strategic plan 2016 - 2022 - the metabolomics innovation centre · 2016-11-07 · strategic plan...

Strategic Plan 2016 - 2022

Disclaimer: This document is made available and presented as an internal management document for the sole purpose of evaluating the opportunities and direction of The Metabolomics Innovation Centre (TMIC). The information contained herein is confidential and is not to be distributed, disclosed or reproduced in any way without prior written consent of TMIC. While the information set forth herein is deemed by management to be accurate at the time of writing, TMIC shall not be held liable for the accuracy of or any omissions from this Business Plan.

Strategic Plan 2016-2022

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Contents

Executive Summary ....................................................................................................................................... 4

Introduction .................................................................................................................................................. 6

Mission/Vision .......................................................................................................................................... 6

Background and History ............................................................................................................................ 7

Key Accomplishments ............................................................................................................................... 8

TMIC Management ................................................................................................................................... 9

SWOT Analysis............................................................................................................................................. 11

Strengths ................................................................................................................................................. 11

Leadership and Personnel ................................................................................................................... 11

Platform and Technology Diversity ..................................................................................................... 13

TMIC Services ...................................................................................................................................... 13

Metabolite Coverage .......................................................................................................................... 15

Chemical Libraries ............................................................................................................................... 15

Software and Databases ..................................................................................................................... 15

Advancing Metabolomics Technologies ............................................................................................. 17

Industry Partnerships .......................................................................................................................... 18

Cost Reduction .................................................................................................................................... 19

Training ............................................................................................................................................... 19

Enhancing Access to TMIC .................................................................................................................. 19

Weaknesses ............................................................................................................................................ 20

Instrument Issues and Mitigation Strategies ...................................................................................... 20

Reliance on Government Funding and Mitigation Strategies ............................................................. 20

Waiting Times and Mitigation Strategies ............................................................................................ 21

Maintenance Contracts and Mitigation Strategies ............................................................................. 21

Opportunities .......................................................................................................................................... 21

Taking Advantage of Metabolomics’ Growth Potential ...................................................................... 22

Developing Kits ................................................................................................................................... 22

Hand-held Metabolomic Devices ........................................................................................................ 22

Clinical Translation .............................................................................................................................. 23

Expanding and Enhancing Services ..................................................................................................... 23

Advanced Certification ........................................................................................................................ 24


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Threats or Risks ....................................................................................................................................... 24

Loss of Funding ................................................................................................................................... 24

Competition from other Core Facilities .............................................................................................. 24

Appearance of Disruptive Technologies ............................................................................................. 25

Catastrophic Instrument Failures........................................................................................................ 25

Staff Retention .................................................................................................................................... 26

Operational and Strategic Objectives ......................................................................................................... 26

Operational Objective - Diversifying Funding ......................................................................................... 26

Operational Objective – Update Infrastructure ...................................................................................... 27

Operational Objective – Expansion ......................................................................................................... 28

Strategic Objectives - Mainstreaming Metabolomics ............................................................................. 28

Metabolomic Kits ................................................................................................................................ 29

Hand-held Devices .............................................................................................................................. 30

Making Metabolomics Matter in Health ............................................................................................. 31

Expanding Capabilities and Offerings ................................................................................................. 31

Acquiring Certifications ....................................................................................................................... 32

Deliverables................................................................................................................................................. 32

Evaluation ................................................................................................................................................... 33

Conclusion ................................................................................................................................................... 34

References .................................................................................................................................................. 35

Appendices .................................................................................................................................................. 38

Appendix 1: Major Equipment ................................................................................................................ 38

Appendix 2: TMIC Success Stories .......................................................................................................... 42

Appendix 3: Metabolomics Facilities Comparison .................................................................................. 45

Appendix 4: Projections (Bar Graphs) ..................................................................................................... 46


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Executive Summary

The metabolome—the complete set of small-molecule metabolites found within a biological sample — represents the end-products derived from thousands of interacting genes, proteins and physiological processes, each of which is responding to the environment. Interest in metabolomics (the study of the metabolome) is growing exponentially as more scientists realize its potential to accurately measure phenotypic traits, probe system-wide interactions, integrate multiple omics measurements and discover novel biomarkers. Over the past decade, Canada has emerged as a world leader in metabolomics research by pioneering the development of innovative hardware, software, databases, chemical libraries and methodologies to perform comprehensive metabolomic analyses of biological samples. To consolidate and exploit this expertise, The Metabolomics Innovation Centre, or TMIC, was formed in 2011. TMIC was established with the vision of becoming one of the world’s premier metabolomics facilities, offering the widest possible range of cutting-edge, comprehensive, quantitative metabolomic research capabilities and services. TMIC’s mission is to enable world-class, discovery-based metabolomics research for Canadian scientists in both the public and private sectors. TMIC uses a combination of high-resolution mass spectrometry (MS), Nuclear Magnetic Resonance (NMR) spectroscopy, advanced chromatographic separation (Liquid Chromatography (LC); Gas Chromatography (GC)) techniques, unique chemical modification techniques, innovative metabolite imaging methods and cutting-edge bioinformatics approaches to help Canadian scientists perform advanced metabolomic research. TMIC is led by 5 internationally acclaimed scientists at the Universities of Alberta and Victoria and its operations are run by experienced, closely networked managers who oversee a team of skilled scientists and technicians. Through TMIC, many important discoveries have been made relating to the human metabolome, human and animal health, livestock and crop productivity, natural product biosynthesis, drug interactions, microbial metabolism and environmental monitoring. These discoveries, combined with TMIC’s unique infrastructure and capabilities, have made TMIC a global leader in the field of metabolomics. TMIC is now regarded as an essential component of the global metabolomics community, helping to drive the pace of discovery in the field and providing valuable tools and services to a growing number of national and international core facilities, users and partners. TMIC’s has many strengths. It is led by some of top metabolomics researchers in the world. It has one of the largest and most diverse collections of cutting-edge metabolomic equipment in the world (>$26 million and >40 instruments). It supports essentially all major metabolomic techniques (NMR, LC-MS, GC-MS, lipidomics, fluxomics, metallomics, volatile measurements, MS-imaging, targeted and untargeted metabolomics, and metabolite synthesis). It has world-leading metabolite measurement capabilities (up to 3500 compounds) and has one of the largest collections of authentic chemical standards (>2000 metabolites or metabolite derivatives) in the world. It has developed and maintains many of the world’s key metabolomics data resources, including the Human Metabolome Database (HMDB), DrugBank, the Food Database (FooDB), the Small Molecule Pathway Database (SMPDB) and MetaboAnalyst. It is also one of only a few core facilities in the world that is able to perform automated or semi-automated quantitative metabolomic analysis, which ensures greater reproducibility, higher quality control and facilitates the translation of discoveries to clinical, veterinary and industrial applications. TMIC is also positioning itself to exploit emerging opportunities in metabolomics, including the rapid (15-25%/yr) growth in the field, the need for standardization and simplification, the need for low-cost and portable metabolomic tools or sensors, the desire to move metabolomics into clinical


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applications, the need for a larger and more diverse array of metabolomics services and, finally, the growing need for certified core facilities. TMIC plans to build on its strengths and exploit these opportunities to help advance the field of metabolomics even further. In particular, from 2017-2022, TMIC will focus on 3 operational objectives and 5 strategic research objectives. The 3 operational objectives are to: 1) expand and diversify its funding base; 2) continue to update its equipment and infrastructure and 3) expand its capabilities and services across Canada by adding new nodes and/or capabilities. The 5 strategic research objectives, which complement the operational objectives, involve: 1) developing and partnering with different companies and agencies to create metabolomic kits for research purposes and (eventually) clinical, veterinary, farm-side or field testing; 2) developing hand-held metabolite-sensing devices to make metabolomics portable; 3) working with clinicians and companies to make metabolomics part of routine diagnostic protocols or tests; 4) continuing to extend the current offerings and capabilities of TMIC while at the same time developing efficiencies to reduce costs (by 20%) and expand metabolite coverage (by 100%); and 5) obtaining Clinical Laboratory Improvement Amendments (CLIA) approval and ISO 17025 certification to allow TMIC to perform clinical and or industrial/legal standard testing. With significant support from users in academia and industry, TMIC has been successful in securing strategic funding partnerships and service contracts that are helping to establish it as a self-sustaining core facility. Indeed, many of the operational and strategic goals outlined above are designed to allow TMIC to move toward self-sustainability or near self-sustainability by 2026. However, these strategic goals cannot be met without additional investment. Furthermore, as demand for metabolomics services grows, TMIC will clearly need to invest more into its core operational activities to meet the demand in a prompt manner. In addition, a substantial commitment of operating funds is required in order to recruit/retain the highly qualified personnel required to maintain TMIC’s infrastructure and provide adequate levels of research service. Therefore, over the next 5 years, a major focus for TMIC is to diversify its funding base by seeking financial support from additional public funding agencies, private donors and industrial funding partners to ensure that expected demands can be met. This document outlines TMIC’s current roles, vision, history and management structure as well as its strengths, weaknesses, opportunities and threats (SWOT). It also provides a multi-pronged, multi-year strategy that will allow TMIC to enhance and maintain itself as Canada’s hub for metabolomics research, development and commercialization. The overall goals of this strategy are to support not only the establishment of core facilities and infrastructure, but also to perform cutting edge metabolomic research to train highly qualified personnel, recruit outstanding research scientists, create viable spin-off companies and contribute to the diversification of Canada’s economy.


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Introduction

The Metabolomics Innovation Centre (TMIC) is a geographically distributed, fee-for-service, university-based core facility providing quantitative metabolomics services for Canada’s public and private research sectors. It operates through 5 “nodes” or laboratories at the University of Alberta (UofA) and the University of Victoria (UVic). TMIC’s primary purpose is to enable research and discovery by providing world-class quantitative metabolomics services to a wide range of users through the application of leading-edge metabolomics technologies, proprietary databases and custom software applications. TMIC is led by Dr. David Wishart (UofA), and is supported by 4 Platform Leaders including Dr. Christoph Borchers (UVic), Dr. James Harynuk (UofA), Dr. Liang Li (UofA) and Dr. Michael Overduin (UofA). These 5 scientists bring complementary expertise, equipment and service offerings that, together, make the whole more than the sum of its parts. TMIC is currently supported by 65 trainees, scientists, technicians, and administrators and houses more than $26 million in state-of-the-art metabolomics equipment, including 5 NMRs (800 MHz, 700 MHz, 600 MHz and 2x500 MHz instruments), 15 LC separation systems and 26 mass spectrometers ranging from low-resolution/high-sensitivity models for targeted metabolomics to Canada’s most powerful ultra-high-resolution Fourier Transform (FT)-MS instruments for untargeted metabolomics. Particularly unique is TMIC’s 500 MHz NMR located within a level 2+ containment facility for metabolomic studies of biohazardous material. TMIC also supports advanced MS imaging technologies, operates a range of GC-MS systems for volatile compound analysis, maintains one of the world’s largest metabolite libraries (the Human Metabolite Library or HML), has developed and implemented many robotic sample-handling systems and operates an extensive collection of equipment for sample processing, separation and biobanking. TMIC routinely analyzes thousands of human, model organism, plant, microbe, soil, water and air samples each year. In addition to its extensive collection of advanced analytical equipment and capabilities, TMIC has developed and now maintains many of the world’s key metabolomic data resources, including the Human Metabolome Database (HMDB)1, DrugBank2, the Toxic Exposome Database (T3DB)3, the E. coli Metabolome Database (ECMDB)4, the Food Database (FooDB)6, and the Small Molecule Pathway Database (SMPDB)6. Moreover, TMIC has also assembled some of the most complete spectral and chemical libraries of metabolites (>2000 compounds) and developed and/or published organic synthetic protocols for more than 500 metabolites. TMIC has also created many popular, freely available software tools for a variety of metabolomics and nutrigenomics applications (such as CFM-ID7, Bayesil8 and MetaboAnalyst9). These unique resources, in combination with its world-class infrastructure and highly qualified personnel, allow TMIC to offer the widest possible range of some of the most cutting-edge, comprehensive, quantitative metabolomic research capabilities and services in the world.

Mission/Vision

The mission of TMIC is to enable research and discovery by providing world-class quantitative metabolomics services using custom software, proprietary databases and leading-edge technology. TMIC’s vision is to become one of the world’s premier metabolomics facilities, offering the widest possible range of cutting-edge, comprehensive, quantitative metabolomic research capabilities and services, with the ultimate goal of enabling the creation of a sustainable metabolomics industry in Canada.


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Background and History

With federal and provincial support, TMIC evolved from the Pan-Alberta Metabolomics Platform (PANAMP, 2009-2011), which, in turn, grew from the Human Metabolome Project or HMP (2005-2009) led by Dr. Wishart. In 2011, TMIC was officially launched as a Genome Canada Science and Technology Innovation Centre (STIC). The initial (2011) version of TMIC included 3 principal scientists (David Wishart (UofA), Christoph Borchers (UVic) and Liang Li (UofA)) located at 3 different nodes or laboratories. In 2013, TMIC added a fourth node (led by James Harynuk, UofA). In early 2015, TMIC became one of 10 inaugural Genomics Innovation Network (GIN) nodes and in late 2015, with the arrival of Michael Overduin from the UK, TMIC added a fifth node (led by Dr. Overduin, UofA). TMIC now operates through 5 “nodes” or laboratories at the University of Alberta and the University of Victoria. TMIC’s infrastructure has been funded primarily through Genome Canada ($3.6 million), the Canada Foundation for Innovation ($8.1 million) and Western Economic Diversification ($4.2 million). Other contributions for TMIC’s infrastructure (approximately $11 million) have come through provincial support (Alberta and BC), direct university support (UVic and UofA), corporate donations, private donors and federal funding agencies such as the Canadian Institutes of Health Research (CIHR), the Natural Sciences and Engineering Research Council (NSERC), the National Research Council (NRC) and the Canada Research Chairs (CRC) program. Operational support for TMIC has been obtained from Genome Canada ($5.7 million), Alberta Innovates ($5.5 million), the NRC ($3.1 million), CIHR ($2.1 million), the CRC ($1 million), NSERC ($500,000), the Universities of Alberta and Victoria ($400,000) and many other agencies, contracts and companies.

