Center for Geometrically Engineered Cellular Systems (GEC)
GEC is a center of excellence funded by the Novo Nordisk Foundation with 60M DKK (9,5M $) for the period 2018 to 2024. The project is an international collaboration between three universities and the laboratories of:
- Dimitrios Stamou, University of Copenhagen, Department of Chemistry
- Jay Groves, University of California Berkeley, Department of Chemistry
- Orion Weiner, University of California San Francisco, Department of Biochemistry and Biophysics
An overarching goal of synthetic biology is to control and direct the behaviour of living cells. At its most basic level, this can be accomplished by modifying the genetic code of the cell. Although this type of synthetic biology has led to major successes, many other applications remain frustratingly out of reach. One major reason for this is that inserting new genes into an organism is often not enough for the new proteins to assemble together into a functional unit in the modified host.
Our fundamental hypothesis is that geometrical arrangement of proteins and other molecules within cellular signalling systems is both critically important to proper function and synthetically controllable.
Our mission is to combine an arsenal of nanotechnologies and optogenetic methods developed in the three labs, to achieve new levels of synthetic control over the behaviour and function of molecular systems and living cells for therapeutical and pharmacological applications. We will focus on Ras signalling, T cell cancer immunotherapy, and GPCR signalling that represent the backbone of pharmaceutical science and industry.
The principle overarching objectives of the Center for Geometrically Engineered Cellular Systems (GEC) are:
- To engineer hybrid physically-templated membrane systems to isolate, manipulate, and study the spatial organization and function of key membrane signalling processes.
- Apply these molecular geometrical engineering tools to modulate cell behaviour, emphasizing T-cells for cancer immunotherapy.
- Engineer the cellular spatial organization of G protein coupled receptors (GPCRs) for development and screening of drug compounds.
The activities in GEC are thus organized around three work packages (WPs).
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WP1
Background: The vast majority of cell signalling processes occur on the cell membrane. While the structural and biochemical properties of the individual proteins are reasonably well known, our understanding of how these molecules assemble and work together on the membrane is in its infancy. This gap in understanding has substantial impact on human health and disease because a majority of therapeutic drugs also target processes occurring on the cell membrane.
Aim: Collectively, we have developed a suite of engineered supported membrane technologies (e.g. (1-7)) as well as optogenetic tools(8, 9) that have been instrumental in a number of significant biological discoveries(4, 7, 10-14). Here, we will integrate these fundamental technologies into a unified engineering platform. We will investigate how the input-output response function relating receptor triggering to the key downstream process of Ras activation is affected by geometric constraint.
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WP2
Background: The prospect of directing a cancer patient’s own immune system to eradicate their cancer is the fundamental basis of cancer immunotherapy, and one of the most promising breakthroughs in cancer treatment in decades. Despite successes, technical challenges to achieve the full potential of this strategy remain immense(15). Among the difficult aspects of engineering T cells is that natural T cell antigen recognition is a hallmark example of how large-scale spatial movement and assembly of proteins plays a key regulatory role in signalling. Early applications of the spatial mutation technology, developed by the Groves lab and based on patterned supported membranes, played a central role revealing spatial aspects of T cell signalling (11).
Aim: Here we aim to apply next-generation advanced engineered membrane technologies and optogenetic tools to systematically analyse spatio-mechanical aspects of T cell signalling with the goal of identifying specific points where engineered control over the living cell can be established.
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WP3
Background: Arguably, the quintessential class of membrane receptors that relays signals across the membrane is G protein coupled receptors (GPCRs). GPCRs comprise the most abundant family of transmembrane proteins in mammalian cells, they control multiple signaling transduction pathways and effect crucial physiological reactions in response to a plethora of endo- and exogenic stimuli.(16) As a result, they are targets to ~40% of all drugs in the market today.
In a recent publication (Nat. Chem. Biol., 2017, Front Cover Page (17)) the Stamou lab demonstrated that membrane geometry can enable the sorting of GPCRs) in live cells.(17) Remarkably, this sorting was specifically regulated by ligands demonstrating that the biomechanical coupling between membrane geometry and the spatial localization of GPCRs is a sensitive reporter of protein structure/conformation.
Aim: In WP3, we will engineer a hybrid-cell platform to investigate and if possible manipulate the coupling between membrane geometry, the structural and functional state of GPCRs, and their spatiotemporal organization.
