By Austėja Čiulkinytė
The Edinburgh University Neurological Society (EUNS) held their 8th annual international conference on 10-11 April 2021. The speakers at this conference share and showcase the latest developments in neuroscience, neurology, and neurosurgery. This year, the focus was on the blood-brain barrier (BBB), including the current understanding of its functions, neuropharmacological implications and recent technological advances surrounding BBB research.
Current understanding of the BBB
The conference opened with a keynote talk from Prof Chenghua Gu from Harvard Medical School on the topic of neurovascular interactions in the brain. Her lab seeks to understand what factors give rise to and maintain the BBB. By using single-cell RNA sequencing, they identified a library of molecules that are found in high concentrations in blood vessels in the brain, but are not found anywhere else in the body. Additionally, they identified pairs of receptors and ligands between endothelial and glial cells that are present in high concentrations in parts of the brain that contain a more permeable BBB than others. Prof Gu’s work concludes that the endothelial cells that form the BBB are not intrinsically different from any other endothelial cell, but it is their interaction with nearby glial cells that induces their specialisation and is required to maintain BBB integrity.
Another talk focusing on the interactions between endothelial and glial cells was delivered by Dr Blanca Diaz-Castro from the University of Edinburgh. Her lab studies BBB alterations in response to peripheral inflammation, which is known to occur in mouse inflammation models. Brains of these mice were analysed by RNA sequencing with the aim to understand how the status of peripheral inflammation is signalled to the brain. The researchers found changes in expression levels of genes involved in immune signalling, cell-cell interactions, receptors, transporters, aquaporins and scaffold proteins. This was occurring in both endothelial cells and glial cells, suggesting that these cell types are the major players in communicating inflammation.
Following on from this, Prof Jorge Ivan Alvarez from the University of Pennsylvania gave a talk on the role of central nervous system barriers in neuroimmune mechanisms of disease. It was previously known that BBB and other barriers prevent immune reactions from happening in the brain as they would in the periphery. To study how this is mediated and maintained, Prof Alvarez’s lab studied mice that produce an inflammatory response to their own myelin. They found that astrocytes surrounding a demyelinated neuron secrete sonic hedgehog (Shh), which inhibits peripheral T cells that would otherwise invade the brain and further damage the myelin. Additionally, they found that simply injecting an agonist of the Shh receptor in these mice reduced demyelination and improved survival, suggesting a potentially druggable pathway for diseases arising from myelin damage, such as multiple sclerosis.
Methods for studying the BBB
Several of the talks in the conference discussed innovative ways of modelling and studying the BBB. In the first one of such talks, Dr Adjanie Patabendige from Newcastle University emphasised the need of physiologically relevant in vitro BBB models, defined a set of requirements, and evaluated common features of BBB models. These include cell cultures where one or several cell types co-exist, stationary and chip-based models, human and animal derived models. Dr Patabendige concluded by saying that no “gold standard” model exists, therefore it is important to understand the features of those that are available and choose one that is best fit for purpose.
Another talk on the topic of BBB models was from Dr Gad Vatine from Ben-Gurion University of the Negev. He presented a way of using patient-derived stem cells to grow a personalised BBB model on a chip. Such chips retain physiologically relevant BBB properties such as permeability, blood vessel structure, ability to be perfused with blood, responsiveness to cytokines and other organ-like functions. Dr Vatine suggested such chips could be used in the future for personalised medicine and high-throughput drug screening.
On a slightly different note, Dr Antoine Vallatos from the University of Edinburgh presented on the techniques and limitations that permit non-invasive magnetic resonance imaging of BBB permeability. He outlined the need for good BBB imaging biomarkers and contrast agents that help understand differences in perfusion, diffusion and permeability across the barrier. Dr Vallatos’s lab has created a 3D phantom model that reproduces BBB permeability parameters and can be infused by various contrast agents. Using this phantom, they have validated a novel biomarker to detect glioblastoma, an aggressive and rapid-growing form of brain tumour.
Delivering drugs across the BBB
The remainder of the presentations focused mainly on advances in transferring drug molecules across the BBB. Dr James Choi from Imperial College London described how ultrasound waves and microbubbles (stable lipid shells injected via IV) can be used to transiently perturb the BBB, allowing non-barrier-permeable drugs in the blood to reach the brain. This method has been proven to work in brains of mice, suggesting a novel non-invasive and localised way to deliver drugs that normally would not cross the BBB.
Prof Chae-Yong Kim from Seoul National University Bundang Hospital described another method that also uses ultrasound waves and nanoparticle complexes to deliver drugs across the BBB, particularly focusing on glioblastoma treatment. Here, the nanoparticles themselves are conjugated with anticancer drugs. Importantly, the anticancer drug can be chosen based on patient-derived glioblastoma cell culture studies such as genomic profiling, drug sensitivity assays, and BBB modelling. Although in vivo studies of this concept have not been reported yet, it is a promising advance in precision and personalised medicine.
The conference ended with another keynote presentation from Prof Moein Moghimi from Newcastle University on the topic of taking nucleic acid medicines to the brain. Prof Moghimi’s lab was aiming to create a simple-by-design method to deliver nucleic acids into the brain via IV administration. To do so, the researchers used phage display to create nucleic acid-containing nanoparticles decorated with a modified BBB-targeting peptide. An important feature of this modification is its ability to drive aggregation and stacking of nanoparticles. This changes the size, flexibility, and affinity of nanoparticles to BBB transporters in a way that allow them to cross the barrier efficiently. Extensive studies were done to confirm nucleic acid entry into the neuronal and glial cells, pharmacological activity, and a good safety profile. Importantly, this conjugate can be administered via IV and is relatively easy to manufacture, paving the way for a novel nucleic acid delivery system.
Other events at the conference
Throughout the conference, the highly scientific presentations were broken up by neuroscience appreciation talks. Prof Phillip Pearl from Boston Children’s Hospital and Harvard Medical School gave a fascinating talk on suspected neurological problems on famous musicians such as Ludwig van Beethoven, Robert Schumann and George Gershwin. Meanwhile, Bradley Harrington from Stellenbosch University presented several interesting case studies of penetrating head injuries such as gunshot, knife, and machete wounds, their mechanisms, and guidelines for management.
An immersive experience was offered by the two workshops held on the second day of the conference. In the first workshop, Simon Lammy and Imran Noorani offered their insights into pursuing academia alongside neurosurgeon training. The second workshop was a lively debate between Dr Richard Chin and Chandrasekaran Kaliaperumal on whether neurology or neurosurgery was a better career option. Both workshops were designed for and valuable to any budding neurosurgeons or neurologists in the audience.
The final, highly entertaining feature of the conference were the student competitions. Six students were shortlisted to deliver a short presentation on a neuroscience topic. Additionally, in the weeks leading up to the conference, attendees were invited to partake in an essay competition and share their thoughts on the great recent neuroscientific advances. The winners were Elizabeth Drinkwater with a presentation titled “Assessing the Impact of APOE Isoform on the spread of Tau pathology in Alzheimer’s Disease – focus on astrocyte contributions”, as well as Moritz Steinruecke’s and the essay discussing “The Impact of Global Neurosurgery”.
Overall, the EUNS 8th International Conference was successful, well organised, with interesting and high-quality presentations. Although the workshops may have seemed biased towards medical students, the presentations were certainly valuable and interesting to those in other specialties, too. A special thank you and congratulations must be extended to Jay Park and Liam Lee, the co-chairs of the conference, who have worked very hard to make it happen.