Prof. Samir K. BrahmachariFormer Director General, CSIR India

Chief Mentor, Open Source Drug DiscoveryJ C Bose National Fellow

CSIR-Institute of Genomics and Integrative BiologyNew Delhi, India

Bellagio Center16th July 2014#opensourcepharma

OSDD: An Innovative Model for Distributed Co-creation

Towards a New, Open Source Pharmaceutical Industry

OSDD: Crowdsourcing with a difference

Drug Discovery is complex(Intermediate milestones in different areas)

Motivation vs Incentive(Prize vs contribution)

The History / Genesis of Crowdsourcing and Distributed Co-Creation

Toyota Holds a Logo Contest

Sydney Opera House Architecture Contest

Wikipedia Launched American Idol

Season 1

Youtube Launched

Crowdsourcing Term Coined

Marine Pocket Clock Invented

1714 1936 1955 2001 2007

CSIR India Launched

OSDD Initiative

Zooniverse Citizen Science Project

2001 2002 2005 2006 2007 2008

Solve Puzzles for ScienceOnline Platform

for Crowdsourcing

2013

Understanding Human Mind

© Copyright: SKB, CSIR India

Distributed Co-Creation: Expanding the glass of innovation ?

Samir K Brahmachari (Manuscript in Preparation)

2000 2009

2013

2008

Fourth Paradigm of Science in Action

• A CSIR Team India Consortium with Global Partnership with a vision to provide affordable healthcare to the developing world.

• The concept is to collaboratively aggregate the available biological and genetic information to facilitate use and hasten the drug discovery process.

• Inspired by the success of Open Source models in Information Technology (Web Technology, Linux) and Biotechnology (Human Genome Sequencing); OSDD too works in a virtual, distributed whole-Earth “macroscope”.

• OSDD provides a global platform where the best minds can collaborate and collectively contribute to solve the complex problems associated with discovering novel therapies for neglected tropical diseases.

• On date OSDD has >8000 registered participants from 130 countries.

Author, Angela Saini

Geek Nation: How Indian Science Is Taking Over The World

http://www.sunday-guardian.com/bookbeat/tour-of-indian-science-that-fails-to-see-full-picture

OSDD is now an internationally reputed drug discovery initiative pioneered by Government of India

Report of the CEWG of WHO Recognised OSDD as an Open Innovation Model5 April 2012 | Geneva

How Open Source Drug Discovery Is Helping India Develop New DrugsApr 9, 2012

DNDi POLICY BRIEF recognised OSDD as part of Global Landscape for Neglected Diseases R&DApril 2012

Crowd Sourcing Innovation: CSIR portal for OSDD2011

Crowd-Sourcing Drug Discovery24 February 2012Vol. 335 no. 6071 p. 909

OSDD Innovation Model Recognised Globally…

Editorial dated: April 17, 2010

Frugal Innovations in Means and EndsNESTA, UK Report 2012

Rel

ativ

e d

ecre

ase

in

cost

of

pro

du

ct

Relative decrease in cost of the innovation process

Why there is need to strengthen Open Innovation Activities ?

Prize vs Price : Decreasing Cost of DNA Sequencing vs Increasing Cost of Drug Discovery

0.0

0.2

0.4

0.6

0.8

1.0

1.2

1.4

The Average Cost to Develop One New Drug Increased More Than 60%

From 2000 To 2005

1975 1987 2000 2005

Year

Source: www.phrma.orgSource: www.synthesis.cc

Year

Cost Per Base of DNA Sequencing and Synthesis

$1000

$3bn

$3mn

$300mn

$30,000

1.0E+02

1.0E+01

1.0E+00

1.0E-01

1.0E-02

1.0E-03

1.0E-04

1.0E-05

1.0E-06

1.0E-07

1988 1993 1998 2003 2008 2013

9

66%

21%

13%

Drug R&D unaffordability is driven byunnecessary research and poor drug candidates

Drug Sponsor Phase III Phase IVRisperdal J&J 111 65Humira Abbott 83 24Seroquel AstraZeneca 72 40Diovan Novartis 61 60Avastin Genentech 57 13Cymbalta Lilly 55 49Singulair Merck 46 21Enbrel Amgen/Wyeth 45 55Actos Takeda 42 20Nexium AstraZeneca 37 43Aranesp Amgen 33 13Lipitor Pfizer 31 49Plavix BMY/Sanofi 30 22Remicade Schering-Plough 28 15Zyprexa Lilly 27 41Herceptin Genentech 25 5

InnoThink

Source: clinicaltrials.gov

Number of trials done by sponsor

FDA only requires 2 phase III trials!

