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SU GSP 2012 McCauley Digital Biology

Digital Biology
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Raymond McCauley

on 14 September 2017

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Transcript of SU GSP 2012 McCauley Digital Biology

Digital Biology:
Life Under Moore's Law
Raymond McCauley
for Singularity U GSP, June 2012
"Wide" Sequencing
Better,
Faster, Cheaper

What
are
your
questions?
Thank you for your attention
Raymond McCauley
+1-650-776-4561
raymond@raymondmccauley.net

Zooming Presentation Software
prezi.com

Peter Arvai
Adam Somlai-Fischer
(alternative from Microsoft Labs: pptPlex)
Why do we care?
Epigenetics
Transcriptomics
Small RNA
...which means
it's a good thing
sequencing
throughput is rising
and
cost is dropping

exponentially
You may need
several sequences in a lifetime...
(c) fotolia, Vinicius Tupinamba
Sequencing DNA only gives us
the parts list...
But the parts list isn't the whole story...
Sequencing is a good tool
for more than just finding DNA sequence
When are genes turned on and off?
Where are genes turned on and off?
What happens during transcription?
We need to know how things go together
Tracking simple variations in DNA (SNPs)
is not enough to explain disease processes
DNA Methylation
A layer of coding on top of DNA
Some bases are methylated
Affects gene expression
DNA Methylation
Why twins are different
How diet affects genes
How environment overrides genes
explains
DNA Methylation and Gene Expression
...CG...
...CG...
ON
OFF
Bisulfite Sequencing
...CG...
...CG...
ON
OFF
...TG...
...CG...
also:
changes in expression level
alternatively spliced variants
fusion transcripts
Transcriptomics
How many
copies are made
of each transcript?
Transcriptomics & Gene Expression
microRNA
microRNAs
regulate 30%-40%
of all genes
genomic DNA
CNV and structural variation
epigenomics - methylation status
gene expression
alternatively spliced transcripts
fusion proteins
small RNA (microRNA)
metagonomics
Transcript Splicing
Transcript Isoforms
You won't get sequenced
just once
in a lifetime
Smaller
less material/reagents
smaller samples
cheaper
Label-Free
direct sensing
electrical readout
less material/reagents
fewer steps
cheaper & faster
Biomimetic
harness nature's machines
"wet nanotech"
old examples: polymerases, ribosomes
Automated
LIMS (Laboratory Information Management Systems)
Liquid Handling Robots
"Lab on a Chip"
source: David Goodsell
Informatics
Bottleneck

Generating huge amounts of data
How to store it? Share it?
How to make sense of it?
If you've got a terabyte of data,
what's the fastest way to move it?
Circos Visualization Tool
Basics
Big Questions
DNA Structure
Tools
Microarrays
Sequencing
How long until
the $1000 genome?
More interesting question:
How long until the $1 genome?
And what do we do when we get it?
"Sequence EVERYTHING"





"Looks cute -- sequence it"

"Tastes good -- sequence it "

- Jun Wang, Beijing Genomics Institute
Illumina HiSeq 2000
200+ gigabases of DNA
2 human genomes
in 5 days
$10,000 each
5 Sequencing Centers
were invited to preview
the new system in
Jun Wang purchased 128
for the BGI.

They are now able to replicate
the entire NCBI GenBank
every 15 minutes.
So What?
Emerging Trends
Biology now falls under Moore's Law
Biology is now an Informatics Discipline
Biology is Personal
Sequencing as
a Commodity Business?
(and becoming more so)
Direct-To-Consumer
Genomics
"Wet Nanotech"

Who is Mother Nature's
patent lawyer?

Sequencing is to nanotechnology
as RAM is to microtechnology

Listen to Ralph Merkle later this week
Race to the bottom for pricing

Rather be in the business that
uses
cheap sequence

But the market size increases exponentially as the price drops...
Biology has come Full Circle
taxonomy / data-gathering
theory-driven
cheap, advanced tools
complexity & data-driven
genomics / data-gathering
Raymond McCauley
biochemistry
biophysics
electrical engineering
computer science
bioinformatics
nanotechnology
microarrays
sequencing
personalized health
DISCLAIMER
These are my opinions and are not intended to reflect the views of any group or organization with which I may be affiliated.
Guess:
What percentage of genes have alternative transcripts?
Sequence
(And You Shall Find)
A Couple of Examples...
Drug Response
Disease Risk
Drugs
1485 approved drugs
277 with genetic information
Just 20 shown in 23andMe
sources:
http://www.drugbank.ca/stats
http://www.pharmgkb.org/
http://www.23andme.com/
Drug:
Clopidogrel (Plavix)
Reduces blood clots. Treats heart attack and stroke

Genotypes:
rs4244285 = AG
rs4986893 = GG
rs28399504 = AA
rs41291556 = TT
rs12248560 = CC

Haplotype:
CYP2C19 *1/*2

Phenotype:
Reduced clopidogrel efficacy
(higher dosage needed).

Patient:
Me!
What can you do about
being at risk for
an incurable disease?!?
It turns out, lots of things:

prevention - vitamins, avoid UV
testing - Amsler grid
new opthamologist
investigate clinical trials
support research
don't put off that trip to the Louvre until retirement...
Courtesy Folch Bioengineering Lab, University of Washington
Again,
So What?
@raymondmccauley #SingularityU
DNA Sequencing Economics
Cost
Time
Just remember...

All of this:
Cheap tools
Greater access
Better understanding

adds up to a future where
people can ask more questions
Advanced Personal Genomics
Tools for:
sharing
learning
investigating
Courtesy: Illumina
Moore's Law
Driven by
Decreasing Feature Size
Biotech begets Nanotech?
Creative Commons 3.0 license
Attribution-NoDerivs 3.0

Exponential Biosciences
Sr. Scientist
doing
Sequencing R&D
in
Gene Expression Applications

Current Research:
Bioinformatics
Non-Coding RNA
Epigenetics
Cancer Sequencing
Crowd Sourced Clinical Trials
not just a neat science project
technology is cheaper
tools are more accessible
locus of control is different
science out of the ivory tower
MTHFR
MTHFR
Vitamin
B9
(inactive)
Vitamin
B9
(active)
Vitamin
B9
(inactive)
Vitamin
B9
(active)
MTHFR
X
X
X
Interventions
SNP
rs1801133
SNP
rs1801131
Nothing (Washout)
Regular Vitamin (inactive B9)
Special Vitamin (active B9)
Testing
Homocysteine Plasma Level
Lessons Learned
MEDIUM
Self-funding
Getting started
Large n
HARD
Institutional Inertia
FAQ
IRB
Frequently
Asked
Questions
Institutional
Review
Board
versus
Actionable Genomics
Methylenetetrahydrofolate Reductase
Do the vitamins I take
do me any good?
MTHFR
Our little Science Project
>>>>
Huge amounts of interest
1
2
EASY
Genetic Testing
Blood Testing
Cheap tools
Huge amounts of data
Usable information scarce

See more than we can understand...
Big Question
How can we
turn genomics data
into information?
Little Question
Do vitamins work
for me?
Hit Lots of People
AMD, Diabetes, Obesity, ...
Nutrition, Supplements
Athletes in training
Unexplained infertility
Genomics
Community
Do vitamins work
for me?
Little Question
Crowd-Sourced
Clinical Trials
Finding, recruiting patients is the bottleneck
$10,000 per subject
time-consuming
Research
Community
n=they
to
n=me
to
n=we
participant run and funded
personalized investigations
~100x cheaper than pharma
MTHFR
Vitamin
B9
(inactive)
Vitamin
B9
(active)
SNP
rs1801133
X
Homocysteine
levels rise
X
SNP
rs1801131
X
DIYgenomics.org
Melanie Swan
MTHFR!
siRNA
Compare to Open Source Software Movement
Getting tech support v. sharing & doing
Copyright 2012, Raymond McCauley
All Rights Reserved
Some portions of this presentation have appeared previously in other works and presentations.
social
(and other bio)
networks
version 3:
Illumina Custom OmniExpress+ BeadChip
Assays about 1,000,000 SNPs
GWAS, Genome Wide Association Study
DNA Sequencing Tech 5X ~ 10X

Computer Tech
1.5X ~ 2X
past:
Chief Science Officer, Genomera
Co-Founder, BioCurious
Principal, Exponential Biosciences

Current Research Areas:
Bioinformatics
Personal Genomics
Cancer Sequencing
Genetic Engineering
How did life begin?
How do organisms grow and develop?
How does conciousness hook into matter?
Human Genome Project
2001, 13 years
$300M - $1.5B

Celera Genome Project
2001, ~3 years
$70M+

James Watson Genome
2007, ~2 months
$1M

Illumina Yoruban Trio
2008, 6 weeks
$100K

Illumina Consumer Sequencing
May 2009, 1 week
$48K

Illumina Consumer Sequencing
June 2010, 1 week
$9500 = $19500


Illumina Consumer Sequencing
June 2011, 1 week
$5000

Personal Genome Project (Various)
Jun 2012, 3-7 days
$2000
}
150,000 X
How long until
the $1000 genome?
No, *really*
2020
2016
2014
2020
=
=
=
=
Try it...
Lin Si Yuan and Nick Koo, BGI Hong Kong
source: BioInfoWorld, September 2010
Source: National Human Genome Research Institute
Low Hanging Fruit
for Genomics
Pharmacogenomics
Cancer
Longevity
People who never got:
cancer
cardiovascular disease
neurological conditions
Treating a patient for
lung cancer

