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

The Kaspar-Hauser Syndrome - What Child Neglect Tells Us About Nature and Nurture

Nuremberg, Germany, 1828: A savage and mysterious adolescent boy named Kaspar Hauser appears in the city. He has little knowledge of language, and both his gait and behavior are reminiscent of a young child [1]. Very likely, he was imprisoned throughout his childhood, and raised under conditions of extreme deprivation. Kaspar Hauser becomes a famous attraction of the 19^th century, scientists and philosophers worldwide study his behavior attempting to uncover his origin. Some think that he is the prince of Baden, who was abducted from his cradle; others claim he is an imposter.

Whatever the truth of Hauser’s life, his case is the oldest documented and most famous case of severe childhood deprivation. Extreme hospitalism, or neglect-mediated failure of development, is thus also called “Kaspar-Hauser Syndrome”. This malady is characterized by retarded physical development, perceptual-motor skills and language as well as extreme anxiety. It is caused by sensory deprivation and lack of social contact or abuse during early childhood.

LACK OF SENSORY INPUT IMPAIRS NEURODEVELOPMENT

 

Another genre of child neglect is the wolf child or feral child, who has lived isolated from human contact and has no experience of  human behavior and language. The most famous example is Mowgly from the fictional story The Jungle Book. The difference between Kaspar-Hauser Syndrome children and feral children can be seen in their behaviour. Feral children behave like the animals with which they lived (e.g.wolfes), because they have learned their behaviour instead of human behaviour. Severely deprived Children do not learn any behaviour and are thus even more retarded in their perceptual-motor skills and development.

Abnormal brain development following sensory neglect in early childhood. Left: CT-scan of a healthy three-year old with an average head size. Right: CT-scan of a three-year old child suffering from severe sensory-deprivation neglect; this child’s brain is significantly smaller and has enlarged ventricles and cortical atrophy.

Studies of child neglect
As it would be brutal to deprive children of care for the sake of science, most studies rely on case reports of severely neglected children [2]. Thereby, often, the child's medical and social history is unknown. As in the case of Kaspar Hauser, scientists usually do not know the exact form of neglect, or whether neurological defects are a direct consequence. Many studies on hospitalism are based on children raised in badly-run orphanages [3]. Children who were adopted from Romanian orphanages in the early 1990s were often considered to be extremely neglected. Studies with them show that early life nurturing is critical for neurodevelopment. If nurturing is absent for the first three years of life before adoption into a social environment, newly made positive experiences may not be sufficient to overcome the malorganization of the neural system.

Principles of neurodevelopment
To understand how deprivation impairs behavioral and cognitive capacities, we need to first understand the principles of neurodevelopment: At birth most neurons are already present, yet they have to organize into functional systems. Thereby activation of recurrent patterns  appears to be an important factor. Neurons that are not sufficiently activated undergo apoptosis in a ‘use it or lose it’ manner. The sculpting and refinement of neural connections is resolved by dendrite and axon sprouting, followed by synaptogenesis. The latter process is tightly regulated by growth factors and adhesion molecules, whose expression is regulated by environmental cues mediated by the senses.
The brain develops in a sequential fashion; different areas form, organize, and become fully functional at different times during childhood. There are thus different sensitive periods for each brain area and neuronal function. Disruption of critical cues can alter the developmental processes and lead to diminished capabilities in the neural system for a given sensory modality. Disruption of critical neurodevelopmental cues can result from (1) lack of sensory experience during sensitive periods (e.g., neglect) or (2) abnormal patterns of necessary cues due to extremes of experience (e.g., abuse).

Clinical impacts of child neglect
Disturbed neurodevelopment results in defects in language, motor delays, impulsivity, disorganized attachment, dysphoria, attention deficits, and hyperactivity. Furthermore neglected children have a reduced frontal-occipital circumference, which is an estimate of brain size in young children. Furthermore, CT scans from neglected children show enlarged ventricles or cortical atrophy [4]. MRI studies with maltreated children also demonstrate decreased metabolic activity in a number of brain areas [5].

EARLY LIFE NURTURING IS CRITICAL FOR NEURODEVELOPMENT

 

The severity of neurological issues increases with the time children spend in an adverse environment: The earlier and more pervasive the neglect, the more indelible the deficits. After the children are removed from the neglectful environment, the degree of recovery is inversely proportional to age in which the child was removed from the neglecting caregivers [4].
We learn from these studies that neurodevelopment depends on both nature and nurture. Many functions of the brain result from a complex interplay between genetic potential and appropriately timed experiences. Child neglect - defined as the absence of input in critical periods of development - leads to abnormalities in cognitive, emotional, behavioral, and social functioning. Healthy neurodevelopment depends upon attentive nurturing during infancy.
To make sure stories like Kaspar Hauser’s and similar horrible stories of child neglect don't happen again, social services provide help for families where neglect is suspected. If parents are unable to meet their children's needs then professionals intervene to safeguard the child's welfare. As stimulation of a child's senses in the early infancy is so important, it is neccessary to act early if child neglect or abuse is suspected. No issue cries out for a more immediate and all-encompassing response than ensuring the safety and well-being of our children – our hope for the future.

[1] Feuerbach, 1835 (Klett, 1963)
[2] Spitz, Psychoanal Study Child, 1945
[3] Barth Spiegel, 1990
[4] Perry, Brain and Mind, 2002
[5] Chughani et al, Neuroimage, 2001

by Claudia Willmes, PhD alumni AG Eickholt / AG Schmitz

This article originally appeared in CNS Volume 7, Issue 3, Nature vs Nurture