As a multi-mode, distributed core facility, TMIC is uniquely configured to offer a wide range of both targeted and non-targeted metabolomic services using NMR spectroscopy, mass spectrometry, ultra-high and high-performance liquid chromatography (UPLC, HPLC), and gas chromatography (Figure 1). TMIC currently houses or has access to 5 NMR spectrometers, 4 GC-MS systems, 1 GC×GC Time-of-Flight (TOF) MS, 2 FT-MS instruments, 19 LC-Electrospray Ionization (ESI) or Matrix Assisted Laser Desorption Ionization (MALDI) MS instruments, 1 Inductively Coupled Plasma (ICP) MS instrument and 15 HPLC/UPLC systems. A list of major equipment available to TMIC and its node locations is shown in Appendix 1. The multi-node model allows each TMIC node to build on its strengths, encourages sharing of technical expertise and

supports the efficient use of equipment. While the “back-end” of TMIC is highly distributed, its “front-end” largely appears as a single entity to its users.


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All TMIC laboratories are interlinked through a custom-developed Laboratory Information Management System (LIMS) called TMIC LIMS. The management system supports sample tracking, sample management, and a wide variety of data uploads and downloads. This software management system allows collaborating facilities to operate in unison by integrating common and standardized operating procedures, analysis software, training programs and equipment platforms. TMIC LIMS enables quality control and assurance of TMIC services and provides users with a great deal of information as well as a high degree of confidence and satisfaction. TMIC, as established in 2011 and through its previous incarnations (PANAMP [2009-2011] and the HMP [2005-2009]), has essentially been running for more than a decade as a distributed metabolomics facility. Consequently, it operates effectively and efficiently through a closely networked team of highly skilled scientists, graduate students, post-doctoral fellows (PDFs) and technicians.

Key Accomplishments

Since 2011, TMIC has performed nearly 51,000 metabolomic assays on >26,000 samples for more than 380 different users involved in >400 projects. Through TMIC, many important discoveries have been made relating to the composition of the human metabolome,1,10-13 how metabolomics relates to human14-17 and animal health,18 livestock and crop productivity,19,20 natural product biosynthesis,21 drug interactions,22 microbial metabolism23-25 and environmental monitoring.26 These discoveries have been described in >160 papers (published over the past 5 years) that have been authored by various TMIC scientists, users and collaborators. This output represents more than 60% of all metabolomics papers published by Canadian scientists since 2011. These papers have already been cited almost 6,000 times, providing a clear indication of their enormous impact in the scientific community. In addition, many of the discoveries enabled by TMIC have been presented at numerous international conferences (>100 abstracts and poster presentations and >170 invited oral presentations in the past 5 years). TMIC has made significant contributions to technology development, training and data analysis. Since 2011, TMIC has developed and made available 47 different metabolomic assays. Additionally it has trained more than 150 undergraduate students, graduate students, technicians and PDFs. Over the past 5 years TMIC has presented 5 metabolomics training workshops in Toronto (2X), Edmonton, Montreal and Vancouver that have trained nearly 100 students, and hosted 24 visiting scientists from 10 countries. TMIC has developed, upgraded or maintained 15+ different metabolomic databases including the Human Metabolome Database (HMDB),1 DrugBank,2 the Toxic Exposome Database (T3DB),3 the E. coli Metabolome Database (ECMDB),4 the Yeast Metabolome Database (YMDB),27 MyCompoundID28 as well as analytical web-servers such as Bayesil,8 CFM-ID,7 GC-AutoFit,29 MetaboAnalyst,9 and many other tools. These resources have become a key component of many metabolomic activities around the world. Indeed, more than 25% of all published metabolomics papers cite the HMDB and nearly 15% cite MetaboAnalyst. Appendix 2 shows additional examples and further details about TMIC’s “success stories.” Since 2011, TMIC has produced MetaboNews, a monthly electronic newsletter that provides the latest information on publications, conferences, training, software, jobs, and products related to metabolomics. Now published in partnership with the Metabolomics Society, MetaboNews has become the official voice of the Metabolomics Society. Its circulation is larger than that of most metabolomics journals. It reaches more than 2,600 subscribers (including almost 300 Canadian scientists) in more than 80 countries.


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In addition to its scientific, training and outreach accomplishments, TMIC has greatly facilitated the funding of metabolomics research in Canada. Over the past 5 years, TMIC staff have helped TMIC’s principal users and its collaborators prepare >60 funding proposals (for CIHR, Genome Canada, CFI, Alberta Innovates - Health Solutions, Alberta Innovates Bio Solutions, NSERC, and others). These grants have brought in a total of $31 million in operating revenue to support TMIC scientists, users and collaborators. TMIC’s contract sales and services have brought in another $2.1 million. Currently, these grants and contracts support the employment of 45 “research” users in TMIC along with another 20 permanent (part-time and full-time) staff for core operations and management.

TMIC Management

Dr. David Wishart serves as TMIC’s director. He is supported by an Executive Committee consisting of the scientific leaders of the other 4 nodes (Borchers, Li, Harynuk, Overduin). The Executive Committee submits quarterly written operational and financial reports to the Board of Directors (see Figure 2). The Director provides annual updates on research, operations, finances, and strategic plans to the stakeholders (VP Research, UVic and UofA). Scientific Oversight Committee (SOC) meetings are held annually with the Board of Directors.

Figure 2: TMIC Governance Model SOC meetings include formal presentations by TMIC scientists on technology development, service delivery, outreach efforts, and overall operations. The SOC’s role is to assess TMIC’s operations, performance, and future directions, and to provide constructive feedback and advice to support strategic planning. Based on recommendations from the SOC, the Executive Committee develops further plans of action and works with the TMIC Management Staff to implement recommended strategies


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and/or policies. TMIC has 20 core management and operational staff members who are organized into specific activities or teams. These teams, which support TMICs daily operations, include Administration and Finance, Operations, Equipment Maintenance, Bioinformatics, Business Development and Services (see Figure 3).

Figure 3: TMIC Management Structure The leader for each team is responsible for daily management, with an emphasis on maintaining existing customer relationships, developing new partnerships, effectively managing facilities and finances, and delivering high-quality services to support TMIC’s strategic plans for growth, collaboration, and cutting-edge science. TMIC’s Research Coordinator, Dr. Dana Chamot, is responsible for daily management of TMIC’s administrative and financial requirements, including reporting, general administration, and human resources. Dr. Chamot is supported by an Administrator (UVic) and a Finance Coordinator (UofA). Many routine administrative activities, such as invoicing, personnel recruitment, accounting, and purchasing are also supported by the UofA. Technical operations and equipment maintenance are overseen by an Operations Manager (Dr. Rupa Mandal) and a Lead Scientist (Dr. Jun Han). Collectively, they are responsible for laboratory operations, communication, customer projects, instrument maintenance and repairs, new equipment purchases, quality control, implementation of new technologies, and allocating resources, personnel and projects. Bioinformatics and biostatistics operations are directed by Dr. Wishart, who manages a team of skilled bioinformaticians and statisticians, with Drs. Jason Grant and Beomsoo Han serving as the team experts. This team not only maintains the informatics infrastructure (the LIMS, servers and databases), but performs upgrades and updates, and develops tools on an as-needed basis to facilitate TMIC’s activities. The bioinformatics team also assists users in experimental design, data reduction, and data presentation, and trains TMIC staff and users on how to use TMIC’s


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many software tools. The business development team, led by Jen Reid, is responsible for identifying potential users or collaborator leads, negotiating partnerships, sales or acquisitions, teaching potential users about TMIC, raising TMIC’s public profile, helping users select the optimal experiments, directing users to the right TMIC staff, proposing pilot projects and facilitating the development of grants, collaborations or contract research. The business team also helps to research and assemble TMIC’s business and strategic plans.

SWOT Analysis

A key component of any strategic plan is an analysis of a facility’s strengths, weaknesses, opportunities and threats (SWOT). Several processes were used to develop this SWOT analysis. First and foremost, we consulted our SOC, which is mandated to assess TMIC operations, performance and future directions, and provide constructive feedback and advice to support strategic planning. This committee consists of Drs. Philip Britz-McKibbin, Oliver Fiehn and Daina Avizonis. Dr. Britz-McKibbin is an Associate Professor of bio-analytical chemistry at McMaster University and a highly regarded metabolomics researcher in Canada. Dr. Fiehn is Professor of molecular and cellular biology at the University of California-Davis Genome Center and is considered a pioneer in metabolomics. He also directs the West Coast Regional Metabolomics Centre. Dr. Avizonis is the facility manager of the Goodman Centre for Cancer Research, a metabolomics core facility established in 2009 at McGill University. All are experts in analytical chemistry and aware of important new developments in the field of metabolomics. In addition to recommendations and feedback provided by the SOC, TMIC received extensive advice from Genome Alberta. As a GIN Node, TMIC must apply for funding every two years. The application review process greatly helps with TMIC’s SWOT analysis and provides an important feedback mechanism to develop strategic plans. TMIC also gathered intelligence by attending meetings, conferences, and workshops, and and performing literature reviews. TMIC personnel consulted with other metabolomics core laboratories to look at their offerings and discuss user needs and emerging technology trends. In addition, TMIC conducts periodic surveys to gather input and feedback from users. Furthermore, TMIC’s software tools have extensive feedback support systems to assess user needs, complaints or concerns.

Strengths

TMIC’s has many strengths as identified by the SOC, Genome Canada and its own intelligence gathering. These include: 1) its leaders and personnel; 2) the diversity of its metabolomic equipment; 3) the range of its services: 4) its level of metabolite coverage; 5) its extensive chemical standards libraries, software and database resources; 6) its ability to advance metabolomic technologies; 7) its links to industry; 8) its focus on making metabolomics more affordable; 9) its training programs and 9) its long-term success in increasing access and outreach.

Leadership and Personnel

TMIC is led by Dr. David Wishart. He is internationally recognized for his pioneering work in metabolomics, NMR spectroscopy and bioinformatics. He has published 322 papers (35,023 citations, h-index = 76), presented 688 abstracts or invited talks, holds 6 patents and has started 5 companies. Based on the impact of his recent research, he was named as one of the world’s 100 most influential biologists by Thomson Reuters in 2014 and again in 2015. Dr. Wishart has been the TMIC director since 2011 and


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has led the facility through 4 successful core-funding applications. Dr. Wishart also conceived, and continues to lead, the Human Metabolome Project (HMP). The HMP is a multi-university, multi-investigator project that is cataloguing all of the known metabolites in human tissues and biofluids. In addition to leading >20 other large, multi-investigator projects (with 2-16 PIs) since 2001, Dr. Wishart has directed 4 other large core facilities, including the Pan-Alberta Metabolomics Platform (2009-2011), the PrioNet prion production core (2010-2012), the Genome Canada Bioinformatics service core (2003-2012) and the PENCE Bioinformatics core facility (2002-2005). Dr. Christoph Borchers is the Victoria-node director of TMIC. He is an internationally recognized expert in MS, proteomics and metabolomics and a world leader in the technology development associated with these fields. He has published over 200 peer-reviewed papers in scientific journals (11,014 citations, h-index = 50) and has presented 243 abstracts and invited talks. He holds 3 patents and has won several national awards, including the Genome BC Award for Scientific Excellence (2016). Since 2007, Dr. Borchers has served as the director of the UVic Proteomics Centre, a core facility that has an operating budget of >$3 million/yr and more than 25 high-end MS and chromatography instruments. He is very experienced in managing and directing large-scale core laboratories. Dr. Liang Li is a world-recognized leader in MS technology development, proteomics and metabolomics. He has published more than 200 papers and given over 220 invited lectures (9261 citations, h-index = 51). He holds 4 US patents and has won several national awards in chemistry, including the Gerhard Herzberg award in 2010. He has also been involved in many large multi-investigator grants and is experienced in managing large instrument facilities. Dr. James Harynuk is internationally recognized for his work in GC-MS and GCxGC-MS; he runs Canada’s leading laboratory for multidimensional GC-MS. Dr. Harynuk has published >50 papers (813 citations, h-index = 17) in a wide variety of top-tier analytical chemistry journals and has presented 143 abstracts and invited talks. Dr. Michael Overduin is an internationally recognized NMR spectroscopist and structural biologist. He is the newest member of TMIC (having arrived in Canada in September 2015) and has recently taken over as Executive Director of NANUC (the National High Field Nuclear Magnetic Resonance Centre) at UofA, which is equipped with 800 MHz NMR, 600 MHz and 500 MHz NMR instruments, as well as a 500 MHz instrument in a level 2+ containment for prion studies. Dr. Overduin has published over 100 papers (h-index = 33; 5225 citations), holds 1 patent and has started 1 company. Dr. Overduin has a special interest in using metabolomics to advance drug discovery and drug screening. He is very experienced in the operations and management of NMR core facilities. With 20 staff dedicated to core operations and management and 45 users paid through various principal user grants, TMIC is now home to 65 students, scientists, technicians, and administrators. All of its key administrators (Dr. Chamot, Mr. Kazala, Mr. Stanley, Ms. Reid) have considerable experience (10+ years) in finance, administration, managing labs, coordinating research centres, business development, spinning-off businesses and operating core facilities. Many of TMIC’s senior scientists (Drs. Rupasri Mandal, Jun Han, Trent Bjorndhal, Pascal Mercier, etc.) have more than 15 years of instrument training and experience. Likewise, TMIC’s informatics and database team members include several outstanding programmer analysts (Drs. Beomsoo Han and Jason Grant) with >10 years of post-degree bioinformatics training or experience. Few metabolomics core facilities have the breadth of experience or the depth of training that TMIC’s staff has. Staff members will be key to realizing TMIC’s strategic plan objectives.


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They will plan and oversee projects that align with TMIC’s vision of “Mainstreaming Metabolomics,” including developing metabolomics kits andhand-held devices, and working with clinicians and companies to make metabolomics part of routine diagnostic protocols or tests. They will also continue to expand TMIC’s current offerings and capabilities while developing efficiencies to reduce costs and expand the level of metabolite coverage. They will also direct efforts toward acquiring CLIA or ISO 17025 compliance so that TMIC can perform clinical and/or industrial/legal standard testing.