0%

10%

20%

30%

40%

50%

60%

70%

Phase 1 Phase 2 Phase 3 Submission

Combined late-stage failure: 70%!

efficacy

safety87% of late-stage failures are due to poor efficacy and safety

Questionable management decisions are driving up R&D costs

Source: Paul et al, NRDD, March 2010; Eichler, EMA Source: CMR, N

RDD, Feb 2011

Courtesy: Bernard Munos

Systems Biology is the integrated approach to studying biological systems— intracellular networks, cells, organs, and any biological entity—by measuring and integrating genetic, proteomic and metabolic data. This approach involves cellular and pathway events that are in flux and interdependent. Its application to drug discovery includes utilizing clinical samples from diseased and healthy (normal) patients to uncover System Biology Markers and Pathways Targets, which are indicators of disease and potential targets for therapeutic intervention.

Need for System Biology Approach :

10.06.2003, ISI, Calcutta

Systems Level Approaches to Identify Non-toxic Targets & Inhibitors

Problem Approach

Results Significance

From systems level analysis: Potential Non-toxic targets Drug like inhibitors Biomarker prediction

Provide prioritize candidates for validation

Provides mechanistic understanding at systems level

Has a potential to reduce attrition

Identify potential choke points & back ups From random prototypes to simulated designs

11 JUNE 1998 VOL 393 NATURE

• The sequencing of the Human Genome created stir in the scientific community with the promise to make a remarkable difference to healthcare• Mycobacterium tuberculosis genome was sequenced over 10 years ago• With both the genome sequences available to the scientific community, no effective therapy/drug has been discovered!

The promise of The Human Genome sequence

16 FEBRUARY 2001 VOL 291 SCIENCE

Motivation For OSDD Launch 15.09.2008

Why OSDD for Tuberculosis

1) Drug resistant TB is a global threat - TB kills 1000 people per day in India & 5000 per day globally

2) It is a complex disease and needs new discovery approaches

3) Integrative solutions from multiple disciplines are required to solve the problem

4) Large volunteer participation from different groups and organizations leading to emotional engagement

5) Facilitate participation for young researchers in drug discovery

6) Drug discovery is prohibitively expensive and does not draw enough investment from MNCs as it is not profitable for Neglected Diseases.

IPR protected product

Generic product

Access & Affordability: Linked to IPR

IPR

Affordability

Affordability (non-exclusive)

IPR

Breakthrough Science

New product

Return on InvestmentFrom Market

Increased Involvement

in R & D

Patent Protection

Virtuous Cycle

Investment

Investment

Traditional Innovation Model

Lack of market incentives for neglected diseases break the traditional innovation cycle

http://ip.thomsonreuters.com/sites/default/files/2014stateofinnovation.pdf

Innovation in Drug Discovery related Needs Alternative Models

The biggest loser in Biotechnology was Drug Discovery related innovation, which fell by 25%; even oncology-related innovation declined by 2%.

Globally: Who is Innovating?

Source : Thomson Reuters

• If we do the same things the same old way, can we expect different results?

• Do we find brilliant minds for Drug Discovery only in the industry?

• Can we bring pharmaceutical research into the open where academia, industry and researchers from different disciplines collaborate as a goal oriented community?

Untapped Pools of Scientific Talent

• Traditional Talent Pools

• Opportunity pools of intellectual capacity

Open Innovation reaches outside the four walls and literally attracts everyone those who are willing to solve problems

Projects likely to be successful under Open Innovation

1) Global Good with benefit to larger population – participants can sense direct impact

2) Challenging problems get the attention of bright minds

3) Amenable for breakdown into smaller projects for distributed participation

4) Should have emotional component not only professional component

5) Must attract young people - incentives are not monetary rewards only

6) What cannot be achieved by small group(s)/individuals

For Open Collaboration : Transparency is a must!

Open Peer Review

Community Monitoring

Result Oriented Projects:Commitment on deliverables and funding based on deliverables ensured through Agreements and periodic reviews

Portal based management and data sharing – Everyone Invited!

