Sharing and Co-locating Cores NIH-ABRF Workshop on Enhancing Efficiency of Research Core Facilities

David GorensteinAssociate Dean for Research

University of Texas HSC Houston

• Vision: Create a network of state-of-the art Core Labs and Centers to help accelerate basic, translational and clinical research – New tools of molecular medicine: proteomics, genomics, metabolomics,

systems biology, bioinformatics, biomedical informatics, CLIA clinical diagnostics

– “Personalized” medicine– Team-based science

• How do we invest in this expensive infrastructure and optimize access?– UTHealth/MDACC CTSA Translational Technologies Core Labs– Texas Regional CTSA Consortium– Hospital and Basic and Clinical Department Partnerships– UT System Core Lab Network– Gulf Coast Research Consortia and shared Cores

Evolving Nature of University/Medical School Pre-20th Century University

- Teaching, knowledge repository/conservator- Monastic “Ivory Tower” set apart from society/world

20th Century Research University/Medical School- Basic Research, knowledge producer- Clinical Research- New mission: V. Bush, The Endless Frontier (1945)- Federal funding, creation ONR, NIH, NSF

21st Century “Translational” University/Medical School?- Translational research- Part of a network of knowledge and product production systems- Multidisciplinary, multi-institutional cooperative partnerships

- Texas Regional CTSA Consortium- Gulf Coast Consortia- UT System Core Lab Network

Core Labs and Precision Medicine Initiative “Tonight, I’m launching a new Precision medicine Initiative to bring us closer to curing diseases

like cancer and diabetes – and to give all of us access to the personalized information we need to keep ourselves and our families healthier.” President Obama, State of the Union Address, 2015.

Collins & Varmus, NEJM, 2/26/15 “A New Initiative on Precision Medicine” “Precision medicine has been dramatically improved by the recent development of large-scale

biologic databases (such as the human genome sequence), powerful methods for characterizing patients (such as proteomics, metabolomics, genomics, diverse cellular assays, and even mobile health technology), and computational tools for analyzing large sets of data.”

Two components, near-term on cancer, longer-term on whole range of health and disease Within our reach due to advances in basic research, including molecular biology, genomics

and bioinformatics Encourage next generation scientists to create approaches for measuring and analyzing range

of biomedical info – molecular, genomics, cellular, clinical, behavioral, physiological, and environmental

Cohort of 1 million for NGS and blood components, RNA, DNA, proteins,… Near term – pharmacogenomics; right drug, at right time, with right dose to the right patient Team approach of biologists, physicians, technology developers, data scientists, others Will require new resources

Threats and Opportunities

x

X President’s FY15

Francis Collins, NIH Director, AAMC Research Deans, 2012

Translational Medicine: Drug & Companion Diagnostics Development

Problem:Still takes 10-14 years and

now Billions $Organize: IMM & nBME

(therapeutics, diagnostics, imaging, nanomedicine, informatics)

UTH / MDACCCenter for Clinical and Translational Sciences /TRCC

Gulf Coast Consortia UT System Core NetworkGoal:Facilitate Translation thru

CoresPersonalized Medicine

Companion Diagnostics

Biologics:• Antibodies• Aptamers

Nanomedicine

UTHealthResearch Service Centers

Atomic Force Microscopy FacilityBioinformatics Service CenterBone Histomorphometry and Biomaterials LaboratoryCenter for Advanced MicroscopyCenter for Laboratory Animal Medicine & Care (CLAMC)Electron MicroscopyFluorescence Microscopy & Imaging Core LaboratoryGenetics Core LabIMM Flow Cytometry Service CenterIMM Histopathology Service CenterIMM Transgenic & Stem Cells Service CenterElectron Microscopy FacilityMedical School Histology LabClinical & Translational Proteomics Service CenterUT MRI FacilityUT Pre-Clinical CT FacilityIMM Research Administrative ServicesHSC Core Labs (Quantitative Genomics & Microarray Facilities Lab)Nanochemistry Service CenterIMM Microscopy Service CenterMolecular Diagnostic (aka Proteopath Clinical Laboratory)

