Dr. Butte describes how his lab uses open public data

1. New uses of drugs
from a trillion points of data
Atul Butte, MD, PhD
abutte@stanford.edu
Chief, Division of Systems Medicine,
@atulbutte
Department of Pediatrics, Genetics,
and by courtesy, Medicine, Pathology, and
Computer Science
Center for Pediatric Bioinformatics, LPCH
Stanford University

2. Disclosures
• Scientific founder and
advisory board membership
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Genstruct
NuMedii
Personalis
Carmenta
• Past or present consultancy
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Lilly
Johnson and Johnson
Roche
NuMedii
Genstruct
Tercica
Ecoeos
Ansh Labs
Prevendia
Samsung
Assay Depot
Regeneron
Verinata
Geisinger
• Honoraria
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Lilly
Pfizer
Siemens
Bristol Myers Squibb
AstraZeneca
• Corporate Relationships
– Aptalis
– Thomson Reuters
• Speakers’ bureau
– None
• Companies started by students
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Carmenta
Serendipity
NuMedii
Stimulomics
NunaHealth
Praedicat
MyTime
Flipora

5. Over 1.2 million microarrays available
Doubles every 2-3 years
Butte AJ. Translational Bioinformatics:
coming of age. JAMIA, 2008.

7. Public big data = retroactive crowd-sourcing

9. Available Cancer Types
# Cases Shipped by BCR
Date Last Updated
(mm/dd/yy)
# Cases with Data
Acute Myeloid Leukemia [LAML]
200
200
Adrenocortical carcinoma [ACC]
80
0
Bladder Urothelial Carcinoma [BLCA]
201
184
7/5/2013
Brain Lower Grade Glioma [LGG]
296
271
7/3/2013
Breast invasive carcinoma [BRCA]
1007
961
7/5/2013
Cervical squamous cell carcinoma and endocervical adenocarcinoma [CESC]
163
163
7/5/2013
Colon adenocarcinoma [COAD]
439
425
6/28/2013
63
63
7/5/2013
Glioblastoma multiforme [GBM]
514
510
6/28/2013
Head and Neck squamous cell carcinoma [HNSC]
427
376
7/3/2013
66
66
7/5/2013
Kidney renal clear cell carcinoma [KIRC]
512
512
7/3/2013
Kidney renal papillary cell carcinoma [KIRP]
158
144
6/28/2013
Liver hepatocellular carcinoma [LIHC]
152
128
7/3/2013
Lung adenocarcinoma [LUAD]
500
499
7/3/2013
Lung squamous cell carcinoma [LUSC]
500
494
7/5/2013
18
18
7/3/2013
0
0
572
570
7/5/2013
71
62
7/3/2013
0
0
Prostate adenocarcinoma [PRAD]
248
201
7/5/2013
Rectum adenocarcinoma [READ]
169
168
6/28/2013
Sarcoma [SARC]
111
75
7/5/2013
Skin Cutaneous Melanoma [SKCM]
357
336
7/5/2013
Stomach adenocarcinoma [STAD]
343
325
7/3/2013
Esophageal carcinoma [ESCA]
Kidney Chromophobe [KICH]
Lymphoid Neoplasm Diffuse Large B-cell Lymphoma[DLBC]
Mesothelioma [MESO]
Ovarian serous cystadenocarcinoma [OV]
Pancreatic adenocarcinoma [PAAD]
Pheochromocytoma and Paraganglioma [PCPG]
6/24/2013

10. Human Disease
Gene Expression Collection
~300 Diseases
and Conditions
Blue: gene goes down
in disease
Yellow: gene goes up
in disease
Butte AJ, Kohane IS. Nature Biotechnology, 2006, 24:55.
Butte AJ, Chen R. Proc AMIA Fall Symposium, 2006.
Chen R, Butte AJ. Nature Methods, 2007.
Dudley J, Tibshirani R, Deshpande T, Butte AJ. Molecular
Systems Biology, 2009.
Shen-Orr S, ... Davis MM, Butte AJ. Nature Methods, 2010.
20k+ Genes

14. 5,178 compounds
·
1,300 off-patent FDA-approved drugs
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700 bioactive tool compounds
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2,000+ screening hits (MLPCN and others)
3,712 genes (shRNA + cDNA)
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targets/pathways of FDA-approved drugs (n=900)
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candidate disease genes (n=600)
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community nominations (n=500+)
15 cell types
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Banked primary cell types
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Cancer cell lines
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Primary hTERT immortalized
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Patient derived iPS cells
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5 community nominated

15. Marina Sirota
Joel Dudley
Lamb J, ..., Golub TR. Science, 2006.
Sirota M, Dudley JT, ..., Sweet-Cordero A, Sage J, Butte AJ.
Science Translational Medicine, 2011.

19. Validation methods are increasingly
commoditized

22. Candidate anti-seizure drug against
inflammatory bowel disease
Marina Sirota
Joel Dudley
Sirota M, Dudley JT, ..., Sweet-Cordero A, Sage J, Butte AJ.
Science Translational Medicine, 2011.

