Jagesh V. Shah Ph.D.

Associate Professor of Systems Biology
Phone Number:
617-525-5912
Fax:
617-525-5960

address

Harvard Institutes of Medicine
4 Blackfan Circle
Room 570
Boston, MA 02115

Research Interests

Jagesh's lab is interested in the principles of how cells make measurements. Much like modern day engineered devices, cells make measurements with exquisite precision in an environment of poor signal to noise. To understanding these biological principles his lab is looking at a variety of systems focused on intracellular and extracellular measurement systems.

1) Spindle assembly checkpoint:  Watching cells go through mitosis is a mind-boggling event.  So many chemical and physical events must be carefully orchestrated to properly segregate the genome.  We are interested in the events leading up to the segregation of the chromosomes.  How does the cell detect that all the chromosomes have become attached (to the mitotic spindle) before activating the segregation machinery?  The signaling device on the chromosome that reports chromosome attachment is the kinetochore.  This structure is approximately 100 nm x 100 nm x 50 nm or 1 attoliter (10e-18), but informs a cellular cytoplasm that is seven orders of magnitude larger in volume.  How does the kinetochore inform the entire cytoplasm of its attachment state to restrict or permit the irreversible event of anaphase?  We are using microscopic imaging, fluorescence correlation spectroscopy and computational modeling to dissect how the cytoplasm measures kinetochore attachment state and makes the decision to execute anaphase.

2) Neutrophil Chemotaxis:  The classic cellular measurement problem — How do cells orient themselves in a chemical gradient ?  Eukaryotic chemotaxis is distinguished from bacterial chemotaxis by the size of the nucleates cell which can provide spatial cues unlike the smaller bacterium.  Like mitosis, watching cells orient themselves in the direction of a gradient and rapidly respond when that gradient moves – like when a cell chases a bacterium (Youtube: neutrophil chasing bacteria) – is a well-orchestrated process.  We are using microfluidics to generate quantitative environments, like an obstacle course for chemotaxing cells.  Through microscopy and modeling, we are beginning to understand how cells can make measurements of their environment and compute the direction of travel.

3) Primary Cilia:  Almost every one of your cells has a single solitary microtubule-based cilium.  It does not move, but without it many of the classical signaling pathways don't function correctly.  The cilium is a small organelle, it's volume is five orders of magnitude smaller than the cytoplasm, but yet it plays a critical role in extracellular measurement and signal tranduction. We are studying the role this organelle plays in determining left-right asymmetry in vertebrates and polycystic kidney disease in humans.  How do defects in this organelle lead to defective measurement and disease?  Using our favorite tool – microscopy –we are monitoring the signaling events in the cilium and building models for understand signal amplification and integration through this unique organelle.

Bio

Jagesh is an electrical engineer by training.  Like many physical scientists, he's been sucked into biology to understand natural design principles of complex cellular behaviors.  He received his BS in Computer Engineering at the University of Waterloo, in Canada and his MS in Electrical Engineering and Computer Science at MIT.  His PhD was in Medical Engineering (MIT) which included a two year stint in medical school (HMS) - but he's not that kind of doctor. His thesis work encompassed the study of interactions between cytoskeletal systems in the cell. Jagesh then moved to San Diego and carried out a post-doctoral fellowship jointly with Don Cleveland and Larry Goldstein where he discovered the fascinating  biology of cell division and cilia.

Jagesh likes to have a lot of diverse people in the lab.  Physicists, engineers and biologists - all have very different takes on science and life in general.  It make the lab a great learning space.  Jagesh loves to read --- mostly sci-fi and fantasy, but recently has taken to understanding the chemistry of cooking and molecular gastronomy and trying to understand what the heck the Higgs Boson actually is.  But he loves video entertainment too --- he can digest an entire season of Doctor Who or Luther in a single seating.  

He's married to a professor-scientist and has two daughters.  These three women keep him pretty busy in the kitchen, in the garden and on the soccer field.  His passion for microscopy has leaked into the home and it's not uncommon to find the family checking out snowflakes, pond water or food with the home microscope.  He also runs the local Science Cafe, where he interviews local scientists and engineers to highlight their work and demystify the path of scientific discovery and innovation.  Science is for everyone.