Then(March 2009)

Now(Last Round of Funding:

September 2013)

Community( Registered members)

718 from 22 Countries(as on 24th Feb 2009)

7685 from 130 Countries

(as on 3rd Sep 2013)

PIs 13 181

Institutions 7 75

Projects 13 261

Implementing Team Size

3 7

Target Diseases TB TB, Malaria, Leishmaniasis

International Collaborations

NONE Several

OSDD : Then & Now*

*(CSIR-OSDD Launched on 15th September 2008 )

OSDD Distributed Virtual Laboratory & Some Current Partners

NIIST

CLRI

Compound RepositoryTB Screening

Compound Repository

Screening for TB & Malaria @CDRI

Compound synthesis

Screening

Clinical Trials

LRS

Screening

Screening

IICB

IIT K

Crowdsourcing

MPDSTB

Phase I2009

Phase II2010

Phase II2011

Phase III2013

Chem-informatics

Phase II2012-13

Genome Annotation for Drug Target Identification through

Systems Level Analysis

Cloning of predicted targets & cheminformatics to predict

potential inhibitors

Identify target-specific filters; Establish Molecular Property

Diagnostic Suite

HostMtb

Systems Approach to Drug Target Identification

In silico growthFlux-balance analysis

Betweenness Centrality

Structural interactome

to predict off-target binding

(ReduceToxicity)

Genome Annotation through Crowdsourcing

Literature

>45,000 publications

Annotation through SOPs

Multiple Rounds of Curation

Annotation Tools

Genomic Databases

PP Functional Network

Metabolic Network

890 Genes1152 Reactions

1434 Proteins2575 Interactions

OSDD Targets for TB Drug Discovery

Target PI/Institution RvID FunctionFAAL/FACL R.Gokhale/IGIB Multiple RvIDs Acyladenylate formation

Dap A/B Ramchandran/IGIB Rv2753c, Rv2773c biosynthesis of diaminopimelate and lysine

GlmU Vinay Nandicoori/NII Rv1018c Peptidoglycan and lipopolysaccharide biosynthesis

NAD dependent DNA Ligase Ravishankar/CDRI Rv3014c DNA replication and repair of damaged DNA

MAP A/B Anthony/IICTNampoothri/NIIST

Rv0734, Rv2861c amino-terminal methionine removal from nascent proteins

Sigma Factors IISc/OSDD unit Rv2710, Rv2069, Rv1221, Rv3286c, Rv3223c, Rv3911

May control the regulons of stationary phase and general stress resistance

Ribosome Biogenesis Balaji Prakash/IIT-K - Ribosome Biogenesis

Mur Pathway Urmi Bajpai/ANDC Rv0482, Rv1315, Rv1338, Rv2152c, Rv2153c, Rv2155c, Rv2156c, Rv2157c, Rv2158c

Cell wall biosynthesis

Rv0079-DATIN Niyaz/Hyderabad University Rv0079 Unknown

Mym operon S.Sharma/MH Rv0186A protects cell from copper toxicity

Rv1258c efflux pump Inshad/IIIM Rv1258c transport of undetermined substrate (possibly macrolide) across the membrane

MMPL3 S. Reddy/NCL Rv0206c Throught to be involved in fatty acid transport

Current Status of translational projects Whole cell or Phenotypic Screening

• >10,000 compounds screened at IICT 11 ‘hits’: further analysis is ongoing (CSIR Labs & CRO) 10 ‘hits’ need to be confirmed

• 20,000+ 30,000 screening: Several ‘hits’ (IIIM)• Pyrrole Based Scaffold: BM212 (MmPL3) analogs (NCL)• Herbal purified fractions: 5 primary hits identified (CRO)

Target based screening• DapA/B Screening in Progress (IGIB & CRO)• LAMS Project: Multi target inhibition on FAAL and FACL (IGIB)

Non radioactive assays being optimized (CRO)• GlmU: in progress (NII/IIT-K/BITS-Hyd)• Mur Pathway: One pot Assay optimized, screening to be initiated (ANDC/DU)• MAP A/B: Assay in progress (NIIST/IICT)• Phage Based lytics: confirmed in BCG; need to be confirmed in Mtb

Target Validation• Knockdown of MAP A and B in progress (CRO)

Mechanism of Action• Mutant generation for Pyrroled Based Scaffolds on BCG (CDRI)

Cytotoxicity Assays• In progress to determine to selectivity for various ‘hits’ (IICT)

Large student community from colleges and university are Cloning, Expressing and Purifying selected Mtb genes

To clone and express select genes of Mycobacterium tuberculosis

Open Access Repository of Mtb clones

120 sequence confirmed clones ready

http://sysborg2.osdd.net/group/sysborgtb/project-details/-/projects/show/3212

Computational Models

Experimental Structures

Human~20,000

Mtb~4000

Predicting Off-target Binding for Potential Inhibitors

PhenotypicScreen

Database

Modeling

OR

Inhibitor(s)

http://proline.biochem.iisc.ernet.in/osdd-osicr/

Platform to assess & estimate the property of molecule(s) using chemoinformatics approaches to diagnose their potential as drug

Molecular Property Diagnostic Suite (MPDS)

CSIR-IICT CSIR-NCL CSIR-IMT BBAU CSIR-CLRI JNU NIPER

32

Innovation

Med

icin

al

Chem

istr

y

Process Driven

Targets Assays

NewMolecules

KnownMolecules

High- throughput screening

AssaysCytotoxicity/Side Effects

Pre-clinical/ Clinical

OSDDCommunity Cloning /

Expression

CROsLibrary

Protein crystals

OSDD - Process flow

Using creativity of students and young researchers

Using experienced low-cost globally competitive Contract Research Organizations

Dovetailing Process Driven Activities to Innovation Activities

Subject Area Partners

Chemistry • M/s Jubilant Chemsys

Biology • M/s Anthem Biosciences• M/s Premas Biotech• M/s Enzene

Clinical Sciences M/s GVK Bio

Information Sciences

• M/s AKS Information Technologies

Research Partners

Chemistry M/s TATA Chemicals

Biology M/s Gangagen

Partners taken through approved process

Novel Combination of TB Drugs

Pre-Clinical Compound offered to OSDD

Assisting to progress OSDD’s in house molecule

Support to Cheminformatics

3 Hit to Lead Candidates offered to OSDD

OSDD is Now an Internationally Reputed Drug Discovery Initiative Pioneered by Government of India

The Open Innovation Model :OSDD strategy

• Porous-walled funnel facilitates free flow of ideas / projects

• Bring in more eyeballs to look at the inside

• Enables Redundancies and Parallelization

Fuzzy Front-End Research DevelopmentInputs

INTEGRATEDOSDD PROJECT

Inputs

Platforms driving the process

Technology

Hits / Lead Molecules

Image Source: Clorox, Andy Gilinkski, www.imaginatik.com

OSDD

OSDD

INDIVIDUAL PIsIDEAS

Marrying The TWO CULTURES

- Academic

- Delivery focused

- OSDD THE FACILITATOR

OSDD the leader- Expertise- Discovery Platforms

CLIMBING THE ‘MAGIC MOUNTAIN’

GLOBALISING THE EFFORT

New CombinationGATB

OSDD: Distributed CollaborativeOpen Source Drug Discovery Platform

and More…

Open Innovation from Best Minds in Academia

& Industry

Industry / CROsOpen Data for

Community Access & Inputs

First Time in India: Clinical Trial of Anti TB

Novel Multi Drug Regimen.

DiscoveryDevelopment

Clinical Trial

Over 100 Labs 15 CROs/ConsultantsPartner: LRS TB Hospital,Ministry of Health & Family Welfare

CRO Partner: GVK Biosciences

OSDD URL : www.osdd.net Sysborg URL: http://sysborg2.osdd.net

OSDD Community8100 Members 130 Countries

Fourth Paradigm in Action

Tuberculosis Malaria Leishmaniasis

Media conditions Biomass

Doubling Biomass as measure of in silico growth

XRv1484

890 Genes: 1152 Reactions

Ammonium SulfateL-Glutamic AcidSodium CitratePyridoxineBiotinDisodium PhosphateMonopotassium PhosphateFerric Ammonium CitrateMagnesium SulfateCalcium ChlorideZinc SulfateCopper Sulfate

mmol/gDW

amino acidsnucleic acidsSugarsCarbohydratesPeptidoglycansFatty AcidsGlycolipidsPhospholipidsMycolic acid…….

X

Simulating the Impact of Antibiotics

Novel Systems Biology Spindle Map (SBSM) of Metabolism

Metabolites (961) Genes (Genomic order) (890) Reactions/Pathways(1152/50)

ExchangeReactions

Systems Biology Spindle Map of Metabolism (SBSM)Simplifying metabolic complexity, enabling analytical analysis

Complete Metabolic Information

Systems Biology Spindle MAP – Under Influence of Isoniazid

Spectrum of Metabolic Persister Genes in M. tuberculosis

Thousand Mtb Genome & Gene Essentiality of All MPG’s – Combination Targets for Existing Antibiotics

PP Functional Network

Metabolic Network

890 Genes1152 Reactions

1434 Proteins2575 Interactions

Carbonic Anhydrases

Type VII Secretion System

Experimental Validation for Predicted Targets

Mur EnzymesEnzymes from

Persistor Phenotypes

Disrupting RNA Pol-Sigma Factor Binding

N-acetylglucosamine-1-phosphate uridyltransferase/glucosamine-1-phosphate acetyltransferase

