Cutting (technological) edges
The necessity to cut edges may for instance occur when you head off to mow the grass properly or trim the hedges (in your garden). In scientific terms cutting edge research refers to a creative idea and/or hypothesis-driven brand new, high-risk project undertaken in the hope to overcome existing hurdles or limitations. In neuroscience during the last three decades particularly the technological developments like patch-clamp, (functional) MRI or PET paved the way for the most incredible research approaches and findings. Such high risk research benefits from two preconditions that may even pose success factors: interdisciplinary (teams and) expertise and (sufficient) funding.
In 2009, the ERA-Net NEURON launched a joint transnational call for proposals on novel methods and technologies in neuroscience. The scope of this call was method development – ranging from optical, genetical and/or electrophysiological to modeling approaches, or combinations thereof - beyond specifically defined diseases. For projects along the "Development and advancement in methods and technologies towards the understanding of brain diseases" only interdisciplinarity and the involvement of 3-5 groups from minimum three different countries were requirements to be met. The research question, technique(s) and methodologies were to be liberately chosen according to the necessities of the addressed problem.
At an ERA-Net NEURON symposium held at the Dead Sea, in January 2013 the ten since February 2010 funded projects presented their results. The symposium demonstrated threefold success, as Dr. Marlies Dorlöchter, the coordinator of the ERA-Net NEURON, summarized:
- First, for the funding organizations within the ERA-Net NEURON. Their representatives highly acknowledged the reward of the funding investments, visible – among other criteria – by a more than reasonable number of outstanding results.
- Second, the researchers themselves. Prof. Rafael Fernández-Chacón appraised the unbureaucratic funding procedures that promoted early-on creative project work and the possibility for intergroup-networking.
- Third and not least, neuroscience because the many methodological and technological developments impact on the understanding of brain functions in normal and disease conditions – cutting edge research!
The symposium was opened by Dr. Benny Leshem of the Chief-Scientist-Office of the Ministry of Health (Israel) that kindly hosted the meeting. He summed up the 2009 intentions of funding organization when the call was launched. Research projects had to be hypothesis-driven and combine cutting-edge technologies with a clear, neuroscience related research question.
Dr. Sumie Leung of Professor Carles Escera’s (coordinator, University of Barcelona) group presented the auditory novelty system probing project. A key principle in cognitive auditory function is the ability of the auditory system to extract the necessary information in the acoustic environment. Such specific functions – called Mismatch Negativity (MMN, the detection of novelty) – decline in neuropsychiatric and neurological diseases and in aging. The multidisciplinary approach in the project encompassed the recording of human (EEG, MEG) and animal (single unit, multi unit, local field and epidural) novelty responses elicited at multiple levels of the auditory system. Thereof, a new testing protocol of cognitive dysfunction was developed by the international consortium of Carles Escera (Spain), Minna Huotilainen (Finland), Israel Nelken (Israel) and Manuel Sanchez Malmierca (Spain).
Using transcranial magnetic stimulation (TMS), a non-invasive technique which delivers magnetic pulses to a specific region of the brain, the international team around Antoni Valero-Cabré (coordinator, France), Juan Lupiáñez (Spain), Paolo Bartolomeo (France) and Claus Hilgetag (Germany) has obtained improvement in the visual abilities of healthy humans. They showed that TMS might have “artificially” activated neurons in the treated area, and that as a result, the functions and behaviors controlled by these neurons were then modified. Researchers think their study could set up a new strategy for the restoration of certain types of visual problems induced by brain damage in stroke or retinal neurodegenerative disorders. “We do not want to replace current therapies based on training attentional abilities with visual exercises but to supplement such interventions and strengthen their outcomes,” explains Valero-Cabré. In a near future, the team envisions a clinical trial in patients afflicted by visual defects following a stroke.
Professor Arthur Konnerth (coordinator, Germany) explained why it is so important to monitor the activity of cells inside the brain. Normally, nerve cells exchange electrical signals at high speed, a signal exchange disturbed in neurological diseases. When in epilepsy too many nerve cells are active at the same time, in Alzheimer’s disease (AD) in contrast nerve cells fail to properly communicate: some fall silent, while others show abnormal levels of activity. Konnerth, Thomas Misgeld (Germany), Marco de Curtis (Italy) and Yosi Yarom (Israel) combined fast two-photon microscopy and transgenic-viral labeling in an imaging platform with in vivo electrophysiology to analyze the neuronal-network-dysfunction in animal disease models. They confirmed not only that hyperactivity precedes plaque formation and is the first functional alteration in hippocampal neurons in vivo but that neuronal silencing is a late event that seems to require the presence of plaques.
A pioneering in vitro system able to identify the cellular and molecular dysfunctions induced by genetic Parkinson’s disease (PD) mutations was presented by Professor Vania Broccoli (coordinator, Italy). About 60 induced pluripotent stem cell (iPS) lines were generated from patients and healthy donors as a system to model various aspects of Parkinson’s disease, e.g. electrical activity. The international consortium with Juan Carlos Izpisua-Belmonte (Spain), Georg Auburger (Germany) and Alexis Brice (France) successfully converted skin fibroblasts into induced dopaminergic neuronal (iDAN) cells that were functionally equivalent to dopaminergic neurons in vitro and that survived and integrated after transplantation into the brain of rat models.