Select Publications:

Courtis, A.M., Santos, S.A., Guan, Y., Hendricks, J.A., Ghosh, B., Szantai-Kis, D.M., Reis, S.A., Shah, J.V. & Mazitschek, R..
(2014).
Monoalkoxy BODIPYs-A Fluorophore Class for Bioimaging.
Bioconjugate Chemistry.
25(6),
1043-51
PMID:
Alcaraz Silva, B., Stambaugh, J.R., Yokomori, K., Shah, J.V. & Berns, M.W..
(2014).
DNA Damage to a single chromosome end delays anaphase onset.
J Biol Chem.
pii: jbc.M113.535955
In Press
PMID:
Rodriguez-Bravo, V., Maciejowski, J., Corona, J., Buch, H.K., Collin, P., Kanemaki, M.T., Shah, J.V. & Jallepalli, P.V..
(2014).
Nuclear pores protect genome integrity by assembling a premitotic and Mad1-dependent anaphase inhibitor.
Cell.
156(5),
1017-31
PMID: PMCID:
Manning, D.K., Sergeev, M., van Heesbeen, R.G., Wong, M.D., Oh, J.H., Liu, Y., Henkelman, R.M., Drummond, I., Shah, J.V. & Beier, D.R..
(2014).
Loss of the ciliary kinase Nek8 causes left-right asymmetry defects.
J Am Soc Nephorl.
24(1),
100-12
In Press
PMID:
Hartlerode, A.J., Guan, Y., Rajendran, A., Ura, K., Schotta, G., Xie, A., Shah, J.V. & Scully, R..
(2012).
Impact of histone H4 lysine 20 methylation on 53BP1 responses to chromosomal double strand breaks.
PLoS One..
7(11),
e49211
In Press
PMID:
Kops, G.J. & Shah, J.V..
(2012).
Connecting up and clearing out: how kinetochore attachment silences the spindle assembly checkpoint.
Chromosoma.
121(5),
509-25
In Press
PMID:
Czarnecki, P.G. & Shah, J.V..
(2012).
The ciliary transition zone: from morphology and molecules to medicine.
Trends in Cell Biol.
22(4),
201-10
PMID:
Saunders, T.E, Pan, K.Z., Angel, A., Guan, Y., Shah, J.V., Howard, M. & Chang, F..
(2012).
. Noise reduction in the intracellular pom1p gradient by a dynamic clustering mechanism.
Dev Cell.
22(3),
558-72
PMID:
Hagan, R.S., Manak, M.S., Buch, H.K., Meier, M.G., Meraldi, P., Shah, J.V. & Sorger, P.K..
(2011).
p31(comet) acts to ensure timely spindle checkpoint silencing subsequent to kinetochore attachment..
Mol Bio Cell.
22(22),
4236-46
PMID:
Aboualaiwi, W.A., Ratnam, S., Booth, R.L., Shah, J.V. & Nauli, S.M. .
(2011).
Endothelial cells from humans and mice with polycystic kidney disease are characterized by polyploidy and chromosome segregation defects through survivin down-regulation.
Human Molecular Genetics.
20(2),
354-67
PMID: PMCID:
Hardwick, K. & Shah, J.V..
(2010).
Spindle checkpoint silencing: ensuring rapid and concerted anaphase onset.
F1000 Biology Reports.
2,
55
PMID:
Kwiatkowski, N., Jelluma, N., Filippakopoulos, P., Soundararajan, M., Manak, M.S., Kwon, M., Choi, H.G., Sim, T., Deveraux, Q.L., Rottmann, S., Pellman, D., Shah, J.V., Kops, G.J.P.L., Knapp, S. & Gray, N.S. .
(2010).
Small Molecule Kinase Inhibitors Provide Novel Insight into Mps1 Cell Cycle Function.
Nature Chemical Biology.
6(5),
359-68
PMID:
(2010).
Cells in tight spaces: the role of cell shape in cell function.
Journal of Cell Biology.
191(2),
233-6
PMID:
Zhang, J., Wu, M., Wang, S., Shah, J.V., Wilson, P.D. & Zhou, J..
(2010).
Polycystic kidney disease protein fibrocystin localizes to the mitotic spindle and regulates spindle bipolarity.
Human Molecular Genetics.
10(17),
3306-19
PMID: PMCID:
Baker, N.M., Zeitlin, S.G., Shi, L.Z., Shah, J.V. & Berns, M.W..
(2010).
Chromosome tips damaged in anaphase inhibit cytokinesis.
PLoS ONE.
5(8),
e12398
PMID: PMCID:
Albrecht, D.R., Underhill, G.H., Resnikoff, J., Mendelson, A., Bhatia, S.N. & Shah, J.V..
(2010).
Microfluidics-integrated time-lapse imaging for analysis of cellular dynamics.
Integrative Biology.
2(5-6),
278-87
PMID:
Albrecht, D.R., Underhill, G.H., Resnikoff, J., Mendelson, A., Bhatia, S.N. & Shah, J.V..
(2010).
Microfluidics-integrated time-lapse imaging for analysis of cellular dynamics.
Integrative Biology.
2(5-6),
278-87
PMID: PMCID:
