JP Morgan Healthcare Conference - January 2018
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JP Morgan Healthcare Conference January 2018 For Research Use Only. Not for use in diagnostics procedures. © Copyright 2018 by Pacific Biosciences of California, Inc. All rights reserved.
FORWARD LOOKING STATEMENTS All statements in this presentation that are not historical are forward-looking statements, including, among other things, statements regarding the attributes and sequencing advantages of SMRT® technology and the Sequel™ System, market opportunities, expectations regarding research and development plans, product development including, among other things, statements relating to future availability uses, quality or performance of, or benefits of using, products or technologies, product improvements, updates, and other future events. You should not place undue reliance on forward- looking statements because they involve known and unknown risks, uncertainties, changes in circumstances and other factors that are, in some cases, beyond the Company’s control and could cause actual results to differ materially from the information expressed or implied by forward-looking statements made in the presentation. Factors that could materially affect actual results can be found in our filings with the Securities and Exchange Commission, including our most recent reports on Forms 8-K, 10K and 10-Q, and include those listed under the caption “Risk Factors.” The Company undertakes no obligation to revise or update information in this presentation to reflect events or circumstances in the future, even if new information becomes available.
SYSTEM & CONSUMABLES REVENUE STREAMS Sequel Instrument Chips & Reagents
SMRT SEQUENCING CHARACTERISTICS
Long Reads Resolving the Complexity of the Human Genome Using
Single-Molecule Sequencing
-Average >10,000 bases Chaisson, Mark J P and Huddleston, John and Dennis, Megan Y and Sudmant, Peter H and
-Longest >60,000 bases
Malig, Maika and Hormozdiari, Fereydoun and Antonacci, Francesca and Surti, Urvashi and
Sandstrom, Richard and Boitano, Matthew and Landolin, Jane M and Stamatoyannopoulos, John
A and Hunkapiller, Michael W and Korlach, Jonas and Eichler, Evan E
ABSTRACT
Characterizing and Measuring Bias in Sequence Data
Michael G Ross*, Carsten Russ, Maura Costello, Andrew Hollinger, Niall J Lennon, Ryan Hegarty,
High Consensus Accuracy
The human Chadgenome is arguably
Nusbaum the most
and David complete mammalian reference assembly, yet more than
B Jaffe
160 euchromatic gaps remain and aspects of its structural variation remain poorly understood ten
years after its completion. To identify missing sequence and genetic variation, here we sequence
->99.999%
and analyse a haploid human genome (CHM1) using single-molecule, real-time DNA sequencing.
We close ABSTRACT
or extend 55% of the remaining interstitial gaps in the human GRCh37 reference
genome--78% of which carried long runs of degenerate short tandem repeats, often several
kilobases Background:
in length, embedded within (G+C)-rich
DNA sequencing genomic
technologies regions.
deviate fromWetheresolve the complete
ideal uniform distribution of reads.
sequenceThese
of 26,079 euchromatic
biases structural
impair scientific andvariants
medicalat the base-pair
applications. level, including
Accordingly, inversions,
we have developed
complex insertions
computationalEntering the Era of Bacterial Epigenomics with
and long tractsfor
methods of discovering,
tandem repeats. Most have
describing not been previously
and measuring bias. reported,
with the greatest increases in sensitivity occurring for events less than 5 kilobases in size.
Single Molecule Real Time DNA Sequencing
Results: We applied these methods to the Illumina, Ion Torrent, Pacific Biosciences and
Complete Genomics sequencing platforms, using data from human and from a set of microbes
Uniform, Unbiased Coverage
Davis BM1, Chao MC, Waldor MK.
with diverse base compositions. As in previous work, library construction conditions significantly
influence sequencing bias. Pacific Biosciences coverage levels are the least biased, followed by
-Lack of GC% or sequence
Illumina, although all technologies exhibit error-rate biases in high- and low-GC regions and at
ABSTRACT
long homopolymer runs. The GC-rich regions prone to low coverage include a number of human
promoters, so we therefore catalog 1,000 that were exceptionally resistant to sequencing. Our
DNA modifications,
results indicate that combining data suchfrom
as methylation guide can
two technologies numerous
reducecritical biological
coverage bias processes, yet
epigenetic information has not routinely been collected as part of DNA sequence analyses.
complexity bias The Advantage of SMRT Sequencing
Recently, the development of single molecule real time (SMRT) DNA sequencing has enabled
detection of modified nucleotides (e.g. 6mA, 4mC, 5mC) in parallel with acquisition of primary
sequence data, based on analysis of the kinetics of DNA
Richard J Roberts*, Mauricio O Carneiro andsynthesis
Michael Creactions.
Schatz In bacteria, genome-
wide mapping of methylated and unmethylated loci is now feasible. This technological advance
sets the stage for comprehensive, mechanistic assessment of the effects of bacterial DNA
methyltransferases
ABSTRACT (MTases)-which are ubiquitous, extremely diverse, and largely
uncharacterized-on gene expression, chromosome structure, chromosome replication, and other
DNA Modification Detection
fundamentalOf biological processes.
the current SMRT sequencing
next-generation sequencingalso enables detection
technologies, of damagedisDNA
SMRT sequencing sometimes
and has the overlooked.
potential to uncover
However, novel DNA modifications.
attributes such as long reads, modified base detection and high accuracy
make SMRT a useful technology and an ideal approach to the complete sequencing of small
-Epigenome characterization
genomes.
CORRESPONDENCE
Pacific Biosciences' single molecule, real-time sequencing technology, SMRT, is one of several
next-generation sequencing technologies that are currently in use. In the past, it has been
somewhat overlooked because of its lower throughput compared with methods such as Illumina
and Ion Torrent, and because of persistent rumors that it is inaccurate. Here, we seek to dispel
these misconceptions and show that SMRT is indeed a highly accurate method with many
advantages when used to sequence small genomes, including the possibility of facile closure of
bacterial genomes without additional experimentation. We also highlight its value in being able to
detect modified bases in DNA.
4
1200
1000
800
>3000 PUBLICATIONS TO DATE
FEATURING SMRT SEQUENCING
600
400
200
0
2003 2004 2005 2006 2007 2008 2009 2010 2011 2012 2013 2014 2015 2016 2017*
APPLICATIONS ENABLED ON PACBIO RSII PLATFORM
Introduction of
Isoform sequencing
Finishing
genomes
De novo Assembly
of single genomes
Epigenetics
in microbes
Infectious
disease studies
Microbial
Sequencing
6
PACBIO RSII SEQUEL SYSTEM
~7X Performance
Improvement
SELLING PRICE
APPLICATIONS ENABLED GOING FORWARD WITH
SEQUEL PLATFORM
Large scale
population studies
Microbial
multiplexing
Large scale plant and
animal sequencing
Isoform
Sequencing
Structural
Variation
8
ADVANCEMENTS ACROSS THE SYSTEM
Library preparation enhancements
-Targeted insert library protocols
-Simplified protocols
-Barcoding
Chemistry and polymerase improvements
-Increase in read length and quality
Secondary software algorithm
developments
-Consensus accuracy
-Additional applications
9
RECENT SMRT CELL 1M RUNS IN PACBIO R&D
-~30 kb insert shear library:
-Yield: 12 Gb
-Average RL: 25 kb
-Longest read: 160 kb
-5 kb amplicon library:
-Yield: 16.5 Gb
-Average RL: 33.5 kb
-Longest read: 135 kb
-Pooled mixed amplicon library:
-Yield: 22 Gb
-Average RL: 37 kb
-Longest read: 200 kb
Sequel System SMRT Cells 1M typically generate ~300,000-600,000 reads each. Read lengths, reads/data per SMRT Cell and other sequencing
performance results vary based on sample quality/type and insert size among other factors.PACBIO INSTRUMENT INSTALL BASE > 370 UNITS
PacBio RS II Sequel
Note: some pins represent multiple placements
11GROWTH IN CHINA
China sales represented over 30% of total 2017 revenue, up from less than 10% in 2016
12PRODUCT AND SERVICE REVENUE (2013 – 2017)
$100
$90
$80
$70
Revenue ($M)
$60
$50
$40
$30
$20
$10
$0
2013 2014 2015 2016 Est 2017
Instrument Revenue Consumables Revenue Service & Other Revenue
13CONSUMABLE REVENUE GROWTH
$45
$40
$35
$30
Revenue ($M)
$25
$20
$15
$10
$5
$0
2016 Est 2017
RS II Sequel
14SEQUEL CONSUMABLE REVENUE GROWTH
$30
$25
Revenue ($M)
$20
$15
$10
$5
$0
2016 Est 2017
15RESOLVE HIDDEN HERITABILITY AND IMPROVE OUR
UNDERSTANDING OF HUMAN HEALTH AND DISEASE
CANCER BIOLOGY IMMUNOLOGY INFECTIOUS DISEASE NEUROSCIENCE
Drive cancer research Advance immune-disease Discover & design better Build a comprehensive
with access to a more association studies through vaccines, treatments and picture of the underlying
complete genomic imputation-free outcomes with full causative biological
cancer landscape characterization of complex characterization of mechanisms of
genes and haplotypes pathogens, their mobile neurological disease
elements and communities
HUMAN BIOMEDICAL RESEARCHETHNIC BACKGROUND AND GERMLINE VARIATION “In a survey of studies … in six cancers assessing the association between cancer susceptibility and allelic variations, we found that a significant result in one ethnic group was usually not reproducible on other ethnicities in well-powered studies.” Jing, L et al. (2014) Ethnic Background and Genetic Variation in the Evaluation of Cancer Risk: A Systematic Review. PLoS ONE. 9(6), e97522.
