Indiana Metabolomics and Cytomics Initiative

METACyt Grant proposal

Executive Summary

The Indiana Metabolomics and Cytomics Initiative (METACyt)
A Proposal to the Lilly Endowment, Inc. from Indiana University

Contact:

Michael A. McRobbie Vice President for Research and Information Technology, and Chief Information Officer 601 East Kirkwood Avenue Bloomington Indiana 47405-1223
812-855-5752 (voice) 812-855-3310 (fax)

5 November 2004

Copyright© 2004, The Trustees of Indiana University

Introduction

This proposal describes the Indiana Metabolomics and Cytomics Initiative (METACyt), a partnership between Indiana University and the Lilly Endowment, to take the next decisive steps in enhancing Indiana University’s accomplishments in fundamental life science research and building the life science economy of Indiana. The Indiana METACyt Initiative builds upon the foundation of the Indiana Genomics Initiative (INGEN) and its focus on genomics (studies of DNA sequences) and proteomics (studies of the proteins that make up living organisms).

The Indiana METACyt Initiative addresses two central areas of cell function: metabolomics (the study of the chemical compounds that take part in cellular metabolism) and cytomics (the study of cell function generally). The cell is the fundamental organizational unit of living organisms, and one level higher than DNA and proteins within the hierarchy of biological organization. By focusing on this fundamental life form, the Indiana METACyt Initiative will enable basic new insights about biological systems that then generate new discoveries and technologies. These will form the basis for new treatments for medical conditions, and will serve to propel Indiana University Bloomington from its current role of prominence to a new level of national and international leadership in cellular biology.

Indiana University has outstanding faculty whose interests lie at the heart of contemporary biology and biomedicine, pre-eminent research groups, and an excellent research environment that fuels interdisciplinary innovation. Cytomics is the new frontier. IU has an opportunity to lead in this area, and the Indiana METACyt Initiative will provide the necessary boost.

Background

Two significant and conflicting forces have been interacting and affecting the Indiana economy. One is the nationwide and irrevocable decline in heavy industry, upon which Indiana’s economy has traditionally depended. The other is the collective efforts of State, university, and private sector to create a new economy in Indiana based on the life sciences and advanced technology. The Indiana METACyt Initiative will be a resolute and purposeful step toward transforming the Indiana economy into one that will provide high-quality, high-paying jobs supported by growth that will be sustained over decades to come.

While the State of Indiana has over the past four years led the nation in negative economic indicators, including job loss, industries related to life sciences and information technology are becoming areas of significant economic strength. But further investment is essential if the Indiana is to make economic progress relative to other states. Research and development are the driving forces of change in the Indiana economy, and while the State of Indiana has made tremendous gains, it still lags behind much of the rest of the nation.

Indiana can be successful in transforming its economy if additional investments in support of science and technology development are strategically aligned with existing State strengths and areas of national opportunity. The Indiana METACyt Initiative will serve as an organizing force that will bring about such an alignment.

Ongoing Revolutions in Biology

So pivotal was the genomics revolution that it spurred a series of new revolutions that correspond to different levels of biological function: genomics and proteomics (understanding the proteins created from DNA sequences), metabolomics (understanding the molecular constituents of a target cell, tissue, or organ), and cytomics (understanding cellular functions. Indiana University is building on the results of the genomic revolution, particularly through the Indiana Genomics Initiative. And in collaboration with Purdue University and Eli Lilly and Company, IU has capitalized on the nationwide boom in proteomics, in part through the proteomics-based companies Inproteo and INCAPS.

The next revolution will be in the molecular study of cellular phenomena, and offers a unique opportunity to position Indiana in the vanguard. IU has a strong base on which to build, thanks to a world-class cadre of biologists and chemists, and the bases of excellence in genomics that the Indiana Genomics Initiative has helped build. In fact, IU created many of the analytical instruments that are the tools of a more profound understanding of cellular functions. IU has a deep pool of talent in genetics and in the functioning of important model organisms (e.g.: bacteria and fruit flies). These will provide platforms for the experiments that will enable critical tests of new theories about cellular function. Indiana University also has the researchers and computational infrastructure that will make possible the development of new models of cell function, and that will lead to new experimental questions and ultimately to new insights.

