Dr Robert Pal
(email at firstname.lastname@example.org)
This is one of our flagship research areas in collaboration with Prof. James M. Tour, Rice Univeristy, Houston, Texas (USA).
Using a new generation of light activated cell type specific molecular nanomachines we have demonstrated the use of molecular mechanical action to open cellular membranes and lipid bilayers and expedite cell death in a fully controlled manner. The efficacy of this method using single photon excitation in the UV domain was demonstrated and has been recently published in Nature (2017, 548, 567-572).
Our overarching future aim is to extend our study beyond in vitro applications. Using UV light to activate these molecular machines in vivo has signification limitations associated with shallow tissue penetration and potential UV damage. In order to overcome this we propose to extend our research into the two-photon-, near-infrared activated domains.
Our vision for the future is to develop and validate a series of light-activated molecular machines to selectively target cancerous cells in the human body and safely eradicate them, in order to pave the way to the development of a fundamentally new photodynamic therapy protocol combining cell type and metabolic/morphological state specific uni-molecular nanomachines and biologically safe near infra-red activation. Once fully developed and validated it could be potentially adopted as a new form of extremely high 3D optical precision, facile and non-invasive Type V photodynamic therapy to eliminate the need of currently used highly invasive surgical or radiotherapeutic procedures that often harmful to administer.
Robert Pal grew up in Hungary and graduated from KLTE University of Debrecen, in 2004. Once completing his undergraduate studies he has moved to Durham to start a Ph.D with Professor David Parker on Responsive Luminescent Lanthanide systems. Completing his Ph.D in late 2007 he began to work as a Postdoctoral researcher within the Parker group, also working closely with Professor Andrew Beeby, moving away from organic chemistry towards bio-physical chemistry, spectroscopy and microscopy. In 2014 he has been awarded with a prestigious University Research Fellowship from the Royal Society to study the Development and Chemical Application of Phase Modulation Nanoscopy.
Robert is also the Technical Director of a successful University spin out company, FScan Ltd, which has developed lanthanide technology to be used as part of a novel test for Prostate Cancer detection that is currently part of an ongoing clincial trial.
He has also founded PB Spectroscopy limited alongside Prof. Andrew Beeby, a company that is dedicated for the development of miniaturised and affordable spectroscopic instrumentation and solutions.
RP is a physical chemist working on the border of organic chemistry and biophysics with expertise in lanthanide based sensors and cellular probes. In recent years he has focused his main research interest on innovation in the development of bespoke optical instrumentation, notably for high resolution, affordable microscopy and in portable optical spectroscopy for emission and circular polarised luminescence. In addition he also strives to capitalise on his new research interest in targeted light activated molecular nanomachines (Nature 2017).
Super-resolution Microscopy or ‘Nanoscopy’
'A picture is worth more than 100 words'
In the field of optical fluorescence microscopy, many researchers have dedicated their entire scientific carrier to develop better and improved cellular stains or associated microscopy techniques and equipment, pushing the boundaries of both signal detection and resolution. However, the intrinsic resolution of fluorescence microscopy is limited by diffraction, which determines the extension of the focused light emitted by a point source object, in other words the point spread function (PSF). In recent years, renewed have efforts emerged in optical microscopy and associated life sciences to break through the optical diffraction barrier and visualize even smaller parts of the ‘living’ cell in ‘super-resolution’. Governed by Abbé’s law (1873) the highest achievable theoretical spatial resolution (d) of a given experimental setup is dictated by the lowest applied excitation light (λexc) d = λexc./2NA (NA: numerical aperture of objective) promoting maximal achievable resolutions of ~200 nm. However, much of the fundamental biology of the cell occurs below this threshold; hence breaking this limit will allow the wide multidisciplinary scientific community to look deeper in higher resolution.
Ever since the step-changing invention of Confocal Microscopy by Minsky in 1953, attention has turned towards the development of new optical (hardware) and computer (software) based methodologies, revolutionising the way in which we investigate nanostructures. Recent years seen many refined and evolved variants of ‘Super-resolution’ techniques by improvements applied either or both to the illumination or detection process leading to improvement in both precision and resolution. No need to say this combined multidisciplinary effort have recently been recognised with the Nobel-prize awarded in Chemistry in 2014. But these new, still fundamentally diffraction limited techniques all have drawbacks too, such as limitation of suitable stains, disruptively high laser powers, slow/limited imaging speed, poor SNR due to loss of information and specialized expensive and bulky instrumentation.
Taking the above into account, the obvious conclusion for me is to introduce novel user friendly resolution enhancing methods (both hard- and sofware) into existing microscope platforms, on what several members of our research group is working on.