Core LaboratoriesCellular Therapy CoreClinical Research Unit (CRU) (CCTS)Electron Paramagnetic Resonance (EPR)Fluorescent/Phosphorescent Imaging Core LaboratoryMMG Core FacilitiesMagnetic Circular Dichroism/Circular (MCD/CD)Sequencing CoreStructural Biology Imaging Center

Other Research Facilities & ServicesBiobank (CCTS)Center for Clinical Research & Evidence-Based MedicineCenter for Clinical and Translational Sciences (CCTS)IMM CARDIA Core Facility

1. DNA Sequencing and Genotyping (Milewicz, Boerwinkle, Gao)2. MR Imaging (Narayana)3. Biomarker Discovery and Quantitation, Expression Profiling (Loose)4. Clinical and Translational Proteomics (Rosenblatt, Wang) 5. CLIA Molecular Diagnostics (Rosenblatt, Wang) 6. Bioinformatics (Chang, Volk, Meric-Bernstam)7. Nanochemistry (Volk, Thiviyanathan)8. Micro CT (Danila)9. Atomic Force Microscopy (Zaske)10. High-throughput Screening Core Laboratory (Davies GCC)11. Texas Therapeutics Institute (An, Liu)12. Antibody Engineering (Zhang)13. Center for Advanced Biomedical Imaging (CABI): Cath, CT, MRI, PET for

animal and human studies (joint GE, UTHealth, MDACC)

Translational Technologies

Core lab personnel can help design the right methods for each study and develop Translational Teams (CCTS Core Lab Pilot grants)

CLIA LabLC- High resolution TOF (time of flight) mass spectrometer Perkin Elmer AxIONsystem for discovery (able to detected different compounds present in the sample by measure their mass with very high precision…4 points after decimal)

Shimadzu 8040 LC-MS/MS For quantification of known compounds by MRM technique

0.0 2.5 5.0 7.5 10.0 12.5 15.0 17.5 20.0 22.5 Conc. Ratio0.000

0.025

0.050

0.075

0.100

0.125

0.150

0.175

Area Ratio

R^2=0.9999782

0.0 2.5 5.0 7.5 10.0 12.5 15.0 17.5 20.0 22.5 Conc. Ratio0.00

0.05

0.10

0.15

0.20

0.25

0.30

0.35

0.40Area Ratio

R^=0.9994768

MorphineAmphetamine

0.00 0.25 0.50 0.75 1.00 1.25 1.50 1.75 2.00 2.25 2.50 2.75 3.00 3.25 3.50 3.75 min

0

500000

1000000

1500000

2000000

2500000

3000000

Ultra Fast5 min Gradient

with42 drugs quant

Samples of calibration curves - overall 4 orders of magnitude (5 ng/ml-2000 ng/ml)

MHHS – UT Pathology – IMM – SBMICenter of Excellence for Personalized

Diagnostics

MHHS - UTHealthCancer Center

MHDL

Patient

CDx, Inc (Genomics)

(blood, tissueurine, ordering)

(Single personalized diagnostics report)

UT*Path (Immunohistology,

Molecular Diagnostics)

IMM Proteopath / SBMI / CCTSCLIA Lab / Informatics

(Genomics, Proteomics, Metabolomics, TDM. Mass Spec analyses, Medical

Informatics, Bioinformatics)

MHHSCORE Lab (Medical

Diagnostics)

Molecular Diagnostics Center of Excellence

UTHealth-Memorial Hermann Molecular Diagnostics Center of Excellence

University of Texas Core Lab Sharing InitiativeCore Lab Sharing Memorandum of Understanding between UT Institutions• Initiative from Texas Regional CTSA Consortium (TRCC) Working group and Dr. Patti Hurn,

Vice Chancellor for Research and Innovation to define a statewide network of cores across UT System (4 CTSAs: UT HSC Houston/MDACC, UT SW Dallas, UTMB, UT HSC San Antonio)

• MOU first between UT Health Institutions now expanded to include all 16 UT Institutions• All cores are included (if they want; currently >100)• The Cores of each Institution will provide their normal services to investigators of the

other Institution at standard rates for internal customers

UT System providing some financial support for shared core labs• Central website maintained by UT System to find core services • Funds for iLabs installation/licensing for shared core lab management (>$3.0M)• Funds to establish a UT System-wide Proteomics Core Network (~$6.0M)

Gulf Coast Consortia MOU for Shared Cores (in progress)• UTHealth, MDACC, UTMB, Rice, Baylor College Medicine, U Houston• Similar to UT System MOU

Importance of increasing cross-institutional cooperation in shared resources

• Constrained research funding increases the importance of efficient operations

• New technologies are increasingly powerful, but also increasingly expensive

• Expertise required to operate some advanced technologies optimally is in short supply

• Some technologies can be operated more efficiently or in greater quality at high volumes

• Institutions have existing strengths in different technologies

• Funding agencies are encouraging cross-institutional collaboration

Where possible, institutions should cooperate in the operation and funding of shared resource facilities

iLabs Overall Timeline (7 UT Institutions)

iLabs UT Network Capability• Network landing page• Institutional landing page

– Detailed list of internal cores and core descriptions– Interface for login and user registration– Institutional branding– Links to listing of cores not currently in the UT System Network

• Search Enhancements– Text search across all cores– Identify core facilities and equipment– Search by equipment availability– Search without user login– Browse by category (sequencing cores, flow core, proteomics, etc)– User must see priority level for core (Mine, Ours, All)

• Reporting Enhancements– Reporting to identify available capacity/percent utilized– Super-institutional user access

Future Features?

• HIPAA compliant• WebEx/Video capabilities• FedEx- like Sample Tracking• Set up an “Institutional Admin/Billing Contact”• Allow for inter-institutional “internal department

transfers”• Yelp-like rating for cores• Publication tracking• Training video/ SOP Central• Core can see priority level for user

Challenges to increasing cross-institutional Core Sharing Area ExamplesSystems/technology • Limited researcher visibility to available resources

• Difficulty managing access, privileges, pricing across institutions

• Multiple usernames and processes• Complex billing across institutions

Scientific/practical • Some technologies are not well-suited to remote usage(e.g., self-service instruments)

• Difficulty in building trust and communication between individuals who do not know each other

Inter-institutionalcoordination

• Complex financial issues, such as partner pricing, allocation of indirect funds, and cost sharing

• Non-financial questions, such as resource location, access rights, and investment prioritization

Intra-institutionalcoordination/politics

• Some individuals or departments can be reluctant to give up autonomy and control

• External resources may be perceived as inconvenient or unreliable

Lesson: New Technologies Jump in (and out)

in situ hybridization(0.9944)

cDNA cloning(0.9952)

northern blot (triangle)(0.9904)

voltage clamping(0.9927)

southern blot(0.9810)

Development of a research technology follows Gaussian distributionJ. Kang et al. unpublished

MODELS FOR CORE SHARING• Federation of Independent Research Cores (current UT MOU model)

• Centralized or Hub/Nodes Core Facility shared by institutions (UT System managed/supported or single institution managed; CyTOF)

• GCC-type multi-institutional organization with centralized staffing – mixed model

– GCC for Magnetic Resonance (Federated)– GCC for Crystallography Beam Line (Centralized)– GCC for Chemical Genomics (Hub and nodes)

• Bilateral partnerships – CCTS UTH/MDACC; UTHealth/BCM• GCC partnership with TRCC Core Lab Consortium

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UT System Institutions and Core Network Participants

UT SouthwesternUT Arlington, UT Dallas

MD AndersonUT Health UTMB

UTHSCSAUTSA

UT Austin

UT Proteomics Network

A. Kurosky, DirectorD. Gorenstein, Assoc. Dir.

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Major Goals for the Proteomics NetworkStrategies• Improve access to existing

core services across the state

• Adopt leading technologies, applications and expertise

• High standards and quality assurance

• Enhance education for trainees and young investigators

Tactics• Centrally coordinated network

with in-house pricing agreements• Common management platform

(iLab) and staff• Funding for instrumentation and

operations• Budget emphasizes Top-Down

technologies and staff for CyTOFand informatics

• Shared best practices and a course curriculum

UT System Institutions and Core Network Participants

LTQ Velos MS, Nano Capillary LC

Orbitrap Fusion,AB QTRAP, Lasers,HPLC, Other peripherals

Orbitrap Fusion and Laser

Major New Equipment Purchases Budgeted

LC/MS Detector

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Promoting the Network Internally

• Communication, communication, communication• Budget for multiple face-to-face meetings for core

directors and staff. • Seminars and campus visits by specialty experts• Hosted events• Email list-serves across institutions• Planning and more on the way

GCC Institutions

GCC is one of the largest inter-institutional cooperatives in the world with a focus on building strong collaborative research groups, sharing of research cores and interdisciplinary training opportunities within the Texas Medical Center

UH

UTMBRice BCM

MDACCUTH

Chosen from more than 800 candidates, GCC was one of 8 national finalists for the 2011 Collaboration Prize and was noted for creating an extraordinarily impactful, innovative collaboration.

UH

GCC office

IBT

GCC Oversight Committee

Keck Center Executive Committee Research Consortia Executive Committee

NLM

Neuro-Engineering

Biomedical informatics

Molecular Biophysics

NanobiologyCancer Biology

NSF

NIGMS NIGMS

CPRIT NIBIB

Keck Center for QuantitativeBioscience Training

Pharmacologic Sciences

Magnetic Resonance

Translational Pain Res.

GCC Research Consortia

Theo. & Comp. Neuroscience

Chemical Genomics

Bioinformatics

Protein Crystallography

Translational Addiction Sci.

Regenerative Medicine

Neuro-Engineering

Equipment-based consortia

Shared Research Instrumentation and Cores

John S. Dunn, Sr. GCC for Magnetic Resonance (funding from Keck Foundation and John S. Dunn Foundation, Dow Chemical; D. Gorenstein, Chair)

• Two 800 MHz NMRs: Molecule imaging (atom location, protein structures); UTMB and Rice

• MRI: Small animal studies and human tissue studies; BCM

John S. Dunn GCC for Chemical Genomics (funding from Dunn Foundation, Welch Foundation and CPRIT, P. Davies, Chair)

• High Throughput Screening core facility: assays, equipment, compounds

• Screening facilities at all six GCC institutions• CPRIT Award in 2011 to establish High Throughput Screening

Center: Texas Screening Alliance for Cancer Therapeutics (TxSACT)

GCC for Protein Crystallography (funding from NSF, NIH, R. Fox, Chair)

• MAD X-ray beamline at Louisiana State Univ.- Baton Rouge for determination of protein crystallographic structures

800 MHz at Rice - Houston

The GCC …

Collaborative efforts have paid off in:

•Training grants awarded: currently 6 training grants providing trainee support (stipend, tuition, fees, health insurance) to currently funded predocs and postdocs

•Equipment purchased and core labs shared:– Drug screening cores

• small satellites at each GCC institution– 800 MHz NMR Cores at UTMB and at Rice– X-ray beamline

$63M in funding awarded since 2001: NIH, NSF, AHRQ, Philanthropy, CPRIT, NSF, NIH

• $39.0M – Training Grants• $19.5M – Research Cores/Equipment Grants• $4.5M – Seed Funding UTMB 800 MHz NMR

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Why are we successful?• Strong, centralized administrative structure (dedicated staff), driven by bottom-

up faculty initiatives

• Combined resources – students (>70 training slots), faculty (>500), core equipment and facilities of seven institutions in geographic proximity

• Focus on collaboration: inter-institutional and interdisciplinary; – Exposure to students and faculty from “across the hall,” “street” and “town”– Novel research approaches– Student recruitment in training program from all participating institutions– Transdisciplinary (Arise2 report, AAAS, 2013)

• Willingness to evolve into new areas of science

• Philanthropy – Foundations prefer to provide funding for joint requests

• 7 Institutions provide annual base budgeting

Acknowledgments

Texas Regional CTSA Consortium (TRCC) University of Texas System Patricia Hurn, Vice Chancellor for Research and

Innovation, UT System Proteomics Network leaders and participants (Alex

Kurosky, Sue Weintraub and many others!) TRCC Core Lab Working Group (Kat Hale, Michael

Wilson and many others!) Gulf Coast Consortia Group