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.

Zymergen Proprietary

2 | Zymergen Proprietary

Outline

Who is Zymergen?

HTP and what it means to us

Next-gen HTP


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


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


Outline

Who is Zymergen?


Taking HTP to the next level


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


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



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



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

11

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?


Taking HTP to the next level


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Drivers for a new Generation of Automation at Zymergen

BenchtopGen 0

Walk-awayGen 1

IntegratedGen 2


e.g. Plate sealer on lab bench


e.g. liquid handler running through programmed set

of instructions


operations


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Drivers for a new Generation of Automation at Zymergen

IntegratedGen 2


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



Zymergen Gen 3: Modular Integrated Automation

BenchtopGen 0

Walk-awayGen 1

IntegratedGen 2

ModularGen 3


e.g. Pipetting


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


e.g. Pipetting


e.g. Tecan

Single Robotic Arm, multiple instruments

Reconfigurable Automation

Carts


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Thank You

“Introducing Reconfigurable Automation Carts”

@ZymergenTechBlog

@Zymergen

[email protected]


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