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PROGRAMMING ANALOG DEVICES WITH JAUNT AND ARCO 2 Programmable - - PowerPoint PPT Presentation

SARA ACHOUR / MIT CSAIL MARTIN RINARD / MIT CSAIL PROGRAMMING ANALOG DEVICES WITH JAUNT AND ARCO 2 Programmable Dynamical Systems Analog Devices x + c 1 x + c 2 x = 0 528 IEEE TRANSACTIONS ON


slide-1
SLIDE 1

PROGRAMMING ANALOG DEVICES WITH JAUNT AND ARCO

SARA ACHOUR / MIT CSAIL MARTIN RINARD / MIT CSAIL

slide-2
SLIDE 2

INTRODUCTION 2

· ES = kf ⋅ E ⋅ S − kr ⋅ ES x′′+ ax′+ x + ax2 = c3 L ⋅ I′′+ R ⋅ I′+ C−1 ⋅ I = 0 x′′+ c1x′+ c2x′′ = 0

528 IEEE TRANSACTIONS ON BIOMEDICAL CIRCUITS AND SYSTEMS, VOL. 9, NO. 4, AUGUST 2015
  • Fig. 1. Poisson chemical reaction flux and Poisson electron flow in
sub-threshold transistors obey the same Boltzmann exponential laws of thermodynamics, and are therefore mathematically similar [13]. Electron copy number is analogous to molecular copy number and temperature represents itself. single cell on a few chips and speedup multi-cell simulations
  • n multi-chip electronic boards [13]. Therefore, we were moti-
vated to create a few fundamental molecular circuits that could be composed and scaled to model large biochemical reaction networks in the future. This paper describes these fundamental building-block cytomorphic circuits. The paper focuses on establishing quantitative agreement of the cytomorphic chip measurements with prior biological measurements and models. The building-block circuits may be classified into seven im- portant categories: 1) Basic BiCMOS current-mode analog circuits exploit the log-domain cytomorphic mapping to capture the exact dy- namics of fundamental mass-action molecular kinetics such as association, dissociation, and degradation. These fundamental circuits are general enough to capture subtle effects such as loading, fan-out, feedback, and substrate de- pletion through the use of a few explicit connections and Kirchhoff’s current law. A wide dynamic range of opera- tion and low power consumption are achieved through the use of bipolar and subthreshold MOS transistors that func- tion at low current levels. 2) The ability to model cooperative binding is enabled by tun- able Hill-function building-block circuits. 3) An “ITD” block built by a composition of above cur- rent-mode circuits enables mapping of the exact differen- tial equations of inducer-transcription-factor binding and transcription-factor-DNA binding including for- ward and reverse reactions, degradation, protection from degradation of transcription factors bound to DNA, and the change in DNA binding affinity of transcription factors when bound by an inducer. 4) An “analogic” current-mode circuit determines the tran- scription rate of genes based on the probability of mul- tiple transcription-factor DNA binding sites being occu- pied or unoccupied in a combinatorial fashion with the rel- ative mRNA production rate of each such combinatorial state programmable by the user. This strategy enables us to implement any arbitrary “analogic promoter function” that is capable of complex saturating digital logic or prob- abilistic analog behavior depending on the molecular con- centration. 5) A current-mode low pass filter (LPF) circuit enables the gain and dynamics of mRNA and protein production and degradation to be represented.
  • Fig. 2. Die micrograph of the
cytomorphic chip fabricated in an AMS BiCMOS process. The left inset is a layout screen capture
  • f one gene block (2x magnification).
6) A stochastics circuit intentionally amplifies analog Poisson noise in transistors to represent biological fluc- tuations in mRNA and protein concentrations at very low copy numbers and at relatively high noise levels. The Poisson nature of biochemical reaction fluxes au- tomatically maps biological noise to electronic noise at high copy numbers and relatively low noise levels [13]. Thus, these circuits are most useful for reliably modeling highly stochastic and relatively low signal-to-noise-ratios in biological cells. 7) ADCs and DACs convert between analog currents and digital bits to enable our chips to communicate with each
  • ther via digital input/output (I/O), and with off-chip dig-
ital processors and computers. Off-chip digital processors synergistically interact with our chips to carry out various functions: reading digital data from the chips; decoding the data; performing high-speed digital signal processing as necessary (e.g., scaling, diffusion, time delay, and error correction); encoding the data to create or modify molecular data packets via address and data strings; storing the programmable address connectivity amongst gene and protein circuits; and communicating data to other chips
  • r to a computer. For simplicity, the data in this paper were
collected with a data-acquisition board (NI PXI-6541) that interacted with our chip and with MATLAB on a computer. A high-performance FPGA (e.g., from the Xilinx Spartan family) could perform all of these functions in the future as well. Shift registers, SRAM blocks, and switches on the chip enable programmability of parameters (e.g., reaction rates, dissocia- tion constants, Hill coefficients, and time constants) as well as connectivity. The organization of this paper is as follows: Section II de- scribes the core building-block circuits of the chip along with chip measurement data. Fig. 2 shows a die micrograph of the chip that reveals the various building blocks. Section III dis- cusses design considerations that are important in BiCMOS cy- tomorphic chip design. Section IV discusses how cytomorphic 528 IEEE TRANSACTIONS ON BIOMEDICAL CIRCUITS AND SYSTEMS, VOL. 9, NO. 4, AUGUST 2015
  • Fig. 1. Poisson chemical reaction flux and Poisson electron flow in
sub-threshold transistors obey the same Boltzmann exponential laws of thermodynamics, and are therefore mathematically similar [13]. Electron copy number is analogous to molecular copy number and temperature represents itself. single cell on a few chips and speedup multi-cell simulations
  • n multi-chip electronic boards [13]. Therefore, we were moti-
vated to create a few fundamental molecular circuits that could be composed and scaled to model large biochemical reaction networks in the future. This paper describes these fundamental building-block cytomorphic circuits. The paper focuses on establishing quantitative agreement of the cytomorphic chip measurements with prior biological measurements and models. The building-block circuits may be classified into seven im- portant categories: 1) Basic BiCMOS current-mode analog circuits exploit the log-domain cytomorphic mapping to capture the exact dy- namics of fundamental mass-action molecular kinetics such as association, dissociation, and degradation. These fundamental circuits are general enough to capture subtle effects such as loading, fan-out, feedback, and substrate de- pletion through the use of a few explicit connections and Kirchhoff’s current law. A wide dynamic range of opera- tion and low power consumption are achieved through the use of bipolar and subthreshold MOS transistors that func- tion at low current levels. 2) The ability to model cooperative binding is enabled by tun- able Hill-function building-block circuits. 3) An “ITD” block built by a composition of above cur- rent-mode circuits enables mapping of the exact differen- tial equations of inducer-transcription-factor binding and transcription-factor-DNA binding including for- ward and reverse reactions, degradation, protection from degradation of transcription factors bound to DNA, and the change in DNA binding affinity of transcription factors when bound by an inducer. 4) An “analogic” current-mode circuit determines the tran- scription rate of genes based on the probability of mul- tiple transcription-factor DNA binding sites being occu- pied or unoccupied in a combinatorial fashion with the rel- ative mRNA production rate of each such combinatorial state programmable by the user. This strategy enables us to implement any arbitrary “analogic promoter function” that is capable of complex saturating digital logic or prob- abilistic analog behavior depending on the molecular con- centration. 5) A current-mode low pass filter (LPF) circuit enables the gain and dynamics of mRNA and protein production and degradation to be represented.
  • Fig. 2. Die micrograph of the
cytomorphic chip fabricated in an AMS BiCMOS process. The left inset is a layout screen capture
  • f one gene block (2x magnification).
6) A stochastics circuit intentionally amplifies analog Poisson noise in transistors to represent biological fluc- tuations in mRNA and protein concentrations at very low copy numbers and at relatively high noise levels. The Poisson nature of biochemical reaction fluxes au- tomatically maps biological noise to electronic noise at high copy numbers and relatively low noise levels [13]. Thus, these circuits are most useful for reliably modeling highly stochastic and relatively low signal-to-noise-ratios in biological cells. 7) ADCs and DACs convert between analog currents and digital bits to enable our chips to communicate with each
  • ther via digital input/output (I/O), and with off-chip dig-
ital processors and computers. Off-chip digital processors synergistically interact with our chips to carry out various functions: reading digital data from the chips; decoding the data; performing high-speed digital signal processing as necessary (e.g., scaling, diffusion, time delay, and error correction); encoding the data to create or modify molecular data packets via address and data strings; storing the programmable address connectivity amongst gene and protein circuits; and communicating data to other chips
  • r to a computer. For simplicity, the data in this paper were
collected with a data-acquisition board (NI PXI-6541) that interacted with our chip and with MATLAB on a computer. A high-performance FPGA (e.g., from the Xilinx Spartan family) could perform all of these functions in the future as well. Shift registers, SRAM blocks, and switches on the chip enable programmability of parameters (e.g., reaction rates, dissocia- tion constants, Hill coefficients, and time constants) as well as connectivity. The organization of this paper is as follows: Section II de- scribes the core building-block circuits of the chip along with chip measurement data. Fig. 2 shows a die micrograph of the chip that reveals the various building blocks. Section III dis- cusses design considerations that are important in BiCMOS cy- tomorphic chip design. Section IV discusses how cytomorphic 528 IEEE TRANSACTIONS ON BIOMEDICAL CIRCUITS AND SYSTEMS, VOL. 9, NO. 4, AUGUST 2015
  • Fig. 1. Poisson chemical reaction flux and Poisson electron flow in
sub-threshold transistors obey the same Boltzmann exponential laws of thermodynamics, and are therefore mathematically similar [13]. Electron copy number is analogous to molecular copy number and temperature represents itself. single cell on a few chips and speedup multi-cell simulations
  • n multi-chip electronic boards [13]. Therefore, we were moti-
vated to create a few fundamental molecular circuits that could be composed and scaled to model large biochemical reaction networks in the future. This paper describes these fundamental building-block cytomorphic circuits. The paper focuses on establishing quantitative agreement of the cytomorphic chip measurements with prior biological measurements and models. The building-block circuits may be classified into seven im- portant categories: 1) Basic BiCMOS current-mode analog circuits exploit the log-domain cytomorphic mapping to capture the exact dy- namics of fundamental mass-action molecular kinetics such as association, dissociation, and degradation. These fundamental circuits are general enough to capture subtle effects such as loading, fan-out, feedback, and substrate de- pletion through the use of a few explicit connections and Kirchhoff’s current law. A wide dynamic range of opera- tion and low power consumption are achieved through the use of bipolar and subthreshold MOS transistors that func- tion at low current levels. 2) The ability to model cooperative binding is enabled by tun- able Hill-function building-block circuits. 3) An “ITD” block built by a composition of above cur- rent-mode circuits enables mapping of the exact differen- tial equations of inducer-transcription-factor binding and transcription-factor-DNA binding including for- ward and reverse reactions, degradation, protection from degradation of transcription factors bound to DNA, and the change in DNA binding affinity of transcription factors when bound by an inducer. 4) An “analogic” current-mode circuit determines the tran- scription rate of genes based on the probability of mul- tiple transcription-factor DNA binding sites being occu- pied or unoccupied in a combinatorial fashion with the rel- ative mRNA production rate of each such combinatorial state programmable by the user. This strategy enables us to implement any arbitrary “analogic promoter function” that is capable of complex saturating digital logic or prob- abilistic analog behavior depending on the molecular con- centration. 5) A current-mode low pass filter (LPF) circuit enables the gain and dynamics of mRNA and protein production and degradation to be represented.
  • Fig. 2. Die micrograph of the
cytomorphic chip fabricated in an AMS BiCMOS process. The left inset is a layout screen capture
  • f one gene block (2x magnification).
6) A stochastics circuit intentionally amplifies analog Poisson noise in transistors to represent biological fluc- tuations in mRNA and protein concentrations at very low copy numbers and at relatively high noise levels. The Poisson nature of biochemical reaction fluxes au- tomatically maps biological noise to electronic noise at high copy numbers and relatively low noise levels [13]. Thus, these circuits are most useful for reliably modeling highly stochastic and relatively low signal-to-noise-ratios in biological cells. 7) ADCs and DACs convert between analog currents and digital bits to enable our chips to communicate with each
  • ther via digital input/output (I/O), and with off-chip dig-
ital processors and computers. Off-chip digital processors synergistically interact with our chips to carry out various functions: reading digital data from the chips; decoding the data; performing high-speed digital signal processing as necessary (e.g., scaling, diffusion, time delay, and error correction); encoding the data to create or modify molecular data packets via address and data strings; storing the programmable address connectivity amongst gene and protein circuits; and communicating data to other chips
  • r to a computer. For simplicity, the data in this paper were
collected with a data-acquisition board (NI PXI-6541) that interacted with our chip and with MATLAB on a computer. A high-performance FPGA (e.g., from the Xilinx Spartan family) could perform all of these functions in the future as well. Shift registers, SRAM blocks, and switches on the chip enable programmability of parameters (e.g., reaction rates, dissocia- tion constants, Hill coefficients, and time constants) as well as connectivity. The organization of this paper is as follows: Section II de- scribes the core building-block circuits of the chip along with chip measurement data. Fig. 2 shows a die micrograph of the chip that reveals the various building blocks. Section III dis- cusses design considerations that are important in BiCMOS cy- tomorphic chip design. Section IV discusses how cytomorphic 528 IEEE TRANSACTIONS ON BIOMEDICAL CIRCUITS AND SYSTEMS, VOL. 9, NO. 4, AUGUST 2015
  • Fig. 1. Poisson chemical reaction flux and Poisson electron flow in
sub-threshold transistors obey the same Boltzmann exponential laws of thermodynamics, and are therefore mathematically similar [13]. Electron copy number is analogous to molecular copy number and temperature represents itself. single cell on a few chips and speedup multi-cell simulations
  • n multi-chip electronic boards [13]. Therefore, we were moti-
vated to create a few fundamental molecular circuits that could be composed and scaled to model large biochemical reaction networks in the future. This paper describes these fundamental building-block cytomorphic circuits. The paper focuses on establishing quantitative agreement of the cytomorphic chip measurements with prior biological measurements and models. The building-block circuits may be classified into seven im- portant categories: 1) Basic BiCMOS current-mode analog circuits exploit the log-domain cytomorphic mapping to capture the exact dy- namics of fundamental mass-action molecular kinetics such as association, dissociation, and degradation. These fundamental circuits are general enough to capture subtle effects such as loading, fan-out, feedback, and substrate de- pletion through the use of a few explicit connections and Kirchhoff’s current law. A wide dynamic range of opera- tion and low power consumption are achieved through the use of bipolar and subthreshold MOS transistors that func- tion at low current levels. 2) The ability to model cooperative binding is enabled by tun- able Hill-function building-block circuits. 3) An “ITD” block built by a composition of above cur- rent-mode circuits enables mapping of the exact differen- tial equations of inducer-transcription-factor binding and transcription-factor-DNA binding including for- ward and reverse reactions, degradation, protection from degradation of transcription factors bound to DNA, and the change in DNA binding affinity of transcription factors when bound by an inducer. 4) An “analogic” current-mode circuit determines the tran- scription rate of genes based on the probability of mul- tiple transcription-factor DNA binding sites being occu- pied or unoccupied in a combinatorial fashion with the rel- ative mRNA production rate of each such combinatorial state programmable by the user. This strategy enables us to implement any arbitrary “analogic promoter function” that is capable of complex saturating digital logic or prob- abilistic analog behavior depending on the molecular con- centration. 5) A current-mode low pass filter (LPF) circuit enables the gain and dynamics of mRNA and protein production and degradation to be represented.
  • Fig. 2. Die micrograph of the
cytomorphic chip fabricated in an AMS BiCMOS process. The left inset is a layout screen capture
  • f one gene block (2x magnification).
6) A stochastics circuit intentionally amplifies analog Poisson noise in transistors to represent biological fluc- tuations in mRNA and protein concentrations at very low copy numbers and at relatively high noise levels. The Poisson nature of biochemical reaction fluxes au- tomatically maps biological noise to electronic noise at high copy numbers and relatively low noise levels [13]. Thus, these circuits are most useful for reliably modeling highly stochastic and relatively low signal-to-noise-ratios in biological cells. 7) ADCs and DACs convert between analog currents and digital bits to enable our chips to communicate with each
  • ther via digital input/output (I/O), and with off-chip dig-
ital processors and computers. Off-chip digital processors synergistically interact with our chips to carry out various functions: reading digital data from the chips; decoding the data; performing high-speed digital signal processing as necessary (e.g., scaling, diffusion, time delay, and error correction); encoding the data to create or modify molecular data packets via address and data strings; storing the programmable address connectivity amongst gene and protein circuits; and communicating data to other chips
  • r to a computer. For simplicity, the data in this paper were
collected with a data-acquisition board (NI PXI-6541) that interacted with our chip and with MATLAB on a computer. A high-performance FPGA (e.g., from the Xilinx Spartan family) could perform all of these functions in the future as well. Shift registers, SRAM blocks, and switches on the chip enable programmability of parameters (e.g., reaction rates, dissocia- tion constants, Hill coefficients, and time constants) as well as connectivity. The organization of this paper is as follows: Section II de- scribes the core building-block circuits of the chip along with chip measurement data. Fig. 2 shows a die micrograph of the chip that reveals the various building blocks. Section III dis- cusses design considerations that are important in BiCMOS cy- tomorphic chip design. Section IV discusses how cytomorphic 528 IEEE TRANSACTIONS ON BIOMEDICAL CIRCUITS AND SYSTEMS, VOL. 9, NO. 4, AUGUST 2015
  • Fig. 1. Poisson chemical reaction flux and Poisson electron flow in
sub-threshold transistors obey the same Boltzmann exponential laws of thermodynamics, and are therefore mathematically similar [13]. Electron copy number is analogous to molecular copy number and temperature represents itself. single cell on a few chips and speedup multi-cell simulations
  • n multi-chip electronic boards [13]. Therefore, we were moti-
vated to create a few fundamental molecular circuits that could be composed and scaled to model large biochemical reaction networks in the future. This paper describes these fundamental building-block cytomorphic circuits. The paper focuses on establishing quantitative agreement of the cytomorphic chip measurements with prior biological measurements and models. The building-block circuits may be classified into seven im- portant categories: 1) Basic BiCMOS current-mode analog circuits exploit the log-domain cytomorphic mapping to capture the exact dy- namics of fundamental mass-action molecular kinetics such as association, dissociation, and degradation. These fundamental circuits are general enough to capture subtle effects such as loading, fan-out, feedback, and substrate de- pletion through the use of a few explicit connections and Kirchhoff’s current law. A wide dynamic range of opera- tion and low power consumption are achieved through the use of bipolar and subthreshold MOS transistors that func- tion at low current levels. 2) The ability to model cooperative binding is enabled by tun- able Hill-function building-block circuits. 3) An “ITD” block built by a composition of above cur- rent-mode circuits enables mapping of the exact differen- tial equations of inducer-transcription-factor binding and transcription-factor-DNA binding including for- ward and reverse reactions, degradation, protection from degradation of transcription factors bound to DNA, and the change in DNA binding affinity of transcription factors when bound by an inducer. 4) An “analogic” current-mode circuit determines the tran- scription rate of genes based on the probability of mul- tiple transcription-factor DNA binding sites being occu- pied or unoccupied in a combinatorial fashion with the rel- ative mRNA production rate of each such combinatorial state programmable by the user. This strategy enables us to implement any arbitrary “analogic promoter function” that is capable of complex saturating digital logic or prob- abilistic analog behavior depending on the molecular con- centration. 5) A current-mode low pass filter (LPF) circuit enables the gain and dynamics of mRNA and protein production and degradation to be represented.
  • Fig. 2. Die micrograph of the
cytomorphic chip fabricated in an AMS BiCMOS process. The left inset is a layout screen capture
  • f one gene block (2x magnification).
6) A stochastics circuit intentionally amplifies analog Poisson noise in transistors to represent biological fluc- tuations in mRNA and protein concentrations at very low copy numbers and at relatively high noise levels. The Poisson nature of biochemical reaction fluxes au- tomatically maps biological noise to electronic noise at high copy numbers and relatively low noise levels [13]. Thus, these circuits are most useful for reliably modeling highly stochastic and relatively low signal-to-noise-ratios in biological cells. 7) ADCs and DACs convert between analog currents and digital bits to enable our chips to communicate with each
  • ther via digital input/output (I/O), and with off-chip dig-
ital processors and computers. Off-chip digital processors synergistically interact with our chips to carry out various functions: reading digital data from the chips; decoding the data; performing high-speed digital signal processing as necessary (e.g., scaling, diffusion, time delay, and error correction); encoding the data to create or modify molecular data packets via address and data strings; storing the programmable address connectivity amongst gene and protein circuits; and communicating data to other chips
  • r to a computer. For simplicity, the data in this paper were
collected with a data-acquisition board (NI PXI-6541) that interacted with our chip and with MATLAB on a computer. A high-performance FPGA (e.g., from the Xilinx Spartan family) could perform all of these functions in the future as well. Shift registers, SRAM blocks, and switches on the chip enable programmability of parameters (e.g., reaction rates, dissocia- tion constants, Hill coefficients, and time constants) as well as connectivity. The organization of this paper is as follows: Section II de- scribes the core building-block circuits of the chip along with chip measurement data. Fig. 2 shows a die micrograph of the chip that reveals the various building blocks. Section III dis- cusses design considerations that are important in BiCMOS cy- tomorphic chip design. Section IV discusses how cytomorphic

Dynamical Systems Programmable 
 Analog Devices

slide-3
SLIDE 3

INTRODUCTION

DYNAMICAL SYSTEMS MODEL THE PHYSICAL WORLD

3

· ES = kf ⋅ E ⋅ S − kr ⋅ ES x′′+ ax′+ x + ax2 = c3 L ⋅ I′′+ R ⋅ I′+ C−1 ⋅ I = 0 x′′+ c1x′+ c2x′′ = 0

slide-4
SLIDE 4

INTRODUCTION 4

· ES = kf ⋅ E ⋅ S − kr ⋅ ES x′′+ ax′+ x + ax2 = c3 L ⋅ I′′+ R ⋅ I′+ C−1 ⋅ I = 0 x′′+ c1x′+ c2x′′ = 0

DYNAMICAL SYSTEMS MODEL BIOLOGICAL PROCESSES

slide-5
SLIDE 5

INTRODUCTION

BIOLOGICAL DYNAMICAL SYSTEMS

5

· ES = kf ⋅ E ⋅ S − kr ⋅ ES E = E0 − ES S = S0 − ES

S E S E

state variables model physical quantities

slide-6
SLIDE 6

INTRODUCTION

BIOLOGICAL DYNAMICAL SYSTEMS

6

· ES = kf ⋅ E ⋅ S − kr ⋅ ES E = E0 − ES S = S0 − ES

differential equations specify continuous dynamics

  • f state variables over time
slide-7
SLIDE 7

INTRODUCTION

GOAL: SIMULATING BIOLOGICAL DYNAMICAL SYSTEMS

7

· ES = kf ⋅ E ⋅ S − kr ⋅ ES E = E0 − ES S = S0 − ES

given initial state of system: compute values of state variables over time

E0 = 6800 S0 = 4400 ES(0) = 0

slide-8
SLIDE 8

INTRODUCTION

GOAL: SIMULATING BIOLOGICAL DYNAMICAL SYSTEMS

8

· ES = kf ⋅ E ⋅ S − kr ⋅ ES E = E0 − ES S = S0 − ES

plot molecule counts/concentrations of compounds

  • ver time

E0 = 6800 S0 = 4400 ES(0) = 0

2 4 6 8 10 time (su) 2000 4000 6000 molecules

slide-9
SLIDE 9

INTRODUCTION 9

  • direct mapping
  • variables → current, voltage
  • dynamics → circuit physics
  • straightforward simulation
  • power up circuit
  • measure current, voltage over time
  • 1970-2010: Age of Digital Computing
  • Analog computes out of fashion