There is national consensus that metabolomics and cytomics represent the next critical steps forward in life sciences, a view embodied in the research roadmap created by the National Institutes of Health. It is crucial that Indiana step in ahead of the curve in developing and applying technology in metabolomics and cytomics. Investment in these areas will permit Indiana University to capitalize on funding opportunities created in alignment with the NIH roadmap, substantially increase competitiveness within the State for NIH-supported centers of excellence, and provide new intellectual property for developing spin-off technologies. Such investment can facilitate and support cross-disciplinary scientific initiatives, leverage and attract new investments in research, and make important progress in developing a better quality of life for Indiana residents through economic growth.

Strengths, Opportunities, and Challenges for Indiana University

The life sciences have been traditional areas of strength at Indiana University Bloomington, which has been home to four Nobel Laureates in the life sciences. During the last decade IU Bloomington’s standing has been enhanced by the execution, campus-wide, of a proactive strategy to establish Indiana University as an international leader in the life sciences. The strategy calls for building on current strengths and bringing new interdisciplinary activities to critical mass through focused, strategic faculty recruiting, creating interdisciplinary research centers to fill critical needs, upgrading the life sciences’ interactions with critical allied disciplines (e.g. information technology), and aggressively pursuing grant opportunities.

A consequence of IU’s national and international stature in the life sciences is that IU faculty are increasingly targets of recruitment by other institutions. Keeping our cadre of first-rate life scientists here is critical to achieving the State’s agenda for economic growth, and the University’s goal of sustained and enhanced intellectual leadership in basic life sciences. Faculty are motivated by the desire to do leading-edge research. The key to retaining life sciences faculty will be for the University to create at IUB an environment where top researchers are confident they can do their the best, most innovative work. The Indiana METACyt Initiative will provide this assurance by creating an interdisciplinary life sciences research community that supports the individual and whose whole is greater than the sum of its parts – an interdisciplinary, collaborative program that makes possible research breakthroughs at Indiana University that are not possible in other places.

Structure of the Indiana METACyt Initiative

A grand dream of the life sciences from the earliest days has been to reach an integrated understanding of the complete function of organisms, from single-celled microbes to human beings. The key to such progress is a deep understanding of the cell, the fundamental unit of life. Understanding a cell means comprehending the myriad biochemical pathways within a cell; deciphering the dynamic relationships among these pathways; and discovering how different cellular constituents change with time and in response to disease, environmental influences, and external chemical influences. With such understanding will come dramatic changes in our ability to treat and cure diseases.

The Indiana METACyt Initiative will comprise five Research Nodes, engaged in basic and applied research, and four Integrating Science and Technology Centers, engaged in scientific research and providing analysis services for METACyt as a whole, supplemented by four major shared infrastructure facilities. It is a challenge for any institution to achieve a position of national and international leadership position in the sciences and it is also a challenge to maintain such a position. We believe that the Indiana METACyt Initiative will make the difference in our advance to leadership and we have a strategy to sustain that position: Each of the Research Nodes and Integrating Science and Technology Centers described below will use Initiative funds to carry out plans designed explicitly to lead to dramatic increases in extramural grant funding with special emphasis on the creation of national research centers and national centers of excellence.

The functions and roles of the METACyt Research Nodes, Integrating Science and Technology Centers, and Major Shared Infrastructure facilities are summarized below.

Indiana METACyt Initiative Research Nodes:

Microbial Systems. In the Microbial Systems Research Node, an outstanding group of faculty in microbiology will work with scientists in the Integrating Science and Technology Centers (ISTC) to develop a global understanding of microbial growth, regulation, and behavior. A principal focus of their effort will be to create the Bacterial Molecular Cell Project – a unique and highly visible institutional effort to extend current understanding by applying global approaches to a single bacterial system. Initial efforts will focus on questions of cellular architecture, cell cycle control, the characterization of regulatory and metabolic pathways, and intercellular communication. By compiling global data sets for one judiciously chosen model and integrating comparative data from the wealth of organisms currently under study, the group will create a unique resource for understanding bacteria. We expect this effort will propel an already outstanding group to a position of leadership in current efforts to apply genomics, proteomics, metabolomics, and bioinformatics to microbial systems, and to pave the way for grant funding that will create a national Center of Excellence in Systems Microbiology at IUB.