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References
- Groves, J.T., N. Ulman, and S.G. Boxer. 1997. Micropatterning fluid lipid bilayers on solid supports. Science. 275: 651–653.
- Baksh, M.M., M. Jaros, and J.T. Groves. 2004. Detection of molecular interactions at membrane surfaces through colloid phase transitions. Nature. 427: 139–141.
- Caculitan, N.G., H. Kai, E.Y. Liu, N. Fay, Y. Yu, T. Lohmüller, G.P. O’Donoghue, and J.T. Groves. 2014. Size-based chromatography of signaling clusters in a living cell membrane. Nano Lett. 14: 2293–2298.
- Hatzakis, N.S., V.K. Bhatia, J. Larsen, K.L. Madsen, P.-Y. Bolinger, A.H. Kunding, J. Castillo, U. Gether, P. Hedegård, and D. Stamou. 2009. How curved membranes recruit amphipathic helices and protein anchoring motifs. Nat Chem Biol. 5: 835–841.
- Mathiasen, S., S.M. Christensen, J.J. Fung, S.G.F. Rasmussen, J.F. Fay, S.K. Jorgensen, S. Veshaguri, D.L. Farrens, M. Kiskowski, B. Kobilka, and D. Stamou. 2014. Nanoscale high-content analysis using compositional heterogeneities of single proteoliposomes. Nat Meth. 11: 931–934.
- Christensen, S.M., P.-Y. Bolinger, N.S. Hatzakis, M.W. Mortensen, and D. Stamou. 2012. Mixing subattolitre volumes in a quantitative and highly parallel manner with soft matter nanofluidics. Nature Nanotech. 7: 51–55.
- Veshaguri, S., S.M. Christensen, G.C. Kemmer, G. Ghale, M.P. Møller, C. Lohr, A.L. Christensen, B.H. Justesen, I.L. Jorgensen, J. Schiller, N.S. Hatzakis, M. Grabe, T.G. Pomorski, and D. Stamou. 2016. Direct observation of proton pumping by a eukaryotic P-type ATPase. Science. 351: 1469–1473.
- Levskaya, A., O.D. Weiner, W.A. Lim, and C.A. Voigt. 2009. Spatiotemporal control of cell signalling using a light-switchable protein interaction. Nature. 461: 997–1001.
- Toettcher, J.E., D. Gong, W.A. Lim, and O.D. Weiner. 2011. Light-based feedback for controlling intracellular signaling dynamics. Nat Meth. 8: 837–839.
- Larsen, J.B., M.B. Jensen, V.K. Bhatia, S.L. Pedersen, T. Bjørnholm, L. Iversen, M. Uline, I. Szleifer, K.J. Jensen, N.S. Hatzakis, and D. Stamou. 2015. Membrane curvature enables N-Ras lipid anchor sorting to liquid-ordered membrane phases. Nat Chem Biol. 11: 192–194.
- Mossman, K.D., G. Campi, J.T. Groves, and M.L. Dustin. 2005. Altered TCR signaling from geometrically repatterned immunological synapses. Science. 310: 1191–1193.
- Salaita, K., P.M. Nair, R.S. Petit, R.M. Neve, D. Das, J.W. Gray, and J.T. Groves. 2010. Restriction of receptor movement alters cellular response: physical force sensing by EphA2. Science. 327: 1380–1385.
- Endres, N.F., R. Das, A.W. Smith, A. Arkhipov, E. Kovacs, Y. Huang, J.G. Pelton, Y. Shan, D.E. Shaw, D.E. Wemmer, J.T. Groves, and J. Kuriyan. 2013. Conformational coupling across the plasma membrane in activation of the EGF receptor. Cell. 152: 543–556.
- Iversen, L., H.-L. Tu, W.-C. Lin, S.M. Christensen, S.M. Abel, J. Iwig, H.-J. Wu, J. Gureasko, C. Rhodes, R.S. Petit, S.D. Hansen, P. Thill, C.-H. Yu, D. Stamou, A.K. Chakraborty, J. Kuriyan, and J.T. Groves. 2014. Ras activation by SOS: allosteric regulation by altered fluctuation dynamics. Science. 345: 50–54.
- Lim, W.A., and C.H. June. 2017. The Principles of Engineering Immune Cells to Treat Cancer. Cell. 168: 724–740.
