Postdoc: Discovering CAR T cell biophysics with single-molecule TIRF microscopy
Work Activities
As a postdoc in the Physics of Cellular Interactions group headed by Dr. Kristina Ganzinger and the Biophysics group headed by Sander Tans, you will analyse the spatiotemporal dynamics of Chimeric Antigen Receptor (CAR) signalling in live T cells with different biophysical techniques. The central question of this project is: How do signaling receptors organize in CAR immune synapses, and hence achieve successful immune cell activation? To answer it, you will study the immune synapses with single molecule microscopy, specifically the contact between CAR T immune cells and either supported lipid bilayers (SLBs) or living tumour cells. In addition, you will study binding avidity with the z-Movi method (https://lumicks.com/products/z-movi-cell-interaction-studies/).
Notably, a complex spatio-temporal dynamics is thought to be central to CAR T cell activation, but is difficult to measure and hence remains poorly understood. That the activation relies on the movement and association of many receptors and accesory proteins in an orchestrated manner is a fascinating notion. By addressing this question at the molecular level, you will have the opportunity to elucidate the underlying dynamic mechanisms for the first time. More generally, the model system for cell-cell contact dynamics that you will use and advance pushes the boundaries of biophysical measurement techniques, and can be applied to many other systems.
Equipping T cells from patients with chimeric antigen receptors (CARs) has promised a new era of cancer therapies. CARs are synthetic transmembrane receptors that are designed to recognise a tumour antigen and activate T cell signalling pathways, directing T cells against the tumour. However, despite the quick success of specific CAR designs, it has become clear that it is extremely difficult to predict how changes to CAR designs affect their signalling and therefore efficiency. This lack of predictability is, at least in part, due to our very limited understanding of the molecular mechanisms of CAR signalling. The aim of this project is to reveal the dynamics of CAR function and signalling for the first time at the single-molecule level. You will use advanced single-molecule and single-cell imaging combined with novel synthetic biology approaches to directly measure the striking hypothesized CAR organisation into signalling clusters in membranes and downstream signalling dynamics to, among other questions, elucidate the role of the co-stimulatory domain of these receptors and parallel activation of co-stimulatory receptors. You will combine these experiments with investigating CAR T cell avidities using Lumicks z-Movi method in collaboration with Lumicks.
This project has now become possible owing to recent technical advances, including new in vitro assays and imaging approaches developed by our lab and others (JACS 2013, Nat Immun 2016, PNAS 2019, Nat Commun 2021, 2023). You will develop new microscopy-based assays to enable this first dynamic view on how CARs re-wire T-cell signalling cascades and to identify design principles for tuning CAR activation.
Qualifications
You need to meet the requirements for a doctors-degree (PhD) and must have research experience in a non-Dutch academic environment. We are looking for an biophysicist who has worked with single-molecule fluorescence techniques, or alternatively a (bio)chemist or molecular immunologist with a strong and demonstratable interest in single-molecule approaches. Experience with quantitative fluorescence microscopy and programming skills to handle automated analysis of image data is highly desired; knowledge of protein biochemistry and/or model lipid systems would be an advantage. You should like the idea of working in a collaborative, ambitious and international environment. Excellent verbal and written English skills are essential.
Work environment
AMOLF is part of NWO-I and initiate and performs leading fundamental research on the physics of complex forms of matter, and to create new functional materials, in partnership with academia and industry. The institute is located at Amsterdam Science Park and currently employs about 140 researchers and 80 support employees. www.amolf.nl.
Ganzinger group – We are a supportive and social research group of about 8 PhD students and postdocs, which work together in small teams on various projects from immunological signalling to signalling in synthetic cells. The collaborative and social atmosphere includes to the other research groups at the AMOLF institute at the Science Park in Amsterdam. Our group has been making recent technical advances, including a new single-molecule tracking method based on DNA-PAINT that we recently developed (Nat Commun 2021, Nat Commun 2023), new in vitro assays (ACS Syn Biol 2021, ACS Omega 2024), and imaging approaches developed by our lab and others (JACS 2013, Nat Immun 2016, PNAS 2019), all to closely investigate the intricate molecular details of cellular signaling.
https://amolf.nl/research-groups/physics-of-cellular-interactions
Tans group: We form a lively and close-knit research group of about 10 PhD students and postdocs, which work together in small teams on various projects in a highly supportive and social atmosphere. The Tans group studies the dynamics of single proteins (Nature 2013, Nature 2016, Nature 2020) and single cells (Nature 2014, Curr. Biol. 2018, Nature 2020) using novel experimental approaches.
Working conditions
- The working atmosphere at the institute is largely determined by young, enthusiastic, mostly foreign employees. Communication is informal and runs through short lines of communication.
- The position is intended as full-time (40 hours / week, 12 months / year) appointment in the service of the Netherlands Foundation of Scientific Research Institutes (NWO-I) for a maximum duration of 2 years.
- Salary is in scale 10 (CAO-OI) which starts at 4.065 Euro’s gross per month, and a range of employment benefits.
- AMOLF assists any new foreign Postdoc with housing and visa applications and compensates their transport costs and furnishing expenses.
More information?
For further information about the position, please contact Kristina Ganzinger: k.ganzinger@amolf.nl or Sander Tans: s.tans@amolf.nl.
Application
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Online screening may be part of the selection.
Diversity code
AMOLF is highly committed to an inclusive and diverse work environment: we want to develop talent and creativity by bringing together people from different backgrounds and cultures. We recruit and select on the basis of competencies and talents. We strongly encourage anyone with the right qualifications to apply for the vacancy, regardless of age, gender, origin, sexual orientation or physical ability.
AMOLF has won the NNV Diversity Award 2022, which is awarded every two years by the Netherlands Physical Society for demonstrating the most successful implementation of equality, diversity and inclusion (EDI).
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