Cutting-edge imaging techniques were also used to study neurogenesis as Professor Jochen Herms (coordinator, Germany) explained. Deficits in olfactory function during ageing cause a not only a decrease in the quality of life but are paralleled by decreases in other brain functions that occur in the absence of obvious disease states, such as changes in other sensory functions and cognition (memory loss, depression, etc.). Also, olfactory deficits are very common in neurodegenerative diseases like PD and AD. These deficits may be in part due to alterations in the maturation of adult-born neurons which incorporate into the neuronal network of the olfactory bulb. Herms and the intentional team, Pierre-Marie Lledo (France), Adi Mizrahi (Israel) and Jacek Jaworski (Poland), confirmed that the in vivo turnover of adult-born neurons is reduced in the PD mouse model due to a decreased survival of newborn neurons, with the dopaminergic subtype being most affected.
Chronic mental diseases (CMD) were addressed by the multidisciplinary team of Carsten Korth, (coordinator, Germany), Orly Reiner (Israel), Jesus Requena (Spain), and Chiara Zurzolo (France). They investigated a certain protein complex with novel cutting-edge technologies on the levels of single proteins, its molecular interactors (protein biochemistry and proteomics), its function in neurons and in the development of the nervous system (live cell imaging), and animal behavior (in vivo dialysis, episodic memory tests). The goals were to characterize sporadic CMD as protein misassembly pathologies and to develop animal models for CMD. A strong focus is on translational research for identifying biological markers as diagnostic tests for CMD and CMD-associated conformers as pharmacological targets. “Results from investigating the biology of this protein complex will provide insights that ultimately translate into much-needed progress in clinical psychiatry: for example, detection methods to establish biological testing or novel pharmacological targets” anticipated Korth.
“The blood brain barrier (BBB) is a delicate guardian of the Central Nervous System (CNS) against the transport of medical drugs” explained Professor Claus Pietrzik (coordinator, Germany). This is of particular importance since large epidemiological studies documented that long-term medication with non-steroidal anti-inflammatory drugs (NSAIDs) reduce the risk and delays the onset of AD significantly. To facilitate the transport across the BBB and allow targeted drug delivery to the brain tissue Pietrzik and his multidisciplinary team, Hagen von Briesen (Germany), Manfred Windisch (Austria), Mordechai Deutsch (Israel), and Reinhold Schmidt (Austria) designed a drug-vehicle nanoparticle system that laid the ground for the translation into animal models of AD. A proof of concept in vivo study confirmed the increase of a specific AD medication transport to the mouse brain. The hope is that such correct transport into the brain tissue will increase the safety and efficacy of pharmacotherapy in the brains of patients.
A “nano” approach was also center to the work of Professor Rafael Fernández-Chacón (coordinator, Spain) and his consortium, Wolfgang Parak (Germany) and Martin Oheim (France). Brain function relies on regulated communication between neurons at contact points called synapses, where nerve terminals release chemical transmitters. These nerve terminals are degenerated in severe neurological human diseases. The project mobilized nanotechnologies to engineer microcapsules loaded with proteins to either substitute damaged proteins within the terminal or to facilitate protein repair. The successful synthesis of biodegradable and non-degradable light responsive capsules for the controlled remote release of repair cargo was confirmed by Structured Illumination Microscope (SIM), a new method combining 3-D super-resolution with high acquisition speed.
Professor Bernard Bioulac (France) represented the consortium of Daniel Choquet (coordinator, France), Robert Tampé (Germany), Leszek Kaczmarek (Poland) and Eckart Gundelfinger (Germany) entitled to study the disturbed synaptic communication by addressing receptor surface trafficking. The team developed dynamic super-resolution imaging of endogenous proteins on living cells at ultra-high density using quantum-yield-optimized fluorophores for site-specific labeling. They discovered not only that the brain extracellular matrix affects the lateral mobility of AMPA receptors but could show with super-resolution imaging that AMPA receptors inside synapses are dynamically organized in nanodomains.
Professor Heinz Beck (coordinator, Germany), Rosa Cossart (France), Benjamin Kaupp (Germany), Ilan Lampl (Israel) and Liset Menendez de la Prida (Spain) used highly advanced electrophysiological recording and electrical stimulation techniques in combination with voltage-dependent dye imaging to investigate the functional changes in the neuronal (micro)circuitry underlying epilepsy. This is important because the cardinal symptom of epilepsy - seizures – consists of synchronized neuronal discharges. So far, the complexity of neuronal networks has hampered the investigation of the cellular basis of seizures using conventional electrophysiological approaches. The team focused the work on the role of inhibitory neurons, which powerfully control neuronal excitability and rhythmogenesis. Effects of the anticonvulsant carbamazepine (CBZ) were examined on different neuronal cell populations.
In concluding remarks all researchers mentioned that they would be keen to collaborate again, should the opportunity arise, because “…the ERA-Net NEURON funding gave much more freedom to do good science compared to other funding measures”.