Cell Signaling and Differentiation. Studies of cell regulation using model organisms are driving the transformation of biological and medical science nationally and internationally. These studies are being transformed by the new global ‘omics technologies, principally at a few leading medical and basic science institutions. Nevertheless Bloomington has maintained a position as a prominent (and in some areas pre-eiminent) center for the study of cell regulation using the leading model organisms – Drosophila, Caenorhabditis, and Arabidopsis. The Cell Signaling and Differentiation Research Node will enable a group of outstanding investigators to continue to play leading roles by catalyzing intragroup contacts and interdisciplinary collaborations through the ISTCs. Members of this Node will work, separately and in collaboration, toward a global understanding of cell regulation at the molecular level. Using genomics technology they will create catalogs of gene expression profiles. Using biocomputing approaches they will learn ways to identify regulatory elements in DNA sequences. Using the technologies provided by the ISTCs they will devise innovative approaches for identifying and characterizing the actions of cell regulators.

Molecular Neurosciences. No research field has benefited more from the molecular genetics revolution than neuroscience. No field is more central to understanding human disease. IUB, with the assistance of the Jack and Linda Gill Endowment, has built strength in molecular neurosciences. The Molecular Neurosciences Research Node will provide these key faculty with the resources and collaborators required to build an outstanding program essential in the State’s life sciences efforts. This Node will be developed around the following cutting-edge neuroscience research topics: endogenous ligands and receptor function; molecular approaches to synaptic plasticity; and molecular approaches to neuro-immune interactions. Research in these areas will lead to significant insights into who we are and how we think. They are also areas in which prominent collaborations with the private sector in, for example, drug and assay development, will help propel the group to prominence.

Molecular Evolutionary and Developmental Biology. The department of biology at IUB is home to one of the world’s most outstanding groups in evolutionary biology. Its scientists have founded new research areas and lead in their study. Evolutionary biology is a fast-moving, key part of modern biological and basic medical science, continually transforming itself along with the evolving technological landscape. To maintain leadership evolutionary biologists must become practitioners of genomics, bioinformatics, proteomics, and metabolomics. The scientists of the Evolutionary and Developmental Biology Research Node have already taken the lead in this transition. They have created large-scale projects to analyze horizontal gene transfer, to use SNPs (Single Nucleotide Polymorphisms – portions of the genomic sequence where there is variability within a population in a single letter of the genome) to analyze speciation, and to study the role of recombination in evolution. With the Center for Genomics and Bioinformatics (and the Joint Genome Institute, Department of Energy) they have begun to make Daphnia a suitable organism for genomics (and environmental) studies. The Indiana METACyt initiative will amplify these efforts and create new ones that ensure the continued pre-eminence of this research group and enhance faculty retention and our competitiveness for funding.

Analytical Technology Development. The Analytical Technology Development Research Node will harness the efforts of a prominent group of IUB faculty who have established worldwide reputations for developing instruments in the mainstream of the life sciences revolution. This Node will help them to move to the front of the pack, framing the directions of new technologies to answer such questions as: What proteins and small molecules are present in a cell? How do these chemical species vary in time or response to a specific perturbation? What are the interactions among these components? The Analytical Technology Development Research Node will leverage all the loci of technology development on the campus – including unique Cyclotron-based resources – to develop next generation technology. We expect that the technologies this Node develops will be adopted by the commercial sector (e.g. Inproteo, INCAPS). And we are confident that this group’s leadership and the congruence between its goals and the NIH roadmap will lead to funding a national center for technology development at IUB.

Integrating Science and Technology Centers (ISTCs)

Biochemical Analysis. State-of-the-art biochemical analysis is essential for all life sciences research. Yet as the power and sophistication of analytical tools increases, many life sciences laboratories find themselves left behind. While this is obviously so for laboratories that are just beginning to use biochemical analysis in their work, it is equally true for many biochemists who simply cannot afford the time or money to become expert in each newly developed procedure. The Biochemical Analysis ISTC will possess the instruments and skills to specialize in the analysis of small hydrophobic molecules (by combined gas chromatography/mass spectroscopy, and combined liquid chromatography/mass spectroscopy, and by high resolution NMR), in the analysis of proteins and glycans (by mass spectroscopy), and in the analysis of metabolomes (by mass spectroscopy). In protein analysis this facility will serve to bridge the gap between small-scale projects, the routine, but large-scale capabilities of a commercial operation like INCAPS, and the new technologies being developed in the Analytical Technology Development Research Node.