- Rosenbaum, D.M., S.G.F. Rasmussen, and B.K. Kobilka. 2009. The structure and function of G-protein-coupled receptors. Nature. 459: 356–363.
- Rosholm, K.R., N. Leijnse, A. Mantsiou, V. Tkach, S.L. Pedersen, V.F. Wirth, L.B. Oddershede, K.J. Jensen, K.L. Martinez, N.S. Hatzakis, P.M. Bendix, A. Callan-Jones, and D. Stamou. 2017. Membrane curvature regulates ligand-specific membrane sorting of GPCRs in living cells. Nat Chem Biol. 52: 4114.
- Groves, J.T., N. Ulman, and S.G. Boxer. 1997. Micropatterning fluid lipid bilayers on solid supports. Science. 275: 651–653.
For the full lists of publications of the three labs please see:
- Dimitrios Stamou, University of Copenhagen, Department of Chemistry
- Jay Groves, University of California Berkeley, Department of Chemistry
- Orion Weiner, University of California San Francisco, Department of Biochemistry and Biophysics
GEC publications
- Huang, W.Y.C., S. Alvarez, Y. Kondo, Y.K. Lee, J.K. Chung, H.Y.M. Lam, K.H. Biswas, J. Kuriyan, and J.T. Groves. 2019. A molecular assembly phase transition and kinetic proofreading modulate Ras activation by SOS. Science. 363: 1098–1103.
- Tischer, D.K., and O.D. Weiner. 2019. Light-based tuning of ligand half-life supports kinetic proofreading model of T cell signaling. Elife. 8.
- Bassereau, P., R. Jin, T. Baumgart, M. Deserno, R. Dimova, V.A. Frolov, P.V. Bashkirov, H. Grubmüller, R. Jahn, H.J. Risselada, L. Johannes, M.M. Kozlov, R. Lipowsky, T.J. Pucadyil, W.F. Zeno, J.C. Stachowiak, D. Stamou, A. Breuer, L. Lauritsen, C. Simon, C. Sykes, G.A. Voth, and T.R. Weikl. 2018. The 2018 biomembrane curvature and remodeling roadmap. J. Phys. D: Appl. Phys. 51: 343001–43.
- Walsh, S.M., S. Mathiasen, S.M. Christensen, J.F. Fay, C. King, D. Provasi, E. Borrero, S.G.F. Rasmussen, J.J. Fung, M. Filizola, K. Hristova, B. Kobilka, D.L. Farrens, and D. Stamou. 2018. Single Proteoliposome High-Content Analysis Reveals Differences in the Homo-Oligomerization of GPCRs. Biophys J. 115: 300–312.
Selected relevant publications from the three labs
- Huang, W.Y.C., S. Alvarez, Y. Kondo, Y.K. Lee, J.K. Chung, H.Y.M. Lam, K.H. Biswas, J. Kuriyan, and J.T. Groves. 2019. A molecular assembly phase transition and kinetic proofreading modulate Ras activation by SOS. Science. 363: 1098–1103.
- Rosholm, K.R., N. Leijnse, A. Mantsiou, V. Tkach, S.L. Pedersen, V.F. Wirth, L.B. Oddershede, K.J. Jensen, K.L. Martinez, N.S. Hatzakis, P.M. Bendix, A. Callan-Jones, and D. Stamou. 2017. Membrane curvature regulates ligand-specific membrane sorting of GPCRs in living cells. Nat Chem Biol. 52: 4114.
- Larsen, J.B., M.B. Jensen, V.K. Bhatia, S.L. Pedersen, T. Bjørnholm, L. Iversen, M. Uline, I. Szleifer, K.J. Jensen, N.S. Hatzakis, and D. Stamou. 2015. Membrane curvature enables N-Ras lipid anchor sorting to liquid-ordered membrane phases. Nat Chem Biol. 11: 192–194.
- Iversen, L., S. Mathiasen, J.B. Larsen, and D. Stamou. 2015. Membrane curvature bends the laws of physics and chemistry. Nat Chem Biol. 11: 822–825.
- Tischer, D., and O.D. Weiner. 2014. Illuminating cell signalling with optogenetic tools. Nat Rev Mol Cell Biol. 15: 551–558.