Kops, G.J., van der Voet, M., Manak, M.S., van Osch, M.H., Naini, S.M., Brear, A., McLeod, I.X., Hentschel, D.M., Yates, J.R. 3rd, van den Heuvel, S. & Shah, J.V..
(2010).
PC16 is a conserved subunit of the anaphase-promoting complex/cyclosome.
J Cell Sci.
123(Pt 10),
1623-33
PMID: PMCID:
Kops, G.J.P.L., van der Voet, M., Manak, M.S., van Osch, M.H.J., Naini, S.M., Brear, A., McLeod, I.X., Hentschel, D.M., Yates III, J.R., van den Heuvel, S. & Shah, J.V..
(2010).
APC16 is a conserved subunit of the anaphase-promoting complex/cyclosome.
Journal of Cell Science.
123(pt 10),
1623-33
PMID: PMCID:
Yang, L., Tatiana, Y., Besschetnova, T.Y., Brooks, C.R., Shah, J.V. & Bonventre, J.V. .
(2010).
Epithelial Cell Cycle Arrest in G2/M Mediates Kidney Fibrosis after Injury.
Nature Medicine.
16(5),
535-43
PMID:
Yang, L., Besschetnova, T.Y., Brooks, C.R., Shah, J.V. & Bonventre, J.V..
(2010).
Epithelial cell cycle arrest in G2/M mediates kidney fibrosis after injury..
Nat Med.
16(5),
535-43
PMID: PMCID:
Besschetnova, T.Y., Kolpakova-Hart, E., Guan, Y., Zhou, J., Olsen, B.R. & Shah, J.V..
(2010).
Identification of signaling pathways regulating primary cilium length and flow-mediated adaptation.
Curr Biol..
20(2),
182-7
PMID: PMCID:
Besschetnova, T.Y. , Kolpakova-Hart, E., Guan, Y., Zhou, J., Olsen, B.R. & Shah, J.V..
(2010).
dentification of signaling pathways regulating primary cilium length and flow-mediated adaptation..
Current Biology.
20(2),
182-7
PMID: PMCID:
Besschetnova, T.Y. , Kolpakova-Hart, E., Zhou, J., Olsen, B.R. & Shah, J.V..
(2010).
Adaptation of cilium-mediated mechanotransductive signaling by regulation of cilium length.
Current Biology.
20,
182-187
PMID:
Ciliberto, A. & Shah, J.V..
(2009).
A quantitative systems view of the spindle assembly checkpoint.
EMBO Journal.
28,
2162-2173
PMID:
Besschetnova, T.Y. , Roy, B. & Shah, J.V..
(2009).
Imaging intraflagellar transport in mammalian primary cilia.
Methods in Cell Biology.
93,
331-46
PMID:
Kong, T., Xu, D., Yu, W., Takakura, A., Boucher, I., Tran, M., Kreidberg, J., Shah, J.V., Zhou, J. & Denker, B.M. .
(2009).
G alpha 12 inhibits alpha2 beta1 integrin-mediated Madin-Darby canine kidney cell attachment and migration on collagen-I and blocks tubulogenesis.
Molecular Cell Biology.
20(21),
4596-610
PMID: PMCID:
Besschetnova, T.Y. , Roy, B. & Shah, J.V..
(2009).
Imaging intraflagellar transport in mammalian primary cilia.
Methods in Cell Biology.
93,
331-46
PMID:
Tran, P.V., Haycraft, C.J., Besschetnova, T.Y., Turbe-Doan, A., Stottmann, R.W., Herron, B.J., Chesebro, A.L., Qiu, H., Scherz, P.J., Shah, J.V., Yoder, B.K. & Beier, D.R..
(2008).
THM1 negatively modulates mouse sonic hedgehog signal transduction and affects retrograde intraflagellar transport in cilia. .
Nature Genetics.
40(4),
403-10
PMID:
Black, B.E., Jansen, L.E., Maddox, P.S., Foltz, D.R., Desai, A.B., Shah, J.V. & Cleveland, D.W..
(2007).
Centromere identity maintained by nucleosomes assembled with histone H3 containing the CENP-A targeting domain.
Molecular Cell.
25(2),
309-22
PMID:
Botvinick, E.L. & Shah, J.V..
(2007).
Laser-based measurements in cell biology.
Methods in Cell Biology.
82,
81-109
PMID:
Wang, Z., Shah, J.V., Berns, M.W. & Cleveland, D.W..
(2006).
In vivo quantitative studies of dynamic intracellular processes using fluorescence correlation spectroscopy.
Biophysical Journal.
91(1),
343-51
PMID: PMCID:
Botvinick, E.L., Venugopalan, V., Shah, J.V., Liaw, L.H. & Berns, M.W..
(2004).
Controlled ablation of microtubules using a picosecond laser.
Biophysical Journal.
87(6),
4203-12
PMID: PMCID:
Shah, J.V., Botvinick, E., Bonday, Z., Furnari, F., Berns, M.W. & Cleveland, D.W..
(2004).
Dynamics of centromere and kinetochore proteins; implications for checkpoint signaling and silencing.
Current Biology.
14(11),
942-52
PMID: