enabling technology through high throughput techniquestools to precisely manipulate biology • edit...
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Enabling technology through high throughput techniques07 November 2019
Bradley DominikDirector of Process Development & Scale UpZymergen, Inc.
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Outline
Who is Zymergen?
HTP and what it means to us
Next-gen HTP
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Zymergen works with partners to use biology to make better products with better economics
Company goal Use biology to make better products, withbetter economics
Who we areBiology and software company, building a platform to improve how we engineer biological systems
What we do
Comprehensively and systematically optimize biological systems
• Discover and develop improved products• Increase speed to market• Improve profitability of mature products
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We have built a platform designed to realize the potential of biology to build better products with better economics
Access to proprietary diversity
• Fully-leverage diversity found in nature• Access new genes, enzymes, pathways, and
compounds
Tools to precisely manipulate biology
• Edit genes, enzymes, pathways, and compounds with precision
• Expand the toolbox with which we can editbiological systems
Robust automation platform
• Execute more experiments• Generate more data• Generate higher quality data
Software and data science technology stack
• Make better predictions with large quantities of data
• Enable continuous improvement as data accumulates
• Surpass limitations of human intuition
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Outline
Who is Zymergen?
HTP and what it means to us
Taking HTP to the next level
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Build and Test are the two components of the DBTAL cycle that are executed in our high-throughput automated environment
Algorithms design experiments and DNA constructs that can be used to empirically validate hypotheses
DBTAL cycle
Design
Build
Test
Transform data and identity areas of interest
Analyze
Refine design strategy given identified hits
Learn
Assay strains with high-throughput automation
Build biological systems to test hypotheses with end-to-end automation
DNA Build
Strain Build
Manufacturing
Data Science and Development
The Build and Test stages of the DBTAL cycle take weeks to execute where as the other stages take days
Automation
Software
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The Design-Build-Test-Analyze-Learn (DBTAL) cycle is our core operational unit
Stra
in p
erfo
rman
ce(y
ield
, tit
er, r
ate,
etc
.)
Effort
DBTAL
DBTAL
DBTAL
DBTAL
DBTAL
DBTAL
DBTAL
DBTAL
DBTAL
DBTAL
DBTAL
DBTAL
DBTAL
DBTAL
DBTALDBTALDBTAL
DBTALDBTAL
DBTAL DBTAL DBTAL DBTAL
DBTAL cycles are used to optimize molecules
DBTAL cycles are used to rapidly prototype proof-of-concept strains
DBTAL cycles are used to optimize production or other phenotypes
At each stage of product development, DBTAL cycles are executed on our automated HTP platform
Each DBTAL cycle yields performance improvements and data which informs the next round of development
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Generations of Automation at Zymergen
BenchtopGen 0
Walk-awayGen 1
IntegratedGen 2
No Automation (Human-only)
e.g. Plate sealer on lab bench
Single Step Automation
e.g. liquid handler running through programmed set
of instructions
Single Robotic Arm, multiple
operations
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Zymergen “Gen 1”: Automation at many levels
Principle Design requirements
Standardized connections Easily accessibleCommon facilities (power, water)
Physical and digital interactionUsers can run protocols in standalone
mode Errors are easily recoverable
Designed as simple as possibleProtocols can be run without user
intervention
Common frameworkModules are queryable for readinessOnly execute on validated protocols
Physical layout
User integration
Walk-away
Software
Standardized data, power etc connections
Digital interaction Common software framework
Walk away (Automatic plate loaders)
Robots acquired by Zymergen are customized by Zymergen to integrate into software infrastructure and to meet our requirements for measurement precision
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As we have grown we have built the automation capabilities and data infrastructure to both capture and store large amounts of data
We have brought automation to bear on more parts of our business in order to expand our capabilities for strain build and test
In 3 years we have increased the number of automation processes we run by >70x. Effectively doubling capacity to build and test strains 6 times over.
Automation protocolsProtocols executed per month in Zymergen strain factories
We have grown our data capture capabilities to expand the number of measurements we can capture and analyze
Case study
0
1,000
2,000
3,000
4,000
5,000
6,000
7,000
8,000
6/2016 6/20176/2015 6/2018
>70x the number of protocols executed
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End-to-end high throughput platform enables a versatile approach to genetic engineering
CONTEXT
Automating our processes has enabled us to generate hundreds to thousands of strains and collect many different types of measurements on each strain.
EXAMPLE
We collect and analyze ~3.5 million readings generated by our High throughput (HTP) assays each week, which are used to:• Identify causes of variation
and measurement error• Identify and correct for
systematic biases• Surface signals of
improvement above noise
36%
34%
14%
3%13%
Measurement data
HTP test data
Relationship data
Process definition
Environmental data
Data captured for HTP Test (1 week)N = 3.5 M readings
Automation and data analytics enables generation and analysis of big data sets to reliably improve operations
Robotics and data science enable adaption of HTP strain engineering platform to work with a wide range of hosts
High throughput screening enables full genome perturbation with thousands of strains modifying individual edits
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Example: Automatically correcting for systematic bias to enable efficient and accurate data analysis
Bottom shaker shelf
Middle shaker shelf
Top shaker shelf
High product production Low product production
Systematic bias: correct by normalizing data
Process error: correct by fixing plate holder
• A strain will perform differently at different positions in a shaker
• Strain performance measurement involves a correction for positional bias
• We have algorithms in place to automatically normalize data based on these conditions to accurately compare strains
Example 3-shelf plate shaker data:Average performance of a control strain in different positions of a 96-well plate shaker (over thousands of runs)
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Increasing our scale of automation has enabled greatly increasing our throughput
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36
68
6
42
79
+88%
Automation Platforms Workflow execution sessionsTotal strains built in automated Production environment
1,039
3,769
+263%
8,528
18,441
+116%
Automation components (Gen 1)
Integrated Platforms (Gen 2)
In 1 year In 3 fiscal quarters In 1 year
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Agenda
Who is Zymergen?
HTP and what it means to us
Taking HTP to the next level
Zymergen Proprietary
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Drivers for a new Generation of Automation at Zymergen
BenchtopGen 0
Walk-awayGen 1
IntegratedGen 2
No Automation (Human-only)
e.g. Plate sealer on lab bench
Single Step Automation
e.g. liquid handler running through programmed set
of instructions
Single Robotic Arm, multiple
operations
Zymergen Proprietary
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Drivers for a new Generation of Automation at Zymergen
IntegratedGen 2
Single Robotic Arm, multiple
operations
Limitations of scaling Gen 2:
1. Time required to build out workflows1. Formalizing Protocols2. Rigorous Equivalence Testing3. Space allocation
2. Integrated system hard to change1. Limited reach of central arm:
closely packed equipment2. Limited capacity of arm limits
utilizing devices at full capacity3. Teaching and aligning robot
arms3. Inflexibility often limits use to locked-
down mature workflows4. Cost and difficulty of experimentation
encourages static workflows
Our Challenge:
All of our projects can benefit from automation:• Standardization• Precision• Reproducibility• Speed
yet…
Our protocols change very rapidly:⇨ Traditional automation would require prohibitive investment
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Zymergen Gen 3: Modular Integrated Automation
BenchtopGen 0
Walk-awayGen 1
IntegratedGen 2
ModularGen 3
No Automation (Human-only)
e.g. Pipetting
Single Step Automation
e.g. Tecan
Single Robotic Arm, multiple instruments
Reconfigurable Automation
Carts
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Reconfigurable Automation Carts (RACs)
Sterility maintained
Vendor- and device-agnostic
Dedicated robot arm
Integrated magnetic track
Standardized connections
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RACs decentralize plate transportation
Modular magnetic track moves plates between RACs
Dedicated, low-cost robot arms transfer plates from RAC track to the RAC device
RAC contains a single device
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RAC in action
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RACs can be (re)arranged for any space or protocol
Insert one of the recent pictures (e.g. of viafill)
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RACs designed for quick connection / disconnection
• Standardized connections between carts and to utilities• Simple geometry for alignment
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RACs can be swapped in a few minutes
• Two technicians can rapidly swap out RACs• Backup replacement unit• Completely different instrument• Blank track
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RACs run complex protocols with simple geometry
Insert one of the recent pictures (e.g. of viafill)
• Adding (or removing) devices simply is a matter of connecting a different set of modular carts
• RAC software is Cloud based• Can interleave workflows for maximum instrument utilization
3D Printed RAC models for prototyping new system layouts
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RACs enable scalable modularity
ModularityFlexible reconfigurationRapid implementation of workflowsSimplifying maintenance
Modular ClustersInterleave multiple projectsReliability through redundancyMaximize asset utilization
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Modular Integrated Automation will help reshape our science
BenchtopGen 0
Walk-awayGen 1
IntegratedGen 2
ModularGen 3
No Automation (Human-only)
e.g. Pipetting
Single Step Automation
e.g. Tecan
Single Robotic Arm, multiple instruments
Reconfigurable Automation
Carts
Zymergen Proprietary
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Thank You
“Introducing Reconfigurable Automation Carts”
@ZymergenTechBlog
@Zymergen
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