- Iversen, L., H.-L. Tu, W.-C. Lin, S.M. Christensen, S.M. Abel, J. Iwig, H.-J. Wu, J. Gureasko, C. Rhodes, R.S. Petit, S.D. Hansen, P. Thill, C.-H. Yu, D. Stamou, A.K. Chakraborty, J. Kuriyan, and J.T. Groves. 2014. Ras activation by SOS: allosteric regulation by altered fluctuation dynamics. Science. 345: 50–54.
- Toettcher, J.E., O.D. Weiner, and W.A. Lim. 2013. Using Optogenetics to Interrogate the Dynamic Control of Signal Transmission by the Ras/Erk Module. Cell. 155: 1422–1434.
- Toettcher, J.E., D. Gong, W.A. Lim, and O.D. Weiner. 2011. Light-based feedback for controlling intracellular signaling dynamics. Nat Meth. 8: 837–839.
- Salaita, K., P.M. Nair, R.S. Petit, R.M. Neve, D. Das, J.W. Gray, and J.T. Groves. 2010. Restriction of receptor movement alters cellular response: physical force sensing by EphA2. Science. 327: 1380–1385.
- Levskaya, A., O.D. Weiner, W.A. Lim, and C.A. Voigt. 2009. Spatiotemporal control of cell signalling using a light-switchable protein interaction. Nature. 461: 997–1001.
- Hatzakis, N.S., V.K. Bhatia, J. Larsen, K.L. Madsen, P.-Y. Bolinger, A.H. Kunding, J. Castillo, U. Gether, P. Hedegård, and D. Stamou. 2009. How curved membranes recruit amphipathic helices and protein anchoring motifs. Nat Chem Biol. 5: 835–841.
- Mossman, K.D., G. Campi, J.T. Groves, and M.L. Dustin. 2005. Altered TCR signaling from geometrically repatterned immunological synapses. Science. 310: 1191–1193.
GEC is a dynamic environment of excellence. We always look for highly motivated and qualified team members. GEC projects are interdisciplinary and are time-shared between the three labs situated in Copenhagen, UC Berkeley and UC San Francisco.
There are currently multiple openings at the MSc, PhD and postdoctoral level.
For more information please send an email to Prof. Dimitrios Stamou with one pdf file containing your motivation letter, CV and publication list. We would prefer if 2-3 letters of reference are included in the pdf, if this is not possible please include the contact details of three referees and ask them to forward their recommendation directly to us.
GEC comprises three sites: at the University of Copenhagen, UC Berkeley and UC San Francisco.
GEC administration is located at the University of Copenhagen.
Center leader
Prof. Dimitrios Stamou
Mob: +45 2498 1658
Email: stamou@nano.ku.dk
Center administration
Lone Mortensen
Dir: +45 35 32 03 00
Email: lone@chem.ku.dk
Mailing address – Copenhagen
Name c/o Stamou Lab
HC Oersted Institute
Building 3/D, 5th floor
Universitetsparken 5
Copenhagen, DK-2100
Denmark
Getting to GEC – Copenhagen
By Taxi
Taxi from the airport to downtown or GEC costs about DKK 300 (€ 40).
Taxi from downtown to GEC costs about DKK 100 (€13).
By public transportation
Airport to downtown: First take the metro from the Airport to Nørreport Station (downtown). Metro runs every ~5 min, traveling time about 15 min. You'll find ticket-automats at the DSB (train station) counter at Terminal 3, and also at the metro station located at the end of Terminal 3. You need a three-zone ticket, price: DKK 36 (€ 4.80). Remember the same ticket is valid on the train, metro, and bus.
Downtown to GEC: Continue by bus from Nørreport Station (downtown) to Nørre Campus (GEC). Take either bus no. 6A, 15E,150S, 184 or 185. Buses run every ~5 min, traveling time ~5 min.
Danish cash
All major credits cards are accepted for most transactions, bus tickets are one of the few exceptions. Cash withdrawal machines (ATMS) for all major credits cards are available in the baggage claim area, when you exit customs in Terminal 3 on your left, and in many places in downtown Copenhagen (outside banks).
