops of 2008 are clear proof that they are succeeding incredibly well in attracting high quality scientists from all sorts of backgrounds and nationalities.

In my particular case, Ikerbasque has provided me with a generous budget to start up my research, and together with the UPV-EHU-University of the Basque Country and the Technology Park of Bizkaia, has created a brand new laboratory, Neurogenomiks, which I am leading. Things have gone well this first year and I have been able to top up my research budget with grants from the 7th Framework Programme of the European Commission, MICINN, ISCIII RETICS and the Basque Government. We are the coordinator of an FP7 Marie Curie Network budgeted at 2.36 million Euros. In conclusion, my research career definitely has not suffered following my move, and if anything, has received a considerable boost.