ANALOG COMPUTING CIRCA 1950

slide-10
SLIDE 10

INTRODUCTION 10

  • same computational model
  • modernized hardware
  • modern semiconductor

technologies

  • new capabilities
  • powerful, heavily optimized

building blocks

  • digital reprogrammability
  • exploit analog noise

PROGRAMMABLE ANALOG DEVICES

528 IEEE TRANSACTIONS ON BIOMEDICAL CIRCUITS AND SYSTEMS, VOL. 9, NO. 4, AUGUST 2015
  • Fig. 1. Poisson chemical reaction flux and Poisson electron flow in
sub-threshold transistors obey the same Boltzmann exponential laws of thermodynamics, and are therefore mathematically similar [13]. Electron copy number is analogous to molecular copy number and temperature represents itself. single cell on a few chips and speedup multi-cell simulations
  • n multi-chip electronic boards [13]. Therefore, we were moti-
vated to create a few fundamental molecular circuits that could be composed and scaled to model large biochemical reaction networks in the future. This paper describes these fundamental building-block cytomorphic circuits. The paper focuses on establishing quantitative agreement of the cytomorphic chip measurements with prior biological measurements and models. The building-block circuits may be classified into seven im- portant categories: 1) Basic BiCMOS current-mode analog circuits exploit the log-domain cytomorphic mapping to capture the exact dy- namics of fundamental mass-action molecular kinetics such as association, dissociation, and degradation. These fundamental circuits are general enough to capture subtle effects such as loading, fan-out, feedback, and substrate de- pletion through the use of a few explicit connections and Kirchhoff’s current law. A wide dynamic range of opera- tion and low power consumption are achieved through the use of bipolar and subthreshold MOS transistors that func- tion at low current levels. 2) The ability to model cooperative binding is enabled by tun- able Hill-function building-block circuits. 3) An “ITD” block built by a composition of above cur- rent-mode circuits enables mapping of the exact differen- tial equations of inducer-transcription-factor binding and transcription-factor-DNA binding including for- ward and reverse reactions, degradation, protection from degradation of transcription factors bound to DNA, and the change in DNA binding affinity of transcription factors when bound by an inducer. 4) An “analogic” current-mode circuit determines the tran- scription rate of genes based on the probability of mul- tiple transcription-factor DNA binding sites being occu- pied or unoccupied in a combinatorial fashion with the rel- ative mRNA production rate of each such combinatorial state programmable by the user. This strategy enables us to implement any arbitrary “analogic promoter function” that is capable of complex saturating digital logic or prob- abilistic analog behavior depending on the molecular con- centration. 5) A current-mode low pass filter (LPF) circuit enables the gain and dynamics of mRNA and protein production and degradation to be represented.
  • Fig. 2. Die micrograph of the
cytomorphic chip fabricated in an AMS BiCMOS process. The left inset is a layout screen capture
  • f one gene block (2x magnification).
6) A stochastics circuit intentionally amplifies analog Poisson noise in transistors to represent biological fluc- tuations in mRNA and protein concentrations at very low copy numbers and at relatively high noise levels. The Poisson nature of biochemical reaction fluxes au- tomatically maps biological noise to electronic noise at high copy numbers and relatively low noise levels [13]. Thus, these circuits are most useful for reliably modeling highly stochastic and relatively low signal-to-noise-ratios in biological cells. 7) ADCs and DACs convert between analog currents and digital bits to enable our chips to communicate with each
  • ther via digital input/output (I/O), and with off-chip dig-
ital processors and computers. Off-chip digital processors synergistically interact with our chips to carry out various functions: reading digital data from the chips; decoding the data; performing high-speed digital signal processing as necessary (e.g., scaling, diffusion, time delay, and error correction); encoding the data to create or modify molecular data packets via address and data strings; storing the programmable address connectivity amongst gene and protein circuits; and communicating data to other chips
  • r to a computer. For simplicity, the data in this paper were
collected with a data-acquisition board (NI PXI-6541) that interacted with our chip and with MATLAB on a computer. A high-performance FPGA (e.g., from the Xilinx Spartan family) could perform all of these functions in the future as well. Shift registers, SRAM blocks, and switches on the chip enable programmability of parameters (e.g., reaction rates, dissocia- tion constants, Hill coefficients, and time constants) as well as connectivity. The organization of this paper is as follows: Section II de- scribes the core building-block circuits of the chip along with chip measurement data. Fig. 2 shows a die micrograph of the chip that reveals the various building blocks. Section III dis- cusses design considerations that are important in BiCMOS cy- tomorphic chip design. Section IV discusses how cytomorphic 528 IEEE TRANSACTIONS ON BIOMEDICAL CIRCUITS AND SYSTEMS, VOL. 9, NO. 4, AUGUST 2015
  • Fig. 1. Poisson chemical reaction flux and Poisson electron flow in
sub-threshold transistors obey the same Boltzmann exponential laws of thermodynamics, and are therefore mathematically similar [13]. Electron copy number is analogous to molecular copy number and temperature represents itself. single cell on a few chips and speedup multi-cell simulations
  • n multi-chip electronic boards [13]. Therefore, we were moti-
vated to create a few fundamental molecular circuits that could be composed and scaled to model large biochemical reaction networks in the future. This paper describes these fundamental building-block cytomorphic circuits. The paper focuses on establishing quantitative agreement of the cytomorphic chip measurements with prior biological measurements and models. The building-block circuits may be classified into seven im- portant categories: 1) Basic BiCMOS current-mode analog circuits exploit the log-domain cytomorphic mapping to capture the exact dy- namics of fundamental mass-action molecular kinetics such as association, dissociation, and degradation. These fundamental circuits are general enough to capture subtle effects such as loading, fan-out, feedback, and substrate de- pletion through the use of a few explicit connections and Kirchhoff’s current law. A wide dynamic range of opera- tion and low power consumption are achieved through the use of bipolar and subthreshold MOS transistors that func- tion at low current levels. 2) The ability to model cooperative binding is enabled by tun- able Hill-function building-block circuits. 3) An “ITD” block built by a composition of above cur- rent-mode circuits enables mapping of the exact differen- tial equations of inducer-transcription-factor binding and transcription-factor-DNA binding including for- ward and reverse reactions, degradation, protection from degradation of transcription factors bound to DNA, and the change in DNA binding affinity of transcription factors when bound by an inducer. 4) An “analogic” current-mode circuit determines the tran- scription rate of genes based on the probability of mul- tiple transcription-factor DNA binding sites being occu- pied or unoccupied in a combinatorial fashion with the rel- ative mRNA production rate of each such combinatorial state programmable by the user. This strategy enables us to implement any arbitrary “analogic promoter function” that is capable of complex saturating digital logic or prob- abilistic analog behavior depending on the molecular con- centration. 5) A current-mode low pass filter (LPF) circuit enables the gain and dynamics of mRNA and protein production and degradation to be represented.
  • Fig. 2. Die micrograph of the
cytomorphic chip fabricated in an AMS BiCMOS process. The left inset is a layout screen capture
  • f one gene block (2x magnification).
6) A stochastics circuit intentionally amplifies analog Poisson noise in transistors to represent biological fluc- tuations in mRNA and protein concentrations at very low copy numbers and at relatively high noise levels. The Poisson nature of biochemical reaction fluxes au- tomatically maps biological noise to electronic noise at high copy numbers and relatively low noise levels [13]. Thus, these circuits are most useful for reliably modeling highly stochastic and relatively low signal-to-noise-ratios in biological cells. 7) ADCs and DACs convert between analog currents and digital bits to enable our chips to communicate with each
  • ther via digital input/output (I/O), and with off-chip dig-
ital processors and computers. Off-chip digital processors synergistically interact with our chips to carry out various functions: reading digital data from the chips; decoding the data; performing high-speed digital signal processing as necessary (e.g., scaling, diffusion, time delay, and error correction); encoding the data to create or modify molecular data packets via address and data strings; storing the programmable address connectivity amongst gene and protein circuits; and communicating data to other chips
  • r to a computer. For simplicity, the data in this paper were
collected with a data-acquisition board (NI PXI-6541) that interacted with our chip and with MATLAB on a computer. A high-performance FPGA (e.g., from the Xilinx Spartan family) could perform all of these functions in the future as well. Shift registers, SRAM blocks, and switches on the chip enable programmability of parameters (e.g., reaction rates, dissocia- tion constants, Hill coefficients, and time constants) as well as connectivity. The organization of this paper is as follows: Section II de- scribes the core building-block circuits of the chip along with chip measurement data. Fig. 2 shows a die micrograph of the chip that reveals the various building blocks. Section III dis- cusses design considerations that are important in BiCMOS cy- tomorphic chip design. Section IV discusses how cytomorphic 528 IEEE TRANSACTIONS ON BIOMEDICAL CIRCUITS AND SYSTEMS, VOL. 9, NO. 4, AUGUST 2015
  • Fig. 1. Poisson chemical reaction flux and Poisson electron flow in
sub-threshold transistors obey the same Boltzmann exponential laws of thermodynamics, and are therefore mathematically similar [13]. Electron copy number is analogous to molecular copy number and temperature represents itself. single cell on a few chips and speedup multi-cell simulations
  • n multi-chip electronic boards [13]. Therefore, we were moti-
vated to create a few fundamental molecular circuits that could be composed and scaled to model large biochemical reaction networks in the future. This paper describes these fundamental building-block cytomorphic circuits. The paper focuses on establishing quantitative agreement of the cytomorphic chip measurements with prior biological measurements and models. The building-block circuits may be classified into seven im- portant categories: 1) Basic BiCMOS current-mode analog circuits exploit the log-domain cytomorphic mapping to capture the exact dy- namics of fundamental mass-action molecular kinetics such as association, dissociation, and degradation. These fundamental circuits are general enough to capture subtle effects such as loading, fan-out, feedback, and substrate de- pletion through the use of a few explicit connections and Kirchhoff’s current law. A wide dynamic range of opera- tion and low power consumption are achieved through the use of bipolar and subthreshold MOS transistors that func- tion at low current levels. 2) The ability to model cooperative binding is enabled by tun- able Hill-function building-block circuits. 3) An “ITD” block built by a composition of above cur- rent-mode circuits enables mapping of the exact differen- tial equations of inducer-transcription-factor binding and transcription-factor-DNA binding including for- ward and reverse reactions, degradation, protection from degradation of transcription factors bound to DNA, and the change in DNA binding affinity of transcription factors when bound by an inducer. 4) An “analogic” current-mode circuit determines the tran- scription rate of genes based on the probability of mul- tiple transcription-factor DNA binding sites being occu- pied or unoccupied in a combinatorial fashion with the rel- ative mRNA production rate of each such combinatorial state programmable by the user. This strategy enables us to implement any arbitrary “analogic promoter function” that is capable of complex saturating digital logic or prob- abilistic analog behavior depending on the molecular con- centration. 5) A current-mode low pass filter (LPF) circuit enables the gain and dynamics of mRNA and protein production and degradation to be represented.
  • Fig. 2. Die micrograph of the
cytomorphic chip fabricated in an AMS BiCMOS process. The left inset is a layout screen capture
  • f one gene block (2x magnification).
6) A stochastics circuit intentionally amplifies analog Poisson noise in transistors to represent biological fluc- tuations in mRNA and protein concentrations at very low copy numbers and at relatively high noise levels. The Poisson nature of biochemical reaction fluxes au- tomatically maps biological noise to electronic noise at high copy numbers and relatively low noise levels [13]. Thus, these circuits are most useful for reliably modeling highly stochastic and relatively low signal-to-noise-ratios in biological cells. 7) ADCs and DACs convert between analog currents and digital bits to enable our chips to communicate with each
  • ther via digital input/output (I/O), and with off-chip dig-
ital processors and computers. Off-chip digital processors synergistically interact with our chips to carry out various functions: reading digital data from the chips; decoding the data; performing high-speed digital signal processing as necessary (e.g., scaling, diffusion, time delay, and error correction); encoding the data to create or modify molecular data packets via address and data strings; storing the programmable address connectivity amongst gene and protein circuits; and communicating data to other chips
  • r to a computer. For simplicity, the data in this paper were
collected with a data-acquisition board (NI PXI-6541) that interacted with our chip and with MATLAB on a computer. A high-performance FPGA (e.g., from the Xilinx Spartan family) could perform all of these functions in the future as well. Shift registers, SRAM blocks, and switches on the chip enable programmability of parameters (e.g., reaction rates, dissocia- tion constants, Hill coefficients, and time constants) as well as connectivity. The organization of this paper is as follows: Section II de- scribes the core building-block circuits of the chip along with chip measurement data. Fig. 2 shows a die micrograph of the chip that reveals the various building blocks. Section III dis- cusses design considerations that are important in BiCMOS cy- tomorphic chip design. Section IV discusses how cytomorphic 528 IEEE TRANSACTIONS ON BIOMEDICAL CIRCUITS AND SYSTEMS, VOL. 9, NO. 4, AUGUST 2015
  • Fig. 1. Poisson chemical reaction flux and Poisson electron flow in
sub-threshold transistors obey the same Boltzmann exponential laws of thermodynamics, and are therefore mathematically similar [13]. Electron copy number is analogous to molecular copy number and temperature represents itself. single cell on a few chips and speedup multi-cell simulations
  • n multi-chip electronic boards [13]. Therefore, we were moti-
vated to create a few fundamental molecular circuits that could be composed and scaled to model large biochemical reaction networks in the future. This paper describes these fundamental building-block cytomorphic circuits. The paper focuses on establishing quantitative agreement of the cytomorphic chip measurements with prior biological measurements and models. The building-block circuits may be classified into seven im- portant categories: 1) Basic BiCMOS current-mode analog circuits exploit the log-domain cytomorphic mapping to capture the exact dy- namics of fundamental mass-action molecular kinetics such as association, dissociation, and degradation. These fundamental circuits are general enough to capture subtle effects such as loading, fan-out, feedback, and substrate de- pletion through the use of a few explicit connections and Kirchhoff’s current law. A wide dynamic range of opera- tion and low power consumption are achieved through the use of bipolar and subthreshold MOS transistors that func- tion at low current levels. 2) The ability to model cooperative binding is enabled by tun- able Hill-function building-block circuits. 3) An “ITD” block built by a composition of above cur- rent-mode circuits enables mapping of the exact differen- tial equations of inducer-transcription-factor binding and transcription-factor-DNA binding including for- ward and reverse reactions, degradation, protection from degradation of transcription factors bound to DNA, and the change in DNA binding affinity of transcription factors when bound by an inducer. 4) An “analogic” current-mode circuit determines the tran- scription rate of genes based on the probability of mul- tiple transcription-factor DNA binding sites being occu- pied or unoccupied in a combinatorial fashion with the rel- ative mRNA production rate of each such combinatorial state programmable by the user. This strategy enables us to implement any arbitrary “analogic promoter function” that is capable of complex saturating digital logic or prob- abilistic analog behavior depending on the molecular con- centration. 5) A current-mode low pass filter (LPF) circuit enables the gain and dynamics of mRNA and protein production and degradation to be represented.
  • Fig. 2. Die micrograph of the
cytomorphic chip fabricated in an AMS BiCMOS process. The left inset is a layout screen capture
  • f one gene block (2x magnification).
6) A stochastics circuit intentionally amplifies analog Poisson noise in transistors to represent biological fluc- tuations in mRNA and protein concentrations at very low copy numbers and at relatively high noise levels. The Poisson nature of biochemical reaction fluxes au- tomatically maps biological noise to electronic noise at high copy numbers and relatively low noise levels [13]. Thus, these circuits are most useful for reliably modeling highly stochastic and relatively low signal-to-noise-ratios in biological cells. 7) ADCs and DACs convert between analog currents and digital bits to enable our chips to communicate with each
  • ther via digital input/output (I/O), and with off-chip dig-
ital processors and computers. Off-chip digital processors synergistically interact with our chips to carry out various functions: reading digital data from the chips; decoding the data; performing high-speed digital signal processing as necessary (e.g., scaling, diffusion, time delay, and error correction); encoding the data to create or modify molecular data packets via address and data strings; storing the programmable address connectivity amongst gene and protein circuits; and communicating data to other chips
  • r to a computer. For simplicity, the data in this paper were
collected with a data-acquisition board (NI PXI-6541) that interacted with our chip and with MATLAB on a computer. A high-performance FPGA (e.g., from the Xilinx Spartan family) could perform all of these functions in the future as well. Shift registers, SRAM blocks, and switches on the chip enable programmability of parameters (e.g., reaction rates, dissocia- tion constants, Hill coefficients, and time constants) as well as connectivity. The organization of this paper is as follows: Section II de- scribes the core building-block circuits of the chip along with chip measurement data. Fig. 2 shows a die micrograph of the chip that reveals the various building blocks. Section III dis- cusses design considerations that are important in BiCMOS cy- tomorphic chip design. Section IV discusses how cytomorphic 528 IEEE TRANSACTIONS ON BIOMEDICAL CIRCUITS AND SYSTEMS, VOL. 9, NO. 4, AUGUST 2015
  • Fig. 1. Poisson chemical reaction flux and Poisson electron flow in
sub-threshold transistors obey the same Boltzmann exponential laws of thermodynamics, and are therefore mathematically similar [13]. Electron copy number is analogous to molecular copy number and temperature represents itself. single cell on a few chips and speedup multi-cell simulations
  • n multi-chip electronic boards [13]. Therefore, we were moti-
vated to create a few fundamental molecular circuits that could be composed and scaled to model large biochemical reaction networks in the future. This paper describes these fundamental building-block cytomorphic circuits. The paper focuses on establishing quantitative agreement of the cytomorphic chip measurements with prior biological measurements and models. The building-block circuits may be classified into seven im- portant categories: 1) Basic BiCMOS current-mode analog circuits exploit the log-domain cytomorphic mapping to capture the exact dy- namics of fundamental mass-action molecular kinetics such as association, dissociation, and degradation. These fundamental circuits are general enough to capture subtle effects such as loading, fan-out, feedback, and substrate de- pletion through the use of a few explicit connections and Kirchhoff’s current law. A wide dynamic range of opera- tion and low power consumption are achieved through the use of bipolar and subthreshold MOS transistors that func- tion at low current levels. 2) The ability to model cooperative binding is enabled by tun- able Hill-function building-block circuits. 3) An “ITD” block built by a composition of above cur- rent-mode circuits enables mapping of the exact differen- tial equations of inducer-transcription-factor binding and transcription-factor-DNA binding including for- ward and reverse reactions, degradation, protection from degradation of transcription factors bound to DNA, and the change in DNA binding affinity of transcription factors when bound by an inducer. 4) An “analogic” current-mode circuit determines the tran- scription rate of genes based on the probability of mul- tiple transcription-factor DNA binding sites being occu- pied or unoccupied in a combinatorial fashion with the rel- ative mRNA production rate of each such combinatorial state programmable by the user. This strategy enables us to implement any arbitrary “analogic promoter function” that is capable of complex saturating digital logic or prob- abilistic analog behavior depending on the molecular con- centration. 5) A current-mode low pass filter (LPF) circuit enables the gain and dynamics of mRNA and protein production and degradation to be represented.
  • Fig. 2. Die micrograph of the
cytomorphic chip fabricated in an AMS BiCMOS process. The left inset is a layout screen capture
  • f one gene block (2x magnification).
6) A stochastics circuit intentionally amplifies analog Poisson noise in transistors to represent biological fluc- tuations in mRNA and protein concentrations at very low copy numbers and at relatively high noise levels. The Poisson nature of biochemical reaction fluxes au- tomatically maps biological noise to electronic noise at high copy numbers and relatively low noise levels [13]. Thus, these circuits are most useful for reliably modeling highly stochastic and relatively low signal-to-noise-ratios in biological cells. 7) ADCs and DACs convert between analog currents and digital bits to enable our chips to communicate with each
  • ther via digital input/output (I/O), and with off-chip dig-
ital processors and computers. Off-chip digital processors synergistically interact with our chips to carry out various functions: reading digital data from the chips; decoding the data; performing high-speed digital signal processing as necessary (e.g., scaling, diffusion, time delay, and error correction); encoding the data to create or modify molecular data packets via address and data strings; storing the programmable address connectivity amongst gene and protein circuits; and communicating data to other chips
  • r to a computer. For simplicity, the data in this paper were
collected with a data-acquisition board (NI PXI-6541) that interacted with our chip and with MATLAB on a computer. A high-performance FPGA (e.g., from the Xilinx Spartan family) could perform all of these functions in the future as well. Shift registers, SRAM blocks, and switches on the chip enable programmability of parameters (e.g., reaction rates, dissocia- tion constants, Hill coefficients, and time constants) as well as connectivity. The organization of this paper is as follows: Section II de- scribes the core building-block circuits of the chip along with chip measurement data. Fig. 2 shows a die micrograph of the chip that reveals the various building blocks. Section III dis- cusses design considerations that are important in BiCMOS cy- tomorphic chip design. Section IV discusses how cytomorphic
slide-11
SLIDE 11 528 IEEE TRANSACTIONS ON BIOMEDICAL CIRCUITS AND SYSTEMS, VOL. 9, NO. 4, AUGUST 2015
  • Fig. 1. Poisson chemical reaction flux and Poisson electron flow in
sub-threshold transistors obey the same Boltzmann exponential laws of thermodynamics, and are therefore mathematically similar [13]. Electron copy number is analogous to molecular copy number and temperature represents itself. single cell on a few chips and speedup multi-cell simulations
  • n multi-chip electronic boards [13]. Therefore, we were moti-
vated to create a few fundamental molecular circuits that could be composed and scaled to model large biochemical reaction networks in the future. This paper describes these fundamental building-block cytomorphic circuits. The paper focuses on establishing quantitative agreement of the cytomorphic chip measurements with prior biological measurements and models. The building-block circuits may be classified into seven im- portant categories: 1) Basic BiCMOS current-mode analog circuits exploit the log-domain cytomorphic mapping to capture the exact dy- namics of fundamental mass-action molecular kinetics such as association, dissociation, and degradation. These fundamental circuits are general enough to capture subtle effects such as loading, fan-out, feedback, and substrate de- pletion through the use of a few explicit connections and Kirchhoff’s current law. A wide dynamic range of opera- tion and low power consumption are achieved through the use of bipolar and subthreshold MOS transistors that func- tion at low current levels. 2) The ability to model cooperative binding is enabled by tun- able Hill-function building-block circuits. 3) An “ITD” block built by a composition of above cur- rent-mode circuits enables mapping of the exact differen- tial equations of inducer-transcription-factor binding and transcription-factor-DNA binding including for- ward and reverse reactions, degradation, protection from degradation of transcription factors bound to DNA, and the change in DNA binding affinity of transcription factors when bound by an inducer. 4) An “analogic” current-mode circuit determines the tran- scription rate of genes based on the probability of mul- tiple transcription-factor DNA binding sites being occu- pied or unoccupied in a combinatorial fashion with the rel- ative mRNA production rate of each such combinatorial state programmable by the user. This strategy enables us to implement any arbitrary “analogic promoter function” that is capable of complex saturating digital logic or prob- abilistic analog behavior depending on the molecular con- centration. 5) A current-mode low pass filter (LPF) circuit enables the gain and dynamics of mRNA and protein production and degradation to be represented.
  • Fig. 2. Die micrograph of the
cytomorphic chip fabricated in an AMS BiCMOS process. The left inset is a layout screen capture
  • f one gene block (2x magnification).
6) A stochastics circuit intentionally amplifies analog Poisson noise in transistors to represent biological fluc- tuations in mRNA and protein concentrations at very low copy numbers and at relatively high noise levels. The Poisson nature of biochemical reaction fluxes au- tomatically maps biological noise to electronic noise at high copy numbers and relatively low noise levels [13]. Thus, these circuits are most useful for reliably modeling highly stochastic and relatively low signal-to-noise-ratios in biological cells. 7) ADCs and DACs convert between analog currents and digital bits to enable our chips to communicate with each
  • ther via digital input/output (I/O), and with off-chip dig-
ital processors and computers. Off-chip digital processors synergistically interact with our chips to carry out various functions: reading digital data from the chips; decoding the data; performing high-speed digital signal processing as necessary (e.g., scaling, diffusion, time delay, and error correction); encoding the data to create or modify molecular data packets via address and data strings; storing the programmable address connectivity amongst gene and protein circuits; and communicating data to other chips
  • r to a computer. For simplicity, the data in this paper were
collected with a data-acquisition board (NI PXI-6541) that interacted with our chip and with MATLAB on a computer. A high-performance FPGA (e.g., from the Xilinx Spartan family) could perform all of these functions in the future as well. Shift registers, SRAM blocks, and switches on the chip enable programmability of parameters (e.g., reaction rates, dissocia- tion constants, Hill coefficients, and time constants) as well as connectivity. The organization of this paper is as follows: Section II de- scribes the core building-block circuits of the chip along with chip measurement data. Fig. 2 shows a die micrograph of the chip that reveals the various building blocks. Section III dis- cusses design considerations that are important in BiCMOS cy- tomorphic chip design. Section IV discusses how cytomorphic 528 IEEE TRANSACTIONS ON BIOMEDICAL CIRCUITS AND SYSTEMS, VOL. 9, NO. 4, AUGUST 2015
  • Fig. 1. Poisson chemical reaction flux and Poisson electron flow in
sub-threshold transistors obey the same Boltzmann exponential laws of thermodynamics, and are therefore mathematically similar [13]. Electron copy number is analogous to molecular copy number and temperature represents itself. single cell on a few chips and speedup multi-cell simulations
  • n multi-chip electronic boards [13]. Therefore, we were moti-
vated to create a few fundamental molecular circuits that could be composed and scaled to model large biochemical reaction networks in the future. This paper describes these fundamental building-block cytomorphic circuits. The paper focuses on establishing quantitative agreement of the cytomorphic chip measurements with prior biological measurements and models. The building-block circuits may be classified into seven im- portant categories: 1) Basic BiCMOS current-mode analog circuits exploit the log-domain cytomorphic mapping to capture the exact dy- namics of fundamental mass-action molecular kinetics such as association, dissociation, and degradation. These fundamental circuits are general enough to capture subtle effects such as loading, fan-out, feedback, and substrate de- pletion through the use of a few explicit connections and Kirchhoff’s current law. A wide dynamic range of opera- tion and low power consumption are achieved through the use of bipolar and subthreshold MOS transistors that func- tion at low current levels. 2) The ability to model cooperative binding is enabled by tun- able Hill-function building-block circuits. 3) An “ITD” block built by a composition of above cur- rent-mode circuits enables mapping of the exact differen- tial equations of inducer-transcription-factor binding and transcription-factor-DNA binding including for- ward and reverse reactions, degradation, protection from degradation of transcription factors bound to DNA, and the change in DNA binding affinity of transcription factors when bound by an inducer. 4) An “analogic” current-mode circuit determines the tran- scription rate of genes based on the probability of mul- tiple transcription-factor DNA binding sites being occu- pied or unoccupied in a combinatorial fashion with the rel- ative mRNA production rate of each such combinatorial state programmable by the user. This strategy enables us to implement any arbitrary “analogic promoter function” that is capable of complex saturating digital logic or prob- abilistic analog behavior depending on the molecular con- centration. 5) A current-mode low pass filter (LPF) circuit enables the gain and dynamics of mRNA and protein production and degradation to be represented.
  • Fig. 2. Die micrograph of the
cytomorphic chip fabricated in an AMS BiCMOS process. The left inset is a layout screen capture
  • f one gene block (2x magnification).
6) A stochastics circuit intentionally amplifies analog Poisson noise in transistors to represent biological fluc- tuations in mRNA and protein concentrations at very low copy numbers and at relatively high noise levels. The Poisson nature of biochemical reaction fluxes au- tomatically maps biological noise to electronic noise at high copy numbers and relatively low noise levels [13]. Thus, these circuits are most useful for reliably modeling highly stochastic and relatively low signal-to-noise-ratios in biological cells. 7) ADCs and DACs convert between analog currents and digital bits to enable our chips to communicate with each
  • ther via digital input/output (I/O), and with off-chip dig-
ital processors and computers. Off-chip digital processors synergistically interact with our chips to carry out various functions: reading digital data from the chips; decoding the data; performing high-speed digital signal processing as necessary (e.g., scaling, diffusion, time delay, and error correction); encoding the data to create or modify molecular data packets via address and data strings; storing the programmable address connectivity amongst gene and protein circuits; and communicating data to other chips
  • r to a computer. For simplicity, the data in this paper were
collected with a data-acquisition board (NI PXI-6541) that interacted with our chip and with MATLAB on a computer. A high-performance FPGA (e.g., from the Xilinx Spartan family) could perform all of these functions in the future as well. Shift registers, SRAM blocks, and switches on the chip enable programmability of parameters (e.g., reaction rates, dissocia- tion constants, Hill coefficients, and time constants) as well as connectivity. The organization of this paper is as follows: Section II de- scribes the core building-block circuits of the chip along with chip measurement data. Fig. 2 shows a die micrograph of the chip that reveals the various building blocks. Section III dis- cusses design considerations that are important in BiCMOS cy- tomorphic chip design. Section IV discusses how cytomorphic 528 IEEE TRANSACTIONS ON BIOMEDICAL CIRCUITS AND SYSTEMS, VOL. 9, NO. 4, AUGUST 2015
  • Fig. 1. Poisson chemical reaction flux and Poisson electron flow in
sub-threshold transistors obey the same Boltzmann exponential laws of thermodynamics, and are therefore mathematically similar [13]. Electron copy number is analogous to molecular copy number and temperature represents itself. single cell on a few chips and speedup multi-cell simulations
  • n multi-chip electronic boards [13]. Therefore, we were moti-
vated to create a few fundamental molecular circuits that could be composed and scaled to model large biochemical reaction networks in the future. This paper describes these fundamental building-block cytomorphic circuits. The paper focuses on establishing quantitative agreement of the cytomorphic chip measurements with prior biological measurements and models. The building-block circuits may be classified into seven im- portant categories: 1) Basic BiCMOS current-mode analog circuits exploit the log-domain cytomorphic mapping to capture the exact dy- namics of fundamental mass-action molecular kinetics such as association, dissociation, and degradation. These fundamental circuits are general enough to capture subtle effects such as loading, fan-out, feedback, and substrate de- pletion through the use of a few explicit connections and Kirchhoff’s current law. A wide dynamic range of opera- tion and low power consumption are achieved through the use of bipolar and subthreshold MOS transistors that func- tion at low current levels. 2) The ability to model cooperative binding is enabled by tun- able Hill-function building-block circuits. 3) An “ITD” block built by a composition of above cur- rent-mode circuits enables mapping of the exact differen- tial equations of inducer-transcription-factor binding and transcription-factor-DNA binding including for- ward and reverse reactions, degradation, protection from degradation of transcription factors bound to DNA, and the change in DNA binding affinity of transcription factors when bound by an inducer. 4) An “analogic” current-mode circuit determines the tran- scription rate of genes based on the probability of mul- tiple transcription-factor DNA binding sites being occu- pied or unoccupied in a combinatorial fashion with the rel- ative mRNA production rate of each such combinatorial state programmable by the user. This strategy enables us to implement any arbitrary “analogic promoter function” that is capable of complex saturating digital logic or prob- abilistic analog behavior depending on the molecular con- centration. 5) A current-mode low pass filter (LPF) circuit enables the gain and dynamics of mRNA and protein production and degradation to be represented.
  • Fig. 2. Die micrograph of the
cytomorphic chip fabricated in an AMS BiCMOS process. The left inset is a layout screen capture
  • f one gene block (2x magnification).
6) A stochastics circuit intentionally amplifies analog Poisson noise in transistors to represent biological fluc- tuations in mRNA and protein concentrations at very low copy numbers and at relatively high noise levels. The Poisson nature of biochemical reaction fluxes au- tomatically maps biological noise to electronic noise at high copy numbers and relatively low noise levels [13]. Thus, these circuits are most useful for reliably modeling highly stochastic and relatively low signal-to-noise-ratios in biological cells. 7) ADCs and DACs convert between analog currents and digital bits to enable our chips to communicate with each
  • ther via digital input/output (I/O), and with off-chip dig-
ital processors and computers. Off-chip digital processors synergistically interact with our chips to carry out various functions: reading digital data from the chips; decoding the data; performing high-speed digital signal processing as necessary (e.g., scaling, diffusion, time delay, and error correction); encoding the data to create or modify molecular data packets via address and data strings; storing the programmable address connectivity amongst gene and protein circuits; and communicating data to other chips
  • r to a computer. For simplicity, the data in this paper were
collected with a data-acquisition board (NI PXI-6541) that interacted with our chip and with MATLAB on a computer. A high-performance FPGA (e.g., from the Xilinx Spartan family) could perform all of these functions in the future as well. Shift registers, SRAM blocks, and switches on the chip enable programmability of parameters (e.g., reaction rates, dissocia- tion constants, Hill coefficients, and time constants) as well as connectivity. The organization of this paper is as follows: Section II de- scribes the core building-block circuits of the chip along with chip measurement data. Fig. 2 shows a die micrograph of the chip that reveals the various building blocks. Section III dis- cusses design considerations that are important in BiCMOS cy- tomorphic chip design. Section IV discusses how cytomorphic 528 IEEE TRANSACTIONS ON BIOMEDICAL CIRCUITS AND SYSTEMS, VOL. 9, NO. 4, AUGUST 2015
  • Fig. 1. Poisson chemical reaction flux and Poisson electron flow in
sub-threshold transistors obey the same Boltzmann exponential laws of thermodynamics, and are therefore mathematically similar [13]. Electron copy number is analogous to molecular copy number and temperature represents itself. single cell on a few chips and speedup multi-cell simulations
  • n multi-chip electronic boards [13]. Therefore, we were moti-
vated to create a few fundamental molecular circuits that could be composed and scaled to model large biochemical reaction networks in the future. This paper describes these fundamental building-block cytomorphic circuits. The paper focuses on establishing quantitative agreement of the cytomorphic chip measurements with prior biological measurements and models. The building-block circuits may be classified into seven im- portant categories: 1) Basic BiCMOS current-mode analog circuits exploit the log-domain cytomorphic mapping to capture the exact dy- namics of fundamental mass-action molecular kinetics such as association, dissociation, and degradation. These fundamental circuits are general enough to capture subtle effects such as loading, fan-out, feedback, and substrate de- pletion through the use of a few explicit connections and Kirchhoff’s current law. A wide dynamic range of opera- tion and low power consumption are achieved through the use of bipolar and subthreshold MOS transistors that func- tion at low current levels. 2) The ability to model cooperative binding is enabled by tun- able Hill-function building-block circuits. 3) An “ITD” block built by a composition of above cur- rent-mode circuits enables mapping of the exact differen- tial equations of inducer-transcription-factor binding and transcription-factor-DNA binding including for- ward and reverse reactions, degradation, protection from degradation of transcription factors bound to DNA, and the change in DNA binding affinity of transcription factors when bound by an inducer. 4) An “analogic” current-mode circuit determines the tran- scription rate of genes based on the probability of mul- tiple transcription-factor DNA binding sites being occu- pied or unoccupied in a combinatorial fashion with the rel- ative mRNA production rate of each such combinatorial state programmable by the user. This strategy enables us to implement any arbitrary “analogic promoter function” that is capable of complex saturating digital logic or prob- abilistic analog behavior depending on the molecular con- centration. 5) A current-mode low pass filter (LPF) circuit enables the gain and dynamics of mRNA and protein production and degradation to be represented.
  • Fig. 2. Die micrograph of the
cytomorphic chip fabricated in an AMS BiCMOS process. The left inset is a layout screen capture
  • f one gene block (2x magnification).
6) A stochastics circuit intentionally amplifies analog Poisson noise in transistors to represent biological fluc- tuations in mRNA and protein concentrations at very low copy numbers and at relatively high noise levels. The Poisson nature of biochemical reaction fluxes au- tomatically maps biological noise to electronic noise at high copy numbers and relatively low noise levels [13]. Thus, these circuits are most useful for reliably modeling highly stochastic and relatively low signal-to-noise-ratios in biological cells. 7) ADCs and DACs convert between analog currents and digital bits to enable our chips to communicate with each
  • ther via digital input/output (I/O), and with off-chip dig-
ital processors and computers. Off-chip digital processors synergistically interact with our chips to carry out various functions: reading digital data from the chips; decoding the data; performing high-speed digital signal processing as necessary (e.g., scaling, diffusion, time delay, and error correction); encoding the data to create or modify molecular data packets via address and data strings; storing the programmable address connectivity amongst gene and protein circuits; and communicating data to other chips
  • r to a computer. For simplicity, the data in this paper were
collected with a data-acquisition board (NI PXI-6541) that interacted with our chip and with MATLAB on a computer. A high-performance FPGA (e.g., from the Xilinx Spartan family) could perform all of these functions in the future as well. Shift registers, SRAM blocks, and switches on the chip enable programmability of parameters (e.g., reaction rates, dissocia- tion constants, Hill coefficients, and time constants) as well as connectivity. The organization of this paper is as follows: Section II de- scribes the core building-block circuits of the chip along with chip measurement data. Fig. 2 shows a die micrograph of the chip that reveals the various building blocks. Section III dis- cusses design considerations that are important in BiCMOS cy- tomorphic chip design. Section IV discusses how cytomorphic 528 IEEE TRANSACTIONS ON BIOMEDICAL CIRCUITS AND SYSTEMS, VOL. 9, NO. 4, AUGUST 2015
  • Fig. 1. Poisson chemical reaction flux and Poisson electron flow in
sub-threshold transistors obey the same Boltzmann exponential laws of thermodynamics, and are therefore mathematically similar [13]. Electron copy number is analogous to molecular copy number and temperature represents itself. single cell on a few chips and speedup multi-cell simulations
  • n multi-chip electronic boards [13]. Therefore, we were moti-
vated to create a few fundamental molecular circuits that could be composed and scaled to model large biochemical reaction networks in the future. This paper describes these fundamental building-block cytomorphic circuits. The paper focuses on establishing quantitative agreement of the cytomorphic chip measurements with prior biological measurements and models. The building-block circuits may be classified into seven im- portant categories: 1) Basic BiCMOS current-mode analog circuits exploit the log-domain cytomorphic mapping to capture the exact dy- namics of fundamental mass-action molecular kinetics such as association, dissociation, and degradation. These fundamental circuits are general enough to capture subtle effects such as loading, fan-out, feedback, and substrate de- pletion through the use of a few explicit connections and Kirchhoff’s current law. A wide dynamic range of opera- tion and low power consumption are achieved through the use of bipolar and subthreshold MOS transistors that func- tion at low current levels. 2) The ability to model cooperative binding is enabled by tun- able Hill-function building-block circuits. 3) An “ITD” block built by a composition of above cur- rent-mode circuits enables mapping of the exact differen- tial equations of inducer-transcription-factor binding and transcription-factor-DNA binding including for- ward and reverse reactions, degradation, protection from degradation of transcription factors bound to DNA, and the change in DNA binding affinity of transcription factors when bound by an inducer. 4) An “analogic” current-mode circuit determines the tran- scription rate of genes based on the probability of mul- tiple transcription-factor DNA binding sites being occu- pied or unoccupied in a combinatorial fashion with the rel- ative mRNA production rate of each such combinatorial state programmable by the user. This strategy enables us to implement any arbitrary “analogic promoter function” that is capable of complex saturating digital logic or prob- abilistic analog behavior depending on the molecular con- centration. 5) A current-mode low pass filter (LPF) circuit enables the gain and dynamics of mRNA and protein production and degradation to be represented.
  • Fig. 2. Die micrograph of the
cytomorphic chip fabricated in an AMS BiCMOS process. The left inset is a layout screen capture
  • f one gene block (2x magnification).
6) A stochastics circuit intentionally amplifies analog Poisson noise in transistors to represent biological fluc- tuations in mRNA and protein concentrations at very low copy numbers and at relatively high noise levels. The Poisson nature of biochemical reaction fluxes au- tomatically maps biological noise to electronic noise at high copy numbers and relatively low noise levels [13]. Thus, these circuits are most useful for reliably modeling highly stochastic and relatively low signal-to-noise-ratios in biological cells. 7) ADCs and DACs convert between analog currents and digital bits to enable our chips to communicate with each
  • ther via digital input/output (I/O), and with off-chip dig-
ital processors and computers. Off-chip digital processors synergistically interact with our chips to carry out various functions: reading digital data from the chips; decoding the data; performing high-speed digital signal processing as necessary (e.g., scaling, diffusion, time delay, and error correction); encoding the data to create or modify molecular data packets via address and data strings; storing the programmable address connectivity amongst gene and protein circuits; and communicating data to other chips
  • r to a computer. For simplicity, the data in this paper were
collected with a data-acquisition board (NI PXI-6541) that interacted with our chip and with MATLAB on a computer. A high-performance FPGA (e.g., from the Xilinx Spartan family) could perform all of these functions in the future as well. Shift registers, SRAM blocks, and switches on the chip enable programmability of parameters (e.g., reaction rates, dissocia- tion constants, Hill coefficients, and time constants) as well as connectivity. The organization of this paper is as follows: Section II de- scribes the core building-block circuits of the chip along with chip measurement data. Fig. 2 shows a die micrograph of the chip that reveals the various building blocks. Section III dis- cusses design considerations that are important in BiCMOS cy- tomorphic chip design. Section IV discusses how cytomorphic

INTRODUCTION 11

  • physical behavior
  • voltage/current operating ranges
  • circuit noise [thermal/shot/flicker]
  • complex building blocks
  • non-linear, non-convex
  • space limitations
  • limitations on number of

available blocks and connections

  • requires creativity when

configuring device

PROGRAMMING CHALLENGES FOR ANALOG DEVICES

slide-12
SLIDE 12 528 IEEE TRANSACTIONS ON BIOMEDICAL CIRCUITS AND SYSTEMS, VOL. 9, NO. 4, AUGUST 2015
  • Fig. 1. Poisson chemical reaction flux and Poisson electron flow in
sub-threshold transistors obey the same Boltzmann exponential laws of thermodynamics, and are therefore mathematically similar [13]. Electron copy number is analogous to molecular copy number and temperature represents itself. single cell on a few chips and speedup multi-cell simulations
  • n multi-chip electronic boards [13]. Therefore, we were moti-
vated to create a few fundamental molecular circuits that could be composed and scaled to model large biochemical reaction networks in the future. This paper describes these fundamental building-block cytomorphic circuits. The paper focuses on establishing quantitative agreement of the cytomorphic chip measurements with prior biological measurements and models. The building-block circuits may be classified into seven im- portant categories: 1) Basic BiCMOS current-mode analog circuits exploit the log-domain cytomorphic mapping to capture the exact dy- namics of fundamental mass-action molecular kinetics such as association, dissociation, and degradation. These fundamental circuits are general enough to capture subtle effects such as loading, fan-out, feedback, and substrate de- pletion through the use of a few explicit connections and Kirchhoff’s current law. A wide dynamic range of opera- tion and low power consumption are achieved through the use of bipolar and subthreshold MOS transistors that func- tion at low current levels. 2) The ability to model cooperative binding is enabled by tun- able Hill-function building-block circuits. 3) An “ITD” block built by a composition of above cur- rent-mode circuits enables mapping of the exact differen- tial equations of inducer-transcription-factor binding and transcription-factor-DNA binding including for- ward and reverse reactions, degradation, protection from degradation of transcription factors bound to DNA, and the change in DNA binding affinity of transcription factors when bound by an inducer. 4) An “analogic” current-mode circuit determines the tran- scription rate of genes based on the probability of mul- tiple transcription-factor DNA binding sites being occu- pied or unoccupied in a combinatorial fashion with the rel- ative mRNA production rate of each such combinatorial state programmable by the user. This strategy enables us to implement any arbitrary “analogic promoter function” that is capable of complex saturating digital logic or prob- abilistic analog behavior depending on the molecular con- centration. 5) A current-mode low pass filter (LPF) circuit enables the gain and dynamics of mRNA and protein production and degradation to be represented.
  • Fig. 2. Die micrograph of the
cytomorphic chip fabricated in an AMS BiCMOS process. The left inset is a layout screen capture
  • f one gene block (2x magnification).
6) A stochastics circuit intentionally amplifies analog Poisson noise in transistors to represent biological fluc- tuations in mRNA and protein concentrations at very low copy numbers and at relatively high noise levels. The Poisson nature of biochemical reaction fluxes au- tomatically maps biological noise to electronic noise at high copy numbers and relatively low noise levels [13]. Thus, these circuits are most useful for reliably modeling highly stochastic and relatively low signal-to-noise-ratios in biological cells. 7) ADCs and DACs convert between analog currents and digital bits to enable our chips to communicate with each
  • ther via digital input/output (I/O), and with off-chip dig-
ital processors and computers. Off-chip digital processors synergistically interact with our chips to carry out various functions: reading digital data from the chips; decoding the data; performing high-speed digital signal processing as necessary (e.g., scaling, diffusion, time delay, and error correction); encoding the data to create or modify molecular data packets via address and data strings; storing the programmable address connectivity amongst gene and protein circuits; and communicating data to other chips
  • r to a computer. For simplicity, the data in this paper were
collected with a data-acquisition board (NI PXI-6541) that interacted with our chip and with MATLAB on a computer. A high-performance FPGA (e.g., from the Xilinx Spartan family) could perform all of these functions in the future as well. Shift registers, SRAM blocks, and switches on the chip enable programmability of parameters (e.g., reaction rates, dissocia- tion constants, Hill coefficients, and time constants) as well as connectivity. The organization of this paper is as follows: Section II de- scribes the core building-block circuits of the chip along with chip measurement data. Fig. 2 shows a die micrograph of the chip that reveals the various building blocks. Section III dis- cusses design considerations that are important in BiCMOS cy- tomorphic chip design. Section IV discusses how cytomorphic 528 IEEE TRANSACTIONS ON BIOMEDICAL CIRCUITS AND SYSTEMS, VOL. 9, NO. 4, AUGUST 2015
  • Fig. 1. Poisson chemical reaction flux and Poisson electron flow in
sub-threshold transistors obey the same Boltzmann exponential laws of thermodynamics, and are therefore mathematically similar [13]. Electron copy number is analogous to molecular copy number and temperature represents itself. single cell on a few chips and speedup multi-cell simulations
  • n multi-chip electronic boards [13]. Therefore, we were moti-
vated to create a few fundamental molecular circuits that could be composed and scaled to model large biochemical reaction networks in the future. This paper describes these fundamental building-block cytomorphic circuits. The paper focuses on establishing quantitative agreement of the cytomorphic chip measurements with prior biological measurements and models. The building-block circuits may be classified into seven im- portant categories: 1) Basic BiCMOS current-mode analog circuits exploit the log-domain cytomorphic mapping to capture the exact dy- namics of fundamental mass-action molecular kinetics such as association, dissociation, and degradation. These fundamental circuits are general enough to capture subtle effects such as loading, fan-out, feedback, and substrate de- pletion through the use of a few explicit connections and Kirchhoff’s current law. A wide dynamic range of opera- tion and low power consumption are achieved through the use of bipolar and subthreshold MOS transistors that func- tion at low current levels. 2) The ability to model cooperative binding is enabled by tun- able Hill-function building-block circuits. 3) An “ITD” block built by a composition of above cur- rent-mode circuits enables mapping of the exact differen- tial equations of inducer-transcription-factor binding and transcription-factor-DNA binding including for- ward and reverse reactions, degradation, protection from degradation of transcription factors bound to DNA, and the change in DNA binding affinity of transcription factors when bound by an inducer. 4) An “analogic” current-mode circuit determines the tran- scription rate of genes based on the probability of mul- tiple transcription-factor DNA binding sites being occu- pied or unoccupied in a combinatorial fashion with the rel- ative mRNA production rate of each such combinatorial state programmable by the user. This strategy enables us to implement any arbitrary “analogic promoter function” that is capable of complex saturating digital logic or prob- abilistic analog behavior depending on the molecular con- centration. 5) A current-mode low pass filter (LPF) circuit enables the gain and dynamics of mRNA and protein production and degradation to be represented.
  • Fig. 2. Die micrograph of the
cytomorphic chip fabricated in an AMS BiCMOS process. The left inset is a layout screen capture
  • f one gene block (2x magnification).
6) A stochastics circuit intentionally amplifies analog Poisson noise in transistors to represent biological fluc- tuations in mRNA and protein concentrations at very low copy numbers and at relatively high noise levels. The Poisson nature of biochemical reaction fluxes au- tomatically maps biological noise to electronic noise at high copy numbers and relatively low noise levels [13]. Thus, these circuits are most useful for reliably modeling highly stochastic and relatively low signal-to-noise-ratios in biological cells. 7) ADCs and DACs convert between analog currents and digital bits to enable our chips to communicate with each
  • ther via digital input/output (I/O), and with off-chip dig-
ital processors and computers. Off-chip digital processors synergistically interact with our chips to carry out various functions: reading digital data from the chips; decoding the data; performing high-speed digital signal processing as necessary (e.g., scaling, diffusion, time delay, and error correction); encoding the data to create or modify molecular data packets via address and data strings; storing the programmable address connectivity amongst gene and protein circuits; and communicating data to other chips
  • r to a computer. For simplicity, the data in this paper were
collected with a data-acquisition board (NI PXI-6541) that interacted with our chip and with MATLAB on a computer. A high-performance FPGA (e.g., from the Xilinx Spartan family) could perform all of these functions in the future as well. Shift registers, SRAM blocks, and switches on the chip enable programmability of parameters (e.g., reaction rates, dissocia- tion constants, Hill coefficients, and time constants) as well as connectivity. The organization of this paper is as follows: Section II de- scribes the core building-block circuits of the chip along with chip measurement data. Fig. 2 shows a die micrograph of the chip that reveals the various building blocks. Section III dis- cusses design considerations that are important in BiCMOS cy- tomorphic chip design. Section IV discusses how cytomorphic 528 IEEE TRANSACTIONS ON BIOMEDICAL CIRCUITS AND SYSTEMS, VOL. 9, NO. 4, AUGUST 2015
  • Fig. 1. Poisson chemical reaction flux and Poisson electron flow in
sub-threshold transistors obey the same Boltzmann exponential laws of thermodynamics, and are therefore mathematically similar [13]. Electron copy number is analogous to molecular copy number and temperature represents itself. single cell on a few chips and speedup multi-cell simulations
  • n multi-chip electronic boards [13]. Therefore, we were moti-
vated to create a few fundamental molecular circuits that could be composed and scaled to model large biochemical reaction networks in the future. This paper describes these fundamental building-block cytomorphic circuits. The paper focuses on establishing quantitative agreement of the cytomorphic chip measurements with prior biological measurements and models. The building-block circuits may be classified into seven im- portant categories: 1) Basic BiCMOS current-mode analog circuits exploit the log-domain cytomorphic mapping to capture the exact dy- namics of fundamental mass-action molecular kinetics such as association, dissociation, and degradation. These fundamental circuits are general enough to capture subtle effects such as loading, fan-out, feedback, and substrate de- pletion through the use of a few explicit connections and Kirchhoff’s current law. A wide dynamic range of opera- tion and low power consumption are achieved through the use of bipolar and subthreshold MOS transistors that func- tion at low current levels. 2) The ability to model cooperative binding is enabled by tun- able Hill-function building-block circuits. 3) An “ITD” block built by a composition of above cur- rent-mode circuits enables mapping of the exact differen- tial equations of inducer-transcription-factor binding and transcription-factor-DNA binding including for- ward and reverse reactions, degradation, protection from degradation of transcription factors bound to DNA, and the change in DNA binding affinity of transcription factors when bound by an inducer. 4) An “analogic” current-mode circuit determines the tran- scription rate of genes based on the probability of mul- tiple transcription-factor DNA binding sites being occu- pied or unoccupied in a combinatorial fashion with the rel- ative mRNA production rate of each such combinatorial state programmable by the user. This strategy enables us to implement any arbitrary “analogic promoter function” that is capable of complex saturating digital logic or prob- abilistic analog behavior depending on the molecular con- centration. 5) A current-mode low pass filter (LPF) circuit enables the gain and dynamics of mRNA and protein production and degradation to be represented.
  • Fig. 2. Die micrograph of the
cytomorphic chip fabricated in an AMS BiCMOS process. The left inset is a layout screen capture
  • f one gene block (2x magnification).
6) A stochastics circuit intentionally amplifies analog Poisson noise in transistors to represent biological fluc- tuations in mRNA and protein concentrations at very low copy numbers and at relatively high noise levels. The Poisson nature of biochemical reaction fluxes au- tomatically maps biological noise to electronic noise at high copy numbers and relatively low noise levels [13]. Thus, these circuits are most useful for reliably modeling highly stochastic and relatively low signal-to-noise-ratios in biological cells. 7) ADCs and DACs convert between analog currents and digital bits to enable our chips to communicate with each
  • ther via digital input/output (I/O), and with off-chip dig-
ital processors and computers. Off-chip digital processors synergistically interact with our chips to carry out various functions: reading digital data from the chips; decoding the data; performing high-speed digital signal processing as necessary (e.g., scaling, diffusion, time delay, and error correction); encoding the data to create or modify molecular data packets via address and data strings; storing the programmable address connectivity amongst gene and protein circuits; and communicating data to other chips
  • r to a computer. For simplicity, the data in this paper were
collected with a data-acquisition board (NI PXI-6541) that interacted with our chip and with MATLAB on a computer. A high-performance FPGA (e.g., from the Xilinx Spartan family) could perform all of these functions in the future as well. Shift registers, SRAM blocks, and switches on the chip enable programmability of parameters (e.g., reaction rates, dissocia- tion constants, Hill coefficients, and time constants) as well as connectivity. The organization of this paper is as follows: Section II de- scribes the core building-block circuits of the chip along with chip measurement data. Fig. 2 shows a die micrograph of the chip that reveals the various building blocks. Section III dis- cusses design considerations that are important in BiCMOS cy- tomorphic chip design. Section IV discusses how cytomorphic 528 IEEE TRANSACTIONS ON BIOMEDICAL CIRCUITS AND SYSTEMS, VOL. 9, NO. 4, AUGUST 2015
  • Fig. 1. Poisson chemical reaction flux and Poisson electron flow in
sub-threshold transistors obey the same Boltzmann exponential laws of thermodynamics, and are therefore mathematically similar [13]. Electron copy number is analogous to molecular copy number and temperature represents itself. single cell on a few chips and speedup multi-cell simulations
  • n multi-chip electronic boards [13]. Therefore, we were moti-
vated to create a few fundamental molecular circuits that could be composed and scaled to model large biochemical reaction networks in the future. This paper describes these fundamental building-block cytomorphic circuits. The paper focuses on establishing quantitative agreement of the cytomorphic chip measurements with prior biological measurements and models. The building-block circuits may be classified into seven im- portant categories: 1) Basic BiCMOS current-mode analog circuits exploit the log-domain cytomorphic mapping to capture the exact dy- namics of fundamental mass-action molecular kinetics such as association, dissociation, and degradation. These fundamental circuits are general enough to capture subtle effects such as loading, fan-out, feedback, and substrate de- pletion through the use of a few explicit connections and Kirchhoff’s current law. A wide dynamic range of opera- tion and low power consumption are achieved through the use of bipolar and subthreshold MOS transistors that func- tion at low current levels. 2) The ability to model cooperative binding is enabled by tun- able Hill-function building-block circuits. 3) An “ITD” block built by a composition of above cur- rent-mode circuits enables mapping of the exact differen- tial equations of inducer-transcription-factor binding and transcription-factor-DNA binding including for- ward and reverse reactions, degradation, protection from degradation of transcription factors bound to DNA, and the change in DNA binding affinity of transcription factors when bound by an inducer. 4) An “analogic” current-mode circuit determines the tran- scription rate of genes based on the probability of mul- tiple transcription-factor DNA binding sites being occu- pied or unoccupied in a combinatorial fashion with the rel- ative mRNA production rate of each such combinatorial state programmable by the user. This strategy enables us to implement any arbitrary “analogic promoter function” that is capable of complex saturating digital logic or prob- abilistic analog behavior depending on the molecular con- centration. 5) A current-mode low pass filter (LPF) circuit enables the gain and dynamics of mRNA and protein production and degradation to be represented.
  • Fig. 2. Die micrograph of the
cytomorphic chip fabricated in an AMS BiCMOS process. The left inset is a layout screen capture
  • f one gene block (2x magnification).
6) A stochastics circuit intentionally amplifies analog Poisson noise in transistors to represent biological fluc- tuations in mRNA and protein concentrations at very low copy numbers and at relatively high noise levels. The Poisson nature of biochemical reaction fluxes au- tomatically maps biological noise to electronic noise at high copy numbers and relatively low noise levels [13]. Thus, these circuits are most useful for reliably modeling highly stochastic and relatively low signal-to-noise-ratios in biological cells. 7) ADCs and DACs convert between analog currents and digital bits to enable our chips to communicate with each
  • ther via digital input/output (I/O), and with off-chip dig-
ital processors and computers. Off-chip digital processors synergistically interact with our chips to carry out various functions: reading digital data from the chips; decoding the data; performing high-speed digital signal processing as necessary (e.g., scaling, diffusion, time delay, and error correction); encoding the data to create or modify molecular data packets via address and data strings; storing the programmable address connectivity amongst gene and protein circuits; and communicating data to other chips
  • r to a computer. For simplicity, the data in this paper were
collected with a data-acquisition board (NI PXI-6541) that interacted with our chip and with MATLAB on a computer. A high-performance FPGA (e.g., from the Xilinx Spartan family) could perform all of these functions in the future as well. Shift registers, SRAM blocks, and switches on the chip enable programmability of parameters (e.g., reaction rates, dissocia- tion constants, Hill coefficients, and time constants) as well as connectivity. The organization of this paper is as follows: Section II de- scribes the core building-block circuits of the chip along with chip measurement data. Fig. 2 shows a die micrograph of the chip that reveals the various building blocks. Section III dis- cusses design considerations that are important in BiCMOS cy- tomorphic chip design. Section IV discusses how cytomorphic 528 IEEE TRANSACTIONS ON BIOMEDICAL CIRCUITS AND SYSTEMS, VOL. 9, NO. 4, AUGUST 2015
  • Fig. 1. Poisson chemical reaction flux and Poisson electron flow in
sub-threshold transistors obey the same Boltzmann exponential laws of thermodynamics, and are therefore mathematically similar [13]. Electron copy number is analogous to molecular copy number and temperature represents itself. single cell on a few chips and speedup multi-cell simulations
  • n multi-chip electronic boards [13]. Therefore, we were moti-
vated to create a few fundamental molecular circuits that could be composed and scaled to model large biochemical reaction networks in the future. This paper describes these fundamental building-block cytomorphic circuits. The paper focuses on establishing quantitative agreement of the cytomorphic chip measurements with prior biological measurements and models. The building-block circuits may be classified into seven im- portant categories: 1) Basic BiCMOS current-mode analog circuits exploit the log-domain cytomorphic mapping to capture the exact dy- namics of fundamental mass-action molecular kinetics such as association, dissociation, and degradation. These fundamental circuits are general enough to capture subtle effects such as loading, fan-out, feedback, and substrate de- pletion through the use of a few explicit connections and Kirchhoff’s current law. A wide dynamic range of opera- tion and low power consumption are achieved through the use of bipolar and subthreshold MOS transistors that func- tion at low current levels. 2) The ability to model cooperative binding is enabled by tun- able Hill-function building-block circuits. 3) An “ITD” block built by a composition of above cur- rent-mode circuits enables mapping of the exact differen- tial equations of inducer-transcription-factor binding and transcription-factor-DNA binding including for- ward and reverse reactions, degradation, protection from degradation of transcription factors bound to DNA, and the change in DNA binding affinity of transcription factors when bound by an inducer. 4) An “analogic” current-mode circuit determines the tran- scription rate of genes based on the probability of mul- tiple transcription-factor DNA binding sites being occu- pied or unoccupied in a combinatorial fashion with the rel- ative mRNA production rate of each such combinatorial state programmable by the user. This strategy enables us to implement any arbitrary “analogic promoter function” that is capable of complex saturating digital logic or prob- abilistic analog behavior depending on the molecular con- centration. 5) A current-mode low pass filter (LPF) circuit enables the gain and dynamics of mRNA and protein production and degradation to be represented.
  • Fig. 2. Die micrograph of the
cytomorphic chip fabricated in an AMS BiCMOS process. The left inset is a layout screen capture
  • f one gene block (2x magnification).
6) A stochastics circuit intentionally amplifies analog Poisson noise in transistors to represent biological fluc- tuations in mRNA and protein concentrations at very low copy numbers and at relatively high noise levels. The Poisson nature of biochemical reaction fluxes au- tomatically maps biological noise to electronic noise at high copy numbers and relatively low noise levels [13]. Thus, these circuits are most useful for reliably modeling highly stochastic and relatively low signal-to-noise-ratios in biological cells. 7) ADCs and DACs convert between analog currents and digital bits to enable our chips to communicate with each
  • ther via digital input/output (I/O), and with off-chip dig-
ital processors and computers. Off-chip digital processors synergistically interact with our chips to carry out various functions: reading digital data from the chips; decoding the data; performing high-speed digital signal processing as necessary (e.g., scaling, diffusion, time delay, and error correction); encoding the data to create or modify molecular data packets via address and data strings; storing the programmable address connectivity amongst gene and protein circuits; and communicating data to other chips
  • r to a computer. For simplicity, the data in this paper were
collected with a data-acquisition board (NI PXI-6541) that interacted with our chip and with MATLAB on a computer. A high-performance FPGA (e.g., from the Xilinx Spartan family) could perform all of these functions in the future as well. Shift registers, SRAM blocks, and switches on the chip enable programmability of parameters (e.g., reaction rates, dissocia- tion constants, Hill coefficients, and time constants) as well as connectivity. The organization of this paper is as follows: Section II de- scribes the core building-block circuits of the chip along with chip measurement data. Fig. 2 shows a die micrograph of the chip that reveals the various building blocks. Section III dis- cusses design considerations that are important in BiCMOS cy- tomorphic chip design. Section IV discusses how cytomorphic

