William Schafer

Last updated
William Schafer
FRS
William Schafer.jpg
Born
William Ronald Schafer

(1964-08-29) August 29, 1964 (age 60)
Boston, Massachusetts, United States
NationalityAmerican, British
EducationLakeside High School, DeKalb County, Georgia, United States
Alma materHarvard University (AB Biology, 1986); University of California, Berkeley (PhD Biochemistry, 1991)
Scientific career
Thesis Protein prenylation in saccharomyces cervesiae  (1990)
Doctoral advisor Jasper Rine
Website https://www2.mrc-lmb.cam.ac.uk/group-leaders/n-to-s/william-schafer/

William Ronald Schafer FRS (born August 29, 1964) is a neuroscientist and geneticist who has made important contributions to understanding the molecular and neural basis of behaviour. His work, principally in the nematode C. elegans , has used an interdisciplinary approach to investigate how small groups of neurons generate behavior, and he has pioneered methodological approaches, including optogenetic neuroimaging and automated behavioural phenotyping, that have been widely influential in the broader neuroscience field. He has made significant discoveries on the functional properties of ionotropic receptors in sensory transduction and on the roles of gap junctions and extrasynaptic modulation in neuronal microcircuits. More recently, he has applied theoretical ideas from network science and control theory to investigate the structure and function of simple neuronal connectomes, with the goal of understanding conserved computational principles in larger brains. He is an EMBO member, Fellow of the Academy of Medical Sciences, and Fellow of the Royal Society. [1]

Contents

Career

Schafer trained as a geneticist and biochemist at the University of California, Berkeley, under the supervision of Jasper Rine. During his PhD research, he discovered that CAAX-box proteins in yeast, including Ras, are prenylated, and showed that this modification is essential for membrane targeting and biological activity. [2]

As a postdoc in the lab of Cynthia Kenyon, he discovered that dopamine inhibits locomotion in C. elegans and identified the first neuronal calcium channel mutant in a screen for worms with abnormal dopamine sensitivity. [3] In 1995 he became an assistant professor at the University of California, San Diego.

Following a sabbatical in 2004–2005, in 2006 he moved his research group to the Laboratory of Molecular Biology in Cambridge, UK. In 2020 he was elected a Fellow of the Royal Society [1]

In 2019 he was appointed full professor, part-time, in the Department of Biology at the Katholieke Universiteit Leuven.

Research

Genetically encoded calcium indicators: The first genetically encoded calcium indicators were developed in 1997, but they initially proved difficult to use in transgenic animals. In 2000, Schafer and his student Rex Kerr showed that the GECI yellow cameleon 2 could be used to record activity in muscles and in single neurons of transgenic worms. [4] This was the first use of an optogenetic sensor to record the dynamics of neural activity in an animal. Using this technique, Schafer and his group have characterized the properties of many identified neurons in the worm, including subtypes of mechanosensory, chemosensory and nociceptive neurons, [5] [6] [7] and shown that molecules such as TMCs and TRP channels play conserved sensory functions in these neurons. [8] [9] [10] His group has since shown that the detection of mechanical stimuli by TMC channels, which form the pore of hair cell mechanotransduction channels in humans, relies upon an intracellular ankyrin-CIB complex rather than force transmission through the cell membrane as was once thought. [11]

Automated phenotyping: Schafer's group also pioneered the use of automated imaging and machine vision for behavioral phenotyping. They first used an automated tracking microscope to record C. elegans behaviour over many hours and measure the timing of egg-laying; these experiments showed that worms fluctuate between behavioral states controlled by serotonin. [12] More sophisticated worm trackers were later used to generate high-content phenotypic data for other behaviors such as locomotion; [13] [14] [15] this approach has proven very useful for precisely measuring and classifying effects of genes on the nervous system.

Connectomics and network science: Schafer has also worked with network scientists to investigate the structure of the C. elegans neural connectome. In particular, he recognised that neuromodulatory signaling, being largely extrasynaptic, forms a parallel wireless connectome whose topological features and modes of interaction with the wired connectome could be analyzed as a multiplex network. [16] In 2023, his lab published the first neuropeptidergic connectome of C. elegans, which is the first extrasynaptic connectome of any organism. [17] Together with Laszlo Barabasi's group his group also carried out the first test of the idea that control theory can be used to predict neural function based on the topology of a complex neuronal connectome [18]

Related Research Articles

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<span class="mw-page-title-main">Excitotoxicity</span> Process that kills nerve cells

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Channelrhodopsins are a subfamily of retinylidene proteins (rhodopsins) that function as light-gated ion channels. They serve as sensory photoreceptors in unicellular green algae, controlling phototaxis: movement in response to light. Expressed in cells of other organisms, they enable light to control electrical excitability, intracellular acidity, calcium influx, and other cellular processes. Channelrhodopsin-1 (ChR1) and Channelrhodopsin-2 (ChR2) from the model organism Chlamydomonas reinhardtii are the first discovered channelrhodopsins. Variants that are sensitive to different colors of light or selective for specific ions have been cloned from other species of algae and protists.

