Scott Laughlin, Associate Professor
B.S. in Biochemistry and Philosophy, University of Michigan, Ann Arbor, 2002
Ph. D. in Chemistry, University of California, Berkeley, 2008
Postdoctoral research at the Helen Wills Neuroscience Institute, University of California, Berkeley, 2008-2013
Phone: (631) 632-2642
Our research uses chemistry to examine how the brain works. How does the brain sense the environment? How does it decode that sensory information and control behavior? All of the brain’s many functions rely on its neural circuits—a complex web of neurons connected to each other in such a way that they can perform the logical operations that allow us to think, respond to stimuli, etc. Precisely how neural circuits perform their calculations is a mystery whose solution has wide ranging implications for human health. Using organic synthesis, molecular biology, and behavioral neurobiology, we create chemical tools to help reveal the structure of neural circuits in living animals.
Chemical Imaging and Manipulation of astrocytes
Once considered mere supporters of the brain’s neural circuitry, astrocytes have recently emerged as active players in neural circuit function. For example, astrocytes mediate the formation of synapses in the brain and adjust the synaptic strength of connected neurons. Like neurons, astrocytes experience cytosolic calcium spikes upon binding neurotransmitters, a process now recognized as a direct astrocyte contribution to information processing in the brain. Beyond sensing neurotransmitters, astrocytes modulate synaptic activity through the release of gliotransmitters, thus participating directly in neuronal signaling on a breadth of timescales inaccessible with neuron-centric brain circuitry. Commensurate with their diverse roles, astrocyte-neuron interactions influence a wide variety of neurological disorders. Nevertheless, there are few tools available for imaging and manipulating astrocytes, especially within the context of specific interactions between astrocytes and neural circuitry. In this research area, my laboratory has developed and utilized a chemical tag that promotes specific labeling of astrocytes with molecules like fluorophores to enable light microscopy-based visualization to drug molecules for astrocyte targeted therapies.
Engineering designer enzymes for recording brain activity
In response to a sensory stimulus, such as a smell, sound or sight, the neurons in a circuit burst with activity in order to process the information. At the same time, most other neurons in the brain, and in other neural circuits, are dormant. We exploit this short burst of activity to highlight the neural circuit responsible for processing a given sensation. In one strategy, we engineer enzymes to permanently turn fluorescent in response to a burst of neural activity. By applying these tools to the brain and exposing the animal to an interesting smell, sound or sight, we make only those neurons or astrocytes responsible for processing the sensation fluorescent, allowing us to image the circuit throughout the brain at high resolution.
Modular, activatable bioorthogonal reactions
Bioorthogonal chemistries involve reactions that occur between partners that react specifically with each other but not with other chemical functional groups in biology. We focus on the development of modular, turn-on bioorthogonal reactions that employ light, enzymes, or disease-relevant small molecules to activate reactivity in space & time or in genetically- or biochemically-defined cell types. Essentially, we have employed modular light-, enzyme-, or small molecule-labile groups as removable inhibitors of the cyclopropene ligation with inverse electron demand Diels Alder substrates, like 1,2,4,5-tetrazines, 1,2-quinones, and 1,3-dipoles. This modular strategy for caging a bioorthogonal reaction has the potential to impact all areas surveyed by bioorthogonal chemistries, from imaging in basic science investigations to new therapies that utilize bioorthogonal reactions.
Jiang, T. & Laughlin, S. T. “Enzyme- or Light-Triggered Cyclopropenes for Bioorthogonal Ligation.” Methods in Enzymology, 2020, 641, 1–34.
Kumar, P., Zainul, O., Camarda, F. M., Jiang, T., Mannone, J. A., Huang, W. & Laughlin, S. T. “Caged cyclopropenes with improved tetrazine ligation kinetics.” Org. Lett., 2019, 21, 3721–3725.
Jiang, T., Kumar, P., Huang, W., Kao, W. -S., Thompson, A. O., Camarda, F. M. & Laughlin, S. T. “Modular enzyme- and light-based activation of the cyclopropene-tetrazine ligation.” ChemBioChem, 2019, in press, available online at https://onlinelibrary.wiley.com/doi/10.1002/cbic.201900137.
Kumar, P., Huang, W., Shukhman, D., Camarda, F.M. & Laughlin, S. T. “Stable, cyclopropene-containing analogs of the amino acid neurotransmitter glutamate.” Tet. Lett, 2019, 60, 1476–1480.
Preston, A. N., Cervasio, D. A. & Laughlin, S. T. “Visualizing the Brain’s Astrocytes.” Methods in Enzymology, 2019, 622, 129–151.
Kumar, P. & Laughlin, S. T. “Modular Activatable Bioorthogonal Reagents.” Methods in Enzymology, 2019, 622, 3721–3725.
Yin, X., Hewitt, D. R. O., Preston, A. N., Heroux, L. A., Agamalian, M. M., Quah, S. P., Zheng, B., Smith, A. J., Laughlin, S. T., Grubbs, R. B. & Bhatia, S. R. “Hierarchical assembly in PLA-PEO-PLA hydrogels with crystalline domains and effect of block stereochemistry.” Colloids and Surfaces B: Biointerfaces, 2019, 180, 102–109.
Ahn, S. H., Thach, D., Vaughn, B. A., Alford, V. M., Preston, A. N., Laughlin, S. T. & Boros, E. “Linear Desferrichrome-linked silicon-rhodamine antibody conjugate enables targeted multimodal imaging of HER2 in vitro and in vivo.” Mol. Pharmaceutics, 2019, 16, 1412–1420.