INTRODUCTION 12

· ES = kf ⋅ E ⋅ S − kr ⋅ ES x′′+ ax′+ x + ax2 = c3 L ⋅ I′′+ R ⋅ I′+ C−1 ⋅ I = 0 x′′+ c1x′+ c2x′′ = 0

Dynamical Systems

A COMPILER FOR PROGRAMMABLE ANALOG DEVICES

Programmable 
 Analog Devices

slide-13
SLIDE 13 528 IEEE TRANSACTIONS ON BIOMEDICAL CIRCUITS AND SYSTEMS, VOL. 9, NO. 4, AUGUST 2015
  • Fig. 1. Poisson chemical reaction flux and Poisson electron flow in
sub-threshold transistors obey the same Boltzmann exponential laws of thermodynamics, and are therefore mathematically similar [13]. Electron copy number is analogous to molecular copy number and temperature represents itself. single cell on a few chips and speedup multi-cell simulations
  • n multi-chip electronic boards [13]. Therefore, we were moti-
vated to create a few fundamental molecular circuits that could be composed and scaled to model large biochemical reaction networks in the future. This paper describes these fundamental building-block cytomorphic circuits. The paper focuses on establishing quantitative agreement of the cytomorphic chip measurements with prior biological measurements and models. The building-block circuits may be classified into seven im- portant categories: 1) Basic BiCMOS current-mode analog circuits exploit the log-domain cytomorphic mapping to capture the exact dy- namics of fundamental mass-action molecular kinetics such as association, dissociation, and degradation. These fundamental circuits are general enough to capture subtle effects such as loading, fan-out, feedback, and substrate de- pletion through the use of a few explicit connections and Kirchhoff’s current law. A wide dynamic range of opera- tion and low power consumption are achieved through the use of bipolar and subthreshold MOS transistors that func- tion at low current levels. 2) The ability to model cooperative binding is enabled by tun- able Hill-function building-block circuits. 3) An “ITD” block built by a composition of above cur- rent-mode circuits enables mapping of the exact differen- tial equations of inducer-transcription-factor binding and transcription-factor-DNA binding including for- ward and reverse reactions, degradation, protection from degradation of transcription factors bound to DNA, and the change in DNA binding affinity of transcription factors when bound by an inducer. 4) An “analogic” current-mode circuit determines the tran- scription rate of genes based on the probability of mul- tiple transcription-factor DNA binding sites being occu- pied or unoccupied in a combinatorial fashion with the rel- ative mRNA production rate of each such combinatorial state programmable by the user. This strategy enables us to implement any arbitrary “analogic promoter function” that is capable of complex saturating digital logic or prob- abilistic analog behavior depending on the molecular con- centration. 5) A current-mode low pass filter (LPF) circuit enables the gain and dynamics of mRNA and protein production and degradation to be represented.
  • Fig. 2. Die micrograph of the
cytomorphic chip fabricated in an AMS BiCMOS process. The left inset is a layout screen capture
  • f one gene block (2x magnification).
6) A stochastics circuit intentionally amplifies analog Poisson noise in transistors to represent biological fluc- tuations in mRNA and protein concentrations at very low copy numbers and at relatively high noise levels. The Poisson nature of biochemical reaction fluxes au- tomatically maps biological noise to electronic noise at high copy numbers and relatively low noise levels [13]. Thus, these circuits are most useful for reliably modeling highly stochastic and relatively low signal-to-noise-ratios in biological cells. 7) ADCs and DACs convert between analog currents and digital bits to enable our chips to communicate with each
  • ther via digital input/output (I/O), and with off-chip dig-
ital processors and computers. Off-chip digital processors synergistically interact with our chips to carry out various functions: reading digital data from the chips; decoding the data; performing high-speed digital signal processing as necessary (e.g., scaling, diffusion, time delay, and error correction); encoding the data to create or modify molecular data packets via address and data strings; storing the programmable address connectivity amongst gene and protein circuits; and communicating data to other chips
  • r to a computer. For simplicity, the data in this paper were
collected with a data-acquisition board (NI PXI-6541) that interacted with our chip and with MATLAB on a computer. A high-performance FPGA (e.g., from the Xilinx Spartan family) could perform all of these functions in the future as well. Shift registers, SRAM blocks, and switches on the chip enable programmability of parameters (e.g., reaction rates, dissocia- tion constants, Hill coefficients, and time constants) as well as connectivity. The organization of this paper is as follows: Section II de- scribes the core building-block circuits of the chip along with chip measurement data. Fig. 2 shows a die micrograph of the chip that reveals the various building blocks. Section III dis- cusses design considerations that are important in BiCMOS cy- tomorphic chip design. Section IV discusses how cytomorphic 528 IEEE TRANSACTIONS ON BIOMEDICAL CIRCUITS AND SYSTEMS, VOL. 9, NO. 4, AUGUST 2015
  • Fig. 1. Poisson chemical reaction flux and Poisson electron flow in
sub-threshold transistors obey the same Boltzmann exponential laws of thermodynamics, and are therefore mathematically similar [13]. Electron copy number is analogous to molecular copy number and temperature represents itself. single cell on a few chips and speedup multi-cell simulations
  • n multi-chip electronic boards [13]. Therefore, we were moti-
vated to create a few fundamental molecular circuits that could be composed and scaled to model large biochemical reaction networks in the future. This paper describes these fundamental building-block cytomorphic circuits. The paper focuses on establishing quantitative agreement of the cytomorphic chip measurements with prior biological measurements and models. The building-block circuits may be classified into seven im- portant categories: 1) Basic BiCMOS current-mode analog circuits exploit the log-domain cytomorphic mapping to capture the exact dy- namics of fundamental mass-action molecular kinetics such as association, dissociation, and degradation. These fundamental circuits are general enough to capture subtle effects such as loading, fan-out, feedback, and substrate de- pletion through the use of a few explicit connections and Kirchhoff’s current law. A wide dynamic range of opera- tion and low power consumption are achieved through the use of bipolar and subthreshold MOS transistors that func- tion at low current levels. 2) The ability to model cooperative binding is enabled by tun- able Hill-function building-block circuits. 3) An “ITD” block built by a composition of above cur- rent-mode circuits enables mapping of the exact differen- tial equations of inducer-transcription-factor binding and transcription-factor-DNA binding including for- ward and reverse reactions, degradation, protection from degradation of transcription factors bound to DNA, and the change in DNA binding affinity of transcription factors when bound by an inducer. 4) An “analogic” current-mode circuit determines the tran- scription rate of genes based on the probability of mul- tiple transcription-factor DNA binding sites being occu- pied or unoccupied in a combinatorial fashion with the rel- ative mRNA production rate of each such combinatorial state programmable by the user. This strategy enables us to implement any arbitrary “analogic promoter function” that is capable of complex saturating digital logic or prob- abilistic analog behavior depending on the molecular con- centration. 5) A current-mode low pass filter (LPF) circuit enables the gain and dynamics of mRNA and protein production and degradation to be represented.
  • Fig. 2. Die micrograph of the
cytomorphic chip fabricated in an AMS BiCMOS process. The left inset is a layout screen capture
  • f one gene block (2x magnification).
6) A stochastics circuit intentionally amplifies analog Poisson noise in transistors to represent biological fluc- tuations in mRNA and protein concentrations at very low copy numbers and at relatively high noise levels. The Poisson nature of biochemical reaction fluxes au- tomatically maps biological noise to electronic noise at high copy numbers and relatively low noise levels [13]. Thus, these circuits are most useful for reliably modeling highly stochastic and relatively low signal-to-noise-ratios in biological cells. 7) ADCs and DACs convert between analog currents and digital bits to enable our chips to communicate with each
  • ther via digital input/output (I/O), and with off-chip dig-
ital processors and computers. Off-chip digital processors synergistically interact with our chips to carry out various functions: reading digital data from the chips; decoding the data; performing high-speed digital signal processing as necessary (e.g., scaling, diffusion, time delay, and error correction); encoding the data to create or modify molecular data packets via address and data strings; storing the programmable address connectivity amongst gene and protein circuits; and communicating data to other chips
  • r to a computer. For simplicity, the data in this paper were
collected with a data-acquisition board (NI PXI-6541) that interacted with our chip and with MATLAB on a computer. A high-performance FPGA (e.g., from the Xilinx Spartan family) could perform all of these functions in the future as well. Shift registers, SRAM blocks, and switches on the chip enable programmability of parameters (e.g., reaction rates, dissocia- tion constants, Hill coefficients, and time constants) as well as connectivity. The organization of this paper is as follows: Section II de- scribes the core building-block circuits of the chip along with chip measurement data. Fig. 2 shows a die micrograph of the chip that reveals the various building blocks. Section III dis- cusses design considerations that are important in BiCMOS cy- tomorphic chip design. Section IV discusses how cytomorphic 528 IEEE TRANSACTIONS ON BIOMEDICAL CIRCUITS AND SYSTEMS, VOL. 9, NO. 4, AUGUST 2015
  • Fig. 1. Poisson chemical reaction flux and Poisson electron flow in
sub-threshold transistors obey the same Boltzmann exponential laws of thermodynamics, and are therefore mathematically similar [13]. Electron copy number is analogous to molecular copy number and temperature represents itself. single cell on a few chips and speedup multi-cell simulations
  • n multi-chip electronic boards [13]. Therefore, we were moti-
vated to create a few fundamental molecular circuits that could be composed and scaled to model large biochemical reaction networks in the future. This paper describes these fundamental building-block cytomorphic circuits. The paper focuses on establishing quantitative agreement of the cytomorphic chip measurements with prior biological measurements and models. The building-block circuits may be classified into seven im- portant categories: 1) Basic BiCMOS current-mode analog circuits exploit the log-domain cytomorphic mapping to capture the exact dy- namics of fundamental mass-action molecular kinetics such as association, dissociation, and degradation. These fundamental circuits are general enough to capture subtle effects such as loading, fan-out, feedback, and substrate de- pletion through the use of a few explicit connections and Kirchhoff’s current law. A wide dynamic range of opera- tion and low power consumption are achieved through the use of bipolar and subthreshold MOS transistors that func- tion at low current levels. 2) The ability to model cooperative binding is enabled by tun- able Hill-function building-block circuits. 3) An “ITD” block built by a composition of above cur- rent-mode circuits enables mapping of the exact differen- tial equations of inducer-transcription-factor binding and transcription-factor-DNA binding including for- ward and reverse reactions, degradation, protection from degradation of transcription factors bound to DNA, and the change in DNA binding affinity of transcription factors when bound by an inducer. 4) An “analogic” current-mode circuit determines the tran- scription rate of genes based on the probability of mul- tiple transcription-factor DNA binding sites being occu- pied or unoccupied in a combinatorial fashion with the rel- ative mRNA production rate of each such combinatorial state programmable by the user. This strategy enables us to implement any arbitrary “analogic promoter function” that is capable of complex saturating digital logic or prob- abilistic analog behavior depending on the molecular con- centration. 5) A current-mode low pass filter (LPF) circuit enables the gain and dynamics of mRNA and protein production and degradation to be represented.
  • Fig. 2. Die micrograph of the
cytomorphic chip fabricated in an AMS BiCMOS process. The left inset is a layout screen capture
  • f one gene block (2x magnification).
6) A stochastics circuit intentionally amplifies analog Poisson noise in transistors to represent biological fluc- tuations in mRNA and protein concentrations at very low copy numbers and at relatively high noise levels. The Poisson nature of biochemical reaction fluxes au- tomatically maps biological noise to electronic noise at high copy numbers and relatively low noise levels [13]. Thus, these circuits are most useful for reliably modeling highly stochastic and relatively low signal-to-noise-ratios in biological cells. 7) ADCs and DACs convert between analog currents and digital bits to enable our chips to communicate with each
  • ther via digital input/output (I/O), and with off-chip dig-
ital processors and computers. Off-chip digital processors synergistically interact with our chips to carry out various functions: reading digital data from the chips; decoding the data; performing high-speed digital signal processing as necessary (e.g., scaling, diffusion, time delay, and error correction); encoding the data to create or modify molecular data packets via address and data strings; storing the programmable address connectivity amongst gene and protein circuits; and communicating data to other chips
  • r to a computer. For simplicity, the data in this paper were
collected with a data-acquisition board (NI PXI-6541) that interacted with our chip and with MATLAB on a computer. A high-performance FPGA (e.g., from the Xilinx Spartan family) could perform all of these functions in the future as well. Shift registers, SRAM blocks, and switches on the chip enable programmability of parameters (e.g., reaction rates, dissocia- tion constants, Hill coefficients, and time constants) as well as connectivity. The organization of this paper is as follows: Section II de- scribes the core building-block circuits of the chip along with chip measurement data. Fig. 2 shows a die micrograph of the chip that reveals the various building blocks. Section III dis- cusses design considerations that are important in BiCMOS cy- tomorphic chip design. Section IV discusses how cytomorphic 528 IEEE TRANSACTIONS ON BIOMEDICAL CIRCUITS AND SYSTEMS, VOL. 9, NO. 4, AUGUST 2015
  • Fig. 1. Poisson chemical reaction flux and Poisson electron flow in
sub-threshold transistors obey the same Boltzmann exponential laws of thermodynamics, and are therefore mathematically similar [13]. Electron copy number is analogous to molecular copy number and temperature represents itself. single cell on a few chips and speedup multi-cell simulations
  • n multi-chip electronic boards [13]. Therefore, we were moti-
vated to create a few fundamental molecular circuits that could be composed and scaled to model large biochemical reaction networks in the future. This paper describes these fundamental building-block cytomorphic circuits. The paper focuses on establishing quantitative agreement of the cytomorphic chip measurements with prior biological measurements and models. The building-block circuits may be classified into seven im- portant categories: 1) Basic BiCMOS current-mode analog circuits exploit the log-domain cytomorphic mapping to capture the exact dy- namics of fundamental mass-action molecular kinetics such as association, dissociation, and degradation. These fundamental circuits are general enough to capture subtle effects such as loading, fan-out, feedback, and substrate de- pletion through the use of a few explicit connections and Kirchhoff’s current law. A wide dynamic range of opera- tion and low power consumption are achieved through the use of bipolar and subthreshold MOS transistors that func- tion at low current levels. 2) The ability to model cooperative binding is enabled by tun- able Hill-function building-block circuits. 3) An “ITD” block built by a composition of above cur- rent-mode circuits enables mapping of the exact differen- tial equations of inducer-transcription-factor binding and transcription-factor-DNA binding including for- ward and reverse reactions, degradation, protection from degradation of transcription factors bound to DNA, and the change in DNA binding affinity of transcription factors when bound by an inducer. 4) An “analogic” current-mode circuit determines the tran- scription rate of genes based on the probability of mul- tiple transcription-factor DNA binding sites being occu- pied or unoccupied in a combinatorial fashion with the rel- ative mRNA production rate of each such combinatorial state programmable by the user. This strategy enables us to implement any arbitrary “analogic promoter function” that is capable of complex saturating digital logic or prob- abilistic analog behavior depending on the molecular con- centration. 5) A current-mode low pass filter (LPF) circuit enables the gain and dynamics of mRNA and protein production and degradation to be represented.
  • Fig. 2. Die micrograph of the
cytomorphic chip fabricated in an AMS BiCMOS process. The left inset is a layout screen capture
  • f one gene block (2x magnification).
6) A stochastics circuit intentionally amplifies analog Poisson noise in transistors to represent biological fluc- tuations in mRNA and protein concentrations at very low copy numbers and at relatively high noise levels. The Poisson nature of biochemical reaction fluxes au- tomatically maps biological noise to electronic noise at high copy numbers and relatively low noise levels [13]. Thus, these circuits are most useful for reliably modeling highly stochastic and relatively low signal-to-noise-ratios in biological cells. 7) ADCs and DACs convert between analog currents and digital bits to enable our chips to communicate with each
  • ther via digital input/output (I/O), and with off-chip dig-
ital processors and computers. Off-chip digital processors synergistically interact with our chips to carry out various functions: reading digital data from the chips; decoding the data; performing high-speed digital signal processing as necessary (e.g., scaling, diffusion, time delay, and error correction); encoding the data to create or modify molecular data packets via address and data strings; storing the programmable address connectivity amongst gene and protein circuits; and communicating data to other chips
  • r to a computer. For simplicity, the data in this paper were
collected with a data-acquisition board (NI PXI-6541) that interacted with our chip and with MATLAB on a computer. A high-performance FPGA (e.g., from the Xilinx Spartan family) could perform all of these functions in the future as well. Shift registers, SRAM blocks, and switches on the chip enable programmability of parameters (e.g., reaction rates, dissocia- tion constants, Hill coefficients, and time constants) as well as connectivity. The organization of this paper is as follows: Section II de- scribes the core building-block circuits of the chip along with chip measurement data. Fig. 2 shows a die micrograph of the chip that reveals the various building blocks. Section III dis- cusses design considerations that are important in BiCMOS cy- tomorphic chip design. Section IV discusses how cytomorphic 528 IEEE TRANSACTIONS ON BIOMEDICAL CIRCUITS AND SYSTEMS, VOL. 9, NO. 4, AUGUST 2015
  • Fig. 1. Poisson chemical reaction flux and Poisson electron flow in
sub-threshold transistors obey the same Boltzmann exponential laws of thermodynamics, and are therefore mathematically similar [13]. Electron copy number is analogous to molecular copy number and temperature represents itself. single cell on a few chips and speedup multi-cell simulations
  • n multi-chip electronic boards [13]. Therefore, we were moti-
vated to create a few fundamental molecular circuits that could be composed and scaled to model large biochemical reaction networks in the future. This paper describes these fundamental building-block cytomorphic circuits. The paper focuses on establishing quantitative agreement of the cytomorphic chip measurements with prior biological measurements and models. The building-block circuits may be classified into seven im- portant categories: 1) Basic BiCMOS current-mode analog circuits exploit the log-domain cytomorphic mapping to capture the exact dy- namics of fundamental mass-action molecular kinetics such as association, dissociation, and degradation. These fundamental circuits are general enough to capture subtle effects such as loading, fan-out, feedback, and substrate de- pletion through the use of a few explicit connections and Kirchhoff’s current law. A wide dynamic range of opera- tion and low power consumption are achieved through the use of bipolar and subthreshold MOS transistors that func- tion at low current levels. 2) The ability to model cooperative binding is enabled by tun- able Hill-function building-block circuits. 3) An “ITD” block built by a composition of above cur- rent-mode circuits enables mapping of the exact differen- tial equations of inducer-transcription-factor binding and transcription-factor-DNA binding including for- ward and reverse reactions, degradation, protection from degradation of transcription factors bound to DNA, and the change in DNA binding affinity of transcription factors when bound by an inducer. 4) An “analogic” current-mode circuit determines the tran- scription rate of genes based on the probability of mul- tiple transcription-factor DNA binding sites being occu- pied or unoccupied in a combinatorial fashion with the rel- ative mRNA production rate of each such combinatorial state programmable by the user. This strategy enables us to implement any arbitrary “analogic promoter function” that is capable of complex saturating digital logic or prob- abilistic analog behavior depending on the molecular con- centration. 5) A current-mode low pass filter (LPF) circuit enables the gain and dynamics of mRNA and protein production and degradation to be represented.
  • Fig. 2. Die micrograph of the
cytomorphic chip fabricated in an AMS BiCMOS process. The left inset is a layout screen capture
  • f one gene block (2x magnification).
6) A stochastics circuit intentionally amplifies analog Poisson noise in transistors to represent biological fluc- tuations in mRNA and protein concentrations at very low copy numbers and at relatively high noise levels. The Poisson nature of biochemical reaction fluxes au- tomatically maps biological noise to electronic noise at high copy numbers and relatively low noise levels [13]. Thus, these circuits are most useful for reliably modeling highly stochastic and relatively low signal-to-noise-ratios in biological cells. 7) ADCs and DACs convert between analog currents and digital bits to enable our chips to communicate with each
  • ther via digital input/output (I/O), and with off-chip dig-
ital processors and computers. Off-chip digital processors synergistically interact with our chips to carry out various functions: reading digital data from the chips; decoding the data; performing high-speed digital signal processing as necessary (e.g., scaling, diffusion, time delay, and error correction); encoding the data to create or modify molecular data packets via address and data strings; storing the programmable address connectivity amongst gene and protein circuits; and communicating data to other chips
  • r to a computer. For simplicity, the data in this paper were
collected with a data-acquisition board (NI PXI-6541) that interacted with our chip and with MATLAB on a computer. A high-performance FPGA (e.g., from the Xilinx Spartan family) could perform all of these functions in the future as well. Shift registers, SRAM blocks, and switches on the chip enable programmability of parameters (e.g., reaction rates, dissocia- tion constants, Hill coefficients, and time constants) as well as connectivity. The organization of this paper is as follows: Section II de- scribes the core building-block circuits of the chip along with chip measurement data. Fig. 2 shows a die micrograph of the chip that reveals the various building blocks. Section III dis- cusses design considerations that are important in BiCMOS cy- tomorphic chip design. Section IV discusses how cytomorphic

INTRODUCTION 13

· ES = kf ⋅ E ⋅ S − kr ⋅ ES x′′+ ax′+ x + ax2 = c3 L ⋅ I′′+ R ⋅ I′+ C−1 ⋅ I = 0 x′′+ c1x′+ c2x′′ = 0

Dynamical Systems compose complex algebraic building blocks reason about operating ranges + circuit noise automatically automatically Programmable 
 Analog Devices

