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

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 (?).

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.

Difference: Crosstalk and Insulation

Deep sub-micron effectsProximity of transistors and leakage of

electrons

Many shared/reused components in natural circuits

Example biological networks that monitor and respond to environment

How do interconnected networks achieve appropriate output to specific inputs?

Annihilation of signaling(degradation)

?

?

One solution: Following the signal

GeneAutomaton: Automation Infrastructure for High-throughput Single Cell Dynamic Measurements

Ignacio Zuleta,, Hao Li

GeneAutomaton is up and running!

Embrace the subtle, dynamic phenotype

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

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

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

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.