TYPES OF STRUCTURAL VARIATION
deletion insertion duplication
inversion translocation repeat expansionTECHNOLOGY TO DETECT STRUCTURAL VARIANTS
Deletions Insertions Missed
PacBio
Illumina repeats + large insertions
Bionano variants ≤1.5 kb
0 5,000 10,000 15,000 20,000 25,000
structural variants“For patients with undiagnosed
conditions, short-read sequencing
can help doctors provide a
diagnosis in about one-third of
cases”
“Though the cost of short-read
sequencing is now below $1,000,
according to Ashley, parts of the
genome are not accessible when
cutting DNA into small fragments.”
- https://med.stanford.edu/news/all-news/2017/06/researchers-use-long-read-genome-sequencing-in-a-patient.htmlMA P OF PA C B IO H U MA N GE N OME P R OJE C T S (2017)
Population-Specific Reference Genome
(de novo assembly)
SV Discovery
(Low-fold WGS)HUMAN POPULATION GENETICS MARKET Novogene Will Use Pacific Biosciences SMRT Technology to Build Novo-Disease SV Genomes Database –First database of long-read whole genome sequencing data– San Diego, July 18, 2017 — Novogene announced today it plans to use Pacific Biosciences SMRT® technology to build a comprehensive Chinese genome database, Novo-Disease SV Genomes. The database will consist of long-read sequencing data of 1000 Chinese genomes from a variety of disease types. As the first ever database of long-read human whole genome sequencing information, Novo- Disease SV Genomes will be a breakthrough step in the understanding of the human genome and in the field of precision medicine.
HUMAN GENETIC DISEASE RESEARCH MARKET
PACBIO HUMAN WGS ROADMAP
A MORE COMPLETE VIEW OF GENETIC DIVERSITY
AGRICULTURAL CONSERVATION INDUSTRIAL MICROBIAL
GENOMICS BIOLOGY BIOTECHNOLOGY RESEARCH
Uncover key genes for Explore evolution and Engineer organisms Fully characterize host-
improved agricultural diversity in high with precision for pathogen interactions and
and livestock products resolution industrial applications symbiotic relationships
PLANT AND ANIMAL SCIENCESUNIQUE CHALLENGES OF PLANT & ANIMAL GENOMES
Size and Complexity
-Loblolly pine, 21 Gb (>6x human)
-Wheat, 17 Gb, hexaploid
-Sugarcane, 10- or 12-ploid
Extreme Repeat Content
-Maize >60%
-Wheat >80%
Each Project is Unique
-Ranges in size, ploidy, and
repeat content mean custom
strategy is commonly needed.
Paris japonica Necturus lewisi
150 Gb, 8-ploid 120 Gb, diploidwww.pacb.com
For Research Use Only. Not for use in diagnostics procedures. © Copyright 2018 by Pacific Biosciences of California, Inc. All rights reserved. Pacific Biosciences, the Pacific Biosciences logo, PacBio,
SMRT, SMRTbell, Iso-Seq, and Sequel are trademarks of Pacific Biosciences. All other trademarks are the sole property of their respective owners.REDUCTION IN COST DRIVES PLANT & ANIMAL
GENOMES
Number of genomes Sequencing approach Cost per sample
Long-read
Sequencing
100s $7,000-20,000
Core genomes
Pan-genomes
Whole-genome sequencing
1,000s Haplotypes $3,000-5,000
Structural variation
Whole-genome skimming
10,000s Haplotypes
~$100s
Exome sequencing and
genotyping by sequencing
100,000s $5-20
SNPs
Alleles
Optimal sequencing systems for crop applications
-Bevan, M.W. et al (2017) Genomic innovation for crop improvement. Nature 543, 346-354.AEDES AEGYPTI GENOME WORKING GROUP (AGWG)
-Led by Drs. Leslie Vosshall
and Ben Matthews, HHMI,
Rockefeller University
-Dozens of academic
researchers and private
companies
wsj.com
-Ancestral subspecies: Aedes
aegypti formosus from Africa
-Anthropophilic A. a. aegypti
nbcnews.com
dispersed by humans
-Vector for yellow fever, Zika, dengue -High selective pressure due to
and other diseases
eradication efforts
-Tropical and semi-tropicalRESOLVE PLASMIDS FROM BACTERIAL GENOME ASSEMBLES Beatson and Walker (2014) Tracking antibiotic resistance. Science. 345(6203),1454-1455.
IMPORTANCE OF METHYLATION IN BACTERIA
www.pacb.com
For Research Use Only. Not for use in diagnostics procedures. © Copyright 2018 by Pacific Biosciences of California, Inc. All rights reserved. Pacific Biosciences, the Pacific Biosciences logo, PacBio,
SMRT, SMRTbell, Iso-Seq, and Sequel are trademarks of Pacific Biosciences. All other trademarks are the sole property of their respective owners.You can also read