Cameleon is an engineered protein based on variant of green fluorescent protein used to visualize calcium levels in living cells. It is a genetically encoded calcium sensor created by Roger Y. Tsien and coworkers. The name is a conflation of CaM (the common abbreviation of calmodulin) and chameleon to indicate the fact that the sensor protein undergoes a conformation change and radiates at an altered wavelength upon calcium binding to the calmodulin element of the Cameleon. Cameleon was the first genetically encoded calcium sensor that could be used for ratiometric measurements and the first to be used in a transgenic animal to record activity in neurons and muscle cells. Cameleon and other genetically encoded calcium indicators (GECIs) have found many applications in neuroscience and other fields of biology, including understanding the mechanisms of cell signaling by conducting time-resolved Ca2+ activity measurement experiments with endoplasmic reticulum (ER) enzymes. It was created by fusing BFP, calmodulin, calmodulin-binding peptide M13 and EGFP.

<span class="mw-page-title-main">Calcium-activated potassium channel subunit alpha-1</span> Voltage-gated potassium channel protein

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Optogenetics is a biological technique to control the activity of neurons or other cell types with light. This is achieved by expression of light-sensitive ion channels, pumps or enzymes specifically in the target cells. On the level of individual cells, light-activated enzymes and transcription factors allow precise control of biochemical signaling pathways. In systems neuroscience, the ability to control the activity of a genetically defined set of neurons has been used to understand their contribution to decision making, learning, fear memory, mating, addiction, feeding, and locomotion. In a first medical application of optogenetic technology, vision was partially restored in a blind patient with Retinitis pigmentosa.

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<span class="mw-page-title-main">GCaMP</span> Genetically encoded calcium indicator

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Optogenetics began with methods to alter neuronal activity with light, using e.g. channelrhodopsins. In a broader sense, optogenetic approaches also include the use of genetically encoded biosensors to monitor the activity of neurons or other cell types by measuring fluorescence or bioluminescence. Genetically encoded calcium indicators (GECIs) are used frequently to monitor neuronal activity, but other cellular parameters such as membrane voltage or second messenger activity can also be recorded optically. The use of optogenetic sensors is not restricted to neuroscience, but plays increasingly important roles in immunology, cardiology and cancer research.