- Ward, Edward N., Torkelsen, Frida H. & Pal, Robert (2018). Enhancing multi-spot structured illumination microscopy with fluorescence difference. Royal Society Open Science 5(3): 171336.
- Foster, A.W., Pernil, R., Patterson, C.J., Scott, A.J.P., Pålsson, L.-O., Pal, R., Cummins, I., Chivers, P.T., Pohl, E. & Robinson, N.J. (2017). A tight tunable range for Ni(II) sensing and buffering in cells. Nature Chemical Biology 13(4): 409-414.
- Yeung, Chi-Tung, Yim, King-Him, Wong, Ho-Yin, Pal, Robert, Lo, Wai-Sum, Yan, Siu-Cheong, Yee-Man Wong, Melody, Yufit, Dmitry, Smiles, Danil E., McCormick, Laura J., Teat, Simon J., Shuh, David K., Wong, Wing-Tak & Law, Ga-Lai (2017). Chiral transcription in self-assembled tetrahedral Eu4L6 chiral cages displaying sizable circularly polarized luminescence. Nature Communications 8(1): 1128.
- Clarke, Rebecca, Ho, Kin Lok, Alsimaree, Abdulrahman Abdullah, Woodford, Owen J., Waddell, Paul G., Bogaerts, Jonathan, Herrebout, Wouter, Knight, Julian G., Pal, Robert, Penfold, Thomas J. & Hall, Michael J. (2017). Circularly Polarised Luminescence from Helically Chiral “Confused” N,N,O,C-Boron-Chelated Dipyrromethenes (BODIPYs). ChemPhotoChem 1(11): 513-517.
- Ward, E. N. & Pal, R. (2017). Image scanning microscopy: an overview. Journal of microscopy 266(2): 221-228.
- Jennings, L., Waters, R.S., Pal, R. & Parker, D. (2017). Induced Europium Circularly Polarised Luminescence Monitors Reversible Drug Binding to Native α1-Acid Glycoprotein. ChemMedChem 12(3): 271-277.
- García-López, Víctor, Chen, Fang, Nilewski, Lizanne G., Duret, Guillaume, Aliyan, Amir, Kolomeisky, Anatoly B., Robinson, Jacob T., Wang, Gufeng, Pal, Robert & Tour, James M. (2017). Molecular machines open cell membranes. Nature 548(7669): 567-572.
- Yang, Xiaoping, Wang, Shiqing, King, Tyler L., Kerr, Christopher J., Blanchet, Clement, Svergun, Dmitri, Pal, Robert, Beeby, Andrew, Vadivelu, Jamuna, Brown, Katherine A., Jones, Richard A., Zhang, Lijie & Huang, Shaoming (2016). Anisotropic lanthanide-based nano-clusters for imaging applications. Faraday Discussions 191: 465-479.
- Neil, E.R., Pal, R., Fox, M.A. & Parker, D. (2016). Induced europium CPL for the selective signalling of phosphorylated amino-acids and O-phosphorylated hexapeptides. Dalton Transactions 45(20): 8355-8366.
- Dai, Lixiong, Lo, Wai-Sum, Coates, Ian D., Pal, Robert & Law, Ga-Lai (2016). New Class of Bright and Highly Stable Chiral Cyclen Europium Complexes for Circularly Polarized Luminescence Applications. Inorganic Chemistry 55(17): 9065-9070.
- Sansee, A., Meksawangwong, S., Chainok, K., Franz, K. J., Gal, M., Palsson, L. -O., Puniyan, W., Traiphol, R., Pal, R. & Kielar, F. (2016). Novel aminoalkyl tris-cyclometalated iridium complexes as cellular stains. Dalton Transactions 45(43): 17420-17430.
- Starck, Matthieu, Pal, Robert & Parker, David (2016). Structural Control of Cell Permeability with Highly Emissive Europium(III) Complexes Permits Different Microscopy Applications. Chemistry-a European Journal 22(2): 570-580.
- Frawley, A.T., Pal, D. & Parker, D. (2016). Very bright, enantiopure europium(III) complexes allow time-gated chiral contrast imaging. Chemical Communications 52(91): 13349-13352.
- Neil, E.R., Fox, M.A., Pal, R., Pålsson, L.O., O'Sullivan, B.A. & Parker, D. (2015). Chiral probe development for circularly polarised luminescence: comparative study of structural factors determining the degree of induced CPL with four heptacoordinate europium(III) complexes. Dalton Transactions 44(33): 14937-14951.