becomes

Treating a patient for
cancer of the PI3K pathway
Cheap tools
and open sharing of knowledge and techniques
bring real contributions within reach
of more and more people.
Tool Makers & Citizen Scientists
Get Involved...
Biotechnology not just
for big corporations and universities
When we talk about garage labs
in Silicon Valley, we aren't kidding...
curing cancer
stem cell immunology
started in garage
now fully funded
Where are they now?
...but also for:
Communities
Entrepreneurs
Special Interest Groups
Hobbyists, Experimenters, Inventors
Non-First-World Societies
The Revolution
is Here!
If you've got US$750000,
a PhD in molecular biology,
and access to lab space
with permits for biohazardous
waste disposal
Some examples...
more bio hackerspaces...
or
is
it?
Take-Aways
Resources
Companies to Watch
Background
Cartoon Guide to Genetics Gonick & Wheelis
Here is a Human Being Misha Angrist
The $1000 Genome Kevin Davies
Biopunk
Marcus Wohlsen
A Hacker's Guide to Biology
Raymond McCauley
forthcoming...
Exponentially cheaper DNA sequencing costs
$1,000,000,000
to
$1,000
in ~15 years
Democratization
of
Biotechnology
More tools in more hands
=
biotech-based breakthroughs
Illumina
Complete Genomics
Ion Torrent / Life Technologies
Oxford Nanopore
Genia
QuantuMDx
DNAnexus
Station X
Personalis
NuMedii
Genomic Health
Vecoy Nanomedicines
Verinata
ImmunePath
Next Gen Sequencing
Next Next Gen Sequencing
Informatics
Diagnostics/Treatment
2020
=
Groups to Watch
Genomes Unzipped
Genomics Law Report
Quantified Self
DIYbio
BioCurious
So What?
Democratization of Technology
cheap tools
=
"The street finds its own uses"
Rapid Prototyping
+
Community
=
has profoundly changed the
way that I work...
time for a story?
Watson, Crick & Franklin
Source: PLoS Biology
Source: Kristina Hathaway
Source: harvardscience.harvard.edu
Makes
a bone cell
different from
a nerve cell...
So
My favorite project
Biotech is Hard...
iGEM =
International
Genetically
Engineered
Machines
competition
Light sensitive bacterial film,
UT Austin iGEM team
& a Garage Near You...
Talk to Me
Really want some background?
Biotech-Driven Renaissance
What is the basis of life's blueprint?
Drug reaction:
980
/1200 =
Negative
10
/1200 =
Positive
Drug reaction:
5
/1200 =
Negative
195
/1200 =
Positive
Source: National Human Genome Research Institute, Exponential Biosciences
Singularity
University

Have we
talked about



yet?
Your chance to try it...
Consumer access to research tool
"Recreational genomics"
Disease risk, carrier status, genealogy
Gene Scan
Gene Sequence
most interesting/best known
1.2 million bases
0.04%
all
3 billion bases
100%
Complete Genomics
Illumina
Life Technologies/Ion Torrent
Pacific Biosciences
and
Genia
GnuBio
NABsys
Oxford Nanopore
And that's old news...
Roche Hostile Takeover
Illumina Stockholders Meeting
18 April 2012
Nicholas Volker's story
"One In A Billion:
A boy's life, a medical mystery"
Milwaukee Wisconsin Journal Sentinel,
by Mark Johnson and Kathleen Gallagher
Breast Cancer
Hormone Receptor Positive
HER2 Positive
Triple Negative
105 different classifications
for cancer of the
PI3K/AKT/mTor pathways
>
>
Human Genome Project
2001, 13 years
$300M

.
.
.
.
.
.

Personal Genome Project (Various)
Jun 2012, 3-7 days
$2000
Biotechnology
Treasure Map

Find an exponential trend,
then hitch-hike
Being interdisciplinary is hard,
but worth it
Keep asking questions
You will be
in school
or re-training
most
of your life
(Almost)
every specialist you meet
will know more than you
about their specialty
Be skeptical.
Don't be swayed by fancy presentations
-- including this one --
but look for people who actually do things
The Evidence Ladder for biology/medicine:
Brilliant minds
are sometimes
brilliantly wrong.
People who can straddle several fields
are in a unique position
to contribute
and to solve problems
in humans?
in primates?
in mammals?
in microbial?
in vivo?
in vitro?
(Also the Expense Ladder)
But still be inspired.
Electrical
Engineering
Computer
Science
Genetics
=
"Insane... What would you possibly do with those majors?"
- My academic advisor,
circa 1984
Multidisciplinary work
is hard

Requires more time, energy, dedication, and communication

And all the grand challenges of the 21st century
require it
Computer
Science
Electrical
Engineering
=
Genetics
What you need
to build DNA Sequencers,
circa 2006
Genetics
Electrical
Engineering
"What a great background... come work on CELSS."
- NASA,
circa 1991
Computer
Science
=
Full transcript