hana el-samad, phd grace boyer jr. endowed chair biochemistry and biophysics
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Design Principles for Cellular Organization. Hana El-Samad, PhD Grace Boyer Jr. Endowed Chair Biochemistry and Biophysics California Institute for Quantitative Biosciences (QB3) University of California, San Francisco. Some shared principles between the computing and biological sciences. - PowerPoint PPT PresentationTRANSCRIPT
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Hana El-Samad, PhDGrace Boyer Jr. Endowed Chair
Biochemistry and BiophysicsCalifornia Institute for Quantitative Biosciences (QB3)University of California, San Francisco
Design Principles for Cellular Organization
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Some shared principlesbetween the computing and biological sciences
• Large number of components and complex interactions.
• Extensive use of feedback.
• Versatile modes of control (centralized and distributed).
• “design” for performance and associated tradeoffs.
• Modularity (?).
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Some Important future research directions
• Deciphering and defining differences between biology and engineering systems.
• Eliminating “the fold-change” mentality (embrace the subtle, dynamic phenotype).
• Understanding stochasticity (beyond simplistic conclusions).
Conceptual:
Methodological
• Dealing with/modeling uncertainty. • Identifiability. • Measuring/exploiting information about dynamics.• Bridging scales in time and space.
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Difference: Crosstalk and Insulation
Deep sub-micron effectsProximity of transistors and leakage of
electrons
Many shared/reused components in natural circuits
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Example biological networks that monitor and respond to environment
How do interconnected networks achieve appropriate output to specific inputs?
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Annihilation of signaling(degradation)
?
?
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One solution: Following the signal
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GeneAutomaton: Automation Infrastructure for High-throughput Single Cell Dynamic Measurements
Ignacio Zuleta,, Hao Li
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GeneAutomaton is up and running!
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Embrace the subtle, dynamic phenotype
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The Unfolded Protein Response (UPR)
An intracellular signaling pathway connecting the ER and the nucleus
The cellular response to protein folding stress in the ER
A model for the regulation of organelle abundance
Activated in cancer, protein folding and neurodegenerative disease
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The UPR in yeast: Ire1 Signaling Pathway in lead role
1. Unfolded proteins trigger Ire1 oligomerization
2. Oligomerization activates Ire1’s endo-ribonuclease domain in the cytoplasm
3. Active RNase cleaves non-conventional intron from its substrate mRNA, HAC1/XBP1
4. Exons ligated by tRNA ligase, and mature transcript translated to produce a transcriptional activator of UPR target genes
5. Feedback that fixes problem: homeostasis
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Doses of DTT that won’t stunt population growth
What regulatory components of UPR modulate dose-to-duration behavior?
Looking at dynamics, and embracing the subtle, a 15-year old enigma is resolved
Pincus et al, PloS Biology, in press
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Some mentoring and resoures for the next generation of scientists
• The obvious: more quantitative training for life-scientists.
• Quantitative vs. qualitative understanding (parts list versus system understanding).
• Lower energy barrier for physical-scientists to transition.– Mathematical vs. biological question– A problem of equity: scarce financial resources (fellowships) for re-
training.