Platform and Technology Diversity

TMIC houses more than $26 million in state-of-the-art metabolomics equipment, including multiple NMR, MS and HPLC/UPLC systems. A list of major equipment available to TMIC and its node locations is shown in Appendix 1. TMIC’s NMR instruments include 800 MHz, 700 MHz, 600 MHz and 2x500 MHz models. Particularly unique is TMIC’s 500 MHz NMR located within a level 2+ containment facility for metabolomic studies of biohazardous material. TMIC’s mass spectrometers range from lower-resolution/moderate-sensitivity models for targeted metabolomics (QTRAPs and triple Quadrupole instruments), to higher-resolution, high-sensitivity QTOF instruments, to Canada’s most powerful ultra-high-resolution FT-MS instruments for untargeted metabolomics. TMIC also supports advanced MS imaging technologies, operates a range of GC-MS systems for volatile compound analysis, has developed and implemented many robotic sample-handling systems and operates an extensive collection of equipment for sample processing, separation and biobanking. Compared to other core facilities in Canada and around the world (see Appendix 3), TMIC has perhaps the greatest diversity of equipment or metabolomics platforms in any core facility. Through its wide range of equipment, TMIC is able to offer targeted metabolite identification and absolute quantitation services via NMR, GC-MS, GC-MS/MS (with multiple ionization techniques available), GC×GC-TOFMS, DI-MS/MS, LC-MS/MS, LC-MS as well as Fatty Acid Methyl Ester (FAMES) + Evaporative Light Scattering Detector (ELSD)+GC-MS for lipidomics, HPLC, isotope-labeled standards, LC-MS, UPLC-Multiple Reaction Monitoring (MRM)-MS and a variety of specialized assays. TMIC has also developed a full range of technologies and integrative software tools to support non-targeted metabolomics. In particular, TMIC offers untargeted metabolomics technologies using GC-MS, GC×GC TOFMS, isotope labeling with 1D and 2D LC-MS; UPLC-FTMS; DI-FTMS; and MALDI Tissue Imaging by MALDI TOF-MS. To manage this wide range of resources and activities, TMIC maintains a common, user-friendly, information-rich core facility website (www.metabolomicscentre.ca), a password-accessible on-line sample-tracking system, and a web-enabled LIMS to handle user enquiries, sample shipping, sample receipt, billings and data dissemination. The LIMS also hosts a large library of up-to-date electronic standard operating procedures (SOPs). All TMIC staff have been trained on how to use these systems and the systems continue to be improved based on user feedback. TMIC’s LIMS permits seamless internal data exchange and sample tracking. It also allows TMIC staff to reference common protocols for both sample analysis and sample preparation and to compare results for Quality Assurance (QA)/Quality Control (QC) purposes.

TMIC Services

TMIC offers some of the widest range of services of any metabolomics core facility in the world. Many of these services are enabled by the diversity of technologies and platforms that it maintains. These services are listed below:

http://www.metabolomicscentre.ca/


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Platform-Specific Metabolomic Assays - Absolute Quantitative Assays: Direct Flow Injection Mass Spectrometry (DI-MS); Quantitative NMR Spectroscopy; Quantitative GC-MS; Quantitative HPLC-UV or HPLC-FD; Quantitative ICP-MS; Quantitative GC-MS/MS (EI, PCI, and NCI available); Quantitative GC/GC-MS/MS (EI, PCI, NCI available); Targeted metabolomic profiling in complex mixtures by GC×GC-TOFMS (EI only); Quantitative Lipidomics Global (Untargeted) Metabolomic Profiling - Untargeted Assays: Untargeted metabolomics by GC-MS (EI only); Untargeted metabolomics by GC×GC-TOFMS (EI only); Untargeted metabolomics by UPLC-FT-MS; Untargeted Metabolomics by RPLC-QTOF-MS and MS/MS; Untargeted Lipidomics by RPLC-QTOF-MS and MS/MS; Untargeted metabolomics by DI-FTICR-MS; Untargeted metabolomics by isotope labeling 1D LC-MS; Untargeted metabolomics by isotope labeling 2D LC-MS; Untargeted Lipidomics by 1D UPLC-MS; Metabolite identification by offline or online LC-MS/MS Targeted Metabolomic Profiling – Class-Specific Assays: Oxylipins Analysis; Vitamin Analysis - Water soluble; Vitamin Analysis - Fat soluble; Endogenous vitamins and vitamin-like compounds analysis; Bile acids analysis; Organic acids analysis; Catecholamines analysis; Lipidomics for cardiolipins; Low-molecular-weight sugars analysis; Acylcarnitines analysis; Aldehydes analysis; Oxysterols analysis; Deoxynucleotide triphosphates (dNTPs) analysis; Volatiles and semi-volatiles profiling by SPME GC×GC-TOFMS (EI only); Nucleoside/Nucleotide Analysis; Polyphenol Analysis; Anthocyanin/Chlorophyll Analysis; Thiol Analysis; Carotenoid Analysis; Acyl Coenzyme A Analysis; Metal Analysis (Metallomics); Lipidomics by MALDI-MS Tissue imaging; Meat Biomarkers; High-value Disease Biomarker Profiling Targeted Metabolomic Profiling – Pathway-Specific Assays: One-carbon metabolism; Central carbon metabolism; Amino acid metabolism/urea cycle metabolism; Lipidomics for sphingolipid metabolism; Fatty acid metabolism - short- to long-chain fatty acids and acyl-carnitines analysis TMIC Customized Assays: High-abundance Metabolites in Plasma/Serum; Low-abundance Metabolites in Plasma/Serum Human Metabolome Library: Chemical resource containing >1000 compounds with the power to help confirm, validate or quantify suspected metabolites in tissues or biofluids Metabolomic Reagents: 13C CIL derivatization reagents as well as >600 dansylated and >300 other chemically 13C derivatized metabolites for CIL-LC-MS reference matching and calibration Metabolomic Profiling Kits: NMR kit plasma/serum and cerebrospinal fluid; GC-MS kit for urine, serum and saliva, Meat consumption biomarker kit (urine); High-value disease biomarker kit (serum/urine); SILOM-Dansylation (Dns) kits for serum and urine analysis Bioinformatics Support: Study Design, Univariate statistical analysis, Multivariate statistical analysis, Metabolite Set Enrichment Analysis, Pathway analysis, Power analysis, Biomarker identification and evaluation, Metabolite identification, Metabolite imaging, Spectral analysis and general Chemometric analysis Specialized Services: Specialized sample extraction; Specialized compound analysis; Methods Development; Metabolite identification by offline or online LC-MS/MS Outreach: Preparation and publication of MetaboNews, production of brochures, co-sponsorship of metabolomics workshops, presentations at metabolomics conferences TMIC continuously assesses, upgrades and updates its metabolomic assays and analytical capabilities, with about 3-4 new assays being added or enhanced each year. Over the next 5 years TMIC will develop new specialized assays for detecting and quantifying steroids, acylcarnitines, oxidative stress markers, pesticides, volatiles, oxylipins, phytosterols, drugs, natural toxins, redox metabolites and hormones. These assays are being developed in response to user requests and prioritized based on user needs and TMIC’s assessment of emerging trends in the field of metabolomics.


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Metabolite Coverage

TMIC is well-known for its “record-breaking” metabolite coverage efforts. These represent a significant strength for the facility. Indeed, TMIC puts considerable emphasis on developing or extending techniques and technologies to maximize metabolite identification and quantification. By assembling one of the world’s largest chemical libraries of authentic metabolite standards (>2000 compounds) as well as some of the most comprehensive in-house MS and NMR spectral libraries, TMIC is often able to identify significantly more compounds than other metabolomics laboratories or facilities. This success can be seen in the papers that TMIC scientists have published on the human serum, urine, fecal and cerebrospinal fluid metabolomes.10-13 Furthermore, by using a very wide variety of complementary metabolomics platforms (NMR for polar molecules, GC-MS for volatiles and organic acids, LC-MS for lipids, ICP-MS for metals, etc.), TMIC is able to further extend that metabolite coverage. TMIC scientists have also developed other techniques, including chemical or chemo-selective isotope labeling (CIL) strategies along with multidimensional LC separations that can further extend the degree of metabolite coverage30-31 . A number of “group-specific” labeling agents that selectively label acids, hydroxyls, amines, aldehydes and ketones have been synthesized by TMIC scientists; these reagents are now available as metabolite characterization kits. The CIL-MS methods are becoming increasingly popular and have been shown to work particularly well for identifying and quantifying compounds for which no 13C or 2H standards exist.

Chemical Libraries

As noted above, TMIC has amassed one of the world’s largest chemical libraries (>2000 metabolites and metabolite derviatives). These libraries include both unlabeled and 13C isotopically labeled compounds. These reference compounds are frequently used as QA and QC controls. They are also used to identify, validate and quantify many of the compounds in TMIC’s targeted and untargeted metabolomics assays. Only 1 or 2 other metabolomic facilities in the world have comparably large chemical libraries. TMIC’s libraries are also being used to assemble reference electron-ionized (EI)-MS spectra, MS/MS spectra (on many different MS instrument models), reference NMR spectra, reference retention times, reference retention indices, and reference ion mobility times. These reference spectra or reference data are being used to develop more effective compound identification tools, better spectral prediction algorithms, improved chromatographic prediction tools and enhanced compound identification workflows. Many TMIC users and collaborators also want access to TMIC’s chemical libraries to perform compound screening as part of drug or ligand discovery efforts. These libraries are also used in efforts to characterize the functions of unknown enzymes or in co-crystallization screening efforts by structural biologists.

Software and Databases

Many of the world’s primary metabolomics databases were developed by, and continue to be maintained by, TMIC. These resources contain most of the known chemical, biological and spectral information about metabolites and other small molecules of biological importance. These freely accessible resources receive >15 million web hits/year. TMIC databases include the Human Metabolome Database or HMDB (which receives 3 million web hits per year), the world’s most comprehensive metabolomics database containing detailed information on nearly 42,000 small molecule metabolites found in the human body (www.hmdb.ca); the DrugBank database (which receives 7 million web hits per year), a unique bioinformatics and cheminformatics resource that combines detailed drug (i.e., chemical, pharmacological and pharmaceutical) data with comprehensive drug target (i.e., sequence,


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structure, and pathway) information for nearly 8200 drugs (www.drugbank.ca); FooDB, a database on food constituents, chemistry and biology with data on 26,600 food compounds and food associations (foodb.ca); the Toxic Exposome Database (T3DB), which contains detailed toxin data with comprehensive toxin target information for over 3600 toxins, including pollutants, pesticides, drugs and food toxins, linked to over 2100 corresponding toxin target records (www.t3db.ca ); the Small Molecule Pathway Database (SMPDB), an interactive, visual database containing more than 700 small molecule pathways found in humans, including metabolic, disease, drug and metabolic signalling pathways (smpdb.ca ); the Yeast Metabolome Database with detailed data on 2027 small-molecule metabolites of Saccharomyces cerevisiae (including compounds found in bread, wine and beer; www.ymdb.ca); the E. coli Metabolome Database (ECMDB), with detailed information on >3760 metabolites found in Escherichia coli (ecmdb.ca ); Phenol-Explorer32, a comprehensive database on ~500 natural phenols and polyphenols including data on their concentrations in raw and processed foods, as well as polyphenol metabolites in human and experimental animals (phenol-explorer.eu ); and MarkerDB, which consolidates information on >15,000 clinical biomarkers into a single source (www.markerdb.ca).

With a cumulative total of >8,000 citations, these databases have been used to enable and interpret many thousands of important discoveries in the areas of model organism metabolomics, human disease, human performance, environmental science, animal health, livestock and crop performance, food chemistry, drug action and drug discovery. These discoveries are benefiting Canadian scientists, research, and industry, and Canadians in general. They are also having positive benefits around the world. A significant amount of TMIC data is the primary data source for the rest of the world’s data resources. DrugBank is used by every major pharmaceutical company, and is the source of data for most pharmaceutical Wikipedia entries, as well as the Pharmaco-Genomics Knowledge Base (PharmGKB) and the Chemical Entities of Biological Interest (ChEBI) dictionary. The HMDB data has been cloned into all major chemical data resources in the world, including PubChem, and has been purchased by every metabolomics instrument vendor. Based on citation frequencies for 2015, roughly 25% of all papers in metabolomics reference the HMDB. TMIC also maintains a number of very popular web servers, including MetaboAnalyst (www.metaboanalyst.ca), which allows researchers to analyze, visualize and interpret data using cutting-edge multivariate statistical techniques. It receives more than 4 million web hits per year, and has been cited over 1000 times in the past 5 years. Based on citation frequencies for 2015, roughly 15% of all papers in metabolomics reference MetaboAnalyst. MetaboAnalyst has been adopted by the European Bioinformatics Institute as the primary analysis tool for metabolomics, and has been mirrored at 2 sites. MyCompoundID (www.mycompoundid.org) and CFM-ID (Competitive Fragmentation Modeling for Metabolite Identification; cfmid.wishartlab.com) are widely used for metabolite identification and have greatly expanded MS-based metabolite coverage (4-5X). ROCCET (roccet.ca) is a popular web server that allows users to perform multivariate receiver operating characteristic (ROC) curve analysis for biomarker discovery and validation. TMIC has developed many other key tools, including Bayesil (bayesil.ca), an easy-to-use web-based tool for fast, automated NMR-based metabolomics; GC-AutoFit (gcms.wishartlab.com), a web-based server for automated analysis of GC-MS spectra; and MetaboMiner, a program that can be used to automatically or semi-automatically identify metabolites in complex biofluids from 2D NMR spectra (wishart.biology.ualberta.ca/metabominer). TMIC also offers PathWhiz, a web-based pathway drawing tool (smpdb.ca/pathwhiz ). All of these tools are freely available.


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Advancing Metabolomics Technologies

TMIC has a very strong track record in advancing technology development. In its original 2011 Genome Canada Science and Technology Innovation Centre (STIC) application, TMIC proposed 9 “technology development” milestones, all of which were met on time and on budget. All have been implemented as new or enhanced user services. These include developing faster, higher resolution and more targeted chromatographic methods for compound separation; automating spectral fitting; developing a more extensive library of chemoselectively labeled standards (for quantitative CIL-LC- or LC-MS-based metabolomics); creating more HPLC and MS assays for plant phytochemicals and secondary metabolites; creating more HPLC and MS assays for microbial metabolites; developing robust vitamin, steroid and oxylipin detection assays; developing or improving methods for metabolite imaging; creating novel software for integrated metabolomic/proteomic/transcriptomic analysis; and developing robust methods to identify novel metabolites. In its 2013 STIC renewal, TMIC proposed 12 new technology development milestones. All have been met on time and on budget. These milestones include the integration of GC×GC TOF-MS metabolomics -- a completely unique resource in Canada -- into TMIC’s pipeline; improved methods for central carbon/urea cycle and whole energy metabolite analysis; expanded lipid profiling and specialized analytics including lipoproteins (LDL, HDL), volatiles, polyphenols, steroids and bile acids; proxy metabolomics (indirect detection of metabolites using proxy signals or proxy metabolites); metabolomics kits for high-value combinations of 30-300 metabolites; and expanded software and databases. In addition to these milestones and through continued development of its software analysis tools and databases, TMIC was able to produce far more detailed, colourful and informative reports over a much shorter period of time. These reports include univariate and multivariate statistical analyses, colourful 2D and 3D Principal Component Analysis (PCA) and Partial Least Squares Discriminant Analysis (PLS-DA) plots, Receiver Operating Characteristic (ROC) curve analyses, pathway analysis and temporal trend analysis. In the latest renewal, this time as a GIN in 2015, TMIC identified 15 technology development milestones that it plans on achieving from 2015-2017, including developing new specialized assays for detecting and quantifying steroids, acylcarnitines, oxidative stress markers, pesticides, volatiles, oxylipins, phytosterols, drugs, natural toxins, redox metabolites and hormones; developing integrative omics informatics tools that link metabolomics with genomics, proteomics and systems biology; democratizing metabolomics by creating easy-to-use metabolomics kits; improving automation and workflows; and creating prototype, hand-held metabolomic devices. TMIC is on track and on time to complete these initiatives. Finally, TMIC articulated four major objectives in its 2015/2016 Applications Technology Development proposal as a GIN node covering the time period from 2016-2018. These include 1) the development of new core capabilities and methods for enhanced services (improving coverage and throughput of 8 assays, developing 7 new assays, including compound class-specific, pathway-specific and substrate-specific assays, and adding four new core capabilities, including serum-based adductomics, cell-based fluxomics, custom isotope standard synthesis and matrix-free MALDI); 2) updating or upgrading 5 existing databases and servers to include additional omics data or capabilities and developing 4 new software resources, including a multi-omics biomarker database (MarkerDB), a multi-omics data-mining tool (DataWrangler), a multi-omics pathway visualization tool (PathWhiz), and a genome-to-metabolome conversion tool (M2M); 3) democratizing metabolomics by producing 6 different metabolomics kits that convert high-demand assays into low-cost, easy-to-use kits that could be readily used by all (or most) TMIC sites; and 4)


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generating expanded chemical libraries (500-600 new compounds), spectral libraries (>2500 spectra) and expanded (rationally predicted) chemical databases (>2 million compounds) using innovative biochemical and computational techniques. These projects have just started, but we have already released PathWhiz and good progress has been achieved in many of the objectives.

Industry Partnerships

TMIC has an excellent track record of developing and maintaining productive and mutually beneficial industry partnerships. A number of companies, including GenomeQuest (software), Pfizer (consultation), Chenomx (automated metabolite identification), TNO-Quality of Life (Netherlands; wiki content development), Dow AgroSciences (agricultural biotechnology) and several instrument companies (Bruker, Waters, ABSciex) have partnered with TMIC. In the past, TMIC has also secured commitments from Bristol Myers Squibb, Keystone Labs, Sinoveda, and Radient Technologies. During the past year, TMIC has formally partnered with a number of established Canadian companies and international companies with a strong Canadian presence. These include Waters, AXYS Analytical Services, Biocrates, Bruker, Chenomx, IBM and Metabolomic Technologies Inc. In addition to these well-established companies, TMIC has been working actively with Canadian start-ups, including Biomark Technologies (Richmond), Intrinsic Analytics (Winnipeg), Molecular You (Vancouver), MRM Proteomics (Victoria) and OMx Personal Health Analytics (Edmonton). Sustained support of TMIC activities is essential for these start-ups to reach their full potential. Likewise, partnerships with TMIC are critical for established companies to continue to expand their businesses into the field of metabolomics. TMIC is also in the process of developing formal partnerships with 2 international companies, Cambridge Isotopes and IROA Technologies (both in Boston) to bring their technologies into TMIC’s operational space. An example of a typical partnership agreement is described here. In 2014, TMIC established a formal partnership with Chenomx (www.chenomx.com), an Edmonton-based metabolomics software and NMR service company. This partnership allows TMIC services to be offered to a wider community through Chenomx’s outreach efforts. In addition, this partnership allows researchers to access TMIC technologies in a very streamlined manner using Chenomx’s established business protocols for client interactions, reporting and billing. This reduces the delays that customers may experience in dealing with university research administration. TMIC is now included on Chenomx’s website as an official service and technology partner. To date, $65,000 in service revenues have been generated for TMIC through this collaboration. Moving forward, TMIC and Chenomx intend to combine efforts to expand their outreach and marketing, as well as explore opportunities for new services, specialty markets, technology development funding and commercialization. TMIC and Chenomx representatives will attend conferences together to promote this partnership and gather intelligence to help TMIC scientists plan future service offerings or technology development activities. Another example of an industrial partnership is the one formed with Molecular You. In 2016, TMIC signed a marketing and service partnership with the Vancouver-based start-up to perform personalized metabolomic testing, develop specialized metabolomic kits and create software/database tools to facilitate efforts in bringing personalized medicine services to the Canadian public. Revenues from Molecular You contracts are expected to be >$100,000 for 2016. Molecular You is just completing its first round of financing (for $1 million) and expects to move to a second round of financing (for $10 million) by early 2017.


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Cost Reduction

A real strength for TMIC has been its focus on and ability to reduce costs for metabolomics assays. This fundamentally makes metabolomics more accessible to a wider group of users. Over the past 5 years, TMIC has done a superb job of reducing costs, shortening analysis times and improving operational efficiencies. Many of TMIC’s technology development efforts, such as faster separations, automated spectral fitting for NMR and GC-MS and software for integrative omics analyses, were specifically directed at improving efficiency. By replacing many of its HPLC systems with UPLC systems, TMIC’s analysis times for its standard LC-MS studies have now dropped by a factor of 3 or 4. Further, by combining 2 HPLC separations, it is now possible to increase LC-MS metabolite coverage by a factor of up to 20 using roughly the same amount of separation time as for a single HPLC run. Using in-house and improved commercial software for automated and semi-automated spectral fitting of NMR and GC-MS data have helped reduce analysis times by a factor of 2-3 (with the latest Chenomx software) and by a factor of 15 (with some of TMIC’s home-built tools). TMIC has also added an auto-sampling robot (increasing throughput by a factor of 3) and reduced volume requirements (by a factor of 5) for its NMR-based metabolomics assays. The availability of improved kits (from Biocrates) has increased TMIC’s coverage for its DI-MS assays by 15%, while a partnership with Biocrates has allowed TMIC to purchase these kits at 25% below retail prices. Recently implemented and improved home-built software has also reduced the costs (by 40%) and improved the efficiency of the CIL-LC-MS metabolomic assays. In addition to these LC-MS improvements, a new, quantitative organic acid analysis protocol has been refined and developed for TMIC’s GC-MS platform. This new protocol generates data for 3X more metabolites than previously measured. Access to more equipment as well as newer/better equipment (through agreements reached through NRC-NINT and the Departments of Chemistry and Biochemistry at UofA) has also reduced instrument downtime and allowed TMIC staff to focus on analysis rather than repairing instruments. Overall, TMIC has reduced costs, increased metabolite coverage or improved throughput for at least 6 different metabolomic assays. These efforts will continue as a major aspect of TMIC’s operations on an ongoing basis.

Training

Another key strength in TMIC is its focus on training and skills upgrading. With sponsorship from the Canadian Bioinformatics Workshop and Genome Canada, TMIC has provided unique metabolomics training to many Canadians through its “Bioinformatics for Metabolomics” course (www.bioinformatics.ca). Launched in 2011, this annual, 2-day workshop has now trained almost 100 scientists, including >80 Canadian researchers and many newcomers to the field. TMIC also offers a free “Research Hotel” in which trainees and scientists (graduate students, PDFs, professors) have access to bench space, instruments, and one-on-one training. To date, TMIC has hosted 24 trainees and scientists from 10 countries including Canada, the United States (US), Spain, New Zealand, Ireland, Denmark and China. Trainees have stayed from 5 days to 9 months and the resulting interactions have led to a number of successful international collaborations, papers or contracts. Several of these trainees have gone on to establish academic or industrial careers in metabolomics.

Enhancing Access to TMIC

TMIC uses a multi-pronged approach to increase access for academic and industry researchers by 1) increasing the number and variety of services to match customer requests; 2) helping researchers


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prepare grants that specifically request TMIC services; 3) reducing costs and offering new, lower-cost assays; and 4) increasing the visibility and awareness of TMIC and metabolomics through various outreach and partnering activities. To further increase awareness, TMIC will continue its “roadshow” efforts based on the success of its 2011/2012 roadshow, which visited 6 different locations across Canada. In 2014, TMIC’s roadshow focused on Genome Canada’s Large-Scale Applied Research Program (LSARP) “Genomics and Feeding the Future.” In Alberta, seminars and information sessions (coordinated by Genome Alberta) were conducted at the UofA, University of Calgary, University of Lethbridge, and Agriculture and Agri-Food Canada (Lethbridge). These efforts led to several joint proposals. In Saskatchewan (through Genome Prairie), TMIC held a very successful seminar with ~50 attendees that led to 5 new collaborations and >$50,000 in revenues for 2014-2015. In Ontario, a University of Guelph seminar by TMIC resulted in a new collaboration with Dr. Julang Li (Department of Animal Science).

Weaknesses

TMIC’s has several potential weaknesses that were identified by the SOC, Genome Canada and TMIC’s surveys. These include: 1) its aging infrastructure (see Appendix 1); 2) its high reliance on a single government funding source to sustain operations; 3) an increase in the length of waiting times for analyses and 4) a lack of sufficient support (staff and service contracts) for equipment maintenance and repair.

Instrument Issues and Mitigation Strategies

Currently, a number of instruments in TMIC’s collection are nearing the end of their useful lifetime (see Appendix 1). These include a number of NMR instruments (3 Varian/Agilent instruments), several MS instruments (QTRAPs and triple quadrupole instruments) and several HPLC instruments. TMIC is applying and intends to apply through several upcoming CFI and Genome Canada competitions to acquire replacement equipment or upgrades. However, this process is slow and success is not guaranteed. As a backup, TMIC is working closely with several instrument vendors to obtain instrument “loaners” or lease-to-own instruments. These can often be obtained in exchange for conducting vendor-specific research or by acting as a laboratory demonstration centre for the vendor(s). This approach has been used successfully by TMIC in the past and has led to the acquisition of 4 new instruments over the past 2 years. As a result, this strategy will be pursued in parallel with more conventional, grant-based infrastructure replacement efforts.

Reliance on Government Funding and Mitigation Strategies

TMIC receives about 60% of its core operational budget from government funding sources, with the remaining component coming from user fees, licences and product sales. Government funding allows TMIC to offer a wide variety of subsidized services to academic and government researchers. However, it is unreasonable to expect that this kind of subsidized support should continue indefinitely. A well-run core facility generally should try to achieve an increasing degree of independence or self-sustainability. However, to make this transition it will be necessary to have some additional up-front or momentum funding to help clear the hurdles that so often prevent core facilities from moving forward. TMIC believes that by expanding its services to private sector clients (which lead to greater revenue), obtaining CLIA and ISO certification, expanding its product portfolio (kits, tests, software and databases), increasing licensing revenue and licensing fees, more aggressively pushing sales of its reagent libraries and spectral libraries, securing patents or other intellectual property, spinning off companies or


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commercial arms and developing/licensing/selling its hand-held metabolomic devices, it may decrease its reliance on federal and provincial funding. Other mechanisms to potentially increase external, non-government support could involve offering more revenue-generating workshops or revenue-generating hands-on training programs. If able to secure a steady source of government funding while at the same time succeeding in increasing other revenue sources, TMIC should be able to further subsidize its services. These savings could then be passed on to the user base. However, to make this transition, TMIC needs a source of funds to help support translational research and business development activities. Applying for CFI Major Science Initiatives (MSI) support or other federal/provincial funding, as well as seeking private donor support, increase the chance of that happening.

Waiting Times and Mitigation Strategies

The average wait-time for TMIC users is approximately 2 months. The delays are primarily due to instrument down-time for certain aging instruments, limited staff availability and heavy use of existing equipment. Funding applications to obtain service contracts for some of the older or more heavily used instruments (e.g., via a CFI-MSI proposal) should limit these problems and increase instrument up-time. Further, having sufficient funds to pay dedicated experts or technicians to service, maintain and troubleshoot on a regular basis will improve instrument up-time. Improving TMIC’s automation protocols (via software and robotics) and developing more efficient workflows will also reduce wait times. Similarly, acquiring new instruments (see above), leasing instruments or buying time on little-used instruments located in the NRC (NINT) or elsewhere on the UofA campus would also provide added throughput and reduce wait times.

Maintenance Contracts and Mitigation Strategies

TMIC currently has no long-term instrument or instrument-maintenance contracts. This is because the equipment is older or was acquired through non-CFI funding mechanisms (which do not normally allow for maintenance contracts). As a result, TMIC staff must perform most of the facility’s maintenance and repairs. This reduces the time that they can spend providing services or training TMIC users. If the repairs are too extensive or expensive, the instrument must remain down until TMIC acquires sufficient funds to cover the costs. If a catastrophic failure happens (as has occurred a few times), the down-time can be many months. In some cases, the instrument may end up being prematurely decommissioned. This is not the best way to operate a national core facility. As noted by the SOC, this issue is closely related to the waiting time problems mentioned above and affects TMIC’s ability to obtain funds for service contract support through its current funding model, or to set aside funds for emergencies or contingencies. These problems could be greatly reduced if TMIC were to obtain support from the CFI-MSI or from other funding bodies (government, private, corporate) for service contracts for the most heavily used or trouble-prone instruments.

Opportunities

Several exciting opportunities have been identified by the SOC, Genome Canada and TMIC’s intelligence gathering surveys. These include 1)taking advantage of the rapid growth in metabolomics interest and activities; 2) the opportunity to simplify and standardize metabolomics assays through the development of kits; 3) the opportunity to develop low-cost, portable metabolomic tools or sensors; 4) the opportunity to move metabolomics into clinical applications; 5) the opportunity to capture more


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metabolomics users by offering a more diverse array of metabolomics services; and 6) the opportunity to attract industry/clinical trial users by creating certified core facilities.