- Butler, S.J., Delbianco, M., Lamarque, L., McMahon, B.K., Neil, E.R., Pal, R., Parker, D., Walton, J.W. & Zwier, J. (2015). EuroTracker® dyes design, synthesis, structure and photophysical properties of very bright europium complexes and their use in bioassays and cellular optical imaging. Dalton Transactions 44(11): 4791-4803.
- Jemmis, E. D., Aravamudhan, Sankarampadi, Arunan, Elangannan, Shahi, Abhishek, Hunt, Neil, Schnedermann, Christoph, Helliwell, John R., Ashfold, Mike, Goswami, Himangshu Prabal, Nenov, Artur, Deckert, Volker, Chowdhury, Priyadarshi Roy, Ghiggino, Kenneth, Miller, R. J. Dwayne, Goswami, Debabrata, Junge, Wolfgang, Howard, Judith, Tominaga, Keisuke, van Driel, Tim Brandt, Zanni, Martin, Umapathy, Siva, Nielsen, Martin Meedom, Pal, R. & Mukamel, Shaul (2015). Future challenges: general discussion. Faraday Discussions 177: 517-545.
- Pal, Robert (2015). Phase modulation nanoscopy: a simple approach to enhanced optical resolution. Faraday Discussions 177: 507-515.
- Zanni, Martin, E D, Jemmis, Aravamudhan, Sankarampadi, Pallipurath, Anuradha, Arunan, Elangannan, Schnedermann, Christoph, Mishra, Ashok Kumar, Warren, Mark, Hirst, Jonathan D., John, Franklin, Pal, R., Helliwell, John R., Moirangthem, Kiran, Chakraborty, Shamik, Dijkstra, Arend G., Roy Chowdhury, Priyadarshi, Ghiggino, Kenneth, Miller, R. J. Dwayne, Meech, Stephen, Medhi, Himani, Hariharan, Mahesh, Ariese, Freek, Edwards, Alison, Mallia, Ajith R., Umapathy, Siva, Meedom Nielsen, Martin, Hunt, Neil, Tian, Zhen-Yu, Skelton, Jonathan, Sankar, Gopinathan & Goswami, Debabrata (2015). Time and Space resolved Methods: general discussion. Faraday Discussions 177(0): 263-292.
- Sim, N., Gottschalk, S., Pal, R., Delbianco, M., Degtyarik, D., Razansky, D., Westmeyer, G.G., Ntziachristos, V., Parker, D. & Mishra, A. (2015). Wavelength-dependent optoacoustic imaging probes for NMDA receptor visualisation. Chemical Communications 51(82): 15149-15152.
- Butler, Stephen J., Lamarque, Laurent, Pal, Robert & Parker, David (2014). EuroTracker dyes: highly emissive europium complexes as alternative organelle stains for live cell imaging. Chemical Science 2014(5): 1750-1756.
- Carr, Rachel, Puckrin, Robert, McMahon, Brian K., Pal, Robert, Parker, David & Pålsson, Lars-Olof (2014). Induced circularly polarized luminescence arising from anion or protein binding to racemic emissive lanthanide complexes. Methods and Applications in Fluorescence 2(2): 024007.
- Sim, N., Pal, R., Parker, D., Engelmann, J., Mishra, A. & Gottschalk, S. (2014). Magnetic resonance and optical imaging probes for NMDA receptors on the cell surface of neurons: synthesis and evaluation in cellulo. Organic and Biomolecular Chemistry 12(46): 9389-9404.
- Pal, Robert & Beeby, Andrew (2014). Simple and versatile modifications allowing time gated spectral acquisition, imaging and lifetime profiling on conventional wide-field microscopes. Methods and Applications in Fluorescence 2(3): 037001.
- Butler, Stephen J., Delbianco, Martina, Evans, Nicholas H., Frawley, Andrew T., Pal, Robert, Parker, David, Puckrin, Robert S. & Yufit, Dmitry S. (2014). Utility of tris(4-bromopyridyl) europium complexes as versatile intermediates in the divergent synthesis of emissive chiral probes. Dalton Transactions 43(15): 5721-5730.
- McMahon, Brian K., Pal, Robert & Parker, David (2013). A bright and responsive europium probe for determination of pH change within the endoplasmic reticulum of living cells. Chemical communications 49(47): 5363-5365.
- Butler, Stephen J., McMahon, Brian K., Pal, Robert, Parker, David & Walton, James W. (2013). Bright Mono-aqua Europium Complexes Based on Triazacyclononane That Bind Anions Reversibly and Permeate Cells Efficiently. Chemistry-a European Journal 19(29): 9511-9517.
- Evans, Nicholas H., Carr, Rachel, Delbianco, Martina, Pal, Robert, Yufit, Dmitry S. & Parker, David (2013). Complete stereocontrol in the synthesis of macrocyclic lanthanide complexes: direct formation of enantiopure systems for circularly polarised luminescence applications. Dalton transactions 42(44): 15610-6.
- Sim, Neil, Gottschalk, Sven, Pal, Robert, Engelmann, Joern, Parker, David & Mishra, Anurag (2013). Responsive MR-imaging probes for N-methyl-D-aspartate receptors and direct visualisation of the cell-surface receptors by optical microscopy. Chemical Science 4(8): 3148-3153.
- Walton, J.W., Bourdoll, A., Butler, S.J., Soulie, M., Delbianco, M., McMahon, B.K., Pal, R., Puschmann, H., Zwier, J.M., Lamarque, L., Maury, O., Andraud, C. & Parker, D. (2013). Very bright europium complexes that stain cellular mitochondria. Chemical Communications 49(16): 1600-1602.
- Tircso, Gyula, Kalman, Ferenc K., Pal, Robert, Banyai, Istvan, Varga, Tamas R., Kiraly, Robert, Lazar, Istvan, Quebatte, Laurent, Merbach, Andre E., Toth, Eva & Bruecher, Erno (2012). Lanthanide Complexes Formed with the Tri- and Tetraacetate Derivatives of Bis(aminomethyl)phosphinic Acid: Equilibrium, Kinetic and NMR Spectroscopic Studies. European Journal of Inorganic Chemistry (12): 2062-2073.
- Smith, David G., McMahon, Brian K., Pal, Robert & Parker, David (2012). Live cell imaging of lysosomal pH changes with pH responsive ratiometric lanthanide probes. Chemical Communications 48(68): 8520-8522.
- Pal, Robert, Beeby, Andrew & Parker, David (2011). Analysis of citrate in low-volume seminal fluid samples using a time-gated measurement of europium luminescence. Journal of Pharmaceutical and Biomedical Analysis 56(2): 352-358.
- Pal, Robert, Parker, David & Costello, Leslie C. (2009). A europium luminescence assay of lactate and citrate in biological fluids. Organic & Biomolecular Chemistry 7(8): 1525-1528.
- Montgomery, Craig P., Murray, Benjamin S., New, Elizabeth J., Pal, Robert & Parker, David (2009). Cell-Penetrating Metal Complex Optical Probes: Targeted and Responsive Systems Based on Lanthanide Luminescence. Accounts of Chemical Research 42(7): 925-937.
- Law, Ga-Lai, Pal, Robert, Palsson, Lars O., Parker, David & Wong, Ka-Leung (2009). Responsive and reactive terbium complexes with an azaxanthone sensitiser and one naphthyl group: applications in ratiometric oxygen sensing in vitro and in regioselective cell killing. Chemical Communications (47): 7321-7323.
- Pal, Robert & Parker, David (2008). A ratiometric optical imaging probe for intracellular pH based on modulation of europium emission. Organic & Biomolecular Chemistry 6(6): 1020-1033.
- Murray, Benjamin S., New, Elizabeth J., Pal, Robert & Parker, David (2008). Critical evaluation of five emissive europium(III) complexes as optical probes: correlation of cytotoxicity, anion and protein affinity with complex structure, stability and intracellular localisation profile. Organic & Biomolecular Chemistry 6(12): 2085-2094.
- Pal, Robert & Parker, David (2007). A single component ratiometric pH probe with long wavelength excitation of europium emission. Chemical Communications (5): 474-476.
- Tircso, Gyula, Benyei, Attila, Kiraly, Robert, Lazar, Istvan, Pal, Robert & Brucher, Erno (2007). Complexation properties of the Di-, Tri-, and tetraacetate derivatives of bis(aminomethyl)phosphinic acid. European Journal of Inorganic Chemistry (5): 701-713.
- Atkinson, P., Findlay, K.S., Kielar, F., Pal, D., Parker, D., Poole, R.A., Puschmann, H., Richardson, S.L., Stenson, P.A., Thompson, A.L. & Yu, J.H. (2006). Azaxanthones and azathioxanthones are effective sensitisers for europium and terbium luminescence. Organic & Biomolecular Chemistry 4(9): 1707-1722.
- Mishra, Anurag , Mishra, Rita, Gottschalk, Sven, Pal, Robert, Sim, Neil, Engelmann, Joern, Goldberg, Martin & Parker, David (2014). Microscopic visualisation of metabotropic glutamate receptors on the surface of living cells using bifunctional magnetic resonance imaging probes. ACS Chemical Neuroscience 5(2): 128-137.