slide-14
SLIDE 14 528 IEEE TRANSACTIONS ON BIOMEDICAL CIRCUITS AND SYSTEMS, VOL. 9, NO. 4, AUGUST 2015
  • Fig. 1. Poisson chemical reaction flux and Poisson electron flow in
sub-threshold transistors obey the same Boltzmann exponential laws of thermodynamics, and are therefore mathematically similar [13]. Electron copy number is analogous to molecular copy number and temperature represents itself. single cell on a few chips and speedup multi-cell simulations
  • n multi-chip electronic boards [13]. Therefore, we were moti-
vated to create a few fundamental molecular circuits that could be composed and scaled to model large biochemical reaction networks in the future. This paper describes these fundamental building-block cytomorphic circuits. The paper focuses on establishing quantitative agreement of the cytomorphic chip measurements with prior biological measurements and models. The building-block circuits may be classified into seven im- portant categories: 1) Basic BiCMOS current-mode analog circuits exploit the log-domain cytomorphic mapping to capture the exact dy- namics of fundamental mass-action molecular kinetics such as association, dissociation, and degradation. These fundamental circuits are general enough to capture subtle effects such as loading, fan-out, feedback, and substrate de- pletion through the use of a few explicit connections and Kirchhoff’s current law. A wide dynamic range of opera- tion and low power consumption are achieved through the use of bipolar and subthreshold MOS transistors that func- tion at low current levels. 2) The ability to model cooperative binding is enabled by tun- able Hill-function building-block circuits. 3) An “ITD” block built by a composition of above cur- rent-mode circuits enables mapping of the exact differen- tial equations of inducer-transcription-factor binding and transcription-factor-DNA binding including for- ward and reverse reactions, degradation, protection from degradation of transcription factors bound to DNA, and the change in DNA binding affinity of transcription factors when bound by an inducer. 4) An “analogic” current-mode circuit determines the tran- scription rate of genes based on the probability of mul- tiple transcription-factor DNA binding sites being occu- pied or unoccupied in a combinatorial fashion with the rel- ative mRNA production rate of each such combinatorial state programmable by the user. This strategy enables us to implement any arbitrary “analogic promoter function” that is capable of complex saturating digital logic or prob- abilistic analog behavior depending on the molecular con- centration. 5) A current-mode low pass filter (LPF) circuit enables the gain and dynamics of mRNA and protein production and degradation to be represented.
  • Fig. 2. Die micrograph of the
cytomorphic chip fabricated in an AMS BiCMOS process. The left inset is a layout screen capture
  • f one gene block (2x magnification).
6) A stochastics circuit intentionally amplifies analog Poisson noise in transistors to represent biological fluc- tuations in mRNA and protein concentrations at very low copy numbers and at relatively high noise levels. The Poisson nature of biochemical reaction fluxes au- tomatically maps biological noise to electronic noise at high copy numbers and relatively low noise levels [13]. Thus, these circuits are most useful for reliably modeling highly stochastic and relatively low signal-to-noise-ratios in biological cells. 7) ADCs and DACs convert between analog currents and digital bits to enable our chips to communicate with each
  • ther via digital input/output (I/O), and with off-chip dig-
ital processors and computers. Off-chip digital processors synergistically interact with our chips to carry out various functions: reading digital data from the chips; decoding the data; performing high-speed digital signal processing as necessary (e.g., scaling, diffusion, time delay, and error correction); encoding the data to create or modify molecular data packets via address and data strings; storing the programmable address connectivity amongst gene and protein circuits; and communicating data to other chips
  • r to a computer. For simplicity, the data in this paper were
collected with a data-acquisition board (NI PXI-6541) that interacted with our chip and with MATLAB on a computer. A high-performance FPGA (e.g., from the Xilinx Spartan family) could perform all of these functions in the future as well. Shift registers, SRAM blocks, and switches on the chip enable programmability of parameters (e.g., reaction rates, dissocia- tion constants, Hill coefficients, and time constants) as well as connectivity. The organization of this paper is as follows: Section II de- scribes the core building-block circuits of the chip along with chip measurement data. Fig. 2 shows a die micrograph of the chip that reveals the various building blocks. Section III dis- cusses design considerations that are important in BiCMOS cy- tomorphic chip design. Section IV discusses how cytomorphic 528 IEEE TRANSACTIONS ON BIOMEDICAL CIRCUITS AND SYSTEMS, VOL. 9, NO. 4, AUGUST 2015
  • Fig. 1. Poisson chemical reaction flux and Poisson electron flow in
sub-threshold transistors obey the same Boltzmann exponential laws of thermodynamics, and are therefore mathematically similar [13]. Electron copy number is analogous to molecular copy number and temperature represents itself. single cell on a few chips and speedup multi-cell simulations
  • n multi-chip electronic boards [13]. Therefore, we were moti-
vated to create a few fundamental molecular circuits that could be composed and scaled to model large biochemical reaction networks in the future. This paper describes these fundamental building-block cytomorphic circuits. The paper focuses on establishing quantitative agreement of the cytomorphic chip measurements with prior biological measurements and models. The building-block circuits may be classified into seven im- portant categories: 1) Basic BiCMOS current-mode analog circuits exploit the log-domain cytomorphic mapping to capture the exact dy- namics of fundamental mass-action molecular kinetics such as association, dissociation, and degradation. These fundamental circuits are general enough to capture subtle effects such as loading, fan-out, feedback, and substrate de- pletion through the use of a few explicit connections and Kirchhoff’s current law. A wide dynamic range of opera- tion and low power consumption are achieved through the use of bipolar and subthreshold MOS transistors that func- tion at low current levels. 2) The ability to model cooperative binding is enabled by tun- able Hill-function building-block circuits. 3) An “ITD” block built by a composition of above cur- rent-mode circuits enables mapping of the exact differen- tial equations of inducer-transcription-factor binding and transcription-factor-DNA binding including for- ward and reverse reactions, degradation, protection from degradation of transcription factors bound to DNA, and the change in DNA binding affinity of transcription factors when bound by an inducer. 4) An “analogic” current-mode circuit determines the tran- scription rate of genes based on the probability of mul- tiple transcription-factor DNA binding sites being occu- pied or unoccupied in a combinatorial fashion with the rel- ative mRNA production rate of each such combinatorial state programmable by the user. This strategy enables us to implement any arbitrary “analogic promoter function” that is capable of complex saturating digital logic or prob- abilistic analog behavior depending on the molecular con- centration. 5) A current-mode low pass filter (LPF) circuit enables the gain and dynamics of mRNA and protein production and degradation to be represented.
  • Fig. 2. Die micrograph of the
cytomorphic chip fabricated in an AMS BiCMOS process. The left inset is a layout screen capture
  • f one gene block (2x magnification).
6) A stochastics circuit intentionally amplifies analog Poisson noise in transistors to represent biological fluc- tuations in mRNA and protein concentrations at very low copy numbers and at relatively high noise levels. The Poisson nature of biochemical reaction fluxes au- tomatically maps biological noise to electronic noise at high copy numbers and relatively low noise levels [13]. Thus, these circuits are most useful for reliably modeling highly stochastic and relatively low signal-to-noise-ratios in biological cells. 7) ADCs and DACs convert between analog currents and digital bits to enable our chips to communicate with each
  • ther via digital input/output (I/O), and with off-chip dig-
ital processors and computers. Off-chip digital processors synergistically interact with our chips to carry out various functions: reading digital data from the chips; decoding the data; performing high-speed digital signal processing as necessary (e.g., scaling, diffusion, time delay, and error correction); encoding the data to create or modify molecular data packets via address and data strings; storing the programmable address connectivity amongst gene and protein circuits; and communicating data to other chips
  • r to a computer. For simplicity, the data in this paper were
collected with a data-acquisition board (NI PXI-6541) that interacted with our chip and with MATLAB on a computer. A high-performance FPGA (e.g., from the Xilinx Spartan family) could perform all of these functions in the future as well. Shift registers, SRAM blocks, and switches on the chip enable programmability of parameters (e.g., reaction rates, dissocia- tion constants, Hill coefficients, and time constants) as well as connectivity. The organization of this paper is as follows: Section II de- scribes the core building-block circuits of the chip along with chip measurement data. Fig. 2 shows a die micrograph of the chip that reveals the various building blocks. Section III dis- cusses design considerations that are important in BiCMOS cy- tomorphic chip design. Section IV discusses how cytomorphic 528 IEEE TRANSACTIONS ON BIOMEDICAL CIRCUITS AND SYSTEMS, VOL. 9, NO. 4, AUGUST 2015
  • Fig. 1. Poisson chemical reaction flux and Poisson electron flow in
sub-threshold transistors obey the same Boltzmann exponential laws of thermodynamics, and are therefore mathematically similar [13]. Electron copy number is analogous to molecular copy number and temperature represents itself. single cell on a few chips and speedup multi-cell simulations
  • n multi-chip electronic boards [13]. Therefore, we were moti-
vated to create a few fundamental molecular circuits that could be composed and scaled to model large biochemical reaction networks in the future. This paper describes these fundamental building-block cytomorphic circuits. The paper focuses on establishing quantitative agreement of the cytomorphic chip measurements with prior biological measurements and models. The building-block circuits may be classified into seven im- portant categories: 1) Basic BiCMOS current-mode analog circuits exploit the log-domain cytomorphic mapping to capture the exact dy- namics of fundamental mass-action molecular kinetics such as association, dissociation, and degradation. These fundamental circuits are general enough to capture subtle effects such as loading, fan-out, feedback, and substrate de- pletion through the use of a few explicit connections and Kirchhoff’s current law. A wide dynamic range of opera- tion and low power consumption are achieved through the use of bipolar and subthreshold MOS transistors that func- tion at low current levels. 2) The ability to model cooperative binding is enabled by tun- able Hill-function building-block circuits. 3) An “ITD” block built by a composition of above cur- rent-mode circuits enables mapping of the exact differen- tial equations of inducer-transcription-factor binding and transcription-factor-DNA binding including for- ward and reverse reactions, degradation, protection from degradation of transcription factors bound to DNA, and the change in DNA binding affinity of transcription factors when bound by an inducer. 4) An “analogic” current-mode circuit determines the tran- scription rate of genes based on the probability of mul- tiple transcription-factor DNA binding sites being occu- pied or unoccupied in a combinatorial fashion with the rel- ative mRNA production rate of each such combinatorial state programmable by the user. This strategy enables us to implement any arbitrary “analogic promoter function” that is capable of complex saturating digital logic or prob- abilistic analog behavior depending on the molecular con- centration. 5) A current-mode low pass filter (LPF) circuit enables the gain and dynamics of mRNA and protein production and degradation to be represented.
  • Fig. 2. Die micrograph of the
cytomorphic chip fabricated in an AMS BiCMOS process. The left inset is a layout screen capture
  • f one gene block (2x magnification).
6) A stochastics circuit intentionally amplifies analog Poisson noise in transistors to represent biological fluc- tuations in mRNA and protein concentrations at very low copy numbers and at relatively high noise levels. The Poisson nature of biochemical reaction fluxes au- tomatically maps biological noise to electronic noise at high copy numbers and relatively low noise levels [13]. Thus, these circuits are most useful for reliably modeling highly stochastic and relatively low signal-to-noise-ratios in biological cells. 7) ADCs and DACs convert between analog currents and digital bits to enable our chips to communicate with each
  • ther via digital input/output (I/O), and with off-chip dig-
ital processors and computers. Off-chip digital processors synergistically interact with our chips to carry out various functions: reading digital data from the chips; decoding the data; performing high-speed digital signal processing as necessary (e.g., scaling, diffusion, time delay, and error correction); encoding the data to create or modify molecular data packets via address and data strings; storing the programmable address connectivity amongst gene and protein circuits; and communicating data to other chips
  • r to a computer. For simplicity, the data in this paper were
collected with a data-acquisition board (NI PXI-6541) that interacted with our chip and with MATLAB on a computer. A high-performance FPGA (e.g., from the Xilinx Spartan family) could perform all of these functions in the future as well. Shift registers, SRAM blocks, and switches on the chip enable programmability of parameters (e.g., reaction rates, dissocia- tion constants, Hill coefficients, and time constants) as well as connectivity. The organization of this paper is as follows: Section II de- scribes the core building-block circuits of the chip along with chip measurement data. Fig. 2 shows a die micrograph of the chip that reveals the various building blocks. Section III dis- cusses design considerations that are important in BiCMOS cy- tomorphic chip design. Section IV discusses how cytomorphic 528 IEEE TRANSACTIONS ON BIOMEDICAL CIRCUITS AND SYSTEMS, VOL. 9, NO. 4, AUGUST 2015
  • Fig. 1. Poisson chemical reaction flux and Poisson electron flow in
sub-threshold transistors obey the same Boltzmann exponential laws of thermodynamics, and are therefore mathematically similar [13]. Electron copy number is analogous to molecular copy number and temperature represents itself. single cell on a few chips and speedup multi-cell simulations
  • n multi-chip electronic boards [13]. Therefore, we were moti-
vated to create a few fundamental molecular circuits that could be composed and scaled to model large biochemical reaction networks in the future. This paper describes these fundamental building-block cytomorphic circuits. The paper focuses on establishing quantitative agreement of the cytomorphic chip measurements with prior biological measurements and models. The building-block circuits may be classified into seven im- portant categories: 1) Basic BiCMOS current-mode analog circuits exploit the log-domain cytomorphic mapping to capture the exact dy- namics of fundamental mass-action molecular kinetics such as association, dissociation, and degradation. These fundamental circuits are general enough to capture subtle effects such as loading, fan-out, feedback, and substrate de- pletion through the use of a few explicit connections and Kirchhoff’s current law. A wide dynamic range of opera- tion and low power consumption are achieved through the use of bipolar and subthreshold MOS transistors that func- tion at low current levels. 2) The ability to model cooperative binding is enabled by tun- able Hill-function building-block circuits. 3) An “ITD” block built by a composition of above cur- rent-mode circuits enables mapping of the exact differen- tial equations of inducer-transcription-factor binding and transcription-factor-DNA binding including for- ward and reverse reactions, degradation, protection from degradation of transcription factors bound to DNA, and the change in DNA binding affinity of transcription factors when bound by an inducer. 4) An “analogic” current-mode circuit determines the tran- scription rate of genes based on the probability of mul- tiple transcription-factor DNA binding sites being occu- pied or unoccupied in a combinatorial fashion with the rel- ative mRNA production rate of each such combinatorial state programmable by the user. This strategy enables us to implement any arbitrary “analogic promoter function” that is capable of complex saturating digital logic or prob- abilistic analog behavior depending on the molecular con- centration. 5) A current-mode low pass filter (LPF) circuit enables the gain and dynamics of mRNA and protein production and degradation to be represented.
  • Fig. 2. Die micrograph of the
cytomorphic chip fabricated in an AMS BiCMOS process. The left inset is a layout screen capture
  • f one gene block (2x magnification).
6) A stochastics circuit intentionally amplifies analog Poisson noise in transistors to represent biological fluc- tuations in mRNA and protein concentrations at very low copy numbers and at relatively high noise levels. The Poisson nature of biochemical reaction fluxes au- tomatically maps biological noise to electronic noise at high copy numbers and relatively low noise levels [13]. Thus, these circuits are most useful for reliably modeling highly stochastic and relatively low signal-to-noise-ratios in biological cells. 7) ADCs and DACs convert between analog currents and digital bits to enable our chips to communicate with each
  • ther via digital input/output (I/O), and with off-chip dig-
ital processors and computers. Off-chip digital processors synergistically interact with our chips to carry out various functions: reading digital data from the chips; decoding the data; performing high-speed digital signal processing as necessary (e.g., scaling, diffusion, time delay, and error correction); encoding the data to create or modify molecular data packets via address and data strings; storing the programmable address connectivity amongst gene and protein circuits; and communicating data to other chips
  • r to a computer. For simplicity, the data in this paper were
collected with a data-acquisition board (NI PXI-6541) that interacted with our chip and with MATLAB on a computer. A high-performance FPGA (e.g., from the Xilinx Spartan family) could perform all of these functions in the future as well. Shift registers, SRAM blocks, and switches on the chip enable programmability of parameters (e.g., reaction rates, dissocia- tion constants, Hill coefficients, and time constants) as well as connectivity. The organization of this paper is as follows: Section II de- scribes the core building-block circuits of the chip along with chip measurement data. Fig. 2 shows a die micrograph of the chip that reveals the various building blocks. Section III dis- cusses design considerations that are important in BiCMOS cy- tomorphic chip design. Section IV discusses how cytomorphic 528 IEEE TRANSACTIONS ON BIOMEDICAL CIRCUITS AND SYSTEMS, VOL. 9, NO. 4, AUGUST 2015
  • Fig. 1. Poisson chemical reaction flux and Poisson electron flow in
sub-threshold transistors obey the same Boltzmann exponential laws of thermodynamics, and are therefore mathematically similar [13]. Electron copy number is analogous to molecular copy number and temperature represents itself. single cell on a few chips and speedup multi-cell simulations
  • n multi-chip electronic boards [13]. Therefore, we were moti-
vated to create a few fundamental molecular circuits that could be composed and scaled to model large biochemical reaction networks in the future. This paper describes these fundamental building-block cytomorphic circuits. The paper focuses on establishing quantitative agreement of the cytomorphic chip measurements with prior biological measurements and models. The building-block circuits may be classified into seven im- portant categories: 1) Basic BiCMOS current-mode analog circuits exploit the log-domain cytomorphic mapping to capture the exact dy- namics of fundamental mass-action molecular kinetics such as association, dissociation, and degradation. These fundamental circuits are general enough to capture subtle effects such as loading, fan-out, feedback, and substrate de- pletion through the use of a few explicit connections and Kirchhoff’s current law. A wide dynamic range of opera- tion and low power consumption are achieved through the use of bipolar and subthreshold MOS transistors that func- tion at low current levels. 2) The ability to model cooperative binding is enabled by tun- able Hill-function building-block circuits. 3) An “ITD” block built by a composition of above cur- rent-mode circuits enables mapping of the exact differen- tial equations of inducer-transcription-factor binding and transcription-factor-DNA binding including for- ward and reverse reactions, degradation, protection from degradation of transcription factors bound to DNA, and the change in DNA binding affinity of transcription factors when bound by an inducer. 4) An “analogic” current-mode circuit determines the tran- scription rate of genes based on the probability of mul- tiple transcription-factor DNA binding sites being occu- pied or unoccupied in a combinatorial fashion with the rel- ative mRNA production rate of each such combinatorial state programmable by the user. This strategy enables us to implement any arbitrary “analogic promoter function” that is capable of complex saturating digital logic or prob- abilistic analog behavior depending on the molecular con- centration. 5) A current-mode low pass filter (LPF) circuit enables the gain and dynamics of mRNA and protein production and degradation to be represented.
  • Fig. 2. Die micrograph of the
cytomorphic chip fabricated in an AMS BiCMOS process. The left inset is a layout screen capture
  • f one gene block (2x magnification).
6) A stochastics circuit intentionally amplifies analog Poisson noise in transistors to represent biological fluc- tuations in mRNA and protein concentrations at very low copy numbers and at relatively high noise levels. The Poisson nature of biochemical reaction fluxes au- tomatically maps biological noise to electronic noise at high copy numbers and relatively low noise levels [13]. Thus, these circuits are most useful for reliably modeling highly stochastic and relatively low signal-to-noise-ratios in biological cells. 7) ADCs and DACs convert between analog currents and digital bits to enable our chips to communicate with each
  • ther via digital input/output (I/O), and with off-chip dig-
ital processors and computers. Off-chip digital processors synergistically interact with our chips to carry out various functions: reading digital data from the chips; decoding the data; performing high-speed digital signal processing as necessary (e.g., scaling, diffusion, time delay, and error correction); encoding the data to create or modify molecular data packets via address and data strings; storing the programmable address connectivity amongst gene and protein circuits; and communicating data to other chips
  • r to a computer. For simplicity, the data in this paper were
collected with a data-acquisition board (NI PXI-6541) that interacted with our chip and with MATLAB on a computer. A high-performance FPGA (e.g., from the Xilinx Spartan family) could perform all of these functions in the future as well. Shift registers, SRAM blocks, and switches on the chip enable programmability of parameters (e.g., reaction rates, dissocia- tion constants, Hill coefficients, and time constants) as well as connectivity. The organization of this paper is as follows: Section II de- scribes the core building-block circuits of the chip along with chip measurement data. Fig. 2 shows a die micrograph of the chip that reveals the various building blocks. Section III dis- cusses design considerations that are important in BiCMOS cy- tomorphic chip design. Section IV discusses how cytomorphic

INTRODUCTION 14

· ES = kf ⋅ E ⋅ S − kr ⋅ ES x′′+ ax′+ x + ax2 = c3 L ⋅ I′′+ R ⋅ I′+ C−1 ⋅ I = 0 x′′+ c1x′+ c2x′′ = 0

Dynamical Systems compose complex algebraic building blocks reason about operating ranges + circuit noise automatically automatically FUNDAMENTALLY NEW COMPILATION TECHNIQUES Programmable 
 Analog Devices

slide-15
SLIDE 15

OUTLINE 15

  • Background: overview of compilation problem
  • Arco Compiler1: automatically configure analog devices to simulate

dynamical systems.

  • Jaunt Solver2: automatically scales dynamical systems to execute

analog hardware with operating range constraints.

  • Closing Remarks

TALK OUTLINE

1. Configuration Synthesis for Programmable Analog Devices with Arco. Sara Achour, Rahul Sarpeshkar and Martin Rinard. June 2016. PLDI 2016. 2. Time Dilation and Contraction for Programmable Analog Devices with Jaunt. Sara Achour and Martin Rinard. December 2017. ASPLOS 2018.

slide-16
SLIDE 16

BACKGROUND

slide-17
SLIDE 17

BACKGROUND 17

Compiler

528 IEEE TRANSACTIONS ON BIOMEDICAL CIRCUITS AND SYSTEMS, VOL. 9, NO. 4, AUGUST 2015
  • Fig. 1. Poisson chemical reaction flux and Poisson electron flow in
sub-threshold transistors obey the same Boltzmann exponential laws of thermodynamics, and are therefore mathematically similar [13]. Electron copy number is analogous to molecular copy number and temperature represents itself. single cell on a few chips and speedup multi-cell simulations
  • n multi-chip electronic boards [13]. Therefore, we were moti-
vated to create a few fundamental molecular circuits that could be composed and scaled to model large biochemical reaction networks in the future. This paper describes these fundamental building-block cytomorphic circuits. The paper focuses on establishing quantitative agreement of the cytomorphic chip measurements with prior biological measurements and models. The building-block circuits may be classified into seven im- portant categories: 1) Basic BiCMOS current-mode analog circuits exploit the log-domain cytomorphic mapping to capture the exact dy- namics of fundamental mass-action molecular kinetics such as association, dissociation, and degradation. These fundamental circuits are general enough to capture subtle effects such as loading, fan-out, feedback, and substrate de- pletion through the use of a few explicit connections and Kirchhoff’s current law. A wide dynamic range of opera- tion and low power consumption are achieved through the use of bipolar and subthreshold MOS transistors that func- tion at low current levels. 2) The ability to model cooperative binding is enabled by tun- able Hill-function building-block circuits. 3) An “ITD” block built by a composition of above cur- rent-mode circuits enables mapping of the exact differen- tial equations of inducer-transcription-factor binding and transcription-factor-DNA binding including for- ward and reverse reactions, degradation, protection from degradation of transcription factors bound to DNA, and the change in DNA binding affinity of transcription factors when bound by an inducer. 4) An “analogic” current-mode circuit determines the tran- scription rate of genes based on the probability of mul- tiple transcription-factor DNA binding sites being occu- pied or unoccupied in a combinatorial fashion with the rel- ative mRNA production rate of each such combinatorial state programmable by the user. This strategy enables us to implement any arbitrary “analogic promoter function” that is capable of complex saturating digital logic or prob- abilistic analog behavior depending on the molecular con- centration. 5) A current-mode low pass filter (LPF) circuit enables the gain and dynamics of mRNA and protein production and degradation to be represented.
  • Fig. 2. Die micrograph of the
cytomorphic chip fabricated in an AMS BiCMOS process. The left inset is a layout screen capture
  • f one gene block (2x magnification).
6) A stochastics circuit intentionally amplifies analog Poisson noise in transistors to represent biological fluc- tuations in mRNA and protein concentrations at very low copy numbers and at relatively high noise levels. The Poisson nature of biochemical reaction fluxes au- tomatically maps biological noise to electronic noise at high copy numbers and relatively low noise levels [13]. Thus, these circuits are most useful for reliably modeling highly stochastic and relatively low signal-to-noise-ratios in biological cells. 7) ADCs and DACs convert between analog currents and digital bits to enable our chips to communicate with each
  • ther via digital input/output (I/O), and with off-chip dig-
ital processors and computers. Off-chip digital processors synergistically interact with our chips to carry out various functions: reading digital data from the chips; decoding the data; performing high-speed digital signal processing as necessary (e.g., scaling, diffusion, time delay, and error correction); encoding the data to create or modify molecular data packets via address and data strings; storing the programmable address connectivity amongst gene and protein circuits; and communicating data to other chips
  • r to a computer. For simplicity, the data in this paper were
collected with a data-acquisition board (NI PXI-6541) that interacted with our chip and with MATLAB on a computer. A high-performance FPGA (e.g., from the Xilinx Spartan family) could perform all of these functions in the future as well. Shift registers, SRAM blocks, and switches on the chip enable programmability of parameters (e.g., reaction rates, dissocia- tion constants, Hill coefficients, and time constants) as well as connectivity. The organization of this paper is as follows: Section II de- scribes the core building-block circuits of the chip along with chip measurement data. Fig. 2 shows a die micrograph of the chip that reveals the various building blocks. Section III dis- cusses design considerations that are important in BiCMOS cy- tomorphic chip design. Section IV discusses how cytomorphic 528 IEEE TRANSACTIONS ON BIOMEDICAL CIRCUITS AND SYSTEMS, VOL. 9, NO. 4, AUGUST 2015
  • Fig. 1. Poisson chemical reaction flux and Poisson electron flow in
sub-threshold transistors obey the same Boltzmann exponential laws of thermodynamics, and are therefore mathematically similar [13]. Electron copy number is analogous to molecular copy number and temperature represents itself. single cell on a few chips and speedup multi-cell simulations
  • n multi-chip electronic boards [13]. Therefore, we were moti-
vated to create a few fundamental molecular circuits that could be composed and scaled to model large biochemical reaction networks in the future. This paper describes these fundamental building-block cytomorphic circuits. The paper focuses on establishing quantitative agreement of the cytomorphic chip measurements with prior biological measurements and models. The building-block circuits may be classified into seven im- portant categories: 1) Basic BiCMOS current-mode analog circuits exploit the log-domain cytomorphic mapping to capture the exact dy- namics of fundamental mass-action molecular kinetics such as association, dissociation, and degradation. These fundamental circuits are general enough to capture subtle effects such as loading, fan-out, feedback, and substrate de- pletion through the use of a few explicit connections and Kirchhoff’s current law. A wide dynamic range of opera- tion and low power consumption are achieved through the use of bipolar and subthreshold MOS transistors that func- tion at low current levels. 2) The ability to model cooperative binding is enabled by tun- able Hill-function building-block circuits. 3) An “ITD” block built by a composition of above cur- rent-mode circuits enables mapping of the exact differen- tial equations of inducer-transcription-factor binding and transcription-factor-DNA binding including for- ward and reverse reactions, degradation, protection from degradation of transcription factors bound to DNA, and the change in DNA binding affinity of transcription factors when bound by an inducer. 4) An “analogic” current-mode circuit determines the tran- scription rate of genes based on the probability of mul- tiple transcription-factor DNA binding sites being occu- pied or unoccupied in a combinatorial fashion with the rel- ative mRNA production rate of each such combinatorial state programmable by the user. This strategy enables us to implement any arbitrary “analogic promoter function” that is capable of complex saturating digital logic or prob- abilistic analog behavior depending on the molecular con- centration. 5) A current-mode low pass filter (LPF) circuit enables the gain and dynamics of mRNA and protein production and degradation to be represented.
  • Fig. 2. Die micrograph of the
cytomorphic chip fabricated in an AMS BiCMOS process. The left inset is a layout screen capture
  • f one gene block (2x magnification).
6) A stochastics circuit intentionally amplifies analog Poisson noise in transistors to represent biological fluc- tuations in mRNA and protein concentrations at very low copy numbers and at relatively high noise levels. The Poisson nature of biochemical reaction fluxes au- tomatically maps biological noise to electronic noise at high copy numbers and relatively low noise levels [13]. Thus, these circuits are most useful for reliably modeling highly stochastic and relatively low signal-to-noise-ratios in biological cells. 7) ADCs and DACs convert between analog currents and digital bits to enable our chips to communicate with each
  • ther via digital input/output (I/O), and with off-chip dig-
ital processors and computers. Off-chip digital processors synergistically interact with our chips to carry out various functions: reading digital data from the chips; decoding the data; performing high-speed digital signal processing as necessary (e.g., scaling, diffusion, time delay, and error correction); encoding the data to create or modify molecular data packets via address and data strings; storing the programmable address connectivity amongst gene and protein circuits; and communicating data to other chips
  • r to a computer. For simplicity, the data in this paper were
collected with a data-acquisition board (NI PXI-6541) that interacted with our chip and with MATLAB on a computer. A high-performance FPGA (e.g., from the Xilinx Spartan family) could perform all of these functions in the future as well. Shift registers, SRAM blocks, and switches on the chip enable programmability of parameters (e.g., reaction rates, dissocia- tion constants, Hill coefficients, and time constants) as well as connectivity. The organization of this paper is as follows: Section II de- scribes the core building-block circuits of the chip along with chip measurement data. Fig. 2 shows a die micrograph of the chip that reveals the various building blocks. Section III dis- cusses design considerations that are important in BiCMOS cy- tomorphic chip design. Section IV discusses how cytomorphic 528 IEEE TRANSACTIONS ON BIOMEDICAL CIRCUITS AND SYSTEMS, VOL. 9, NO. 4, AUGUST 2015
  • Fig. 1. Poisson chemical reaction flux and Poisson electron flow in
sub-threshold transistors obey the same Boltzmann exponential laws of thermodynamics, and are therefore mathematically similar [13]. Electron copy number is analogous to molecular copy number and temperature represents itself. single cell on a few chips and speedup multi-cell simulations
  • n multi-chip electronic boards [13]. Therefore, we were moti-
vated to create a few fundamental molecular circuits that could be composed and scaled to model large biochemical reaction networks in the future. This paper describes these fundamental building-block cytomorphic circuits. The paper focuses on establishing quantitative agreement of the cytomorphic chip measurements with prior biological measurements and models. The building-block circuits may be classified into seven im- portant categories: 1) Basic BiCMOS current-mode analog circuits exploit the log-domain cytomorphic mapping to capture the exact dy- namics of fundamental mass-action molecular kinetics such as association, dissociation, and degradation. These fundamental circuits are general enough to capture subtle effects such as loading, fan-out, feedback, and substrate de- pletion through the use of a few explicit connections and Kirchhoff’s current law. A wide dynamic range of opera- tion and low power consumption are achieved through the use of bipolar and subthreshold MOS transistors that func- tion at low current levels. 2) The ability to model cooperative binding is enabled by tun- able Hill-function building-block circuits. 3) An “ITD” block built by a composition of above cur- rent-mode circuits enables mapping of the exact differen- tial equations of inducer-transcription-factor binding and transcription-factor-DNA binding including for- ward and reverse reactions, degradation, protection from degradation of transcription factors bound to DNA, and the change in DNA binding affinity of transcription factors when bound by an inducer. 4) An “analogic” current-mode circuit determines the tran- scription rate of genes based on the probability of mul- tiple transcription-factor DNA binding sites being occu- pied or unoccupied in a combinatorial fashion with the rel- ative mRNA production rate of each such combinatorial state programmable by the user. This strategy enables us to implement any arbitrary “analogic promoter function” that is capable of complex saturating digital logic or prob- abilistic analog behavior depending on the molecular con- centration. 5) A current-mode low pass filter (LPF) circuit enables the gain and dynamics of mRNA and protein production and degradation to be represented.
  • Fig. 2. Die micrograph of the
cytomorphic chip fabricated in an AMS BiCMOS process. The left inset is a layout screen capture
  • f one gene block (2x magnification).
6) A stochastics circuit intentionally amplifies analog Poisson noise in transistors to represent biological fluc- tuations in mRNA and protein concentrations at very low copy numbers and at relatively high noise levels. The Poisson nature of biochemical reaction fluxes au- tomatically maps biological noise to electronic noise at high copy numbers and relatively low noise levels [13]. Thus, these circuits are most useful for reliably modeling highly stochastic and relatively low signal-to-noise-ratios in biological cells. 7) ADCs and DACs convert between analog currents and digital bits to enable our chips to communicate with each
  • ther via digital input/output (I/O), and with off-chip dig-
ital processors and computers. Off-chip digital processors synergistically interact with our chips to carry out various functions: reading digital data from the chips; decoding the data; performing high-speed digital signal processing as necessary (e.g., scaling, diffusion, time delay, and error correction); encoding the data to create or modify molecular data packets via address and data strings; storing the programmable address connectivity amongst gene and protein circuits; and communicating data to other chips
  • r to a computer. For simplicity, the data in this paper were
collected with a data-acquisition board (NI PXI-6541) that interacted with our chip and with MATLAB on a computer. A high-performance FPGA (e.g., from the Xilinx Spartan family) could perform all of these functions in the future as well. Shift registers, SRAM blocks, and switches on the chip enable programmability of parameters (e.g., reaction rates, dissocia- tion constants, Hill coefficients, and time constants) as well as connectivity. The organization of this paper is as follows: Section II de- scribes the core building-block circuits of the chip along with chip measurement data. Fig. 2 shows a die micrograph of the chip that reveals the various building blocks. Section III dis- cusses design considerations that are important in BiCMOS cy- tomorphic chip design. Section IV discusses how cytomorphic 528 IEEE TRANSACTIONS ON BIOMEDICAL CIRCUITS AND SYSTEMS, VOL. 9, NO. 4, AUGUST 2015
  • Fig. 1. Poisson chemical reaction flux and Poisson electron flow in
sub-threshold transistors obey the same Boltzmann exponential laws of thermodynamics, and are therefore mathematically similar [13]. Electron copy number is analogous to molecular copy number and temperature represents itself. single cell on a few chips and speedup multi-cell simulations
  • n multi-chip electronic boards [13]. Therefore, we were moti-
vated to create a few fundamental molecular circuits that could be composed and scaled to model large biochemical reaction networks in the future. This paper describes these fundamental building-block cytomorphic circuits. The paper focuses on establishing quantitative agreement of the cytomorphic chip measurements with prior biological measurements and models. The building-block circuits may be classified into seven im- portant categories: 1) Basic BiCMOS current-mode analog circuits exploit the log-domain cytomorphic mapping to capture the exact dy- namics of fundamental mass-action molecular kinetics such as association, dissociation, and degradation. These fundamental circuits are general enough to capture subtle effects such as loading, fan-out, feedback, and substrate de- pletion through the use of a few explicit connections and Kirchhoff’s current law. A wide dynamic range of opera- tion and low power consumption are achieved through the use of bipolar and subthreshold MOS transistors that func- tion at low current levels. 2) The ability to model cooperative binding is enabled by tun- able Hill-function building-block circuits. 3) An “ITD” block built by a composition of above cur- rent-mode circuits enables mapping of the exact differen- tial equations of inducer-transcription-factor binding and transcription-factor-DNA binding including for- ward and reverse reactions, degradation, protection from degradation of transcription factors bound to DNA, and the change in DNA binding affinity of transcription factors when bound by an inducer. 4) An “analogic” current-mode circuit determines the tran- scription rate of genes based on the probability of mul- tiple transcription-factor DNA binding sites being occu- pied or unoccupied in a combinatorial fashion with the rel- ative mRNA production rate of each such combinatorial state programmable by the user. This strategy enables us to implement any arbitrary “analogic promoter function” that is capable of complex saturating digital logic or prob- abilistic analog behavior depending on the molecular con- centration. 5) A current-mode low pass filter (LPF) circuit enables the gain and dynamics of mRNA and protein production and degradation to be represented.
  • Fig. 2. Die micrograph of the
cytomorphic chip fabricated in an AMS BiCMOS process. The left inset is a layout screen capture
  • f one gene block (2x magnification).
6) A stochastics circuit intentionally amplifies analog Poisson noise in transistors to represent biological fluc- tuations in mRNA and protein concentrations at very low copy numbers and at relatively high noise levels. The Poisson nature of biochemical reaction fluxes au- tomatically maps biological noise to electronic noise at high copy numbers and relatively low noise levels [13]. Thus, these circuits are most useful for reliably modeling highly stochastic and relatively low signal-to-noise-ratios in biological cells. 7) ADCs and DACs convert between analog currents and digital bits to enable our chips to communicate with each
  • ther via digital input/output (I/O), and with off-chip dig-
ital processors and computers. Off-chip digital processors synergistically interact with our chips to carry out various functions: reading digital data from the chips; decoding the data; performing high-speed digital signal processing as necessary (e.g., scaling, diffusion, time delay, and error correction); encoding the data to create or modify molecular data packets via address and data strings; storing the programmable address connectivity amongst gene and protein circuits; and communicating data to other chips
  • r to a computer. For simplicity, the data in this paper were
collected with a data-acquisition board (NI PXI-6541) that interacted with our chip and with MATLAB on a computer. A high-performance FPGA (e.g., from the Xilinx Spartan family) could perform all of these functions in the future as well. Shift registers, SRAM blocks, and switches on the chip enable programmability of parameters (e.g., reaction rates, dissocia- tion constants, Hill coefficients, and time constants) as well as connectivity. The organization of this paper is as follows: Section II de- scribes the core building-block circuits of the chip along with chip measurement data. Fig. 2 shows a die micrograph of the chip that reveals the various building blocks. Section III dis- cusses design considerations that are important in BiCMOS cy- tomorphic chip design. Section IV discusses how cytomorphic 528 IEEE TRANSACTIONS ON BIOMEDICAL CIRCUITS AND SYSTEMS, VOL. 9, NO. 4, AUGUST 2015
  • Fig. 1. Poisson chemical reaction flux and Poisson electron flow in
sub-threshold transistors obey the same Boltzmann exponential laws of thermodynamics, and are therefore mathematically similar [13]. Electron copy number is analogous to molecular copy number and temperature represents itself. single cell on a few chips and speedup multi-cell simulations
  • n multi-chip electronic boards [13]. Therefore, we were moti-
vated to create a few fundamental molecular circuits that could be composed and scaled to model large biochemical reaction networks in the future. This paper describes these fundamental building-block cytomorphic circuits. The paper focuses on establishing quantitative agreement of the cytomorphic chip measurements with prior biological measurements and models. The building-block circuits may be classified into seven im- portant categories: 1) Basic BiCMOS current-mode analog circuits exploit the log-domain cytomorphic mapping to capture the exact dy- namics of fundamental mass-action molecular kinetics such as association, dissociation, and degradation. These fundamental circuits are general enough to capture subtle effects such as loading, fan-out, feedback, and substrate de- pletion through the use of a few explicit connections and Kirchhoff’s current law. A wide dynamic range of opera- tion and low power consumption are achieved through the use of bipolar and subthreshold MOS transistors that func- tion at low current levels. 2) The ability to model cooperative binding is enabled by tun- able Hill-function building-block circuits. 3) An “ITD” block built by a composition of above cur- rent-mode circuits enables mapping of the exact differen- tial equations of inducer-transcription-factor binding and transcription-factor-DNA binding including for- ward and reverse reactions, degradation, protection from degradation of transcription factors bound to DNA, and the change in DNA binding affinity of transcription factors when bound by an inducer. 4) An “analogic” current-mode circuit determines the tran- scription rate of genes based on the probability of mul- tiple transcription-factor DNA binding sites being occu- pied or unoccupied in a combinatorial fashion with the rel- ative mRNA production rate of each such combinatorial state programmable by the user. This strategy enables us to implement any arbitrary “analogic promoter function” that is capable of complex saturating digital logic or prob- abilistic analog behavior depending on the molecular con- centration. 5) A current-mode low pass filter (LPF) circuit enables the gain and dynamics of mRNA and protein production and degradation to be represented.
  • Fig. 2. Die micrograph of the
cytomorphic chip fabricated in an AMS BiCMOS process. The left inset is a layout screen capture
  • f one gene block (2x magnification).
6) A stochastics circuit intentionally amplifies analog Poisson noise in transistors to represent biological fluc- tuations in mRNA and protein concentrations at very low copy numbers and at relatively high noise levels. The Poisson nature of biochemical reaction fluxes au- tomatically maps biological noise to electronic noise at high copy numbers and relatively low noise levels [13]. Thus, these circuits are most useful for reliably modeling highly stochastic and relatively low signal-to-noise-ratios in biological cells. 7) ADCs and DACs convert between analog currents and digital bits to enable our chips to communicate with each
  • ther via digital input/output (I/O), and with off-chip dig-
ital processors and computers. Off-chip digital processors synergistically interact with our chips to carry out various functions: reading digital data from the chips; decoding the data; performing high-speed digital signal processing as necessary (e.g., scaling, diffusion, time delay, and error correction); encoding the data to create or modify molecular data packets via address and data strings; storing the programmable address connectivity amongst gene and protein circuits; and communicating data to other chips
  • r to a computer. For simplicity, the data in this paper were
collected with a data-acquisition board (NI PXI-6541) that interacted with our chip and with MATLAB on a computer. A high-performance FPGA (e.g., from the Xilinx Spartan family) could perform all of these functions in the future as well. Shift registers, SRAM blocks, and switches on the chip enable programmability of parameters (e.g., reaction rates, dissocia- tion constants, Hill coefficients, and time constants) as well as connectivity. The organization of this paper is as follows: Section II de- scribes the core building-block circuits of the chip along with chip measurement data. Fig. 2 shows a die micrograph of the chip that reveals the various building blocks. Section III dis- cusses design considerations that are important in BiCMOS cy- tomorphic chip design. Section IV discusses how cytomorphic

Dynamical
 System Analog Device

slide-18
SLIDE 18

BACKGROUND 18

Compiler

Analog Device Specification Dynamical
 System

slide-19
SLIDE 19

BACKGROUND 19

Compiler

Analog Device Specification Dynamical
 System Analog Device Configuration

slide-20
SLIDE 20

BACKGROUND 20

Compiler

Analog Device Specification Dynamical
 System Analog Device Configuration

slide-21
SLIDE 21

BACKGROUND 21

DYNAMICAL SYSTEM SPECIFICATION · ES = 10−4 ⋅ E ⋅ S − 10−2 ⋅ ES E = 6800 − ES S = 4400 − ES ES(0) = 0

slide-22
SLIDE 22

BACKGROUND 22

Compiler

Analog Device Specification Dynamical
 System Analog Device Configuration

slide-23
SLIDE 23

BACKGROUND 23

ANALOG DEVICE SPECIFICATION

IADD

x 3

MM

x 3

ADC

x 5

DAC

x 5

slide-24
SLIDE 24

BACKGROUND 24

ANALOG DEVICE SPECIFICATION

MM

x 3

inp X0, Y0, Z0 inp A, B

  • ut X, Y, Z

Input and Output Ports

slide-25
SLIDE 25

BACKGROUND 25

ANALOG DEVICE SPECIFICATION

MM

x 3

inp X0, Y0, Z0 inp A, B

  • ut X, Y, Z

rel X.I = X0.I - Z.I rel Y.I = Y0.I - Z.I rel Z.I’ = A.V X.I Y.I - B.V Z.I and Z.I(0) = Z0 Block Dynamics

slide-26
SLIDE 26

BACKGROUND 26

ANALOG DEVICE SPECIFICATION

DAC

x 5

ADC

x 5

inp X digital

  • ut Z

inp X

  • ut Z digital

rel Z.I = X rel Z = X.I

slide-27
SLIDE 27

BACKGROUND 27

ANALOG DEVICE SPECIFICATION

IADD

x 3

MM

x 3

ADC

x 5

DAC

x 5

conn MM[*].Z and ADC[*].X conn DAC[*].Z and MM[*].A conn MM[1].Z and MM[2].X Available Connections

slide-28
SLIDE 28

BACKGROUND 28

Compiler

Analog Device Specification Dynamical
 System Analog Device Configuration

slide-29
SLIDE 29

BACKGROUND 29

ANALOG DEVICE CONFIGURATION

DAC 1 ADC 2 ADC 3 ADC 4 DAC 2 DAC 3 DAC 5 DAC 4 mm.1 X0 Z0 Y0 A B X Z Y ADC 1 ADC 5 iadd.1 B A D C iadd.2 B A D C iadd.3 B A D C

slide-30
SLIDE 30

BACKGROUND 30

ANALOG DEVICE CONFIGURATION

DAC 1 ADC 2 ADC 3 ADC 4 DAC 2 DAC 3 DAC 5 DAC 4 mm.1 X0 Z0 Y0 A B X Z Y ADC 1 ADC 5 iadd.1 B A D C iadd.2 B A D C iadd.3 B A D C 0.0001 6800 4400 0.01

slide-31
SLIDE 31

BACKGROUND 31

ANALOG DEVICE CONFIGURATION

DAC 1 ADC 2 ADC 3 ADC 4 DAC 2 DAC 3 DAC 5 DAC 4 mm.1 X0 Z0 Y0 A B X Z Y ADC 1 ADC 5 iadd.1 B A D C iadd.2 B A D C iadd.3 B A D C 0.0001 6800 4400 0.01

slide-32
SLIDE 32

BACKGROUND 32

ANALOG DEVICE CONFIGURATION

DAC 1 ADC 2 ADC 3 ADC 4 DAC 2 DAC 3 DAC 5 DAC 4 mm.1 X0 Z0 Y0 A B X Z Y ADC 1 ADC 5 iadd.1 B A D C iadd.2 B A D C iadd.3 B A D C 0.0001 6800 4400 0.01 S E ES

slide-33
SLIDE 33

BACKGROUND 33

ANALOG DEVICE CONFIGURATION

DAC 1 ADC 1 mm ADC 2 ADC 3 DAC 2 DAC 3 DAC 5 DAC 4 X0 Z0 Y0 A B X Z Y S E ES 0.0001 6800 4400 0.01

slide-34
SLIDE 34

BACKGROUND 34

ANALOG DEVICE CONFIGURATION

set DAC[0].X = 0.003 set DAC[5].X = 0.006 … DAC Values

slide-35
SLIDE 35

BACKGROUND 35

ANALOG DEVICE CONFIGURATION

set DAC[0].X = 0.003 set DAC[5].X = 0.006 … lbl ADC[0].Z = “E” lbl ADC[1].Z = “S” lbl ADC[2].Z = “ES” ADC Values

slide-36
SLIDE 36

BACKGROUND 36

ANALOG DEVICE CONFIGURATION

set DAC[0].X = 0.003 set DAC[5].X = 0.006 … lbl ADC[0].Z = “E” lbl ADC[1].Z = “S” lbl ADC[2].Z = “ES” conn MM[0].Y to ADC[2].X conn MM[0].Z to ADC[3].X conn DAC[0].Z to MM[0].X0 … Connections

slide-37
SLIDE 37

BACKGROUND 37

Compiler

Analog Device Specification Dynamical
 System Analog Device Configuration

slide-38
SLIDE 38

OUTLINE 38

  • Background: overview of compilation problem
  • Arco Compiler1: automatically configure analog devices to simulate

dynamical systems.

  • Jaunt Solver2: automatically scales dynamical systems to execute

analog hardware with operating range constraints.

  • Closing Remarks

TALK OUTLINE

1. Configuration Synthesis for Programmable Analog Devices with Arco. Sara Achour, Rahul Sarpeshkar and Martin Rinard. June 2016. PLDI 2016. 2. Time Dilation and Contraction for Programmable Analog Devices with Jaunt. Sara Achour and Martin Rinard. December 2017. ASPLOS 2018.

slide-39
SLIDE 39

ARCO COMPILER

slide-40
SLIDE 40

ARCO COMPILER 40

ARCO COMPILER OVERVIEW

Arco performs a search over tableaus

slide-41
SLIDE 41

ARCO COMPILER 41

ARCO COMPILER

tableau : search state

{ }

Blocks Goals Wires Config Used Blocks

slide-42
SLIDE 42

ARCO COMPILER 42

ARCO COMPILER OVERVIEW

Arco starts with an initial tableau

slide-43
SLIDE 43

ARCO COMPILER 43

ARCO COMPILER

initial tableau : the initial state of the search

{ }

Blocks Goals Wires Config Used Blocks

slide-44
SLIDE 44

ARCO COMPILER 44

ARCO COMPILER

initial tableau : the initial state of the search

{ }

Blocks Goals Wires Config Used Blocks

· ES = 10−4E ⋅ S − 10−2ES E = 6800 − ES S = 4400 − ES ES(0) = 0

slide-45
SLIDE 45

ARCO COMPILER 45

ARCO COMPILER

initial tableau : the initial state of the search

{ }

Blocks Goals Wires Config Used Blocks

· ES = 10−4E ⋅ S − 10−2ES E = 6800 − ES S = 4400 − ES ES(0) = 0

DAC[0] ADC[0] MM[0] DAC[1]

DAC[0] . O MM[0] . A DAC[0] . O MM[0] . X0 MM[0] . Z ADC[0] . X MM[0] . X ADC[0] . X

slide-46
SLIDE 46

ARCO COMPILER 46

ARCO COMPILER

initial tableau : the initial state of the search

{ }

Blocks Goals Wires Config Used Blocks

· ES = 10−4E ⋅ S − 10−2ES E = 6800 − ES S = 4400 − ES ES(0) = 0

DAC[0] ADC[0] MM[0] DAC[1]

DAC[0] . O MM[0] . A DAC[0] . O MM[0] . X0 MM[0] . Z ADC[0] . X MM[0] . X ADC[0] . X

∅ ∅

analog hardware is not configured yet

slide-47
SLIDE 47

ARCO COMPILER 47

ARCO COMPILER OVERVIEW

new tableaus derived using transition rules

slide-48
SLIDE 48

ARCO COMPILER 48

ARCO COMPILER OVERVIEW

Arco searches until a solved tableau is found

slide-49
SLIDE 49

ARCO COMPILER 49

ARCO COMPILER

solved tableau : the final state of the search

{ }

Blocks Goals Wires Config Used Blocks

slide-50
SLIDE 50

ARCO COMPILER 50

ARCO COMPILER

solved tableau : the final state of the search

{ }

Blocks Goals Wires Config Used Blocks

no goals left

slide-51
SLIDE 51

ARCO COMPILER 51

ARCO COMPILER

solved tableau : the final state of the search

{ }

Blocks Goals Wires Config Used Blocks DAC[0] . O MM[0] . X0 MM[0] . X ADC[0] . X

ADC[3] ADC[4]

remaining blocks, wires

slide-52
SLIDE 52

ARCO COMPILER 52

ARCO COMPILER

solved tableau : the final state of the search

{ }

Blocks Goals Wires Config Used Blocks

ADC[0]

DAC[0] . O MM[0] . X0 MM[0] . X ADC[0] . X

MM[0] DAC[0] ADC[3] ADC[1] ADC[4]

blocks in use

slide-53
SLIDE 53

ARCO COMPILER 53

ARCO COMPILER

solved tableau : the final state of the search

{ }

Blocks Goals Wires Config Used Blocks

ADC[0]

DAC[0] . O MM[0] . X0 MM[0] . X ADC[0] . X

MM[0] DAC[0] ADC[3] ADC[1] ADC[4]

set DAC[0].X = 10-4 lbl ADC[2].O = “ES” conn DAC[0].Z 
 to MM[0].A conn MM[0].Z 
 to ADC[0].X

analog device configuration

slide-54
SLIDE 54

ARCO COMPILER 54

ARCO COMPILER OVERVIEW

Arco derives new tableaus using transition rules Unify Connect Variable Map

slide-55
SLIDE 55

ARCO COMPILER 55

ARCO COMPILER OVERVIEW

Arco derives new tableaus using transition rules Unify Connect Variable Map

slide-56
SLIDE 56

ARCO COMPILER 56

{ }

Blocks Goals Wires Config Used Blocks

· ES = 10−4E ⋅ S − 10−2ES E = 6800 − ES S = 4400 − ES ES(0) = 0

DAC[0] ADC[0] MM[0] DAC[1]

DAC[0] . O MM[0] . A DAC[0] . O MM[0] . X0 MM[0] . Z ADC[0] . X MM[0] . X ADC[0] . X

E = 6800 − ES UNIFICATION TRANSITION

slide-57
SLIDE 57

ARCO COMPILER 57

Goals

· ES = 10−4E ⋅ S − 10−2ES E = 6800 − ES S = 4400 − ES ES(0) = 0

Blocks

MM[0]

UNIFICATION TRANSITION

slide-58
SLIDE 58

ARCO COMPILER 58

Goals

E = 6800 − ES

mm X0 Z0 Y0 A B X Z Y

· ES = 10−4E ⋅ S − 10−2ES E = 6800 − ES S = 4400 − ES ES(0) = 0

MM[0]

slide-59
SLIDE 59

ARCO COMPILER 59

Goals

E = 6800 − ES

mm X0 Z0 Y0 A B X Z Y

· ES = 10−4E ⋅ S − 10−2ES E = 6800 − ES S = 4400 − ES ES(0) = 0

X = X0 − Z

MM[0]

slide-60
SLIDE 60

ARCO COMPILER 60

Goals

E = 6800 − ES

mm X0 Z0 Y0 A B X Z Y

· ES = 10−4E ⋅ S − 10−2ES E = 6800 − ES S = 4400 − ES ES(0) = 0

X = X0 − Z

E 6800 ES

MM[0] . X0 = 6800 MM[0] . X = E MM[0] . Z = ES

MM[0]

slide-61
SLIDE 61

ARCO COMPILER 61

Goals

mm X0 Z0 Y0 A B X Z Y

· ES = 10−4E ⋅ S − 10−2ES E = 6800 − ES S = 4400 − ES ES(0) = 0

E 6800 ES

MM[0] . X0 = 6800 MM[0] . X = E MM[0] . Z = ES

· ES = 10−4E ⋅ S − 10−2ES ES(0) = 0 · Z = A ⋅ X ⋅ Y − B ⋅ Z Z(0) = Z0

MM[0]

slide-62
SLIDE 62

ARCO COMPILER 62

Goals

mm X0 Z0 Y0 A B X Z Y

· ES = 10−4E ⋅ S − 10−2ES E = 6800 − ES S = 4400 − ES ES(0) = 0

E 6800 ES

MM[0] . X0 = 6800 MM[0] . X = E MM[0] . Z = ES

· ES = 10−4E ⋅ S − 10−2ES ES(0) = 0 · ES = A ⋅ E ⋅ Y − B ⋅ ES ES(0) = Z0 ES E ES ES

MM[0]

slide-63
SLIDE 63

ARCO COMPILER 63

Goals

mm X0 Z0 Y0 A B X Z Y

· ES = 10−4E ⋅ S − 10−2ES E = 6800 − ES S = 4400 − ES ES(0) = 0

E 6800 ES

MM[0] . X0 = 6800 MM[0] . X = E MM[0] . Z = ES

· ES = 10−4E ⋅ S − 10−2ES ES(0) = 0 · ES = A ⋅ E ⋅ Y − B ⋅ ES ES(0) = Z0 ES E ES ES

S

10−4 10−2

MM[0] . A = 10−4 MM[0] . B = 10−2 MM[0] . Y = S MM[0] . Z0 = 0

MM[0]

slide-64
SLIDE 64

ARCO COMPILER 64

Goals

mm X0 Z0 Y0 A B X Z Y

· ES = 10−4E ⋅ S − 10−2ES E = 6800 − ES S = 4400 − ES ES(0) = 0

E 6800 ES

MM[0] . X0 = 6800 MM[0] . X = E MM[0] . Z = ES

S

10−4 10−2

MM[0] . A = 10−4 MM[0] . B = 10−2 MM[0] . Y = S MM[0] . Z0 = 0

S = 4400 − ES S = Y0 − ES ES S

MM[0]

slide-65
SLIDE 65

ARCO COMPILER 65

Goals

mm X0 Z0 Y0 A B X Z Y

· ES = 10−4E ⋅ S − 10−2ES E = 6800 − ES S = 4400 − ES ES(0) = 0

E 6800 ES

MM[0] . X0 = 6800 MM[0] . X = E MM[0] . Z = ES

S

10−4 10−2

MM[0] . A = 10−4 MM[0] . B = 10−2 MM[0] . Y = S MM[0] . Z0 = 0

S = 4400 − ES S = Y0 − ES ES S

4400

MM[0] . Y0 = 4400

MM[0]

slide-66
SLIDE 66

ARCO COMPILER 66

Goals

mm X0 Z0 Y0 A B X Z Y

· ES = 10−4E ⋅ S − 10−2ES E = 6800 − ES S = 4400 − ES ES(0) = 0

E 6800 ES

MM[0] . X0 = 6800 MM[0] . X = E MM[0] . Z = ES

S

10−4 10−2

MM[0] . A = 10−4 MM[0] . B = 10−2 MM[0] . Y = S MM[0] . Z0 = 0

S = 4400 − ES S = Y0 − ES ES S

4400

MM[0] . Y0 = 4400

MM[0]

slide-67
SLIDE 67

ARCO COMPILER 67

{ }

Blocks Goals Wires Config Used Blocks

· ES = 10−4E ⋅ S − 10−2ES E = 6800 − ES S = 4400 − ES ES(0) = 0

DAC[0] ADC[0] MM[0] DAC[1]

DAC[0] . O MM[0] . A DAC[0] . O MM[0] . X0 MM[0] . Z ADC[0] . X MM[0] . X ADC[0] . X

UNIFICATION TRANSITION

slide-68
SLIDE 68

ARCO COMPILER 68

{ }

Blocks Goals Wires Config Used Blocks

· ES = 10−4E ⋅ S − 10−2ES E = 6800 − ES S = 4400 − ES ES(0) = 0

DAC[0] ADC[0] DAC[1]

DAC[0] . O MM[0] . A DAC[0] . O MM[0] . X0 MM[0] . Z ADC[0] . X MM[0] . X ADC[0] . X

MM[0] . X0 = 6800 MM[0] . X = E MM[0] . Z = ES

MM[0] MM[0]

UNIFICATION TRANSITION

slide-69
SLIDE 69

ARCO COMPILER 69

ARCO COMPILER OVERVIEW

Arco derives new tableaus using transition rules Unify Connect Variable Map

slide-70
SLIDE 70

ARCO COMPILER 70

{ }

Blocks Goals Wires Config Used Blocks

MM[1] MM[2] ADC[3]

DAC[0] . O MM[0] . A DAC[0] . O MM[0] . X0 MM[0] . Z ADC[0] . X MM[0] . X ADC[0] . X MM[0] . A = DAC[0] . O

MM[0]

DAC[0] . X = 10−4 ADC[0] . X = MM[0] . Z ADC[0] . O = ES MM[0] . B = DAC[0] . O DAC[0] . X = 10−2 ADC[1] . X = MM[0] . X ADC[1] . O = E

DAC[0] DAC[1] ADC[0] ADC[1] ADC[4]

CONNECTION TRANSITION

slide-71
SLIDE 71

ARCO COMPILER 71

{ }

Blocks Goals Wires Config Used Blocks

MM[1] MM[2] ADC[3]

DAC[0] . O MM[0] . A DAC[0] . O MM[0] . X0 MM[0] . Z ADC[0] . X MM[0] . X ADC[0] . X MM[0] . A = DAC[0] . O

MM[0]

DAC[0] . X = 10−4 ADC[0] . X = MM[0] . Z ADC[0] . O = ES MM[0] . B = DAC[0] . O DAC[0] . X = 10−2 ADC[1] . X = MM[0] . X ADC[1] . O = E

DAC[0] DAC[1] ADC[0] ADC[1] ADC[4]

CONNECTION TRANSITION

slide-72
SLIDE 72

ARCO COMPILER 72

{ }

Blocks Goals Wires Config Used Blocks

MM[1] MM[2] ADC[3]

DAC[0] . O MM[0] . A DAC[0] . O MM[0] . X0 MM[0] . Z ADC[0] . X MM[0] . X ADC[0] . X MM[0] . A = DAC[0] . O

MM[0]

DAC[0] . X = 10−4 ADC[0] . X = MM[0] . Z ADC[0] . O = ES MM[0] . B = DAC[0] . O DAC[0] . X = 10−2 ADC[1] . X = MM[0] . X ADC[1] . O = E

DAC[0] DAC[1] ADC[0] ADC[1] ADC[4]

conn DAC[0].Z 
 to MM[0].A

CONNECTION TRANSITION

slide-73
SLIDE 73

ARCO COMPILER 73

ARCO COMPILER OVERVIEW

Arco derives new tableaus using transition rules Unify Connect Variable Map

slide-74
SLIDE 74

ARCO COMPILER 74

{ }

Blocks Goals Wires Config Used Blocks

MM[1] MM[2] ADC[3]

DAC[0] . O MM[0] . X0 MM[0] . Z ADC[0] . X MM[0] . X ADC[0] . X MM[0] . A = DAC[0] . O

MM[0]

DAC[0] . X = 10−4 ADC[0] . X = MM[0] . Z ADC[0] . O = ES MM[0] . B = DAC[0] . O DAC[0] . X = 10−2 ADC[1] . X = MM[0] . X ADC[1] . O = E

DAC[0] DAC[1] ADC[0] ADC[1] ADC[4]

conn DAC[0].Z 
 to MM[0].A MM[0] . Y ADC[0] . X

VARIABLE/VALUE MAPPING TRANSITION

slide-75
SLIDE 75

ARCO COMPILER 75

{ }

Blocks Goals Wires Config Used Blocks

MM[1] MM[2] ADC[3]

DAC[0] . O MM[0] . X0 MM[0] . Z ADC[0] . X MM[0] . X ADC[0] . X MM[0] . A = DAC[0] . O

MM[0]

DAC[0] . X = 10−4 ADC[0] . X = MM[0] . Z ADC[0] . O = ES MM[0] . B = DAC[0] . O DAC[0] . X = 10−2 ADC[1] . X = MM[0] . X ADC[1] . O = E

DAC[0] DAC[1] ADC[0] ADC[1] ADC[4]

conn DAC[0].Z 
 to MM[0].A MM[0] . Y ADC[0] . X set DAC[0].X = 10-4

VARIABLE/VALUE MAPPING TRANSITION

slide-76
SLIDE 76

ARCO COMPILER 76

{ }

Blocks Goals Wires Config Used Blocks

MM[1] MM[2] ADC[3]

DAC[0] . O MM[0] . X0 MM[0] . Z ADC[0] . X MM[0] . X ADC[0] . X MM[0] . A = DAC[0] . O

MM[0]

ADC[0] . X = MM[0] . Z ADC[0] . O = ES MM[0] . B = DAC[0] . O DAC[0] . X = 10−2 ADC[1] . X = MM[0] . X ADC[1] . O = E

DAC[0] DAC[1] ADC[0] ADC[1] ADC[4]

conn DAC[0].Z 
 to MM[0].A MM[0] . Y ADC[0] . X

VARIABLE/VALUE MAPPING TRANSITION

DAC[0] . X = 10−4 set DAC[0].X = 10-4

slide-77
SLIDE 77

ARCO COMPILER 77

{ }

Blocks Goals Wires Config Used Blocks

MM[1] MM[2] ADC[3]

DAC[0] . O MM[0] . X0 MM[0] . Z ADC[0] . X MM[0] . X ADC[0] . X MM[0] . A = DAC[0] . O

MM[0]

DAC[0] . X = 10−4 ADC[0] . X = MM[0] . Z ADC[0] . O = ES MM[0] . B = DAC[0] . O DAC[0] . X = 10−2 ADC[1] . X = MM[0] . X ADC[1] . O = E

DAC[0] DAC[1] ADC[0] ADC[1] ADC[4]

conn DAC[0].Z 
 to MM[0].A MM[0] . Y ADC[0] . X set DAC[0].X = 10-4

VARIABLE/VALUE MAPPING TRANSITION

lbl ADC[0].O = ES

slide-78
SLIDE 78

ARCO COMPILER 78

ARCO COMPILER RECAP

Arco starts with an initial tableau

slide-79
SLIDE 79

ARCO COMPILER 79

ARCO COMPILER RECAP

derives new tableaus using transition rules Unify Connect Variable Map

slide-80
SLIDE 80

ARCO COMPILER 80

ARCO COMPILER RECAP

until a solved tableau is found

slide-81
SLIDE 81

ARCO COMPILER 81

ARCO COMPILER RECAP

analog device configuration in solved tableau

slide-82
SLIDE 82

ARCO COMPILER 82

ARCO COMPILER RECAP

analog device configuration in solved tableau

ALGEBRAICALLY EQUIVALENT TO DYNAMICAL SYSTEM

creative use of available analog blocks to model dynamics respects connectivity, block instance constraints

slide-83
SLIDE 83

TEXT 83

CASE STUDY 1: PERK-4

iadd

O = A + B + C

O A B C

switch

O S K M n

O = M (S ⋅ K−1 + 1)n

  • 1

PERK 4 1 1 PERK-4

O = M ((A + B + C) ⋅ K−1 + 1)n O = 1 ((PERK + (−1) + 0) ⋅ 1−1 + 1)4

PERK-4

Task: model PERK-4 using analog hardware that does not directly support exponentiation.

slide-84
SLIDE 84

ARCO COMPILER 84

ARCO COMPILER RECAP

analog device configuration in solved tableau doesn’t take into consideration

PHYSICAL LIMITATIONS OF HARDWARE

slide-85
SLIDE 85

ARCO COMPILER 85

ARCO COMPILER RECAP

analog device configuration in solved tableau doesn’t take into consideration

PHYSICAL LIMITATIONS OF HARDWARE

OPERATING RANGE CONSTRAINTS SAMPLING RATES OF ADCS/DACS

slide-86
SLIDE 86

BACKGROUND 86

ANALOG DEVICE CONFIGURATION REVISITED

DAC1 ADC1

mm

ADC2 ADC3 DAC2 DAC3 DAC5 DAC4 X0 A X Z Y B Y0 Z0

S E ES 0.0001 6800 4400 0.01

slide-87
SLIDE 87

DAC1 ADC1

mm

ADC2 ADC3 DAC2 DAC3 DAC5 DAC4 X0 A X Z Y B Y0 Z0

S E ES 0.0001 6800 4400 0.01

BACKGROUND 87

ANALOG DEVICE CONFIGURATION REVISITED

2 4 6 8 10 time (su) 2000 4000 6000 molecules

Expected Simulation Dynamics

slide-88
SLIDE 88

BACKGROUND 88

ANALOG DEVICE CONFIGURATION REVISITED

DAC1

[0,10]

ADC1

[0,3300]

mm

ADC2

[0,3300]

ADC3

[0,3300]

DAC2

[0,3300]

DAC3

[0,3300]

DAC5

[0,10]

DAC4

[0,3300]

X0

[0,1000]

A

[10-5,10-3] [0,1600]

X

[0,1600]

Z

[0,1600]

Y B

[10-4,1]

Y0

[0,1000]

Z0

[0,1000]

S E ES 0.0001 6800 4400 0.01

slide-89
SLIDE 89

BACKGROUND 89

ANALOG DEVICE CONFIGURATION REVISITED

DAC1

[0,10]

ADC1

[0,3300]

mm

ADC2

[0,3300]

ADC3

[0,3300]

DAC3

[0,3300]

DAC5

[0,10]

X0

[0,1000]

A

[10-5,10-3] [0,1600]

X

[0,1600]

Z

[0,1600]

Y B

[10-4,1]

Y0

[0,1000]

Z0

[0,1000]

DAC2

[0,3300]

DAC4

[0,3300]

S E ES 0.0001 6800 4400 0.01

slide-90
SLIDE 90

DAC1

[0,10]

ADC1

[0,3300]

mm

ADC2

[0,3300]

ADC3

[0,3300]

DAC3

[0,3300]

DAC5

[0,10]

X0

[0,1000]

A

[10-5,10-3] [0,1600]

X

[0,1600]

Z

[0,1600]

Y B

[10-4,1]

Y0

[0,1000]

Z0

[0,1000]

DAC2

[0,3300]

DAC4

[0,3300]

S E ES 0.0001 6800 4400 0.01

BACKGROUND 90

ANALOG DEVICE CONFIGURATION REVISITED

2 4 6 8 10 time (su) 2000 4000 6000 molecules

2 4 6 8 10 time (su) 2000 4000 6000 molecules

Actual Simulation Dynamics

slide-91
SLIDE 91

BACKGROUND 91

UNIFORMLY SCALED ANALOG DEVICE CONFIGURATION

DAC1

[0,10]

ADC1

[0,3300]

mm

ADC2

[0,3300]

ADC3

[0,3300]

DAC2

[0,3300]

DAC3

[0,3300]

DAC5

[0,10]

DAC4

[0,3300]

X0

[0,1000]

A

[10-5,10-3] [0,1600]

X

[0,1600]

Z

[0,1600]

Y B

[10-4,1]

Y0

[0,1000]

Z0

[0,1000]

a15•S a13•E a14•ES 0.1•10-4 0.1•6800 0.1• 0.1•4400 0.1•10-2

slide-92
SLIDE 92

BACKGROUND 92

UNIFORMLY SCALED ANALOG DEVICE CONFIGURATION

DAC1

[0,10]

ADC1

[0,3300]

mm

ADC2

[0,3300]

ADC3

[0,3300]

DAC2

[0,3300]

DAC3

[0,3300]

DAC5

[0,10]

DAC4

[0,3300]

X0

[0,1000]

A

[10-5,10-3] [0,1600]

X

[0,1600]

Z

[0,1600]

Y B

[10-4,1]

Y0

[0,1000]

Z0

[0,1000]

a15•S a13•E a14•ES 0.1•10-4 0.1•6800 0.1• 0.1•4400 0.1•10-2

DOES NOT WORK!

slide-93
SLIDE 93

BACKGROUND 93

UNIFORMLY SCALED ANALOG DEVICE CONFIGURATION

DAC1

[0,10]

ADC1

[0,3300]

mm

ADC2

[0,3300]

ADC3

[0,3300]

DAC2

[0,3300]

DAC3

[0,3300]

DAC5

[0,10]

DAC4

[0,3300]

X0

[0,1000]

A

[10-5,10-3] [0,1600]

X

[0,1600]

Z

[0,1600]

Y B

[10-4,1]

Y0

[0,1000]

Z0

[0,1000]

a15•S a13•E a14•ES 0.1•10-4 0.1•6800 0.1• 0.1•4400 0.1•10-2

DOES NOT WORK!

SCALED SIGNAL CHANGES SIMULATION ORIGINAL SIMULATION NOT RECOVERABLE

slide-94
SLIDE 94

OUTLINE 94

  • Background: overview of compilation problem
  • Arco Compiler1: automatically configure analog devices to simulate

dynamical systems.

  • Jaunt Solver2: automatically scales dynamical systems to execute

analog hardware with operating range constraints.

  • Closing Remarks

TALK OUTLINE

1. Configuration Synthesis for Programmable Analog Devices with Arco. Sara Achour, Rahul Sarpeshkar and Martin Rinard. June 2016. PLDI 2016. 2. Time Dilation and Contraction for Programmable Analog Devices with Jaunt. Sara Achour and Martin Rinard. December 2017. ASPLOS 2018.

slide-95
SLIDE 95

JAUNT SOLVER

slide-96
SLIDE 96

BACKGROUND 96

Jaunt

Analog Device Specification Scaled Analog Device Configuration Analog Device Configuration

slide-97
SLIDE 97

BACKGROUND 97

Jaunt

Analog Device Specification Analog Device Configuration Scaled Analog Device Configuration physically realizable: signals within port operating ranges recoverable: recover original simulation at ADCs

slide-98
SLIDE 98

BACKGROUND 98

ANALOG DEVICE CONFIGURATION

DAC1

[0,10]

ADC1

[0,3300]

mm

ADC2

[0,3300]

ADC3

[0,3300]

DAC2

[0,3300]

DAC3

[0,3300]

DAC5

[0,10]

DAC4

[0,3300]

X0

[0,1000]

A

[10-5,10-3] [0,1600]

X

[0,1600]

Z

[0,1600]

Y B

[10-4,1]

Y0

[0,1000]

Z0

[0,1000]

S E ES 10-4 6800 4400 10-2

slide-99
SLIDE 99

BACKGROUND 99

SCALED ANALOG DEVICE CONFIGURATION

mm

DAC1

[0,10]

ADC1

[0,3300]

ADC2

[0,3300]

ADC3

[0,3300]

DAC2

[0,3300]

DAC3

[0,3300]

DAC5

[0,10]

DAC4

[0,3300]

a7•X0

[0,1000]

a6•A

[10-5,10-3] [0,1600]

a11•X

[0,1600]

a12•Z

[0,1600]

a13•Y a10•B

[10-4,1]

a9•Y0

[0,1000]

a8•Z0

[0,1000]

a16•S a14•E a15•ES a1•10-4 a2•6800 a3•0 a4•4400 a5•10-2

τ

simulation speed

slide-100
SLIDE 100

BACKGROUND 100

SCALED ANALOG DEVICE CONFIGURATION

mm

DAC1

[0,10]

ADC1

[0,3300]

ADC2

[0,3300]

ADC3

[0,3300]

DAC2

[0,3300]

DAC3

[0,3300]

DAC5

[0,10]

DAC4

[0,3300]

a7•X0

[0,1000]

a6•A

[10-5,10-3] [0,1600]

a11•X

[0,1600]

a12•Z

[0,1600]

a13•Y a10•B

[10-4,1]

a9•Y0

[0,1000]

a8•Z0

[0,1000]

a16•S a14•E a15•ES a1•10-4 a2•6800 a3•0 a4•4400 a5•10-2

τ

simulation speed

slide-101
SLIDE 101

BACKGROUND 101

SCALED ANALOG DEVICE CONFIGURATION

DAC1

[0,10]

ADC1

[0,3300]

mm

ADC2

[0,3300]

ADC3

[0,3300]

DAC2

[0,3300]

DAC3

[0,3300]

DAC5

[0,10]

DAC4

[0,3300]

a7•X0

[0,1000]

a6•A

[10-5,10-3] [0,1600]

a11•X

[0,1600]

a12•Z

[0,1600]

a13•Y a10•B

[10-4,1]

a9•Y0

[0,1000]

a8•Z0

[0,1000]

a16•S a14•E a15•ES a1•10-4 a2•6800 a3•0 a4•4400 a5•10-2

τ

simulation speed

slide-102
SLIDE 102

BACKGROUND 102

SCALED ANALOG DEVICE CONFIGURATION

τ

simulation speed

DAC1

[0,10]

ADC1

[0,3300]

mm

ADC2

[0,3300]

ADC3

[0,3300]

DAC2

[0,3300]

DAC3

[0,3300]

DAC5

[0,10]

DAC4

[0,3300]

a7•X0

[0,1000]

a6•A

[10-5,10-3] [0,1600]

a11•X

[0,1600]

a12•Z

[0,1600]

a13•Y a10•B

[10-4,1]

a9•Y0

[0,1000]

a8•Z0

[0,1000]

a16•S a14•E a15•ES a1•10-4 a2•6800 a3•0 a4•4400 a5•10-2

multiply parameters by scaling factors

slide-103
SLIDE 103

BACKGROUND 103

SCALED ANALOG DEVICE CONFIGURATION

τ

simulation speed

DAC1

[0,10]

ADC1

[0,3300]

mm

ADC2

[0,3300]

ADC3

[0,3300]

DAC2

[0,3300]

DAC3

[0,3300]

DAC5

[0,10]

DAC4

[0,3300]

a7•X0

[0,1000]

a6•A

[10-5,10-3] [0,1600]

a11•X

[0,1600]

a12•Z

[0,1600]

a13•Y a10•B

[10-4,1]

a9•Y0

[0,1000]

a8•Z0

[0,1000]

a16•S a14•E a15•ES a1•10-4 a2•6800 a3•0 a4•4400 a5•10-2

physically realizable: signals in port operating ranges

slide-104
SLIDE 104

BACKGROUND 104

SCALED ANALOG DEVICE CONFIGURATION

DAC1

[0,10]

ADC1

[0,3300]

mm

ADC2

[0,3300]

ADC3

[0,3300]

DAC2

[0,3300]

DAC3

[0,3300]

DAC5

[0,10]

DAC4

[0,3300]

a7•X0

[0,1000]

a6•A

[10-5,10-3] [0,1600]

a10•X

[0,1600]

a11•Z

[0,1600]

a12•Y a9•B

[10-4,1]

a8•Y0

[0,1000]

a8•Z0

[0,1000]

a15•S a13•E a14•ES a1•10-4 a2•6800 a3•0 a4•4400 a5•10-2

τ

simulation speed

  • Recover Simulation:
  • divide ADC samples by a13-a15
  • multiply hardware time by τ
slide-105
SLIDE 105

BACKGROUND 105

JAUNT SOLVER

  • Objective: Find numerical assignments for scaling

factors that produces fastest simulation

  • Scaling Factors: τ,a1, …, a15
  • Values: real numbers > 0
slide-106
SLIDE 106

BACKGROUND 106

JAUNT SOLVER

  • Objective: Find numerical assignments for scaling

factors that produces fastest simulation

  • Scaling Factors: τ,a1, …, a15
  • Values: real numbers > 0
  • Geometric Program: Convex optimization problem
  • Device Configuration → Geometric Program

slide-107
SLIDE 107

TEXT 107

  • Maximize τ subject to:
  • Factor Constraints
  • Sampling Constraints
  • Connection Constraints
  • Operating Range Constraints

GEOMETRIC PROGRAM GENERATION

slide-108
SLIDE 108

TEXT 108

  • Maximize τ subject to:
  • Factor Constraints
  • Sampling Constraints
  • Connection Constraints
  • Operating Range Constraints

GEOMETRIC PROGRAM GENERATION

given block with scaled input signals: → original output signal is recoverable from scaled output signal

slide-109
SLIDE 109

TEXT 109

FACTOR CONSTRAINTS

mm

a7•X0

[0,1000]

a6•A

[10-5,10-3] [0,1600]

a11•X

[0,1600]

a12•Z

[0,1600]

a13•Y a10•B

[10-4,1]

a9•Y0

[0,1000]

a8•Z0

[0,1000]

τ

simulation speed

a12 ⋅ Z = ∫ [a6a11a13 ⋅ A ⋅ X ⋅ Y − a9a12 ⋅ B ⋅ Z]τ−1 ⋅ dt a6a11a13 a9a12 τ−1 a12

slide-110
SLIDE 110

TEXT 110

FACTOR CONSTRAINTS

mm

a7•X0

[0,1000]

a6•A

[10-5,10-3] [0,1600]

a11•X

[0,1600]

a12•Z

[0,1600]

a13•Y a10•B

[10-4,1]

a9•Y0

[0,1000]

a8•Z0

[0,1000]

τ

simulation speed

a12 ⋅ Z = ∫ a6a11a13 ⋅ [A ⋅ X ⋅ Y − ⋅B ⋅ Z]τ−1 ⋅ dt a6a11a13 = a9a12 τ−1 a12 a6a11a13

slide-111
SLIDE 111

TEXT 111

FACTOR CONSTRAINTS

mm

a7•X0

[0,1000]

a6•A

[10-5,10-3] [0,1600]

a11•X

[0,1600]

a12•Z

[0,1600]

a13•Y a10•B

[10-4,1]

a9•Y0

[0,1000]

a8•Z0

[0,1000]

τ

simulation speed

a6a11a13τ−1[Z = ∫ ⋅ [A ⋅ X ⋅ Y − ⋅B ⋅ Z] ⋅ dt] a6a11a13τ−1 a6a11a13τ−1 = a12 a6a11a13 = a9a12

slide-112
SLIDE 112

TEXT 112

  • Maximize τ subject to:
  • Factor Constraints
  • Sampling Constraints
  • Connection Constraints
  • Operating Range Constraints

GEOMETRIC PROGRAM GENERATION

given DAC/ADC: → ensure simulation is executed slowly enough for adequate sampling

slide-113
SLIDE 113

ADC1

[0,3300]

mm

ADC2

[0,3300]

ADC3

[0,3300]

[0,1600]

a11•X

[0,1600]

a12•Z

[0,1600]

a13•Y

a16•S a14•E a15•ES

BACKGROUND 113

SAMPLE CONSTRAINTS

simulation speed

1 sample/hu 1 sample/hu 1 sample/hu

2 sample/su ≤ 1 sample/hu ⋅ τ−1 τ−1 τ : hu → su τ

minimum number of samples / simulation time unit

slide-114
SLIDE 114

ADC1

[0,3300]

mm

ADC2

[0,3300]

ADC3

[0,3300]

[0,1600]

a11•X

[0,1600]

a12•Z

[0,1600]

a13•Y

a16•S a14•E a15•ES

BACKGROUND 114

SAMPLE CONSTRAINTS

simulation speed

1 sample/hu 1 sample/hu 1 sample/hu

2 sample/su ≤ 1 sample/hu ⋅ τ−1 τ−1 τ : hu → su τ

number of samples in one hardware time unit

slide-115
SLIDE 115

ADC1

[0,3300]

mm

ADC2

[0,3300]

ADC3

[0,3300]

[0,1600]

a11•X

[0,1600]

a12•Z

[0,1600]

a13•Y

a16•S a14•E a15•ES

BACKGROUND 115

SAMPLE CONSTRAINTS

simulation speed

1 sample/hu 1 sample/hu 1 sample/hu

2 sample/su ≤ 1 sample/hu ⋅ τ−1 τ−1 τ : hu → su τ

number of samples in one hardware time unit

τ−1 : hu su

slide-116
SLIDE 116

TEXT 116

  • Maximize τ subject to:
  • Factor Constraints
  • Sampling Constraints
  • Connection Constraints
  • Operating Range Constraints

GEOMETRIC PROGRAM GENERATION

given a connection: → ensure signal is scaled equally on both sides of connection

slide-117
SLIDE 117

BACKGROUND 117

CONNECTION CONSTRAINTS

DAC1

[0,10]

mm

DAC2

[0,3300]

DAC3

[0,3300]

DAC5

[0,10]

DAC4

[0,3300]

a7•X0

[0,1000]

a6•A

[10-5,10-3]

a10•B

[10-4,1]

a9•Y0

[0,1000]

a8•Z0

[0,1000]

a1•10-4 a2•6800 a3•0 a4•4400 a5•10-2

a1 = a6 a2 = a7 a3 = a8 a1 a2 a3 a7 a6 a8

slide-118
SLIDE 118

TEXT 118

  • Maximize τ subject to:
  • Factor Constraints
  • Sampling Constraints
  • Connection Constraints
  • Operating Range Constraints

GEOMETRIC PROGRAM GENERATION

given an input/output port: → ensure signal stays within the operating range of the port

slide-119
SLIDE 119

BACKGROUND 119

OPERATING RANGE RANGE CONSTRAINTS

DAC1

[0,10]

mm

DAC2

[0,3300]

DAC3

[0,3300]

DAC5

[0,10]

DAC4

[0,3300]

a7•X0

[0,1000]

a6•A

[10-5,10-3]

a10•B

[10-4,1]

a9•Y0

[0,1000]

a8•Z0

[0,1000]

a1•10-4 a2•6800 a3•0 a4•4400 a5•10-2

0 ≤ a7 ⋅ 6800 ≤ 1000

slide-120
SLIDE 120

TEXT 120

  • Maximize τ subject to:
  • Factor Constraints
  • Sampling Constraints
  • Connection Constraints
  • Operating Range Constraints

GEOMETRIC PROGRAM GENERATION

slide-121
SLIDE 121

TEXT 121

GEOMETRIC PROGRAM GENERATION

GEOMETRIC PROGRAMMING LIBRARY CONVERT TO CONVEX PROGRAM CONVEX SOLVER [CVXOPT]

Scaled Analog Device Configuration

Geometric Program

slide-122
SLIDE 122

BACKGROUND 122

SCALED ANALOG DEVICE CONFIGURATION

DAC1

[0,10]

ADC1

[0,3300]

mm

ADC2

[0,3300]

ADC3

[0,3300]

DAC2

[0,3300]

DAC3

[0,3300]

DAC5

[0,10]

DAC4

[0,3300]

0.06•X0

[0,1000]

8.28•A

[10-5,10-3] [0,1600]

0.06•X

[0,1600]

0.06•Z

[0,1600]

0.06•Y 0.5•B

[10-4,1]

0.06•Y0

[0,1000]

0.06•Z0

[0,1000]

0.06•S 0.06•E 0.06•ES 8.28•10-4 0.06•6800 0.06•0 0.06•4400 0.5•10-2

0.5

simulation speed

slide-123
SLIDE 123

TEXT 123

CASE STUDY: REPRISSILATOR

200 400 600 800 1000 time (su) 25 50 75 100 125 molecules

gene network that generates oscillations “synthetic genetic clock”

reference simulation

slide-124
SLIDE 124

TEXT 124

CASE STUDY: REPRISSILATOR

200 400 600 800 1000 time (su) 25 50 75 100 125 molecules

simulation using unscaled configuration

200 400 600 800 1000 time (su) 50 100 150 molecules

reference simulation simulation without jaunt

saturates, loses oscillations

slide-125
SLIDE 125

TEXT 125

CASE STUDY: REPRISSILATOR

200 400 600 800 1000 time (su) 25 50 75 100 125 molecules

200 400 600 800 1000 time (su) 50 100 150 molecules

Reference Simulation

100 200 300 time (hu) 200 400 600 800 1000 signal

simulation with jaunt before recovery

simulation using scaled configuration executes 2.839x faster than unscaled configuration

slide-126
SLIDE 126

TEXT 126

CASE STUDY: REPRISSILATOR

200 400 600 800 1000 time (su) 25 50 75 100 125 molecules

200 400 600 800 1000 time (su) 50 100 150 molecules

Reference Simulation simulation with jaunt after recovery

200 400 600 800 1000 time (su) 25 50 75 100 125 molecules

simulation using scaled configuration scaling samples and time recovers original simulation

slide-127
SLIDE 127

OUTLINE 127

  • Background: overview of compilation problem
  • Arco Compiler1: automatically configure analog devices to simulate

dynamical systems.

  • Jaunt Solver2: automatically scales dynamical systems to execute

analog hardware with operating range constraints.

  • Closing Remarks

TALK OUTLINE

1. Configuration Synthesis for Programmable Analog Devices with Arco. Sara Achour, Rahul Sarpeshkar and Martin Rinard. June 2016. PLDI 2016. 2. Time Dilation and Contraction for Programmable Analog Devices with Jaunt. Sara Achour and Martin Rinard. December 2017. ASPLOS 2018.

slide-128
SLIDE 128

WHAT NEXT?

slide-129
SLIDE 129

CLOSING REMARKS 129

SENDYNE HYBRID DIGITAL-ANALOG COMPUTATION CHIP

slide-130
SLIDE 130

TEXT

WHAT IS THE DIFFERENCE BETWEEN THESE CIRCUITS?

130

CURRENT MIRROR CONSTANT GAIN (2) CURRENT MULT LUT F(X) = 2X

X X X X

NO-CLK DAC NO-CLK ADC

2X 2X 2X 2 2X

slide-131
SLIDE 131

TEXT

WHAT IS THE DIFFERENCE BETWEEN THESE CIRCUITS?

131

CURRENT MIRROR CONSTANT GAIN (2) CURRENT MULT LUT F(X) = 2X

X X X X

NO-CLK DAC NO-CLK ADC

2X 2X 2X 2 2X

NOISE BEHAVIOR! HIGH NOISE LOW NOISE

slide-132
SLIDE 132

TEXT

WHAT IS THE DIFFERENCE BETWEEN THESE CIRCUITS?

132

CURRENT MIRROR CONSTANT GAIN (2) CURRENT MULT LUT F(X) = 2X

X X X X

NO-CLK DAC NO-CLK ADC

2X 2X 2X 2 2X

NOISE BEHAVIOR! HIGH NOISE LOW NOISE

IS THIS BAD?

slide-133
SLIDE 133

TEXT 133

IS THIS BAD?

inherent variance in physical systems SDES circuit noise = stochastic behavior

  • ther stochastic processes
slide-134
SLIDE 134

TEXT 134

IS THIS BAD?

uncertainty in modeling physical systems unmodeled dynamics empirically derived models circuit noise <= uncertainty

slide-135
SLIDE 135

TEXT

TECHNIQUES FOR MANIPULATING NOISE

135

Option 1: Rearrange circuit to reduce noise

CURRENT MULT

X Y

CURRENT MIRROR

2XY

CURRENT MULT

X Y

CURRENT MIRROR

2XY 2X

[ noise-aware circuit generation ]

time signal time signal

Noise Signal

slide-136
SLIDE 136

TEXT

TECHNIQUES FOR MANIPULATING NOISE

136

CURRENT MIRROR

a1X 2a1X

Option 2: Increase dynamic range of X

CURRENT MIRROR

X 2X

[ noise-aware parameter scaling ]

time signal time signal time signal time signal

Noise Signal

slide-137
SLIDE 137

TEXT

TECHNIQUES FOR MANIPULATING NOISE

137

CURRENT MIRROR

X 2X

Option 3: Insert filter that removes noise

CURRENT MIRROR

X 2X

LPF

[ automated filter configuration ]

frequency energy frequency energy frequency energy

ω ω ω Noise Signal

slide-138
SLIDE 138

TEXT

WHAT NEXT?

138

Legno: noise-aware configuration generation noise-aware scaling transforms ranked configuration generation automated filter generation

slide-139
SLIDE 139

BACKGROUND 139

Legno

Analog Device Specification Stochastic
 Differential Equations Analog Device Configuration

+

Analytical 
 Noise Model

slide-140
SLIDE 140

BACKUP SLIDES

slide-141
SLIDE 141

CLOSING REMARKS

SARPSHKAR GROUP PROTEIN CHIP

141

528 IEEE TRANSACTIONS ON BIOMEDICAL CIRCUITS AND SYSTEMS, VOL. 9, NO. 4, AUGUST 2015
  • Fig. 1. Poisson chemical reaction flux and Poisson electron flow in
sub-threshold transistors obey the same Boltzmann exponential laws of thermodynamics, and are therefore mathematically similar [13]. Electron copy number is analogous to molecular copy number and temperature represents itself. single cell on a few chips and speedup multi-cell simulations
  • n multi-chip electronic boards [13]. Therefore, we were moti-
vated to create a few fundamental molecular circuits that could be composed and scaled to model large biochemical reaction networks in the future. This paper describes these fundamental building-block cytomorphic circuits. The paper focuses on establishing quantitative agreement of the cytomorphic chip measurements with prior biological measurements and models. The building-block circuits may be classified into seven im- portant categories: 1) Basic BiCMOS current-mode analog circuits exploit the log-domain cytomorphic mapping to capture the exact dy- namics of fundamental mass-action molecular kinetics such as association, dissociation, and degradation. These fundamental circuits are general enough to capture subtle effects such as loading, fan-out, feedback, and substrate de- pletion through the use of a few explicit connections and Kirchhoff’s current law. A wide dynamic range of opera- tion and low power consumption are achieved through the use of bipolar and subthreshold MOS transistors that func- tion at low current levels. 2) The ability to model cooperative binding is enabled by tun- able Hill-function building-block circuits. 3) An “ITD” block built by a composition of above cur- rent-mode circuits enables mapping of the exact differen- tial equations of inducer-transcription-factor binding and transcription-factor-DNA binding including for- ward and reverse reactions, degradation, protection from degradation of transcription factors bound to DNA, and the change in DNA binding affinity of transcription factors when bound by an inducer. 4) An “analogic” current-mode circuit determines the tran- scription rate of genes based on the probability of mul- tiple transcription-factor DNA binding sites being occu- pied or unoccupied in a combinatorial fashion with the rel- ative mRNA production rate of each such combinatorial state programmable by the user. This strategy enables us to implement any arbitrary “analogic promoter function” that is capable of complex saturating digital logic or prob- abilistic analog behavior depending on the molecular con- centration. 5) A current-mode low pass filter (LPF) circuit enables the gain and dynamics of mRNA and protein production and degradation to be represented.
  • Fig. 2. Die micrograph of the
cytomorphic chip fabricated in an AMS BiCMOS process. The left inset is a layout screen capture
  • f one gene block (2x magnification).
6) A stochastics circuit intentionally amplifies analog Poisson noise in transistors to represent biological fluc- tuations in mRNA and protein concentrations at very low copy numbers and at relatively high noise levels. The Poisson nature of biochemical reaction fluxes au- tomatically maps biological noise to electronic noise at high copy numbers and relatively low noise levels [13]. Thus, these circuits are most useful for reliably modeling highly stochastic and relatively low signal-to-noise-ratios in biological cells. 7) ADCs and DACs convert between analog currents and digital bits to enable our chips to communicate with each
  • ther via digital input/output (I/O), and with off-chip dig-
ital processors and computers. Off-chip digital processors synergistically interact with our chips to carry out various functions: reading digital data from the chips; decoding the data; performing high-speed digital signal processing as necessary (e.g., scaling, diffusion, time delay, and error correction); encoding the data to create or modify molecular data packets via address and data strings; storing the programmable address connectivity amongst gene and protein circuits; and communicating data to other chips
  • r to a computer. For simplicity, the data in this paper were
collected with a data-acquisition board (NI PXI-6541) that interacted with our chip and with MATLAB on a computer. A high-performance FPGA (e.g., from the Xilinx Spartan family) could perform all of these functions in the future as well. Shift registers, SRAM blocks, and switches on the chip enable programmability of parameters (e.g., reaction rates, dissocia- tion constants, Hill coefficients, and time constants) as well as connectivity. The organization of this paper is as follows: Section II de- scribes the core building-block circuits of the chip along with chip measurement data. Fig. 2 shows a die micrograph of the chip that reveals the various building blocks. Section III dis- cusses design considerations that are important in BiCMOS cy- tomorphic chip design. Section IV discusses how cytomorphic 528 IEEE TRANSACTIONS ON BIOMEDICAL CIRCUITS AND SYSTEMS, VOL. 9, NO. 4, AUGUST 2015
  • Fig. 1. Poisson chemical reaction flux and Poisson electron flow in
sub-threshold transistors obey the same Boltzmann exponential laws of thermodynamics, and are therefore mathematically similar [13]. Electron copy number is analogous to molecular copy number and temperature represents itself. single cell on a few chips and speedup multi-cell simulations
  • n multi-chip electronic boards [13]. Therefore, we were moti-
vated to create a few fundamental molecular circuits that could be composed and scaled to model large biochemical reaction networks in the future. This paper describes these fundamental building-block cytomorphic circuits. The paper focuses on establishing quantitative agreement of the cytomorphic chip measurements with prior biological measurements and models. The building-block circuits may be classified into seven im- portant categories: 1) Basic BiCMOS current-mode analog circuits exploit the log-domain cytomorphic mapping to capture the exact dy- namics of fundamental mass-action molecular kinetics such as association, dissociation, and degradation. These fundamental circuits are general enough to capture subtle effects such as loading, fan-out, feedback, and substrate de- pletion through the use of a few explicit connections and Kirchhoff’s current law. A wide dynamic range of opera- tion and low power consumption are achieved through the use of bipolar and subthreshold MOS transistors that func- tion at low current levels. 2) The ability to model cooperative binding is enabled by tun- able Hill-function building-block circuits. 3) An “ITD” block built by a composition of above cur- rent-mode circuits enables mapping of the exact differen- tial equations of inducer-transcription-factor binding and transcription-factor-DNA binding including for- ward and reverse reactions, degradation, protection from degradation of transcription factors bound to DNA, and the change in DNA binding affinity of transcription factors when bound by an inducer. 4) An “analogic” current-mode circuit determines the tran- scription rate of genes based on the probability of mul- tiple transcription-factor DNA binding sites being occu- pied or unoccupied in a combinatorial fashion with the rel- ative mRNA production rate of each such combinatorial state programmable by the user. This strategy enables us to implement any arbitrary “analogic promoter function” that is capable of complex saturating digital logic or prob- abilistic analog behavior depending on the molecular con- centration. 5) A current-mode low pass filter (LPF) circuit enables the gain and dynamics of mRNA and protein production and degradation to be represented.
  • Fig. 2. Die micrograph of the
cytomorphic chip fabricated in an AMS BiCMOS process. The left inset is a layout screen capture
  • f one gene block (2x magnification).
6) A stochastics circuit intentionally amplifies analog Poisson noise in transistors to represent biological fluc- tuations in mRNA and protein concentrations at very low copy numbers and at relatively high noise levels. The Poisson nature of biochemical reaction fluxes au- tomatically maps biological noise to electronic noise at high copy numbers and relatively low noise levels [13]. Thus, these circuits are most useful for reliably modeling highly stochastic and relatively low signal-to-noise-ratios in biological cells. 7) ADCs and DACs convert between analog currents and digital bits to enable our chips to communicate with each
  • ther via digital input/output (I/O), and with off-chip dig-
ital processors and computers. Off-chip digital processors synergistically interact with our chips to carry out various functions: reading digital data from the chips; decoding the data; performing high-speed digital signal processing as necessary (e.g., scaling, diffusion, time delay, and error correction); encoding the data to create or modify molecular data packets via address and data strings; storing the programmable address connectivity amongst gene and protein circuits; and communicating data to other chips
  • r to a computer. For simplicity, the data in this paper were
collected with a data-acquisition board (NI PXI-6541) that interacted with our chip and with MATLAB on a computer. A high-performance FPGA (e.g., from the Xilinx Spartan family) could perform all of these functions in the future as well. Shift registers, SRAM blocks, and switches on the chip enable programmability of parameters (e.g., reaction rates, dissocia- tion constants, Hill coefficients, and time constants) as well as connectivity. The organization of this paper is as follows: Section II de- scribes the core building-block circuits of the chip along with chip measurement data. Fig. 2 shows a die micrograph of the chip that reveals the various building blocks. Section III dis- cusses design considerations that are important in BiCMOS cy- tomorphic chip design. Section IV discusses how cytomorphic 528 IEEE TRANSACTIONS ON BIOMEDICAL CIRCUITS AND SYSTEMS, VOL. 9, NO. 4, AUGUST 2015
  • Fig. 1. Poisson chemical reaction flux and Poisson electron flow in
sub-threshold transistors obey the same Boltzmann exponential laws of thermodynamics, and are therefore mathematically similar [13]. Electron copy number is analogous to molecular copy number and temperature represents itself. single cell on a few chips and speedup multi-cell simulations
  • n multi-chip electronic boards [13]. Therefore, we were moti-
vated to create a few fundamental molecular circuits that could be composed and scaled to model large biochemical reaction networks in the future. This paper describes these fundamental building-block cytomorphic circuits. The paper focuses on establishing quantitative agreement of the cytomorphic chip measurements with prior biological measurements and models. The building-block circuits may be classified into seven im- portant categories: 1) Basic BiCMOS current-mode analog circuits exploit the log-domain cytomorphic mapping to capture the exact dy- namics of fundamental mass-action molecular kinetics such as association, dissociation, and degradation. These fundamental circuits are general enough to capture subtle effects such as loading, fan-out, feedback, and substrate de- pletion through the use of a few explicit connections and Kirchhoff’s current law. A wide dynamic range of opera- tion and low power consumption are achieved through the use of bipolar and subthreshold MOS transistors that func- tion at low current levels. 2) The ability to model cooperative binding is enabled by tun- able Hill-function building-block circuits. 3) An “ITD” block built by a composition of above cur- rent-mode circuits enables mapping of the exact differen- tial equations of inducer-transcription-factor binding and transcription-factor-DNA binding including for- ward and reverse reactions, degradation, protection from degradation of transcription factors bound to DNA, and the change in DNA binding affinity of transcription factors when bound by an inducer. 4) An “analogic” current-mode circuit determines the tran- scription rate of genes based on the probability of mul- tiple transcription-factor DNA binding sites being occu- pied or unoccupied in a combinatorial fashion with the rel- ative mRNA production rate of each such combinatorial state programmable by the user. This strategy enables us to implement any arbitrary “analogic promoter function” that is capable of complex saturating digital logic or prob- abilistic analog behavior depending on the molecular con- centration. 5) A current-mode low pass filter (LPF) circuit enables the gain and dynamics of mRNA and protein production and degradation to be represented.
  • Fig. 2. Die micrograph of the
cytomorphic chip fabricated in an AMS BiCMOS process. The left inset is a layout screen capture
  • f one gene block (2x magnification).
6) A stochastics circuit intentionally amplifies analog Poisson noise in transistors to represent biological fluc- tuations in mRNA and protein concentrations at very low copy numbers and at relatively high noise levels. The Poisson nature of biochemical reaction fluxes au- tomatically maps biological noise to electronic noise at high copy numbers and relatively low noise levels [13]. Thus, these circuits are most useful for reliably modeling highly stochastic and relatively low signal-to-noise-ratios in biological cells. 7) ADCs and DACs convert between analog currents and digital bits to enable our chips to communicate with each
  • ther via digital input/output (I/O), and with off-chip dig-
ital processors and computers. Off-chip digital processors synergistically interact with our chips to carry out various functions: reading digital data from the chips; decoding the data; performing high-speed digital signal processing as necessary (e.g., scaling, diffusion, time delay, and error correction); encoding the data to create or modify molecular data packets via address and data strings; storing the programmable address connectivity amongst gene and protein circuits; and communicating data to other chips
  • r to a computer. For simplicity, the data in this paper were
collected with a data-acquisition board (NI PXI-6541) that interacted with our chip and with MATLAB on a computer. A high-performance FPGA (e.g., from the Xilinx Spartan family) could perform all of these functions in the future as well. Shift registers, SRAM blocks, and switches on the chip enable programmability of parameters (e.g., reaction rates, dissocia- tion constants, Hill coefficients, and time constants) as well as connectivity. The organization of this paper is as follows: Section II de- scribes the core building-block circuits of the chip along with chip measurement data. Fig. 2 shows a die micrograph of the chip that reveals the various building blocks. Section III dis- cusses design considerations that are important in BiCMOS cy- tomorphic chip design. Section IV discusses how cytomorphic 528 IEEE TRANSACTIONS ON BIOMEDICAL CIRCUITS AND SYSTEMS, VOL. 9, NO. 4, AUGUST 2015
  • Fig. 1. Poisson chemical reaction flux and Poisson electron flow in
sub-threshold transistors obey the same Boltzmann exponential laws of thermodynamics, and are therefore mathematically similar [13]. Electron copy number is analogous to molecular copy number and temperature represents itself. single cell on a few chips and speedup multi-cell simulations
  • n multi-chip electronic boards [13]. Therefore, we were moti-
vated to create a few fundamental molecular circuits that could be composed and scaled to model large biochemical reaction networks in the future. This paper describes these fundamental building-block cytomorphic circuits. The paper focuses on establishing quantitative agreement of the cytomorphic chip measurements with prior biological measurements and models. The building-block circuits may be classified into seven im- portant categories: 1) Basic BiCMOS current-mode analog circuits exploit the log-domain cytomorphic mapping to capture the exact dy- namics of fundamental mass-action molecular kinetics such as association, dissociation, and degradation. These fundamental circuits are general enough to capture subtle effects such as loading, fan-out, feedback, and substrate de- pletion through the use of a few explicit connections and Kirchhoff’s current law. A wide dynamic range of opera- tion and low power consumption are achieved through the use of bipolar and subthreshold MOS transistors that func- tion at low current levels. 2) The ability to model cooperative binding is enabled by tun- able Hill-function building-block circuits. 3) An “ITD” block built by a composition of above cur- rent-mode circuits enables mapping of the exact differen- tial equations of inducer-transcription-factor binding and transcription-factor-DNA binding including for- ward and reverse reactions, degradation, protection from degradation of transcription factors bound to DNA, and the change in DNA binding affinity of transcription factors when bound by an inducer. 4) An “analogic” current-mode circuit determines the tran- scription rate of genes based on the probability of mul- tiple transcription-factor DNA binding sites being occu- pied or unoccupied in a combinatorial fashion with the rel- ative mRNA production rate of each such combinatorial state programmable by the user. This strategy enables us to implement any arbitrary “analogic promoter function” that is capable of complex saturating digital logic or prob- abilistic analog behavior depending on the molecular con- centration. 5) A current-mode low pass filter (LPF) circuit enables the gain and dynamics of mRNA and protein production and degradation to be represented.
  • Fig. 2. Die micrograph of the
cytomorphic chip fabricated in an AMS BiCMOS process. The left inset is a layout screen capture
  • f one gene block (2x magnification).
6) A stochastics circuit intentionally amplifies analog Poisson noise in transistors to represent biological fluc- tuations in mRNA and protein concentrations at very low copy numbers and at relatively high noise levels. The Poisson nature of biochemical reaction fluxes au- tomatically maps biological noise to electronic noise at high copy numbers and relatively low noise levels [13]. Thus, these circuits are most useful for reliably modeling highly stochastic and relatively low signal-to-noise-ratios in biological cells. 7) ADCs and DACs convert between analog currents and digital bits to enable our chips to communicate with each
  • ther via digital input/output (I/O), and with off-chip dig-
ital processors and computers. Off-chip digital processors synergistically interact with our chips to carry out various functions: reading digital data from the chips; decoding the data; performing high-speed digital signal processing as necessary (e.g., scaling, diffusion, time delay, and error correction); encoding the data to create or modify molecular data packets via address and data strings; storing the programmable address connectivity amongst gene and protein circuits; and communicating data to other chips
  • r to a computer. For simplicity, the data in this paper were
collected with a data-acquisition board (NI PXI-6541) that interacted with our chip and with MATLAB on a computer. A high-performance FPGA (e.g., from the Xilinx Spartan family) could perform all of these functions in the future as well. Shift registers, SRAM blocks, and switches on the chip enable programmability of parameters (e.g., reaction rates, dissocia- tion constants, Hill coefficients, and time constants) as well as connectivity. The organization of this paper is as follows: Section II de- scribes the core building-block circuits of the chip along with chip measurement data. Fig. 2 shows a die micrograph of the chip that reveals the various building blocks. Section III dis- cusses design considerations that are important in BiCMOS cy- tomorphic chip design. Section IV discusses how cytomorphic 528 IEEE TRANSACTIONS ON BIOMEDICAL CIRCUITS AND SYSTEMS, VOL. 9, NO. 4, AUGUST 2015
  • Fig. 1. Poisson chemical reaction flux and Poisson electron flow in
sub-threshold transistors obey the same Boltzmann exponential laws of thermodynamics, and are therefore mathematically similar [13]. Electron copy number is analogous to molecular copy number and temperature represents itself. single cell on a few chips and speedup multi-cell simulations
  • n multi-chip electronic boards [13]. Therefore, we were moti-
vated to create a few fundamental molecular circuits that could be composed and scaled to model large biochemical reaction networks in the future. This paper describes these fundamental building-block cytomorphic circuits. The paper focuses on establishing quantitative agreement of the cytomorphic chip measurements with prior biological measurements and models. The building-block circuits may be classified into seven im- portant categories: 1) Basic BiCMOS current-mode analog circuits exploit the log-domain cytomorphic mapping to capture the exact dy- namics of fundamental mass-action molecular kinetics such as association, dissociation, and degradation. These fundamental circuits are general enough to capture subtle effects such as loading, fan-out, feedback, and substrate de- pletion through the use of a few explicit connections and Kirchhoff’s current law. A wide dynamic range of opera- tion and low power consumption are achieved through the use of bipolar and subthreshold MOS transistors that func- tion at low current levels. 2) The ability to model cooperative binding is enabled by tun- able Hill-function building-block circuits. 3) An “ITD” block built by a composition of above cur- rent-mode circuits enables mapping of the exact differen- tial equations of inducer-transcription-factor binding and transcription-factor-DNA binding including for- ward and reverse reactions, degradation, protection from degradation of transcription factors bound to DNA, and the change in DNA binding affinity of transcription factors when bound by an inducer. 4) An “analogic” current-mode circuit determines the tran- scription rate of genes based on the probability of mul- tiple transcription-factor DNA binding sites being occu- pied or unoccupied in a combinatorial fashion with the rel- ative mRNA production rate of each such combinatorial state programmable by the user. This strategy enables us to implement any arbitrary “analogic promoter function” that is capable of complex saturating digital logic or prob- abilistic analog behavior depending on the molecular con- centration. 5) A current-mode low pass filter (LPF) circuit enables the gain and dynamics of mRNA and protein production and degradation to be represented.
  • Fig. 2. Die micrograph of the
cytomorphic chip fabricated in an AMS BiCMOS process. The left inset is a layout screen capture
  • f one gene block (2x magnification).
6) A stochastics circuit intentionally amplifies analog Poisson noise in transistors to represent biological fluc- tuations in mRNA and protein concentrations at very low copy numbers and at relatively high noise levels. The Poisson nature of biochemical reaction fluxes au- tomatically maps biological noise to electronic noise at high copy numbers and relatively low noise levels [13]. Thus, these circuits are most useful for reliably modeling highly stochastic and relatively low signal-to-noise-ratios in biological cells. 7) ADCs and DACs convert between analog currents and digital bits to enable our chips to communicate with each
  • ther via digital input/output (I/O), and with off-chip dig-
ital processors and computers. Off-chip digital processors synergistically interact with our chips to carry out various functions: reading digital data from the chips; decoding the data; performing high-speed digital signal processing as necessary (e.g., scaling, diffusion, time delay, and error correction); encoding the data to create or modify molecular data packets via address and data strings; storing the programmable address connectivity amongst gene and protein circuits; and communicating data to other chips
  • r to a computer. For simplicity, the data in this paper were
collected with a data-acquisition board (NI PXI-6541) that interacted with our chip and with MATLAB on a computer. A high-performance FPGA (e.g., from the Xilinx Spartan family) could perform all of these functions in the future as well. Shift registers, SRAM blocks, and switches on the chip enable programmability of parameters (e.g., reaction rates, dissocia- tion constants, Hill coefficients, and time constants) as well as connectivity. The organization of this paper is as follows: Section II de- scribes the core building-block circuits of the chip along with chip measurement data. Fig. 2 shows a die micrograph of the chip that reveals the various building blocks. Section III dis- cusses design considerations that are important in BiCMOS cy- tomorphic chip design. Section IV discusses how cytomorphic
slide-142
SLIDE 142
  • Frontier (F): Tableau

configurations to explore

  • choose: chooses the

tableau t in F to explore.

  • select: chooses the set of

transitions to apply to t

Algorithm: F = initial tableau while F, choose t in F: if t is terminal return Z

  • therwise:

select T: set of t’ where t→t’ remove t from F, add T to F

The Search Algorithm

142

slide-143
SLIDE 143
  • Search Heuristics
  • choose lowest

complexity tableau configuration.

  • select a simple

goal, and prioritize transitions that solve it.

Algorithm: F = initial tableau while F, choose t in F: if t is terminal return Z

  • therwise:

select T: set of t’ where t→t’ remove t from F, add T to F

Search Optimizations

143

slide-144
SLIDE 144
  • Component Aggregation: aggregate instances of

the same component

  • Pro: smaller search space
  • Con: instance constraints must be handled

separately

  • Partial Configuration Caching
  • Compact Search Tree Data Structure

Search Optimizations

144

slide-145
SLIDE 145
  • 1. Transitions Over Tableau

b { | h

unify

r 2 R [ ˙ R e r 2 e R

unify(r,e

r, R, ˙ R, e R) = hR

0, ˙

R0, e R

0i

hR, ˙ R, W, e R, Zi ! hR

0, ˙

R0, W, e R

0, Zi

145

slide-146
SLIDE 146
  • 1. Transitions Over Tableau

b ;i ! ⇤ h ; i}

connect

e r : iq = oq 2 e R w : ho, ii 2 W hR, ˙ R, W, e R, Zi ! hR, ˙ R, W {w}, e R { e r}, Z [ {o i}i

  • 146
slide-147
SLIDE 147
  • 1. Transitions Over Tableau
  • e

e e e e h e i ! h e i

input-var-map

e r : id =b i 2 e R b i 2b I i @ c c 2 IC hR, ˙ R, W, e R, Zi ! hR, ˙ R, W, e R { e r}, Z [ { b i 7! id}i

147

slide-148
SLIDE 148

Geometric Programming Problem

monomial mi

2 mi = ci xi,τ Y

p 2P

axi,p

p

mi  1,i = 1, ...,n sj = 1, j = 1, ...,m Here the are

  • f the following form,

j

2 minimize sopt

posynomial pi

si = X

i

The variables in a geometric

i i i =

X

i

ci xi,τ Y

p 2P

axi,p

p

in a geometric program (i.e., ) take

slide-149
SLIDE 149

Analog Hardware Components

Component Quantity Description iin 25 current input vin 125 voltage input

  • uti

10 current output vout 75 voltage output vgain 40 voltage gain iadd 30 current adder vadd 35 voltage adder vtoi 30 voltage to current converter itov 30 current to voltage converter ihill 8 hill function for activation/repression igenebind 8 gene binding switch 15 genetic switch mm 2 Michaelis-Menten dynamics Relation ZI = XD ZV = XD ZD = XI ZD = XV OV = (XV · ZV)/(YV · 25) OI = AI + BI + CI + DI capacitor ∂O2V/∂t = 0.1(AV + BV − CV − DV · O2V) O1V = 0.1(AV + BV − CV − DV) OI = XV/KV OI = KV · XI SI = MV(SI/KI)nV/((SI/KI)nV + 1) RI = MV/((SI/KI)nV + 1) OI = MI/(1 + KI · TI) OI = MI/(SI/KI + 1)nV XV = XtV − XYV YV = YtV − XYV ∂XYV/∂t = KI · XV · YV − RI · XYV

selection of analog components from collaborators, textbooks and publications


  • G. Cowan, R. Melville, and Y. Tsividis. A VLSI analog computer/digital computer accelerator. Solid-State Circuits, IEEE Journal of, 41(1):42–53, Jan 2006. ISSN 0018-9200. doi: 10.1109/
JSSC.
  • R. Daniel, S. S. Woo, L. Turicchia, and R. Sarpeshkar. Analog transistor models of bacterial genetic circuits. In Biomedical Circuits and Systems Conference (BioCAS), 2011 IEEE, IEEE, 2011.
  • R. Sarpeshkar. Ultra Low Power Bioelectronics: Funda- mentals, Biomedical Applications, and Bio-Inspired Systems. Cambridge University Press, 2010. ISBN 0521857279.
  • J. J. Y. Teo, S. S. Woo, and R. Sarpeshkar. Synthetic biology: A unifying view and review using analog circuits. IEEE Trans. Biomed. Circuits and Systems, 9(4):453–474, 2015.
  • S. S. Woo, J. Kim, and R. Sarpeshkar. A cytomorphic chip for quantitative modeling of fundamental bio-molecular circuits. IEEE Trans. Biomed. Circuits and Systems, 9(4):527–542, 2015.

149

slide-150
SLIDE 150
  • menten: Michaelis-Menten equation reaction. D. R. F. PhD. Biochemistry (Lippincott Illustrated Reviews Series). LWW, 2013. ISBN
1451175620.
  • gentoggle: genetic toggle switch in E.col. T. S. Gardner, C. R. Cantor, and J. J. Collins. Construction of a genetic toggle switch in
escherichia coli. Nature, 403(6767): 339–342, 2000.
  • repri: synthetic oscillatory network of transcriptional regulators. M. B. Elowitz and S. Leibler. A synthetic oscillatory network of
transcriptional regulators. Nature, 403(6767):335–338, 2000.
  • osc: circadian oscillation utilizing activator / repressor. J. M. Vilar, H. Y. Kueh, N. Barkai, and S. Leibler. Mechanisms of noise-
resistance in genetic oscillators. Proceedings of the National Academy of Sciences, 99(9):5988–5992, 2002
  • apop: protein stress response. K. Erguler, M. Pieri, and C. Deltas. A mathematical model of the unfolded protein stress response
reveals the decision mechanism for recovery, adaptation and apoptosis. BMC systems biology, 7(1):16, 2013. 
 
 https://www.ebi.ac.uk/biomodels-main/

Dynamical Systems Benchmarks

Benchmark Parameters Functions Differential Equations menten 3 4 gentoggle 9 3 2 repr 7 3 6

  • sc

16 16 9 apop 87 48 27 [11]

selection of published artifacts from well- cited computational biology papers from Biomodels database 


150

slide-151
SLIDE 151

Components

Fraction of each Component 0% 25% 50% 75% 100% menten gtoggle repri

  • sc

apop

vgain vadd mm vtoi itov iadd switch ihill igenebind

151

slide-152
SLIDE 152

Arco Runtime

Number of Equations 20 40 60 80 menten gentoggle repri

  • sc

apop Runtime (m) 15 30 45 60 menten gentoggle repri

  • sc

apop

152

slide-153
SLIDE 153

Geometric Programming Problem

monomial mi

2 mi = ci xi,τ Y

p 2P

axi,p

p

mi  1,i = 1, ...,n sj = 1, j = 1, ...,m Here the are

  • f the following form,

j

2 minimize sopt

posynomial pi

si = X

i

The variables in a geometric

i i i =

X

i

ci xi,τ Y

p 2P

axi,p

p

in a geometric program (i.e., ) take

slide-154
SLIDE 154

benchmark speedup No Jaunt Jaunt

smol

0.50x

sconc

1.00x

mmrxnp

77.48x

repri

2.839x

bont

5.00x

✓* ✓

epor

0.142x

gtoggle

0.1x

Correctness+Speedup Results

slide-155
SLIDE 155

Simulation Speed Analysis

155

slide-156
SLIDE 156

Jaunt Execution Times

156