Chemical Imaging and Assaying. Like biochemical analysis, biochemical assays and imaging methods are at the heart of the life sciences. With appropriately labeled “probe” molecules we can often decipher pathways and interactions by biochemical assays or discover the provenances of molecules by high-resolution microscopy. Still most life scientists are not prepared to develop new imaging probes or substrates for biochemical assays. They depend on commercial sources and the occasional gifts from colleagues. The Chemical Imaging and Assaying ISTC is intended to change that situation and by making it possible for life scientists to develop new assays and imaging procedures.

The Center for Genomics and Bioinformatics (CGB) has been operating as a campus-wide research center since 2001. Its staff of experts in functional genomics, computer services for life scientists, and bioinformatics operates along the general principles described above for ISTCs and the CGB has been very successful in obtaining funding for its own functional genomics projects and assisting faculty to develop competitive grant proposals in these areas. It is evident that many scientists in the Research Nodes will wish to carry out functional genomics experiments: microarray analyses of gene expression, cDNA projects to identify transcripts, SNP discovery projects. In a long-standing arrangement with the Center for Medical Genomics (INGEN) those IUB scientists who use commercial microarrays (Affymetrix) use the Indianapolis facility. The CGB specializes in the manufacture, use, and analysis of custom-made two-color microarrays. Under the Indiana METACyt Initiative the core staff of the CGB – those available to help faculty develop functional genomics proposals – will be enlarged, and more “seed” funds will be provided to help jump-start the many ideas in the pipeline.

Center for Computational Cytomics. All contemporary life scientists make heavy use of digital databases and of biocomputing and bioinformatics tools to analyze masses of data. Many are learning to integrate their data with that produced in other laboratories by creating federated databases and publishing large datasets on the web. At the cutting edge of research all these activities require specialized skills and the average life scientist needs help. At present, at IUB, some help is available in the Center for Genomics and Bioinformatics and some help is available at the University Information Technology Services (UITS). The Indiana METACyt Initiative will permit us to combine and significantly expand these facilities into a single Computation Cytomics ISTC (housed centrally in the CGB) and fully integrated with the powerful hardware and software resources available through UITS.

Major Shared Infrastructure

One of the primary goals of this proposal is to create a research environment and support structure conducive to the retention of the world-class life scientists at IUB, and to recruiting additional such talent. While the Research Nodes are focused on new research in metabolomics and cytomics as a part of getting a head start on the next challenges in life sciences research, the Integrating Science and Technology Centers will impact scientists all across the campus and the university. It should be noted that a little more than 50% of the requested budget goes into shared equipment and facilities, such as the 800 MHz NMR and the transgenic mouse facility. Such state-of-the-art items will be useful not only to the METACyt scientists and students, but to all scientists (e.g., optometry, environmental science, speech and hearing, biochemistry at the School of Medicine). The upgrade in the computing infrastructure, likewise, has direct benefits to researchers across the university. Details of these major infrastructure efforts are as follows:

Greenhouse Facilities. Upgrade, renovation, and expansion of the Molecular Evolutionary and Developmental Biology Research Node. These scientists are among the world’s most outstanding in evolutionary biology, but IU Bloomington is limited by its collection of 1950’s-vintage greenhouses.

800 MHz NMR. This advanced analytical instrument will be operated and managed by the Analytical Technology Develop Research Node in support of the research activities described in this proposal. This massive and advanced NMR facility will greatly expand IU Bloomington’s capabilities to identify biologically active molecules.

Transgenic Mouse Facility. Transgenic mice – mice with experimentally manipulated genomes – are a critical tool on modern metabolomic and cytomic research. This facility will be operated by the Molecular Neurosciences Research Node, but will benefit the campus as a whole.

Computational Cytomics. IU will significantly upgrade its supercomputing and massive data storage infrastructure to enable the highly intensive data analysis and modeling that has become a basic element of life sciences research. This would place IU’s computing facility to be among the largest supercomputer systems in existence, and would open new doors for IU to lead in fundamental new insights in cell function.

METACyt and Economic Development in Indiana

A critical goal for the Indiana METACyt Initiative is to ensure that new innovations translate into economic benefit for the State of Indiana. The core elements of the Indiana METACyt Initiative economic development strategy are as follows:

• Ensure that IU’s top life science researchers stay at Indiana University, and are able to increase their acquisition of federal grant monies and their production of new knowledge and innovations.
• Actively foster the transfer of new innovations from laboratory to the private sector, working with the IU Research Technology Corporation (IURTC)
• Operate the METACyt Innovation Fund that will support technology transfer and the founding of new businesses based on METACyt discoveries.

Indiana University Bloomington has been successful in substantially increasing its rate of invention disclosures and its technology transfer licensing income. Both have more than doubled in the past five years. IU has also created new businesses in Indiana, nine as spin-offs to commercialize technology developed by Indiana University, of which seven are headquartered in Indiana. All are related to either the Pervasive Technology Laboratories, INGEN, or areas of research that will be enhanced by the Indiana METACyt Initiative. Another Indiana business has been started, and another substantially enhanced, as a result of licenses of new technologies from IU.

Technology transfer is important for two reasons. First, new innovations that produce better products or medicines, or produce existing products more economically, improve the quality of life. Second, economic growth and better, safer, and higher-paying jobs do the same. Given a supply of new discoveries and innovations propelled in part by METACyt, and an effective technology transfer office (IU Research and Technology Corporation), IU needs an effective agent to manage the transformation of a patentable idea into a protected, licensed piece of intellectual property. The Indiana METACyt Initiative will invest skilled and effective effort on this critical transition.

The Indiana METACyt Initiative will create a METACyt Innovation Fund managed by the IU Research and Technology Corporation. This fund will provide early-stage funding for promising METACyt innovations and technologies. This early funding is the most risky, and the hardest to get, but it can yield fantastic economic benefits and considerable returns. The METACyt Innovation Fund will focus on this early funding, with special attention paid to companies that stand to benefit the economies of south and south-central Indiana.

The METACyt Innovation Fund will focus on a small number of investments, two to four per year, enabling the IU Research and Technology Corporation to work extensively with each start-up and maximizing the chances of favorable business outcomes and significant impact on the Indiana economy.

With well executed objectives and marginally positive economic conditions, the METACyt Innovation Fund will enjoy returns on its investment that will build it into a growing force in propelling forward the life sciences economy in Indiana.

Space for METACyt

Though there is a severe space situation at IUB, Indiana University is committed to providing most of the space for the Indiana METACyt Initiative. For example, many of the METACyt Research Nodes and the Integrating Science and Technology Centers will be located in Bloomington's visionary new Simon Hall. Simon Hall is planned specifically to support multi-disciplinary research of the kind that will be central to METACyt. Indiana University also seeks support for part of the cost of a new building currently being designed for multi-disciplinary research that would house remaining significant components of METACyt.

Organization and Management of METACyt

The components of the organizational structure of METACyt are as follows:

• METACyt Steering Committee. This committee will be responsible for the oversight of METACyt. IU’s commitment to this project will be guaranteed by the appointment of the IU VP for Research and IT, Dr. Michael McRobbie, as Chair of this Committee, and the appointment of the Dean of COAS at IUB, Dr. Kumble Subbaswamy, as Deputy Chair.
• METACyt External Advisory Board. This board of distinguished life science researchers, industrialists, and entrepreneurs will be chosen from IU alumni, Indiana life science companies, and internationally renowned researchers and technologists.
• METACyt Investment Evaluation Committee. This sub-committee of the METACyt Steering Committee will be chaired by the METACyt Chair, and will administer the $2-million METACyt Innovation Fund.
• METACyt Administration. Reporting to the METACyt Steering Committee, this will consist of the METACyt CEO, Dr. Ted Widlanski, Associate Dean for Research and Professor of Chemistry in COAS, and the other leaders of the METACyt administration.
• METACyt Operations Committee. Responsible for operational oversight of METACyt and chaired by the METACyt CEO, this committee will initially meet four to six times a year to ensure coordination and progress in METACyt activities.

Milestones

The Indiana METACyt Initiative will set clear milestones for key accomplishments, to include the following critical goals:

18 Months

• Director of Chemical Imaging and Assaying center hired.
• All METACyt Integrating Science and Technology Centers and Research Nodes staffed and functional
• METACyt awareness efforts well established; ties with BioCrossroads fully implemented as METACyt becomes known statewide as an available resource.
• First proposal for investment of METACyt Innovation Fund monies.

36 Months

• All Nodes and Centers develop proposals for centers of national excellence.
• First completely new intellectual property from research in Nodes or Centers is patented.
• First investment of monies from METACyt Innovation Fund into establishment of METACyt spin-offs
• