The DESIRE Project for Epilepsy: Is Collaboration in Science More Efficient Than Competition?

700 million people will have a seizure in their life - that means 1 out 10 human beings. Epilepsy, which can only be diagnosed after a minimum of two seizures (more than 24h apart) is the third most common neurological condition in the European Union following Alzheimer’s disease and stroke.

Despite these facts, the disease is still widely misunderstood and often stigmatizing.  On September 15th 2011, a new piece of legislation entitled the EU Written Declaration on Epilepsy was approved by the European Parliament after being signed by a strong majority of 459 members (out of 751) [1]. The Declaration initiated a change in the funding strategies of the EU: new funds were allocated, and several research projects were created. Today, the EU is handing out 173 million euros that fund a dozen or so European research projects [2]. Among them: the DESIRE project [3].

Epilepsy : a Misunderstood Disease
This enticing acronym stands for “Development and Epilepsy - Strategies for Innovative Research to Improve Diagnosis, Prevention and Treatment in Children with Difficult-to-Treat Epilepsy”. Now that I’m re-reading this I do not think it’s an acronym- if you take the initials of all important words, then remove half of them, you’ll get „DESIRE“. Anyway, the important words here are “children”, and “hard to treat epilepsy”. Epilepsy can hijack the life of people of all ages and it can have many causes [4]. DESIRE focuses on abnormal early (intrauterine) development of the cerebral cortex and its association with epilepsy [4,5]. During neurodevelopment, precursor cells formed in the periventricular region migrate to their correct location where synapses are made and later edited to produce a mature brain. Any interruption of these processes can create cortical abnormalities [5-7]. Most of these malformations have genetic underpinnings, however, environmental factors such as lack of oxygen or intrauterine infection also play a role [4]. These types of epilepsy are difficult to treat because the underlying pathology varies substantially and patients often have severe comorbidities. 

'DESIRE'  FUNDS MORE THAN 250 RESEARCHERS FROM 11 COUNTRIES

The DESIRE project funds the research activities of more than 250 researchers from 25 universities in 11 countries [3]. Since the Charité is one of the partners and DESIRE funds my PhD, I have attended the last four yearly meetings of the project. The last one was in Valetta (Malta) mid-october. I know what you’re wondering and yes, the weather in Malta is beautiful this time of the year. More seriously, it has been fascinating to see the projects evolve over the years. Researchers don't necessarily need a big European project to collaborate and exchange information, but I have personally never seen cooperation between researchers on this scale before.

DESIRE Leads to Scientific Collaboration
Let me explain. One of the eight work packages within the DESIRE project aims to “Identify genetic causes and pathomechanisms of epileptogenic brain malformations”. The first step is to pin down germinal or somatic mutations in patients with a specific type of malformation. Once you have identified a new interesting mutation in a patient you need at least one more patient to be able to claim a possible causality. Since these malformations are extremely rare this can be nearly impossible. In 2014, during the first meeting that I attended, 20-30 researchers and group leaders sat around a table and started exchanging genetic mutations. The amount of information exchanged in one afternoon was overwhelming. In the following years, databanks were created, pools of interesting genes were selected, and samples were sent across Europe to be systematically tested. Today, 150 patients with malformations of the cortical development and 450 with encephalopathies have been included in the project. This led to the identification or confirmation of several mutations (notably in the PIK3/mTOR pathway and in different types of voltage gated sodium channels) [8-10]. In the meantime, samples were analysed in Erlangen (DE) and a pattern of methylation in a specific type of malformation was identified. Epigenetics were previously known to have a role in epilepsy [11] but this was a breakthrough.

Once a mutation is identified, it needs to be tested. Using in-utero electroporation, these mutated gene sequences were introduced into mice, rat, or ferret embryos to create better models for cortical malformations (the latter is a good model for cortical development because it is convoluted like higher mammals [12]). In many cases, the models showed malformations comparable to those observed in patients, and the pathomechanisms could be studied [7], [13].
Every meeting is extremely dense, each member presents the advancement of their project within their work package, even negative results, often before they are published. There is a sense of community; even competitive teams exchange tips and comment on each other’s data. DESIRE ends in September 2018 and it will certainly meet most of the objectives set in 2013. One of the concluding remarks in Malta by Prof Jeffrey L. Noebels member of the Scientific Advisory Committee was that the most impressive work had been done by collaborations between teams within DESIRE. Let us hope this spirit of collaboration will continue on after the end of DESIRE.

by Aliénor Ragot, PhD student AG Holtkamp
This article originally appeared December 2017 in CNS Volume 10, Issue 04, Sleep 

[1] http://bit.ly/2zfet2n/ 
[2] http://bit.ly/2yAAqaU
[3] http://bit.ly/2Am5jBq
[4] http://bit.ly/1wgpTup
[5] Romero DM, Semin Cell Dev Biol, 2017
[6] Fernandez V, EMBO J, 2016
[7] Khalaf-Nazzal R, Hum Mol Genet,2017
[8] Alcantara D, Brain, 2017
[9] Parrini E, Hum Mutation, 2017
[10] Møller RS, Neurol Genet, 2016
[11] Kobow K, Neurosci Lett,2017
[12] Neal J, J Anat, 2007 
[13] Martinez-Martinez MA, Nat Commun, 2016