Dihydrodipicolinate synthase & reductase

Predicting Potential Inhibitors for Mtb Targets

http://c2d.osdd.net/home/p2i

DBT Star CollegeDU Innovation Project

Prioritized Targets (OSDD)

Whole cell screening hits

Assays

Structure

Essentiality (system based)

GSK (177)

OSDD

Public domainStructure (PDF)

Structure (SDF)

DOCKING MOLECULAR MODELLING

PHARMACOPHORE FEATURES

1. Compounds with pharmacophoric features2. New scaffolds

BIOCHEMISTRY/MOLECULAR BIOLOGY MICROBIOLOGY

COMPUTATIONAL BIOLOGY/CHEMOINFORMAT

ICS

CHEMISTRY

The Work in progress to Identify Potential Pharmacophore Features

Flow chart representation of the planned in silico DD

Training Workshop Dates No. of Students

Colleges/Universities involved

1. Intensive Hands on training in Protein

Modeling and docking studies for rational

drug design

23rd – 24th December

2013

27 Bhaskaracharya College of Applied Science (DU), Shivaji College (DU),

Dr. B.R. Ambedkar institute of Biomedical Research (DU),

Hamdard University, IIT Kanpur

2. Protein Modeling and Docking Studies

for Rational Drug design: A Workshop for

Science Students

12th – 13th March 2014

22 Miranda House

60 members!!

Worksh

ops

in IGIB-

Mathura

road and

Miranda

House

Molecular Docking Training Workshops

Molecule Property Diagnostic Suite• Compound and Target Library• Docking (AutoDock Vina1.12)

– Single protein-single ligand– Single protein-multiple ligand– Multiple protein-single ligand

• Descriptor Calculators– PADEL & CDK

• QSAR– Weka & SVM

• Filters – DruLiTo – Toxicophores– BCS classification

• Molecule library generation & Molecule cloud

Database Number of Unique Compounds

DRUGBANK 6583KEGG 7718ASINEX 46754NCI 257679ZINC 8337260PUBCHEM 48717726TOTAL 57373720

Evaluating drug-like properties of 57 Million compounds

http://stage.mpds.osdd.net

Developing finger printing rules for classification of the compound library

Over 1000 students trained on state-of-the-art methods

The Royal Society of Chemistry (RSC) – Open Source Drug Discovery (OSDD) Meet, 3-5 Feb 2014

Workshop on Drug Discovery (predictive approaches) for OSDD Chemists

•Potential to identify subset of patients predisposed to toxicity from specific medication. Give them alternatives, if available

Pharmacogenomics: A customized approach to therapy

A. Current state of drug development research Desired response

Patients receiving drug

Population of patients with given disease

B. Ideal future objective of drug development research

Population of patients with given disease all or nearly all respond to different drugs according to genotype

No response

Adverse response

•Identify responders, slow responders & adverse responders. Adjust drug doasage accordingly

• Gene Involved in anti-TB drug metabolism

• 38 Host drug metabolising & transporter genes

Gene List

• Extract SNPs documented for each gene in literature & database (dbSNP, ENCODE etc).

• ~40,000 SNPs

SNP List• Approx. 120SNPs

polymorphic in Indian population, data for most others not available

Polymorphic SNPs

Pipeline for SNP shortlisting from DMETs associated with anti-TB drugs (see SNP map)

Good quality DNA available from patients sputam

For pilot study, 96SNPs will be studied in patients & controls (Total 48)

8100 members from over 130 countries

Prof. Samir BrahmachariChief Mentor, OSDD

Dr. T. S BalganeshHead, OSDD

Dr. Sarla Balachandran Project Coordinator

CSIR-OSDD

Dr. Geetha Vani Rayasam CSIR-OSDD

Zakir ThomasFormer Project Director CSIR- OSDD

Dr. Anshu BhardwajCSIR-OSDD

Dr. U.C Jaleel OSDD

What did we learn ?

How group fall in in place?

A good PI is worth a pot of honey!

How do you make a group collaborate? Birds of same feather flock to each other!

On the web they find each other!

But the PI has a job!

Need to guide the flock!

If the task is challenging…

They know when they can’t do it alone

When they cant do it alone…they collaborate

A structuring takes place even in a crowd

Short-term vs long-term

Incentive vs Motivation

63

• Together we can …• .. and we should !

Matt Smadley | Flickr.com

http://c2d.osdd.nethttp://www.osdd.net

Email: info@osdd.net

“Earth provides enough to satisfy every man's need, but not every man's greed.”

-Mahatma Gandhi

“When it comes to health, we need to have a balanced view between health as a right and health as a business”

Cell (2008) v.133, pp. 201-203