Taking Advantage of Metabolomics’ Growth Potential

Because metabolomics provides a unique window on gene-environment interactions and permits robust, quantitative phenotyping of difficult-to-characterize organisms, it has experienced near exponential growth over the past 16 years. In 1999, only 2 papers were published on this subject; in 2015, more than 2,400 papers were published. Based on studies reported by several consulting agencies, the global metabolomics market is expected to grow at a compounded annual rate of 26% to reach $1.4 billion by 2017 and $2.8 billion by 2020. Analysis of the numbers of metabolomics publications indicates that metabolomics research activities are growing at a rate of about 15%/yr. TMIC needs to take advantage of this growth by providing the necessary services and building the capacity to meet anticipated demands. Some of the routes that TMIC could follow to exploit this growth are to 1) increase awareness of metabolomics and TMIC through outreach, advertising and marketing; 2) increase TMIC’s efficiencies and overall throughput; 3) hire more staff; 4) acquire more (and better) equipment; 5) obtain more funding or financial support; 6) train other scientists to conduct metabolomics activities in their own laboratories or facilities; and, finally, 7) make metabolomics more accessible (portable, easier) and less dependent on centralized core facilities or highly trained personnel. Some of these approaches could significantly increase TMICs user base, while others would have the effect of redirecting users to other facilities or metabolomics options. However, if TMIC can facilitate, pursue, drive or participate in all of these scenarios, it will lead to a net benefit to TMIC. It will also benefit Canadian researchers in the field of metabolomics, as well as the Canadian public. Many of the objectives outlined in the strategic plan are aligned with pursuing these ideas and addressing the anticipated growth in metabolomics activities over the next 5-6 years.

Developing Kits

As technologies mature, they become increasingly simpler, more routine and more standardized. This eventually allows complex techniques or processes to be converted to kits. Kit development is widely pursued in molecular biology and is also beginning to appear in clinical testing. Metabolomics has already seen the release of several kit systems (especially by Biocrates Inc.) for quantitative metabolomics. Many vendors are now packaging or selling “methods” or kit-like systems with their NMR or MS instruments. There are several potential benefits to TMIC’s continued development of kits. Preparing and distributing kits internally will ensure that all of the TMICs nodes adhere to the same protocols and follow the same high QA/QC standards. It will also help standardize many TMIC operations. Developing kits will also allow TMIC to share its many unique protocols, software and automation ideas with other researchers – thereby improving the quality and throughput of metabolomics activities elsewhere. Kits can also provide an additional source of revenue through sales or licensing fees. TMIC is already marketing some of its CIL-LS-MS and NMR kits and is negotiating a licensing/marketing agreement to sell these (and other) kits through Molecular You.

Hand-held Metabolomic Devices

Miniaturization is a growing trend in many fields of science. Micro- and nano-scale technologies are also leading to disruptive changes in many fields, including DNA sequencing, portable computing, energy storage and sporting equipment. There is increasing evidence that metabolomics could be subject to a similar disruptive technology innovation. More and more researchers are pursuing “tricorder” devices or


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remote sensing devices for monitoring health or measuring chemicals. Miniaturization of GC, LC and MS instruments is also occurring. Because metabolites can be detected and quite specifically identified and quantified using proteins or DNA aptamers, it is possible to imagine that the metabolomic devices of the future will no longer be MS- or NMR-based, but rather aptamer- or protein-based. Rather than waiting for these disruptive changes to occur or viewing them as a threat, TMIC is striving to lead the way by developing aptamer-and protein-based metabolite sensors. TMIC is currently developing reagents (metabolite conjugates), metabolite sensing proteins (antibodies, periplasmic binding proteins), metabolite sensing aptamers (DNA and RNA), and sensing systems (impedance-based electronic devices and lateral flow assays) to create hand-held devices. TMIC scientists have already built a device that can detect up to 4 metabolites (glucose, betaine, citrate and tetrahydrofolate) using impedance sensing. These activities are leading to TMIC’s pursuit of patents and establishment of spin-off companies to develop and market these devices. TMIC is also negotiating a licence agreement for these technologies with Molecular You.

Clinical Translation

Every year, more than 5 million clinical metabolomic tests are performed. However, most people (including physicians) are not even aware that metabolomics has already entered the clinical world. This is because almost all metabolomic tests are done on newborns as part of MS-based newborn screening programs conducted in North America, Europe and parts of Asia. The fact that MS-based metabolomics is widely practiced suggests that it is well adapted to being translated into other clinical modalities and applications. There are also several companies (Metabolon, Biocrates and Metabolomic Technologies Inc.) that are developing and seeking formal approval of metabolomic tests for diabetes, steroids and cancer. Given that TMIC has discovered and validated a number of clinically useful biomarkers, and given its expertise in quantitative metabolomics and kit development, it is ideally positioned to conduct clinical translation. Indeed, TMIC has already obtained funding from Alberta Innovates—Health Solutions (AIHS), Western Economic Development (WD) and Mitacs to facilitate clinical translation of several biomarkers for clinical use. By actively pursuing further clinical translation and creating the tools, resources and workflows to encourage other clinicians to pursue the same path, it should be possible for TMIC to have a significant impact on Canadian health care delivery and clinical technology development within Canada.

Expanding and Enhancing Services

New technologies, protocols, software algorithms and reagents for metabolomics are appearing all the time. In fact, the field of metabolomics is experiencing a real boom. TMIC has the expertise, equipment and resources to not only emulate newly developed metabolomics protocols and technologies, but also to make these better, faster and cheaper. By expanding the breadth, depth and quality of its metabolomic assays, software and capabilities, TMIC will be able to attract many more users. This kind of effort will also allow TMIC’s users to perform much more useful, cutting-edge metabolomics research. Any core facility that wishes to stay in business must devote a significant portion of its resources to not only delivering services but expanding, improving and enhancing them. TMIC needs to exploit its world-class resources and fully embrace the rapid evolution of metabolomic techniques and technologies that are sweeping through the field.


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Advanced Certification

Most university-based core facilities are designed to pursue university (research-only) activities. However, to translate many discoveries from the bench to industrial, legal, veterinary or clinical applications, these discoveries must be validated or repeated in certified laboratories. Likewise, companies wishing to pursue late-stage development or pre-market testing need access to certified analytical laboratories. Currently, there are very few labs in the world that are capable of performing “certified” metabolomics assays. Given the dearth of these kinds of labs – especially in North America – there is a clear opportunity for TMIC to enhance its user base (and its quality) by pursuing ISO 17025 certification and Clinical Laboratory Improvement Amendments (CLIA; USA) or Health Canada certification. ISO 17025 is the typical level of certification required for legal/court submissions, pesticide testing, food testing, drug testing, pollutant or environmental analysis and contaminant testing. CLIA (or Health Canada) certification is the typical level of certification required by a laboratory conducting clinical testing or performing clinical testing validation.

Threats or Risks

Some of the main threats or risks to TMIC, as identified by the SOC, Genome Alberta and TMIC surveys, are loss of primary (government/agency) funding sources, competition from other metabolomics core facilities, the appearance of disruptive technologies, catastrophic failures of key instruments leading to significant delays, and difficulties in staff retention. These are discussed in more detail below.

Loss of Funding

Currently more than 60% of TMIC’s budget is dependent on government- or agency-based (primarily Genome Canada) funding. This funding allows it to provide subsidized metabolomic services, train highly qualified personnel, provide important metabo-informatic resources, develop technology, and maintain its laboratory (and equipment) in a state of constant readiness. Depending so heavily on a single agency for most of its funding puts TMIC at somewhat greater risk of suffering serious consequences should funding be terminated. Loss of Genome Canada funding would significantly handicap TMIC, perhaps to the point that it would have to be disbanded. Partial loss of or decrease in current Genome Canada support would likely mean that TMIC would have to increase fees, reduce services, and limit its research and development activities. One strategy to mitigate this risk is to seek funding support from more than one agency. In this regard, TMIC is pursuing operational funding from CFI through a CFI-MSI proposal. Obtaining funding from two or more agencies spreads out or reduces the risk of a catastrophic funding loss. Additional efforts are also being undertaken to obtain other kinds of support that are independent of agency funding. This includes efforts to increase service revenue, licensing revenue and product sales revenue. Efforts are also being made to partner with Canadian industry to obtain additional kinds of support. TMIC’s long-term (10 year) strategy is to significantly reduce its reliance on government or agency funding.

Competition from other Core Facilities

One threat or risk is loss of users or service requests due to competition from other centres. Several other smaller metabolomics centres exist across Canada (the Goodman Cancer Research Centre Metabolomics Core Facility at McGill University, the BioNMR Centre at the University of Calgary, the Analytical Facility for Bioactive Molecules at the Hospital for Sick Children, Toronto, and the Nutritional Metabolomics Centre of Agriculture and Agri-Food Canada in Winnipeg). These are much smaller-scale,


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single-investigator facilities with one or two dedicated instruments for investigator-driven research in specialized areas. Consequently, they are not able to offer the breadth of analytical services, nor do they have the equipment, expertise or resources that are available through TMIC. In other words, these are not significant threats to draw away TMIC users or erode TMIC’s user base. A second threat is competition from other international metabolomics centres. There have been several significant investments in metabolic core facilities around the world, typically at the national or regional level. These include 6 NIH Regional Comprehensive Metabolomics Resource Cores in the USA (2012, $53 million), Metabolomics Australia (2007, $49 million), the Netherlands Metabolomics Centre (2007, $69.2 million) and the MRC-NIHR Phenome Centre in the UK (2012, $45.7 million). While each centre has its own strengths and brings tremendous talent and resources, none offer the breadth of equipment, capacity for absolute metabolite quantification, diversity of imaging resources, depth of informatics infrastructure, or extensive databases and chemical libraries available through TMIC. Indeed, TMIC appears to be unique, both nationally and internationally, in the breadth of metabolomics and related services that it provides. Appendix 3 provides a comparison of national and international facilities. A detailed comparison of the user fees charged by these centres is difficult as most no longer post their information. However, discussions with many users indicate that TMIC’s fees are 20-40% lower than most facilities – partly due to the low Canadian dollar, partly due to TMIC’s efficiencies, and partly due to the high level of subsidized support that TMIC receives. Overall, our assessment is that as long as TMIC is able to retain its staff and infrastructure and continue to receive some level of agency/government support, it will remain highly competitive in the international metabolomics sphere.

Appearance of Disruptive Technologies

The appearance of cars put horse-and-buggy makers out of business. Likewise, the development of digital cameras put film-based cameras and film companies out of business. The current pace of scientific discovery almost guarantees the emergence of disruptive technologies on a regular basis. Next-generation DNA sequencing is an example of one technology that will eventually make microarrays obsolete. In metabolomics, it is possible that novel, unexpected technologies will appear that will make metabolomics (which is relatively costly and difficult) incredibly inexpensive and easy. Certainly, the near-absolute dependence on expensive and large NMR and MS instruments is a significant issue in metabolomics. Should a technology appear that permits metabolomics research to move away from NMR and MS, this would be highly disruptive and would put TMIC’s operations at risk and make most of its infrastructure obsolete. Rather than waiting for disruptive technologies, TMIC is taking a proactive approach and aggressively seeking disruptive technologies. Not only are a number of TMIC’s principal users conducting research to develop kits, hand-held devices, and automated systems, TMIC staff are also tracking developments in several “orthogonal” fields to identify and evaluate some of these types of disruptive technologies. TMIC will continue this strategy and has made it a central component of its 5-year strategic plan. Certainly, the expectation is that metabolomics will be a very different science in 5 years. TMIC intends to be at the forefront of that change.

Catastrophic Instrument Failures

Significant, large-scale or expensive equipment failures can cripple a service operation. With a relatively large inventory of infrastructure, TMIC has already experienced several catastrophic instrument failures and it was only able to respond due to the good fortune of receiving unexpected funding or through months of difficult repair work. Ideally, the establishment of a contingency fund for these instrument failures, along with support for service contracts for critical, failure-prone instruments, would mitigate


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this risk. Certainly the CFI-MSI funding model supports this kind of risk-mitigation strategy. TMIC has also developed a number of emergency access plans and agreements with other scientists and departments across the UofA and UVic. This plan has been successful during previous (minor) instrument failures. TMIC is also building redundancy in its instrumentation, and now nearly every major instrument has a near-duplicate model in another node or within the same node. Additionally, TMIC plans to leverage already-developed instrument-vendor relationships, which may include priority access to beta instruments, discounted instruments and software, or leasing options.

Staff Retention

TMIC has hired and trained many outstanding individuals. Almost all of these scientists, technicians, and administrators have highly desirable and marketable skills. Indeed, as the field of metabolomics heats up, TMIC is seeing a higher level of turnover than in past years. One way to prevent or reduce staff turnover is to provide competitive salaries and to reduce stressors in the workplace. A key stressor in TMIC is equipment maintenance and repair. Having funds to support repair (service contracts) or to hire instrument experts would reduce this stress. Likewise, having newer equipment would also help with staff retention and recruitment. These issues could be partially addressed through a larger, more diversified funding base, such as CFI-MSI or CFI infrastructure funding. Another, less costly approach to mitigate the effects of the loss of key staff is to ensure a high degree of skill redundancy within the organization. In this regard, TMIC actively trains all of its staff members so that they can perform the tasks of at least one other staff member. This skill redundancy helps ensure some institutional “memory,” while at the same time allowing staff members to expand their expertise into new areas, thus improving workplace satisfaction.

Operational and Strategic Objectives

Based on the threats and weaknesses in the SWOT analysis, TMIC has identified 3 operational and 5 strategic objectives. We will initially discuss the operational objectives which focus on expanding and diversifying TMIC’s funding base, continuing to update TMIC’s equipment and infrastructure, and expanding TMIC’s capabilities and services across Canada by adding new nodes and/or new capabilities.

Operational Objective - Diversifying Funding

In working towards objective #1, TMIC has decided to submit a proposal to the 2016/2017 CFI-MSI competition to seek operational support as a national facility. Funding from the CFI-MSI would address many of the Threats and Weaknesses identified in the latest SWOT analysis, including loss of funding, lack of support or contingencies for catastrophic equipment failures, staff retention and competition from other facilities located outside of Canada. TMIC is also working hard to obtain funding from at least one other external agency (CIHR, provincial agencies) to reduce the threat of funding loss from TMIC’s single funding agency (Genome Canada) Additional funding would go a long way towards limiting the current challenges with staff retention. It would also allow TMIC to remain competitive (technologically and in terms of cost), and to allow it to be nimble enough to respond to disruptive technological innovations. To appreciate the financial challenges facing TMIC, several financial projection tables have been prepared. TMIC operating and maintenance (O&M) costs currently exceed $2,000,000 per year (Table 1). These include expenses related to the support for technical and administrative personnel, equipment operations and maintenance, and general laboratory operations. TMIC revenues from all sources are shown in Table 2.


