Biology subjects

Suter, A.

Publications and source records attributed to Suter, A..

3 recordsLinked to original sources

bioRxiv2025

An Integrated In Vitro Platform and Biophysical Modeling Approach for Studying Synaptic Transmission in Isolated Neuronal Pairs

Studying synaptic transmission and plasticity is facilitated in experimental systems that isolate individual neuronal connections. We developed an integrated platform combining polydimethylsiloxane (PDMS) microstructures with high-density microelectrode arrays to isolate and record single neuronal pairs from human induced pluripotent stem cell (hiPSC)-derived neurons. The system maintained hundreds of parallel neuronal pairs for over 100 days, demonstrating functional synapses through pharmacological validation and long-term potentiation studies. We coupled this platform with a biophysical Hodgkin-Huxley model and simulation-based inference to extract mechanistic parameters from electrophysiological data. The analysis of long-term potentiation stimulation using a biophysical model revealed (-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid) AMPA and (N-methyl-D-aspartate) NMDA receptor-specific alterations, providing quantitative insights into synaptic plasticity mechanisms. This integrated approach represents the first system combining isolated synaptic pairs, long-term stability, and mechanistic modeling, offering unprecedented opportunities for studying human synaptic function and plasticity.

neuroscience↗

bioRxiv2025

Efficient installation of heterozygous mutations in human pluripotent stem cells using prime editing

The utility of human pluripotent stem cells (hPSCs) is greatly enhanced by the ability to introduce precise, site-specific genetic modifications with minimal off-target effects. Although Cas9 endonuclease is an exceptionally efficient gene-editing tool, its propensity for generating biallelic modifications often limits its capacity for introducing heterozygous variants. Here, we use prime editing (PE) to install heterozygous edits in over ten distinct genetic loci, achieving knock-in efficiencies of up to 40% without the need for subsequent purification or drug selection steps. Moreover, PE enables the precise introduction of heterozygous edits in paralogous genes that are otherwise extremely challenging to achieve using endonuclease-based editing approaches. We also show that PE can be successfully combined with reprogramming to derive heterozygous iPSC clones directly from human fibroblasts and peripheral blood mononuclear cells. Our findings highlight the utility of PE for generating hPSCs with complex edits and represents a powerful platform for modelling disease-associated dominant mutations and gene-dosage effects in an entirely isogenic context.

cell biology↗

bioRxiv2023

Contextualising the developability risk of antibodies with lambda light chains using enhanced therapeutic antibody profiling

Antibodies with lambda light chains ({lambda}-antibodies) are generally considered to be less developable than those with kappa light chains ({kappa}-antibodies), leading to substantial systematic biases in drug discovery pipelines. This has contributed to kappa dominance amongst clinical-stage therapeutics. However, the identification of increasing numbers of epitopes preferentially engaged by{lambda} -antibodies shows there is a functional cost to neglecting them as potential lead candidates during discovery campaigns. Here, we update our Therapeutic Antibody Profiler (TAP) tool to use the latest data and machine learning-based structure prediction methods, and apply this new protocol to evaluate developability risk profiles for{kappa} -antibodies and{lambda} -antibodies based on their surface physicochemical properties. We find that{lambda} -antibodies are on average at a higher risk of poor developability -- as an indication, over 40% of single-cell sequenced human{lambda} -antibodies are flagged by TAP for risk-prone patches of surface hydrophobicity (PSH), compared to around 11% of human{kappa} -antibodies. Nonetheless, a substantial proportion of natural{lambda} -antibodies are assigned more moderate risk profiles by TAP and should therefore represent more tractable candidates for therapeutic development. We also analyse the populations of high and low risk antibodies, highlighting opportunities for strategic design that TAP suggests would enrich for more developable{lambda} -based candidates. Overall, we provide context to the differing developability of{kappa} - and{lambda} -antibodies, enabling a rational approach to incorporate more diversity into the initial pool of immunotherapeutic candidates.

bioinformatics↗