References

  1. 1 2 "William Schafer". Royal Society. Retrieved 20 September 2020.
  2. ↑ Schafer WR, Kim R, Sterne R, Thorner J, Kim SH, Rine J (July 1989). "Genetic and pharmacological suppression of oncogenic mutations in ras genes of yeast and humans". Science. 245 (4916): 379–85. Bibcode:1989Sci...245..379S. doi:10.1126/science.2569235. PMID   2569235.
  3. ↑ Schafer WR, Kenyon CJ (May 1995). "A calcium-channel homologue required for adaptation to dopamine and serotonin in Caenorhabditis elegans". Nature. 375 (6526): 73–8. Bibcode:1995Natur.375...73S. doi:10.1038/375073a0. PMID   7723846. S2CID   4327412.
  4. ↑ Kerr R, Lev-Ram V, Baird G, Vincent P, Tsien RY, Schafer WR (June 2000). "Optical imaging of calcium transients in neurons and pharyngeal muscle of C. elegans". Neuron. 26 (3): 583–94. doi: 10.1016/S0896-6273(00)81196-4 . PMID   10896155. S2CID   311998.
  5. ↑ Hilliard MA, Apicella AJ, Kerr R, Suzuki H, Bazzicalupo P, Schafer WR (January 2005). "In vivo imaging of C. elegans ASH neurons: cellular response and adaptation to chemical repellents". The EMBO Journal. 24 (1): 63–72. doi:10.1038/sj.emboj.7600493. PMC   544906 . PMID   15577941.
  6. ↑ Suzuki H, Thiele TR, Faumont S, Ezcurra M, Lockery SR, Schafer WR (July 2008). "Functional asymmetry in Caenorhabditis elegans taste neurons and its computational role in chemotaxis". Nature. 454 (7200): 114–7. Bibcode:2008Natur.454..114S. doi:10.1038/nature06927. PMC   2984562 . PMID   18596810.
  7. ↑ Suzuki H, Kerr R, Bianchi L, Frøkjaer-Jensen C, Slone D, Xue J, Gerstbrein B, Driscoll M, Schafer WR (September 2003). "In vivo imaging of C. elegans mechanosensory neurons demonstrates a specific role for the MEC-4 channel in the process of gentle touch sensation". Neuron. 39 (6): 1005–17. doi: 10.1016/j.neuron.2003.08.015 . PMID   12971899. S2CID   11990506.
  8. ↑ Kindt KS, Viswanath V, Macpherson L, Quast K, Hu H, Patapoutian A, Schafer WR (May 2007). "Caenorhabditis elegans TRPA-1 functions in mechanosensation". Nature Neuroscience. 10 (5): 568–77. doi:10.1038/nn1886. PMID   17450139. S2CID   13490958.
  9. ↑ Chatzigeorgiou M, Yoo S, Watson JD, Lee WH, Spencer WC, Kindt KS, Hwang SW, Miller DM, Treinin M, Driscoll M, Schafer WR (July 2010). "Specific roles for DEG/ENaC and TRP channels in touch and thermosensation in C. elegans nociceptors". Nature Neuroscience. 13 (7): 861–8. doi:10.1038/nn.2581. PMC   2975101 . PMID   20512132.
  10. ↑ Chatzigeorgiou M, Bang S, Hwang SW, Schafer WR (February 2013). "tmc-1 encodes a sodium-sensitive channel required for salt chemosensation in C. elegans". Nature. 494 (7435): 95–99. Bibcode:2013Natur.494...95C. doi:10.1038/nature11845. PMC   4021456 . PMID   23364694.
  11. ↑ Tang, Yi-Quan; Lee, Sol Ah; Rahman, Mizanur; Vanapalli, Siva A.; Lu, Hang; Schafer, William R. (2020-07-08). "Ankyrin Is An Intracellular Tether for TMC Mechanotransduction Channels". Neuron. 107 (1): 112–125.e10. doi:10.1016/j.neuron.2020.03.026. ISSN   0896-6273. PMC   7343241 . PMID   32325031.
  12. ↑ Waggoner LE, Zhou GT, Schafer RW, Schafer WR (July 1998). "Control of alternative behavioral states by serotonin in Caenorhabditis elegans". Neuron. 21 (1): 203–14. doi: 10.1016/S0896-6273(00)80527-9 . PMID   9697864. S2CID   15043008.
  13. ↑ Geng W, Cosman P, Berry CC, Feng Z, Schafer WR (October 2004). "Automatic tracking, feature extraction and classification of C elegans phenotypes". IEEE Transactions on Biomedical Engineering. 51 (10): 1811–20. CiteSeerX   10.1.1.523.8395 . doi:10.1109/TBME.2004.831532. PMID   15490828. S2CID   8977741.
  14. ↑ Yemini E, Jucikas T, Grundy LJ, Brown AE, Schafer WR (September 2013). "A database of Caenorhabditis elegans behavioral phenotypes". Nature Methods. 10 (9): 877–9. doi:10.1038/nmeth.2560. PMC   3962822 . PMID   23852451.
  15. ↑ Brown AE, Yemini EI, Grundy LJ, Jucikas T, Schafer WR (January 2013). "A dictionary of behavioral motifs reveals clusters of genes affecting Caenorhabditis elegans locomotion". Proceedings of the National Academy of Sciences of the United States of America. 110 (2): 791–6. Bibcode:2013PNAS..110..791B. doi: 10.1073/pnas.1211447110 . PMC   3545781 . PMID   23267063.
  16. ↑ Bentley B, Branicky R, Barnes CL, Chew YL, Yemini E, Bullmore ET, Vértes PE, Schafer WR (December 2016). "The Multilayer Connectome of Caenorhabditis elegans". PLOS Computational Biology. 12 (12): e1005283. arXiv: 1608.08793 . Bibcode:2016PLSCB..12E5283B. doi: 10.1371/journal.pcbi.1005283 . PMC   5215746 . PMID   27984591.
  17. ↑ Ripoll-Sánchez, Lidia; Watteyne, Jan; Sun, HaoSheng; Fernandez, Robert; Taylor, Seth R.; Weinreb, Alexis; Bentley, Barry L.; Hammarlund, Marc; Miller, David M.; Hobert, Oliver; Beets, Isabel; Vértes, Petra E.; Schafer, William R. (2023-11-15). "The neuropeptidergic connectome of C. elegans". Neuron. 111 (22): 3570–3589.e5. doi:10.1016/j.neuron.2023.09.043. ISSN   0896-6273. PMC   7615469 . PMID   37935195.
  18. ↑ Yan G, Vértes PE, Towlson EK, Chew YL, Walker DS, Schafer WR, Barabási AL (October 2017). "Network control principles predict neuron function in the Caenorhabditis elegans connectome". Nature. 550 (7677): 519–523. Bibcode:2017Natur.550..519Y. doi:10.1038/nature24056. PMC   5710776 . PMID   29045391.

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