1. Biochemical Reactions computationinputsoutputs Molecular Triggers Molecular Products Synthesizing Biological Computation Protein-Protein Chemistry at the Cellular Level

2. Design a system that computes output quantities as functions of input quantities. Synthesizing Biological Computation Biochemical Reactions givenobtain Quantities of Different Types

3. Design a system that computes output quantities as functions of input quantities. Synthesizing Biological Computation Biochemical Reactions independent for us to design specified XY Z

4. Logic Gates: how digital values are computed. Biochemical Reactions: how types of molecules combine. “XOR” gate 0 0 1 1 0 1 0 1 0 1 1 0 Basic Mechanisms + + 2a2a b c

5. Biochemical Reactions 9 6 7 cell speciescount + 8 5 9 Discrete chemical kinetics; spatial homogeneity.

6. Biochemical Reactions + + + slow medium fast Relative rates or (reaction propensities): Discrete chemical kinetics; spatial homogeneity.

7. Design a system that computes output quantities as functions of input quantities. Synthesizing Biological Computation Biochemical Reactions givenobtain Quantities of Different Types M N independent for us to design specified

8. Example: Multiplication Use working types a, y′. slow ax med. y y′y′ fast a v. z y′y′ ya  a obtain of z YX  Produce of type z. YX  Start with of type x. X Start with of type y. Y Iterate!

9. Start with no amount of types b and c. Example: Exponentiation Start with M of type m. Produce of type n. M 2 Use working types a, b, c. Start with any non-zero amount of types a and n. nana   fast 2 med a obtain 1 of n bm slow cbn b  2 v.fast b nc med. obtain of n M 2

10. Functional Dependencies Logarithm Linear Raising-to-a-Power Exponentiation

11. The probability that a given reaction is the next to fire is proportional to: Its rate. The quantities of its reactants. See D. Gillespie, “Stochastic Chemical Kinetics”, 2006. Stochastic Kinetics + + + k1k1 k2k2 k3k3

12. 12 Modular Synthesis Deterministic Module... Stochastic Module...... initializing, reinforcing, stabilizing, purifying, and working reactions linear, exponentiation, logarithm, raising-to-a-power, etc.

13. 13 Modular Synthesis Stochastic Module Deterministic Module...... Compose modules to achieved desired probabilistic response. Composition requires “regulatory gluing”.......

14. Structure computation to obtain initial choice probabilistically. Then amplify this choice and inhibit other choices. Method is: Precise. Robust. Programmable. Strategy: With “locking”, produces designs that are independent of rates. Modular Synthesis

15. CAD Tool Library of biochemical models. Designated input and output types. Specific quantities (or ranges) of input types. Target functional dependencies. Target probability distribution. Brian’s Automated Modular Biochemical Instantiator (BAMBI) Given: Outputs: Reactions/parameters implementing specification. Detailed measures of accuracy and robustness. Targets can be nearly any analytic function or data set.

16. Computational Infrastructure Implementing a “front-end” database of biochemical models in Structured Query Language (SQL) from online repositories: BioBricks, SBML.org, … Implementing “back-end” number crunching algorithms for analysis and synthesis on a farm of high-performance processors. IBM System Z Mainframe Farm of Cell B.E. processors (from Sony Playstations 3’s)