Staff at GEC
| Name | Role | University | |
|---|---|---|---|
| Dimitrios Stamou | Faculty | stamou@chem.ku.dk | University of Copenhagen, Department of Chemistry |
| Jay Groves | Faculty | University of California Berkeley, Department of Chemistry | |
| Orion Weiner | Faculty | University of California San Francisco, Department of Biochemistry and Biophysics | |
| Shalini Low-Nam | Postdoc | slownam@gmail.com | University of California Berkeley |
| Christopher Shuttle | Postdoc | c.shuttle@chem.ku.dk | University of Copenhagen |
| Salome Veshaguri | Postdoc | salome.veshaguri@chem.ku.dk | University of Copenhagen |
| Steven Alvarez | PhD | saalvarez@berkeley.edu | University of California Berkeley, |
| Derek Britain | PhD | derek.Britain@ucsf.edu | University of California San Francisco |
| Rachel Brunetti | PhD | rachel.Brunetti@ucsf.edu | University of California San Francisco |
| Joey DeGrandchamp | PhD | jdegrand@berkeley.edu | University of California Berkeley |
| Brian Graziano | PhD | brian.Graziano@ucsf.edu | University of California San Francisco |
| Zhongwen Chen | PhD | chenzw@berkeley.edu | University of California Berkeley |
| Jesper Holmkvist | PhD | jflh@chem.ku.dk | University of Copenhagen |
| Eleftheria Kazepidou | PhD | elka@chem.ku.dk | University of Copenhagen |
| Neil Kim | PhD | neilhkim@berkeley.edu | University of California Berkeley |
| Lefteris Kosmidis | PhD | lefteris@chem.ku.dk | University of Copenhagen |
| Line Lauritsen | PhD | line.lauritsen@nbi.ku.dk | University of Copenhagen |
| Albert Lee, graduate student | PhD | albertayhlee@gmail.com | Grooves Lab, University of California Berkeley |
| Chun-Wei Lin | PhD | chunweilin01@gmail.com | University of California Berkeley |
| Jenny Lin | PhD | jianyijennylin@gmail.com | University of California Berkeley |
| Darren McAffee | PhD | dmcaffee@berkeley.edu | University of California Berkeley |
| Mads Peter Møller | PhD | mads.moeller@nano.ku.dk | University of Copenhagen |
| Laura Nocka | PhD | lnocka@berkeley.edu | University of California Berkeley |
| Mark O'Dair | PhD | markodair@berkeley.edu | University of California Berkeley |
| Anne Pipathsouk | PhD | anne.pipathsouk@ucsf.edu | University of California San Francisco |
| Suvrajit Saha | PhD | suvra17@gmail.com | University of California San Francisco |
| Doug Tischer | PhD | doug.tischer@ucsf.edu | University of California San Francisco |
| Jason Town, graduate student | PhD | jason.town@ucsf.edu | Weiner Lab, University of California San Francisco |
| Kiera Wilhelm | PhD | wilhelmk@berkeley.edu | University of California Berkeley |
| Tamas Nagy | PhD | tamas@tamasnagy.com | University of California San Francisco |
| Michelle Berling | MSc student | hfk576@alumni.ku.dk | University of Copenhagen |
| Gabriele Kockelkoren | Msc student | gabriele@chem.ku.dk | University of Copenhagen |
| Lone Mortensen | Administration | lone@chem.ku.dk Phone: +45 35 32 03 00 |
University of Copenhagen |
GEC news
2019.05.01
Eleftheria and Jesper start their PhD in the Stamou lab. Welcome to GEC!
2019.04.08*
Breakthrough study on T-cell signaling published in Science. Congratulations to William!
2019.04.01
Optogenetic control of T-cell signaling accepted in eLife. Congratulations to Doug!
2019.03.05
Prof. Stamou visits UC Berkeley and presents at the PChem departmental seminar.
2019.03.02
Prof. Stamou is awarded the prestigious Thomas E. Thompson award by the (American) Biophysical Society. Congratulations to Dimitrios!
2018.08.01
Chris is starting his postdoc in the Stamou lab. Welcome to GEC!
2018.11.19
Dr. Low-Nam from UC Berkeley visits U. Copenhagen and presents at the Department of Chemistry
2018.11.14
Prof. Groves and Prof, Weiner visit Copenhagen and present at PANUM.
2018.10.01
Prof. Groves visits U. Copenhagen and presents at the Maersk tower.
2018.09.01
GEC kick-off meeting in Yosemite. 35 participants from the three labs and two invited guest speakers. Fantastic science, in a fantastic location!