23. Anti-seizure drug works against a rat model of
inflammatory bowel disease
Dudley JT, Sirota M, ..., Pasricha J, Butte AJ. Science Translational Medicine, 2011.
Marina Sirota
Joel Dudley
Mohan M Shenoy
Jay Pasricha

24. Anti-seizure drug works against a rat model of
inflammatory bowel disease
Rat colonoscopy
Rat with
Inflammatory
Bowel Disease
Dudley JT, Sirota M, ..., Pasricha J, Butte AJ. Science Translational Medicine, 2011.
Inflammatory
Bowel Disease
After
Anti-seizure Drug

25. Anti-ulcer drug works for
lung adenocarcinoma
• Human lung adenocarcinoma
cell lines explanted into
mouse models
• Followed growth 11 days
• Positive-control doxorubicin
grew to 2x original volume
• Tumors in mice treated with
vehicle grew to 3.25x original
volume
• Not only did our compound
work statistically better than
control, it worked in a dosedependent manner
• Tumors in mice treated with
50 mg/kg/day grew 2.8x
• Those treated with 100
mg/kg/day grew only 2.3x.
Control
With Cimetidine
Sirota M, Dudley JT,..., Sage J, Butte AJ. Science Translational Medicine, 2011,
Joel Dudley
Marina Sirota
Julien Sage

26. Anti-depressant Imipramine Shows Significant Activity
Against Small Cell Lung Cancer
p53/Rb/p130
triple knockout
model of SCLC
Mice dosed after
tumor formation
Joel Dudley
Nadine Jahchan
Julien Sage
Joel Neal
NuMedii
Vehicle control
Imipramine
Cancer Discovery,
2013.

27. Drug development
NuMedii lands 1st deal to spin drug data into product gold
San Francisco Business Times by Ron Leuty, Reporter
Date: Wednesday, October 3, 2012, 5:30am PDT - Last Modified: Wednesday, October 3, 2012, 6:27am PDT
Ron Leuty
Reporter- San Francisco Business
Times
NuMedii Inc. is looking to make a big difference in drug
development with Big Data.
The Mountain View company co-founded by Stanford
University’s Atul Butte and his wife, former Affymetrix
executive Gini Deshpande, said Wednesday that it inked a
deal to help drug developer Aptalis Pharma Inc. find new
treatments for gastrointestinal disorders and cystic fibrosis.
Stanford University professor and NuMedii
co-founder Atul Butte.
Using data to find new drug-disease matches
wins startup NuMedii its first pharma deal
October 3, 2012 4:02 pm by Deanna Pogorelc | 1 Comments
Pairing existing drugs with new disease applications, using not wet labs but
computers, has landed a Stanford startup its first contract with a pharmaceutical
company.

28. 108 million substances x
650,000 assays
1 billion points of data
within a grid of
70 trillion cells

30. Five Lessons Learned
• Public molecular data has incredible utility
– All public-funded data should eventually become publicly-available
– Consider mechanisms to promote secondary uses and computation
• Sufficient high quality data already exists to impact medicine
– More is better, but no reason to wait for more data
– Should never wait for perfect data, experiment, conditions
– Requiring perfection can even slow secondary use
• It’s not just about infrastructure, it’s about using it
– Too many tools. Those who build platforms  use them too!
• Need to train students to initiate science with data
– High school  higher education  career changers
– Scaling through students
• Entrepreneurship from public-funded data is not a dirty word!
– Academics and industry can coexist and thrive together

31. Collaborators
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Jeff Wiser, Patrick Dunn, Mike Atassi / Northrop Grumman
Ashley Xia and Quan Chen / NIAID
Takashi Kadowaki, Momoko Horikoshi, Kazuo Hara, Hiroshi Ohtsu / U Tokyo
Kyoko Toda, Satoru Yamada, Junichiro Irie / Kitasato Univ and Hospital
Shiro Maeda / RIKEN
Alejandro Sweet-Cordero, Julien Sage / Pediatric Oncology
Mark Davis, C. Garrison Fathman / Immunology
Russ Altman, Steve Quake / Bioengineering
Euan Ashley, Joseph Wu, Tom Quertermous / Cardiology
Mike Snyder, Carlos Bustamante, Anne Brunet / Genetics
Jay Pasricha / Gastroenterology
Rob Tibshirani, Brad Efron / Statistics
Hannah Valantine, Kiran Khush/ Cardiology
Ken Weinberg / Pediatric Stem Cell Therapeutics
Mark Musen, Nigam Shah / National Center for Biomedical Ontology
Minnie Sarwal / Nephrology
David Miklos / Oncology

32. Support
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Lucile Packard Foundation for Children's Health
National Institutes of Health
March of Dimes
Hewlett Packard
Howard Hughes Medical Institute
California Institute for Regenerative Medicine
Scleroderma Research Foundation
Clayville Research Fund
Admin and Tech Staff
PhRMA Foundation
• Susan Aptekar
Stanford Cancer Center, Bio-X
• Rhonda Pisk
• Alex Skrenchuk
• Tarangini Deshpande
• Kimayani Butte