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Table 1: Actual and forecast TMIC operating and maintenance costs

Table 2: Actual and forecast TMIC revenue from all funding sources

Taken together, Tables 1 and 2 show that revenues are sufficient to meet forecast O&M costs through 2016-2017. However, based on our projections, it is apparent that additional funding support is required to meet TMIC’s O&M needs from 2017-2018 forward. This is the motivation behind TMIC seeking additional funding support through the 2016/2017 CFI-MSI competition.

Operational Objective – Update Infrastructure

In working towards objective #2, TMIC is now involved in several preliminary proposals for the 2017 CFI infrastructure competition. These proposals are focusing on acquiring infrastructure for phenotyping and will emphasize new technologies for cellular and tissue imaging (such as mass spectrometry and NMR-based metabolite imaging methods). TMIC users and principal scientists could be involved in as


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many as 4 CFI proposals, which could lead to the acquisition of several MALDI imaging systems as well as higher resolution OrbiTrap mass spectrometers. These instruments would allow TMIC to update some of the oldest pieces of equipment in its arsenal (mostly MALDI instruments). Additionally, TMIC is continuing to work with a variety of instrument vendors and is seeking favorable conditions to have beta-test equipment, short-term loaners or low-cost lease-to-own instruments acquired. These “alternative” routes to equipment acquisition have generally proven to be faster and less onerous than conventional routes. Indeed, this approach to infrastructure improvement appears to be quite commonly pursued by other metabolomics core facilities around the world.

Operational Objective – Expansion

In working towards objective #3, TMIC will be considering the feasibility of its operational base to other nodes. Currently TMIC is very much based in Western Canada and the majority of its Canadian users are from West of Ontario. By establishing a presence in Eastern Canada through the addition of another node, it may be possible to further raise the awareness of TMIC as well as enhance the utility/accessibility of metabolomics to a greater proportion of Canadians. Dr. Borchers has recently established a proteomics facility in Montreal through the Jewish General Hospital (in affiliation with McGill University). The equipment in Montreal, which is housed in a clinically approved facility, can be easily adapted to perform metabolomic experiments. Obviously, expanding TMIC to include additional nodes or additional personnel will require some additional seed funding. Efforts are underway to see if donors (or the Quebec provincial government) may be willing to provide start-up funds to establish a TMIC node in Montreal in 2018 or earlier. The inclusion of another node from another university would obviously add some complexity to TMIC’s governance model. Another route, which may be less expensive and less onerous at a governance level, is to “contract” or “franchise” different facilities across Canada to perform metabolomic analyses on behalf of TMIC. Further planning and discussions regarding future expansion will be dependent on the success of TMIC’s 2016/2017 funding proposals.

Strategic Objectives - Mainstreaming Metabolomics

Based on the Strengths and Opportunities identified in the SWOT analysis, TMIC has decided to pursue a general strategy of “Mainstreaming Metabolomics”. This will take advantage of TMIC’s many strengths and build on many emerging opportunities in metabolomics. Through the external research funding of TMIC’s primary users, TMIC will facilitate research to make metabolomic more accessible to the Canadian community. This will including making metabolomic measurements far faster, cheaper, more portable and much more comprehensive. This, in turn, will make metabolomics much more of a “mainstream” science appealing to a wider range of Canadian scientists and users. The 5 key areas that TMIC will focus on include the following: 1) Developing and partnering with companies or agencies to create metabolomic kits for both research applications and (eventually) clinical, veterinary, farm-side or field testing. This will involve helping TMIC users create software, protocols, reagents and other tools to make metabolomics faster, easier, cheaper and more reproducible -- the same way that molecular biology kits have been used to make many common or essential molecular biology techniques faster, easier and cheaper. 2) Developing hand-held devices to make metabolomics portable. This will include the development of bed-side devices for home or medical office use, as well as devices for field/farm work. These will be used for medical monitoring, tracking and testing livestock, monitoring water quality, and conducting


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field-based fecal assays for surveying the prevalence of different diseases in wild animals, such as testing for chronic wasting disease in cervidae (deer family). By helping its primary users make portable metabolomic devices (via lateral flow assays or impedance-based sensors), TMIC will ultimately be able reduce assay costs and make metabolomics faster and much more accessible. 3) Working with clinicians and clinical testing companies to make metabolomics part of routine diagnostic protocols or tests. This will involve helping TMIC users translate metabolomic tests into reimbursable clinical assays (colon polyp tests, pre-eclampsia tests, heart failure tests, organic acids in urine tests). It will also involve TMIC working with its users to develop custom "health" panels for precision medicine or for personal health monitoring companies, such as Molecular You or 23andMe. 4) Continuing to expand TMIC’s current offerings and capabilities, while at the same time developing efficiencies to reduce costs and expand the level of metabolite coverage. This will include expanding TMIC’s databases and software; developing more robotic approaches for sample preparation and handling; moving slower, more expensive assays to lower-cost, faster, multi-well formats; expanding the capabilities of MALDI for very rapid metabolite detection and quantification; and continuing to push the boundaries in what is possible with metabolite imaging. 5) Acquiring Clinical Laboratory Improvement Amendments (CLIA) approval in at least one TMIC node. CLIA standards are federal regulatory standards that apply to all clinical laboratory testing performed on humans in the USA, except clinical trials and basic research. TMIC will also acquire ISO 17025 certification, the main ISO standard used by testing and calibration laboratories, to allow it to perform clinical and or industrial/legal standard testing. Through the realization of these strategic objectives, many other TMIC users will have access to inexpensive, high-quality metabolomic services and research capabilities. While public sector collaborators and users will have access to these new services at reduced rates, private sector clients will be charged higher rates in order to provide TMIC with sustainable cash flow. A successful TMIC will enable Canadian researchers (in both academia and industry) to apply metabolomics to a wide variety of life science challenges in the health, pharmaceutical, agri-food, energy and environment sectors.

Metabolomic Kits

TMIC will work with its users and principal scientists to develop metabolomic kits for both research applications and clinical, veterinary, farm-side or field testing. Funding for this development will be aided by a number of external grants as well as through partnerships with various companies and agencies. Kit development will involve the creation of software, protocols, reagents and other tools to make metabolomics faster, easier, cheaper and more reproducible. Many TMIC users and customers request data for the same or similar sets of high-value metabolites, but to measure this combination of compounds requires that TMIC perform multiple assays on multiple platforms. This is costly and inefficient for TMIC, its users and its collaborators. As a result, TMIC has been converting many of its most popular assays into kits that permit rapid, inexpensive measurement of these popular or high-value metabolites. The kits include all the reagents (reference standards, isotopically labeled standards or labeling reagents), software and protocols needed to easily perform the assays. Many isotopic standards are already in TMIC’s chemical libraries, while others are either purchased or synthesized. Depending on the combination of metabolites to be measured, some of these kits will use DI-MS or LC-MS methods, some will use NMR methods, some will use GC-MS methods, while yet others will use CIL-


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LC-MS methods. The first NMR kits are nearly ready to be released (May 2016) and the first GC-MS kits are expected to be ready by December 2016. The DI/LC-MS kits, expected for September 2017, will be modeled after the Biocrates kits (which use a 96-well plate format). A LC-MS bile-acid kit will be released in late 2016, while the CIL-LC-MS kits are being developed as a single sample format and are on the verge of release. It is expected that 1-2 new kits (NMR, GC-MS, LC-MS, CIL-LC-MS) will be prepared or released each year for the next 5 years. Over the coming years, the NMR kits will be expanded to permit the measurement of a wider range of biofluids (urine, cell extracts, beverage products) and to operate over a wider range of instrument platforms (700-900 MHz). Likewise, the GC-MS kits will be expanded to work with a wider range of biofluids and to permit sample preparation for a wider range of substrates. Over the next 5 years, the DI-MS and LC-MS kits will be expanded from being able to measure 30-40 different metabolites to being able to measure 150-200 different metabolites, as well as up to 500 lipids. The SILOM-LC-MS kits will be similarly expanded to support the identification and relative quantification of about 300-400 metabolites in different biofluids. The expectation is that the NMR and GC-MS kits will require about 100-200 μL of fluid while the MS kits will require no more than 20 μL of fluid to identify and quantify the target metabolites.

The intent of these kits is to consolidate TMIC’s most frequently requested or most expensive metabolite assays into a simple, cost-effective format. Initially the kits will be for internal use only, but after suitable testing and validation they will be commercialized. Molecular You, MRM Proteomics Inc. (a UVic spinoff), Cambridge Isotopes and several other companies have expressed an interest in co-marketing some of these kits. We believe these kits could eventually become TMIC’s most popular and lowest cost (<$30 per sample) assays. They could also go a long way to making

metabolomics cheaper and empowering a wider community of scientists to include metabolomics as part of their research programs.

Hand-held Devices

TMIC will be involved in developing hand-held devices to make metabolomics portable. This will include the development of bed-side devices for home or medical office use, as well as devices for field work. These will eventually be used for medical monitoring, tracking and testing livestock, monitoring water quality, and conducting field-based fecal assays for surveying the prevalence of disease in wild animals. By making portable metabolomic devices via lateral flow assays or impedance-based sensors, TMIC will be able to reduce assay


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costs and make metabolomics faster and much more accessible. This strategic objective is called "democratizing metabolomics." TMIC’s principal scientists have already teamed up with a number of collaborators to develop inexpensive, hand-held metabolomics devices. These devices are modeled after the portable glucose sensors used by diabetic patients and will employ innovative nano- and micro-sensor technologies to identify and quantify sets of 20-30 metabolites. The devices will use microfluidics as well as lateral flow assays to perform sample processing and metabolite separation, protein or DNA-aptamers as the molecular recognition elements, and impedance sensing, fluorescence or surface plasmon resonance (SPR) to detect metabolites. A working device, using impedance sensing and gold nanoparticle-labeled metabolites, has already been developed. It detects 4 metabolites (glucose, betaine, citrate and tetrahydrofolate) and a report of invention has been filed. The device, which is the size of an iPhone, is eventually expected to be able to detect 10 metabolites. The plan is to have at least 2 working hand-held devices that can detect a distinct set of 15-20 metabolites each by the end of 2018. These novel devices could potentially revolutionize metabolomics, making it far more accessible to a much larger community – including physicians, field scientists and home users.

Making Metabolomics Matter in Health

TMIC users have discovered and validated a number of clinically useful biomarkers. Given its expertise in quantitative metabolomics and kit development, TMIC is ideally positioned to conduct clinical translation. Indeed, TMIC’s principal users have already obtained funding from AIHS, WD and Mitacs to facilitate translation of several biomarkers for clinical use. In particular, TMIC will work with a number of its users (clinicians and clinical testing companies) to make metabolomics part of routine diagnostic protocols or tests. This will include translating metabolomic tests into reimbursable clinical assays (colon polyp tests, pre-eclampsia tests, heart failure tests, organic acids in urine tests). It will also include developing custom health panels for precision medicine or personal health monitoring companies, such as Molecular You or 23andMe. By actively pursuing further clinical translation and creating the tools, resources and workflows to encourage other clinicians to pursue the same path, it should be possible for TMIC to have a significant impact on health care delivery and clinical technology development within Canada.

Expanding Capabilities and Offerings

TMIC will continue to expand its current offerings and capabilities, while at the same time developing efficiencies to reduce costs and expand the level of metabolite coverage. This includes expanding TMIC’s databases and software, developing more robotic approaches for sample preparation and handling, moving slower, more expensive assays to lower-cost, faster, multi-well formats, expanding the capabilities of MALDI for very rapid metabolite detection and quantification, and continuing to push the boundaries in what is possible with metabolite imaging. Over the next 5 years, TMIC will focus on further developing innovative methods for new metabolomics applications, including fluxomics (kinetic measurements of metabolic reaction rates), adductomics (characterizing exposures to reactive electrophiles), exposomics (to assess environmental exposures), environmental testing (identifying sulfide-containing compounds in oil sands process-affected water), food composition analysis, juice, wine and alcoholic beverage testing, forensic analysis, and metabolomic analysis of hair (for measuring long-term exposures). TMIC has demonstrated proof-of-concept in several of these areas, including fluxomics, food analysis, wine analysis, general forensics, and metabolite analysis of hair. TMIC is refining methods for these new and specialized metabolomic applications so that they can be offered as high-throughput, routine services. TMIC will also develop new specialized assays for detecting and


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quantifying steroids, acylcarnitines, oxidative stress markers, pesticides, volatiles, oxylipins, phytosterols, drugs, natural toxins, redox metabolites and hormones. These assays will be developed in response to user requests and have been prioritized based on user need and TMIC’s assessment of emerging trends in the field of metabolomics. TMIC intends to maintain its status as the world leader in metabo-informatics by improving on its existing tools that link metabolomics with genomics, proteomics and systems biology. New integrative tools that are under development include Microbes-to-Metabolites, a tool to complete metabolomes from microbial genomes, Plant2Met, a suite of tools to aid in plant-based omics studies, and GMWAS, software to perform combined Genome-Metabolome Wide Association Studies. TMIC will continue to add to its large collection of databases (www.metabolomicscentre.ca/software) by releasing PlantDB, a plant metabolome database of 240,000 compounds, and HMDB-Pred, a database of ~2,000,000 known and predicted Phase I/Phase II transformed human metabolites. Additionally, new tools that more accurately predict NMR, ESI-MS and EI-MS spectra via machine learning, along with new software that automates pre-processing of GC-MS and GC×GC-TOFMS data through intelligent integration of thermodynamic and mass spectral information, will be developed. TMIC scientists will also work towards developing much more efficient metabolomics workflows. These include more automated sample preparation and loading protocols, faster spectral acquisition, automated compound identification and quantification, and more automated data analysis or data reduction. Automating target compound identification and quantification has been a major objective of TMIC’s democratization initiative for the past 3 years. TMIC plans to expand the breadth of compound identification/quantification by a factor of 2 for NMR and GC-MS, and by a factor of 10 for LC-MS. The ultimate goal is to create an almost fully automated metabolomic pipeline that would allow one sample to be processed and annotated in 30 minutes by GC-MS (allowing 45 samples/day), in 15 minutes by LC-MS (allowing 100 samples/day), and in 10 minutes by NMR (allowing 150 samples/day).

Acquiring Certifications

Currently there are very few labs in the world that are capable of performing certified metabolomics assays. Given the dearth of these kinds of labs, especially in North America, there is a clear opportunity for TMIC to enhance its user base (and its quality) by pursuing ISO 17025 certification and CLIA (or Health Canada) certification. ISO 17025 is the typical level of certification required for legal/court submissions, pesticide testing, food testing, drug testing, pollutant or environmental analysis and contaminant testing. CLIA (or Health Canada) certification is the typical level of certification required by a laboratory conducting clinical testing or performing clinical testing validation.