Preston, A. N., Farr, J. D., Tan, K. C., Cervasio, D. A., Butkus, L. R. & Laughlin, S. T. “Design principles for cationic astrocyte-targeted probes.” ChemBioChem, 2019, 20, 366–370.
Kumar, P., Jiang, T., Zainul, O., Preston, A. N., Li, S., Farr, J. D., Suri, P. & Laughlin, S. T. “Lipidated cyclopropenes via a stable 3N-spirocyclopropene scaffold.” Tet. Lett., 2018, 59,3435–3438.
Kumar, P., Jiang, T., Li, S., Zainul, O. & Laughlin, S. T. “Caged cyclopropenes for controlling bioorthogonal reactivity.” Org. Biomol. Chem., 2018, 16, 4081–4085. Featured on the Organic & Biomolecular Chemistry Blog (https://goo.gl/9V35AL)
Preston, A. N., Farr, J. D., O’Neill, B. K., Thompson, K. K., Tsirka, S. E. & Laughlin, S. T. “Visualizing the brain’s astrocytes with diverse chemical scaffolds.” ACS Chem. Biol., 2018, 13, 1493–1498.
O’Neill, B.K. & Laughlin, S. T. “Neuronal calcium recording with an engineered TEV protease.” ACS Chem. Biol., 2018, 13, 1159–1164.
Kumar, P., Zainul, O. & Laughlin, S. T. “Inexpensive multigram-scale synthesis of cyclic enamines and 3-N spirocyclopropyl systems.” Org. Biomol. Chem., 2018, 16, 652–656.
Quah, S. P., Smith, A. J., Preston, A. N., Laughlin, S. T. & Bhatia, S. R. “Large-area alginate/PEO-PPO-PEO hydrogels with thermoreversible rheology at physiological temperatures.” Polymer, 2018, 135, 171–177.
Kumar, P., Shukhman, D. & Laughlin, S. T. “A photocaged, cyclopropene-containing analog of the amino acid neurotransmitter glutamate.” Tet. Lett., 2016, 57, 5750–5752.
Shah, L., Laughlin, S. T. & Carrico, I. S. “Light-activated Staudinger-Bertozzi ligation within living animals.” J. Am. Chem. Soc., 2016, 138, 5186–5189.
Dehnert, K.W., Baskin, J.M., Laughlin, S.T., Beahm, B.J., Naidu, N.N., Amacher, S.L. & Bertozzi, C.R. Imaging the sialome during zebrafish development with copper-free click chemistry. Chembiochem, 2012, 13, 353–7.
Dehnert, K.W., Beahm, B.J., Huynh, T.T., Baskin, J.M., Laughlin, S.T., Wang, W., Wu, P., Amacher, S.L. & Bertozzi, C.R. Metabolic labeling of fucosylated glycans in developing zebrafish. ACS Chem. Biol., 2011, 6, 547–52.
Baskin, J.M.*, Dehnert, K.W.*, Laughlin, S.T.*, Amacher, S.L. & Bertozzi, C.R. Visualizing enveloping layer glycans during zebrafish early embryogenesis. *These authors contributed equally to this work. Proc. Natl Acad. Sci. U.S.A., 2010, 107, 10360–5.
Laughlin, S.T. & Bertozzi, C.R. In vivo imaging of Caenorhabditis elegans glycans. ACS Chem. Biol., 2009, 4, 1068–72.
Laughlin, S.T. & Bertozzi, C.R. Imaging the glycome. Proc. Natl Acad. Sci. U.S.A., 2009, 106, 12–7.
Czlapinski, J.L., Schelle, M.W., Miller, L.W., Laughlin, S.T., Kohler, J. J., Cornish, V. & Bertozzi, C. R. Conditional glycosylation in eukaryotic cells using a biocompatible chemical inducer of dimerization. J. Am. Chem. Soc., 2008, 130, 13186–7.
Laughlin, S.T., Baskin, J.M., Amacher, S.L. & Bertozzi, C.R. In vivo imaging of membrane‐associated glycans in developing zebrafish. Science, 2008, 320, 664–7.
Laughlin, S.T. & Bertozzi, C.R. Metabolic labeling of glycans with azido sugars for visualization and glycoproteomics. Nat. Protoc., 2007, 11, 2930–44.
Baskin, J.M., Prescher, J.A., Laughlin, S.T., Agard, N.J., Chang, P.V., Miller, I.A.
& Bertozzi, C.R.
Copper‐free click chemistry for covalent labeling in living systems. Proc. Natl Acad. Sci. U.S.A., 2007, 104, 16793–97.
Rabuka, D.R., Hubbard, S.C., Laughlin, S.T., Argade, S.P. & Bertozzi, C.R. A chemical reporter strategy to probe glycoprotein fucosylation. J. Am. Chem. Soc., 2006, 128, 12078–79.
Laughlin, S.T., Agard, N.J., Baskin, J.M., Carrico, I.S., Chang, P.V., Ganjuli, A.S.,
Lo, A., Prescher, J.A. & Bertozzi, C.R. Metabolic labeling of glycans with azido sugars for visualization and glycoproteomics. Meth. Enzymol., 2006, 415, 230–250.
de Graffenried, C.L., Laughlin, S.T., Kohler, J.J. & Bertozzi, C.R. A small‐molecule switch for Golgi sulfotransferases. Proc. Natl Acad. Sci. U.S.A., 2004, 101, 16715–20.
Kohler, J.J., Czlapinski, J.L., Laughlin, S.T., Schelle, M.W., de Graffenried, C.L.
& Bertozzi, C.R.
Directing flux in glycan biosynthetic pathways with a small molecule switch. Chembiochem, 2004, 5, 1455–8.