Deliverables

Over the next 5 years, TMIC (through the support of CFI and/or Genome Canada and the research activities funded by its principal users) anticipates achieving the following deliverables: a) Training of 15-20 highly qualified personnel who are experts in metabo-informatics,

metabolomics, analytical chemistry and clinical chemistry - experts who will move into academia or industry - 3 per year for the next 5-6 years;

b) Implementation of at least 1 clinically approved metabolomic test in Canada by year 2 and several more by year 5;

c) Spin-off companies or partnerships to enable start-up companies in metabolomics or precision

http://www.metabolomicscentre.ca/software


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medicine or related areas - 1 every 2 years for the next 5-6 years; d) Metabolomics kits for research, environmental or clinical applications - 2 per year for the next 2-3

years; e) Hand-held metabolomic devices, with the first appearing in year 2 and several others appearing

by years 4-5; f) Improved health care and quality-of-life for Canadians through the integration of metabolomics

into standard clinical practice and personalized/precision medicine initiatives - tangible benefits appearing in year 3 and beyond with the implementation of TMIC-derived or TMIC-inspired metabolomic tests in the clinic;

g) Firmly establishing Canada as the international leader in the fields of metabo-informatics, as well as quantitative and clinical metabolomics - year 3;

h) Widespread use of metabolomics in many fields of science and industry (health, veterinary, environment, water quality, agriculture), i.e., "Mainstreaming Metabolomics" - years 3 and beyond;

i) Establishment of TMIC as the first CLIA or ISO 17025 metabolomics facility in North America (year 3 or 4). This will allow TMIC to perform many kinds of tests for government, clinical, legal or industrial applications;

j) Continued availability and improvement of databases and software tools for which TMIC is internationally recognized;

k) A 60% increase in sample numbers processed per year, with a corresponding 75% decrease in sample processing time by 2022;

l) A 110% increase in service revenues and a 400% increase in licensing, reagent sales and training revenues by 2022.

m) A 75% increase in external user numbers and external collaborators, with a goal of servicing at least one lab from every province in Canada and at least 20 states in the US;

n) An 80-90% increase in external grant support; and o) A total of 250-260 TMIC-associated papers published from 2017-2022. Year-to-year projections and targets from 2016-2022 for several other activities are provided as graphs in Appendix 4.

Evaluation

TMIC has established processes for tracking and measuring success, including project progress according to milestones and deliverables. The deliverables are clearly stated both above and in Appendix 4. In addition to assessing its performance against these deliverables and targets, TMIC uses a number of other measures to assess its success. Numerous performance indicators are collected on an ongoing basis, including number of users, amount of revenue, amount of grant funding secured and leveraged, number of publications coming from TMIC principal scientists as well as TMIC collaborators and users, number of citations for these papers, number of web hits to its informatics resources and web pages, access times and numbers of visitors to its databases, number of jobs submitted to its web servers, total number of software tools and databases created, total number of tools available online, number of samples processed, number and types of analyses, number of assays, number of metabolites that TMIC can measure, costs of individual assays, trends in analytical service prices, time required per assay, number of compounds in TMIC’s chemical libraries, number of spectra (NMR and MS) derived from TMIC’s chemical libraries, number of subscribers to the MetaboNews newsletter, number of visitors to


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TMIC or TMIC’s “research hotel,” number of staff, number of staff trained, number of trainees, number of training programs offered through outreach, number of partnerships and licensing agreements, number of awards to its staff, newspaper/radio/TV stories about TMIC or TMIC-enabled research, and number of spin-off companies generated. As a GIN node, TMIC must report on most of these measures on a quarterly basis to Genome Canada. TMIC thus has dedicated staff and established processes to keep track of all measures on an on-going basis and is able to easily assess progress against milestones. TMIC has a very strong track record in setting and meeting objectives. Indeed, since it launched in 2011, TMIC has met or exceeded all of its milestones, either on time or ahead of time and on budget.

Conclusion

As metabolomics gains prominence, more scientists and clinicians are looking to incorporate these analyses into their research. TMIC’s goal is to meet the growing demand for metabolomics services by improving the quality of its core services and throughput over the medium- to long-term. Past investments in TMIC have provided Canada with state-of-the-art metabolomics infrastructure, comprehensive databases and chemical libraries, as well as highly skilled technical personnel in quantitative metabolomics. A continued investment in TMIC, along with revenues brought in through its fee-for-service business model, will ensure the maintenance of resources that are essential to the metabolomics industry both in Canada and around the world. Looking to the future, strengthening TMIC support will pave the way for a larger, national metabolomics service that fully harnesses the potential for metabolomics discovery and commercialization, for the benefit of all Canadians.


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10. Bouatra, S., Aziat, F., Mandal, R., Guo, A.C., Wilson, M.R., Knox, C., Bjorndahl, T.C., Krishnamurthy, R.,

Saleem, F., Liu, P., Dame, Z.T., Poelzer, J., Huynh, J., Yallou, F.S., Psychogios, N., Dong, E., Bogumil, R.,

Roehring, C., Wishart, D.S. The human urine metabolome. PLoS One. 8(9):e73076 (2013).

11. Psychogios, N., Hau, D.D., Peng, J., Guo, A.C., Mandal, R., Bouatra, S., Sinelnikov, I., Krishnamurthy,

R., Eisner, R., Gautam, B., Young, N., Xia, J., Knox, C., Dong, E., Huang, P., Hollander, Z., Pedersen, T.L.,


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Smith, S.R., Bamforth, F., Greiner, R., McManus, B., Newman, J.W., Goodfriend, T. & Wishart, D.S. The

human serum metabolome. PLoS One 6, e16957 (2011).

12. Mandal, R., Guo, A.C., Chaudhary, K.K., Liu, P., Yallou, F.S., Dong, E., Aziat, F. & Wishart, D.S. Multi-

platform characterization of the human cerebrospinal fluid metabolome: a comprehensive and

quantitative update. Genome Med 4, 38 (2012).

13. Xu, W., Chen, D., Wang, N., Zhang, T., Zhou, R., Huan, T., Lu, Y., Su, X., Xie, Q., Li, L. & Li, L.

Development of High-Performance Chemical Isotope Labeling LC-MS for Profiling the Human Fecal

Metabolome. Anal. Chem. 87, 829-836 (2015).

14. Brown, E.M., Wlodarska, M., Willing, B.P., Vonaesch, P., Han, J., Reynolds, L.A., Arrieta, M.C., Uhrig,

M., Scholz, R., Partida, O., Borchers, C.H., Sansonetti, P.J., Finlay, B.B. Diet and specific microbial

exposure trigger features of environmental enteropathy in a novel murine model. Nat. Commun. 6, 7806

(2015).

15. Bahado-Singh, R.O., Syngelaki, A., Akolekar, R., Mandal, R., Bjondahl, T.C., Han, B., Dong, E., Bauer,

S., Alpay-Savasan, Z., Graham, S., Turkoglu, O., Wishart, D.S., Nicolaides, K.H. Validation of metabolomic

models for prediction of early-onset preeclampsia. Am J Obstet Gynecol. 213, 530.e1-530.e10 (2015).

16. Rappaport, S.M., Barupal, D.K., Wishart, D.S., Vineis, P. & Scalbert, A. The Blood Exposome and Its

Role in Discovering Causes of Disease. Environ Health Perspect. 122(8):769-74 (2014).

17. Sulek, K., Han, T.L., Villas-Boas, S.G., Wishart, D.S., Soh, S.E., Kwek, K., Gluckman, P.D., Chong, Y.S.,

Kenny, L.C. Baker, P.N. Hair Metabolomics: Identification of Fetal Compromise Provides Proof of Concept

for Biomarker Discovery. Theranostics 4, 953-959 (2014).

18. Hailemariam, D., Mandal, R., Saleem, F., Dunn, S.M., Wishart, D.S., Ametaj, B.N. Identification of

predictive biomarkers of disease state in transition dairy cows. J Dairy Sci. 97, 2680-93 (2014).

19. Saleem, F., Ametaj, B.N., Bouatra, S., Mandal, R., Zebeli, Q., Dunn, S.M. & Wishart, D.S. A

metabolomics approach to uncover the effects of grain diets on rumen health in dairy cows. J Dairy Sci

95, 6606-6623 (2012).

20. Canam, T., Li, X., Holowachuk, J., Yu, M., Xia, J., Mandal, R., Krishnamurthy, R., Bouatra, S.,

Sinelnikov, I., Yu, B., Grenkow, L., Wishart, D. S., Steppuhn, H., Falk, K.C., Dumonceaux, T.J. & Gruber,

M.Y. Differential metabolite profiles and salinity tolerance between two genetically related brown-

seeded and yellow-seeded Brassica carinata lines. Plant Sci 198, 17-26 (2013).

21. Hagel, J.M., Mandal, R., Han, B., Han, J., Dinsmore, D.R., Borchers, C.H., Wishart, D.S. & Facchini, P.J.

Metabolome analysis of 20 taxonomically related benzylisoquinoline alkaloid-producing plants. BMC

Plant Biol. 15:220 (2015).


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22. Law, V., Knox, C., Djoumbou, Y., Jewison, T., Guo, A.C., Liu, Y., Maciejewski, A., Arndt, D., Wilson, M.,

Neveu, V., Tang, A., Gabriel, G., Ly, C., Adamjee, S., Dame, Z.T., Han, B., Zhou, Y., Wishart, D.S. DrugBank

4.0: shedding new light on drug metabolism. Nucleic Acids Res. 42, D1091-7 (2014).

23. Mattos, K.A., Oliveira, V.C., Berrêdo-Pinho, M., Amaral, J.J., Antunes, L.C., Melo, R.C., Acosta, C.C.,

Moura, D.F., Olmo, R., Han, J., Rosa, P.S., Almeida, P.E., Finlay, B.B., Borchers, C.H., Sarno, E.N., Bozza,

P.T., Atella, G.C., Pessolani, M.C. Mycobacterium leprae intracellular survival relies on cholesterol

accumulation in infected macrophages: a potential target for new drugs for leprosy treatment. Cell

Microbiol. 16, 797-815 (2014).

24. Antunes, L.C., Wang, M., Andersen, S.K., Ferreira, R.B., Kappelhoff, R., Han, J., Borchers, C.H. &

Finlay, B.B. Repression of Salmonella enterica phoP expression by small molecules from physiological

bile. J Bacteriol 194, 2286-2296 (2012).

25. Saleem, F., Bouatra, S., Guo, A.C., Psychogios, N, Mandal, R., Dunn, S.M., Ametaj, B.N. and Wishart,

D.S. The Bovine Ruminal Fluid Metabolome. Metabolomics 9, 360-378 (2013).

26. Nyakas, A., Han, J., Peru, K.M., Headley, J.V., Borchers, C.H. Comprehensive analysis of oil sands

processed water by direct-infusion Fourier-transform ion cyclotron resonance mass spectrometry with

and without offline UHPLC sample prefractionation. Environ Sci Technol. 47(9):4471-9. (2013).

27. Jewison, T., Knox, C., Neveu, V., Djoumbou, Y., Guo, A.C., Lee, J., Liu, P., Mandal, R., Krishnamurthy,

R., Sinelnikov, I., Wilson, M. & Wishart, D.S. YMDB: the Yeast Metabolome Database. Nucleic Acids Res

40, D815-D820 (2012).

28. Li, L., Li, R., Zhou, J., Zuniga, A., Stanislaus, A.E., Wu, Y., Huan, T., Zheng, J., Shi, Y., Wishart, D.S. & Lin,

G. MyCompoundID: Using an Evidence-based Metabolome Library for Metabolite Identification. Anal

Chem. 85(6):3401-8 (2013).

29. http://gcms.wishartlab.com

30. Guo, K., Bamforth, F. & Li, L. Qualitative metabolome analysis of human cerebrospinal fluid by 13C-

/12C-isotope dansylation labeling combined with liquid chromatography Fourier transform ion cyclotron

resonance mass spectrometry. J Am Soc Mass Spectrom 22, 339-347 (2011).

31. Huan, T., Wu, Y., Tang, C., Lin, G. & Li, L. DnsID in MyCompoundID for Rapid Identification of

Dansylated Amine- and Phenol-Containing Metabolites in LC-MS-Based Metabolomics. Anal. Chem. 87,

9838-9845 (2015).

32. Rothwell, J.A., Urpi-Sarda, M., Boto-Ordonez, M., Knox, C., Llorach, R., Eisner, R., Cruz, J., Neveu, V.,

Wishart, D.S., Manach, C., Andres-Lacueva, C. & Scalbert, A. Phenol-Explorer 2.0: a major update of the

Phenol-Explorer database integrating data on polyphenol metabolism and pharmacokinetics in humans

and experimental animals. Database (Oxford) 2012, bas031 (2012).


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Appendices

Appendix 1: Major Equipment

A list of all major equipment in TMIC, including funding source, date placed into operation, life expectancy and capacity calculations.

Equipment Type

Funded by In Operation as of (mm/yyyy)

Capacity

Thermo Fusion Orbitrap (UVic)

Genome Canada 11/2013 50-75% access, 2900 samples/year

Thermo Velos Pro Orbitrap (UVic)

Genome Canada / Western Economic Diversification (WD)

11/2011 Upgraded 11/2013

50-75% access, 2900 samples/year

Agilent 6490 with MALDI source (UVic)

UVic-Genome BC Proteomics Centre

01/2013 10-20% access, 7000 samples/year

Agilent 6490 QQQ (UVic)

Genome Canada / WD 01/2011 10-20% access, 7000 samples/year

Agilent 6490 QQQ (UVic)

Genome BC, UVic-Genome BC Proteomics Centre


AB QTRAP 4000 (UVic)

Enabling Technologies 01/2007 100% access, 7000 samples/year


UVic-Genome BC Proteomics Centre

04/2008 100% access, 7000 samples/year


Western Economic Diversification

04/2011 100% access, in use as training instrument

AB 4800 MALDI TOF/TOF (UVic)

Genome Canada 06/2006 50-75% access, 2900 samples/year

AB Voyager DE-STR MALDI TOF (UVic)

Natural Sciences and Engineering Research Council (NSERC)

01/2000

100% access, 10,000 samples/year

Bruker Ultraflex III MALDI TOF/TOF (UVic)

WD, UVic-Genome BC Proteomics Centre


Bruker 12T FT-MS (UVic)

Genome Canada, UVic, BC Gov’t


Waters Synapt HDMS (UVic)



Agilent 1290 HPLC (UVic)










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Equipment Type


Capacity




Waters NanoAcquity UPLC system (UVic)


06/2008 25% access, 15,000 samples / year







Agilent Bravo Liquid Handling System (UVic)


01/2013 20% access, 22,000 samples/year

Bruker 800MHz NMR with cryoprobe (UofA)

NSERC, CIHR, AHFMR, UofA and CFI

06/1999 (upgrade 09/2016)

10% access, 30 samples/week

Bruker 700 MHz NMR with cryoprobe and autosampler (UofA)


09/2015 100% access, 300 samples/week

Varian/Agilent 600 MHz NMR with autosampler (UofA)

NSERC, Canadian Institutes of Health Research (CIHR), AHFMR, UofA


Varian/Agilent 500 MHz NMR with cryoprobe (UofA)

CFI (Prion Centre) 08/2013 25% access, 75 samples/week

Varian/Agilent 500 MHz NMR with cryoprobe (UofA)

NSERC, CIHR, AHFMR, UofA


ABI QTRAP 4000 MS with Turbo ESI (UofA)

CFI, AAET 06/2008 60% access, 180 samples/week

ABI QTRAP 4000 MS with Turbo ESI (UofA)

Alberta Innovates – Health Solutions (AIHS)


Bruker Ion TRAP MS with Agilent HPLC system (UofA)



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Equipment Type


Capacity

Bruker maXis II QTOF (UofA)

Bruker, Canada Research Chairs


Bruker maXis II QTOF (UofA)



Waters Synapt HDMS/QTOF (UofA)

Waters, IROA 06/2016 100% access, 80 samples/week

Waters HDMS/QTOF (UofA)

NSERC 08/2015 20-40% access, 60 samples/week

AB 4800 MALDI TOF/TOF (UofA)

CFI, Alberta Advanced Education and Technology (AAET)


Bruker 9.4 Tesla FT-ICR with HPLC and ESI/MALDI sources (UofA)

CFI, Alberta Advanced Education and Technology (AAET)


Bruker Ion Trap MS with Agilent HPLC system (UofA)


Perkin-Elmer NexIon 350XX ICP-MS (UofA)

Genome Canada 03/2016 100% access, 300 samples/week (estimated)

Bruker SCION TQ GC456 GC-MS/MS with cryo cooling and backflush option (UofA)

NSERC 12/2012 100% access, 75 samples/week

Leco GCxGC FID/TOF-MS with liquid N2 cryogenic quad jet modulator (UofA)

CFI, UofA, Leco Instruments, Alberta Small Equipment Grants Program (SEGP)

07/2009 20-40% access, 60 samples/week

Agilent 7890A GC-MS with autosampler (UofA)

National Research Council - National Institute for Nanotechnology (NRC-NINT)


Agilent 7890A GC-MS with autosampler (UofA)

Genome Canada 01/2014 100% access, 150 samples/week

Agilent/HP Series 5890 GC-MS (UofA)

AAET, Alberta Livestock and Meat Agency (ALMA)



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Equipment Type


Capacity

Beckman System Gold HPLC with UV detector

AHFMR, UofA 09/1996 100% access, 50 samples/week

Beckman System Gold HPLC with ELSD (UofA)

Genome Canada, AAET 06/2006 100% access, 50 samples/week

Agilent 1290 HPLC with Fluorescent detector (UofA)

AAET, ALMA 06/2009 100% access, 50 samples/week

Agilent 1290 HPLC with Fluorescent detector (UofA)

External Revenue 01/2014 70% access, 40 samples/week

Waters NanoAcquity UPLC system with UV detector (UofA)


Waters UHPLC system with UV detector (UofA)

NSERC 03/2011 100% access, 80 samples/week

Agilent 1290 HPLC system (UofA)


Agilent 1290 HPLC system (UofA)

AAET, ALMA 06/2009 100% access, 50 samples/week

Biomek 2000 Liquid Handling System (UofA)

NSERC/CFI 02/2008 100% access, 100,000 samples/year

Biomek 2000 Liquid Handling System (UofA)

Genome Canada 05/2015 100% access, 100,000 samples/year


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Appendix 2: TMIC Success Stories

While we have highlighted and quantified a significant number of accomplishments for TMIC in this document, it is also useful to describe some of TMIC’s successes through stories. Below is a brief synopsis of some of the more interesting success stories for TMIC over the past 1-2 years. . 1) How TMIC helped a Canadian company launch a new cancer screening test Metabolomics Technologies Inc. (MTI) is an Edmonton-based startup http://www.metabolomictechnologies.ca that had used NMR of urine to discover a 10 metabolite biomarker panel that identified individuals at risk for colon cancer. However, NMR cannot be routinely used for clinical assays or clinical screening tests. By working with TMIC staff and equipment, MTI was able to convert a slow and expensive, 10 component NMR test to a fast, cheap 3 component mass spectrometry test. Making this conversion allowed MTI to sell its assay to 3 testing labs in the US in March 2016. Efforts are being undertaken to offer MTI’s PolypDX test in Alberta. PolypDX is among the first clinical metabolomics tests ever to be marketed. 2) How TMIC’s DrugBank led to the discovery of new rheumatoid arthritis drugs Okada, Y. et al. (2014) Genetics of rheumatoid arthritis contributes to biology and drug discovery Nature 506, 376–381. The authors did a large (>100,000 subjects) genome wide scan of SNPs associated with rheumatoid arthritis (RA). They identified 42 novel RA risk loci. Using DrugBank, they found that many of the risk genes were already targets for approved RA therapies. Through DrugBank they also found several drugs already approved for other indications could be repurposed for the treatment of RA. This has apparently opened the door to fast-tracking several new therapies for RA. This paper has already been cited 372 times. 3) How TMIC is automating metabolomics Ravanbakhsh S, et al. (2015) Accurate, fully-automated NMR spectral profiling for metabolomics. PLoS One. 10(5):e0124219. Current methods for metabolomics are very slow and manually intensive. Most techniques depend on using NMR or mass spectrometry and require some level of manual deconvolution. In the field of NMR-based metabolomics, most methods require 45-60 minutes of manual effort to interpret and characterize an NMR spectrum. Manual interpretation of NMR spectra is also fraught with potential errors and inconsistencies. TMIC scientists, teaming up with machine learning researchers at the University of Alberta developed a probabilistic graphical model (GGM) method that allows NMR spectra to be automatically interpreted. The program (called Bayesil) is able to process a NMR spectrum and identify and quantify >50 compounds in <3 minutes. It is as accurate as a human expert and it never gets tired. Bayesil is now being bundled with a special kit that TMIC is producing for widespread use in NMR-based metabolomics. 4) How TMIC’s HMDB is being used to discover and interpret cancer biomarkers Many researchers use the massive collection of metabolite data and spectral information in the HMDB to help with biomarker interpretation and discovery. While many diseases are being studied via metabolomics, here we will just highlight a few recent papers in cancer research where HMDB played a key role in helping to identify or rationalize novel cancer biomarkers:


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a) Kanaan YM et al. (2014) Metabolic profile of triple-negative breast cancer in African-American women reveals potential biomarkers of aggressive disease. Cancer Genomics Proteomics. 11(6):279-94. b) Zhang T, et al., (2013) Application of Holistic Liquid Chromatography-High Resolution Mass Spectrometry Based Urinary Metabolomics for Prostate Cancer Detection and Biomarker Discovery. PLoS One. 8(6):e65880. c) Dowling P, et al. (2014) Metabolomic and proteomic analysis of breast cancer patient samples suggests that glutamate and 12-HETE in combination with CA15-3 may be useful biomarkers reflecting tumour burden. Metabolomics 11:620-635 d) Huang Z, et al. (2011) Bladder cancer determination via two urinary metabolites: a biomarker pattern approach. Mol Cell Proteomics. 10(10):M111.007922. e) Fahrmann JF, et al. (2016) Serum phosphatidylethanolamine levels distinguish benign from malignant solitary pulmonary nodules and represent a potential diagnostic biomarker for lung cancer. Cancer Biomark. Mar 11. [Epub ahead of print] f) Duscharla D, et al. (2016) Prostate Cancer Associated Lipid Signatures in Serum Studied by ESI-Tandem Mass Spectrometryas Potential New Biomarkers. PLoS One. 11(3):e0150253.

5) How TMIC’s new CIL-LC-MS kits are changing food and nutritional science Achaintre D, et al. (2016) Differential Isotope Labeling of 38 Dietary Polyphenols and Their Quantification in Urine by Liquid Chromatography Electrospray Ionization Tandem Mass Spectrometry. Anal Chem. 88(5):2637-44. The authors, all based at the International Agency for Research on Cancer (IARC) in France, used the CIL-LC-MS kit developed by TMIC to conduct the most comprehensive quantitative analysis of dietary polyphenols in urine ever undertaken. This new approach now allows food and nutritional scientists to routinely measure dozens of polyphenols and polyphenolic derivatives in urine. Given the many reported health benefits of dietary polyphenols, this technique should open the door to readily assessing their level of dietary consumption and how certain types are associated with reduced disease burden. This is just one example of how the CIL-LC-MS method can be used. By making the CIL-LC-MS kits more widely available, it is expected that the technique could be used in a wide range of biomedical, nutritional and nutraceutical applications. 6) TMIC’s CFM-ID software wins the international CASMI contest For the past 4 years the annual Critical Assessment of Small Molecular Identification (CASMI) contest has been held. CASMI brings in many top international scientists and scientific teams together to compete to identify dozens of small molecule compounds using only their MS/MS spectra. This competition requires the use/development of advanced software tools for MS/MS spectral prediction and interpretation. TMIC has been developing the CFM-ID software for the last 3 years. In 2014, CFM-ID was used to submit predictions for all 42 CASMI entries in 2 different categories. CFM-ID won first place in both categories. The results are posted at http://www.casmi-contest.org/2014/results.shtml. CFM-ID is now widely recognized as the best software tool for MS/MS spectral prediction. 7) How CFM-ID is changing pharmacognosy Allard PM, et al. (2016) Integration of Molecular Networking and In-Silico MS/MS Fragmentation for Natural Products Dereplication. Anal Chem. 88(6):3317-23. Pharmacognosy is a branch of medicinal chemistry aimed at finding novel drugs in newly discovered natural products. The identification of natural products along with their structure determination is a very slow and difficult process. A group based in Switzerland used CFM-ID to greatly accelerate this


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process. By using CFM-ID to predict the MS/MS spectra of hundreds of thousands of known natural products (from the Dictionary of Natural Products), they were then able to take the observed MS/MS spectra of newly isolated natural products and figure out their most likely structures. As described in this paper, this new approach was successfully used in several case studies and could soon become the standard practice in pharmacognosy labs around the world. 8) How TMIC is making the diagnosis of organ transplant rejection far easier Blydt-Hansen TD et al. (2014) Urinary metabolomics for noninvasive detection of borderline and acute T cell-mediated rejection in children after kidney transplantation. Am J Transplant. 14(10):2339-49. Every year thousands of kidney transplants are performed in North America. However, the maintenance of a successful kidney transplant requires close monitoring and painful, invasive biopsies where a long needle is inserted into an individual’s back and a portion of the kidney tissue extracted for histopathological analysis. The process is not without risks and it is not particularly accurate at diagnosing organ rejection. It is particularly challenging for monitoring children with transplants. By developing a metabolomic test based on urine (as described in the above paper) it should be possible to non-invasively detect organ rejection with greater accuracy and often sooner than could be done via histopathology. Efforts are now underway to validate these findings on a larger cohort and to convert the test to a general-use test for kidney patients across Canada. 9) How TMIC’s HMDB helped launch the field of ‘omics based exposure science Rappaport SM, et al. (2014). The blood exposome and its role in discovering causes of disease. Environ Health Perspect. 122(8):769-7. The authors used the HMDB to compile the concentrations of 1500+ endogenous metabolites, drugs, food components and pollutants/exposures in human blood. They determined that the average concentration of pollutants is >1000 times lower than other classes of compounds (foods, drugs, endogenous compounds). They also showed clear associations with higher concentrations of certain pollutants and the incidence of major human diseases. This paper is now frequently cited to show how metabolomics could benefit pollution monitoring and exposure science. Since this paper’s appearance many scientists have started using metabolomics to help measure the exposome.


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Appendix 3: Metabolomics Facilities Comparison


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Appendix 4: Projections (Bar Graphs)

The following graphs provide more details regarding TMIC’s expected or targeted performance.

Figure A4.1: This figure shows actual and projected numbers of highly qualified personnel (HQP) trained annually through TMIC and its offerings. Note that HQP trained at/by TMIC for more than one year are counted in each year that they receive training. Currently, TMIC employs 20 core operational personnel. Another 45 research scientists, supported by Principal Users’ grant, work in TMIC on a daily basis. Abbreviations used: Tech/Prog – Technician or Programmer BSc – Undergraduate student MSc/PhD – Graduate student RA/PDF – Research Associate or Postdoctoral Fellow


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Figure A4.2: This graph shows TMIC shows actual and projected data regarding samples processed and the assays performed. Most samples submitted to TMIC undergo more than one type of assay, as a single assay usually provides incomplete coverage of the metabolites of interest. Currently, samples are subject to an average of 2.1 assays each. We also expect this number to continue to grow as we add to our collection of quantifiable metabolites.


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Figure A4.3: This figure depicts TMIC operational support and service revenue projections over the next 5 years. We expect service revenue to support an increasing amount of TMIC operational costs in the near future as we strive for self-sufficiency.


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Figure A4.4: This graph depicts our goal of expanding the current “external” user base by 75% over the next 5 years, while also increasing the proportion of service to industry. Note that from 2011-2015 TMIC has had 266 total external users, corresponding to 200 different external users. Note this graph excludes TMIC’s “internal” users (amounting to >180 different students, PDFs, RAs, visitors and technicians over the past 5 years) who are funded by the TMIC’s platform leaders and principal users.


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Figure A4.5: With the majority of TMIC users in academia, peer-reviewed publications are a priority for many of our colleagues and collaborators, as well as for all of TMIC’s Principal Users. The number and quality of manuscripts are expected to grow substantially as TMIC expands and matures as a leading metabolomics research and service centre.


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Figure A4.6: Actual and projected TMIC acquisitions of major equipment (NMR, MS, LC and robotic liquid handling systems) are shown here. TMIC plans to acquire new instruments to increase metabolite coverage, improve quantification capabilities and ease analysis bottlenecks.


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Figure A4.7: The number of types of analytical assays offered by TMIC by year. A single sample submitted for analysis by a user may undergo one or more separate assays, depending on the desired metabolite coverage and budget.

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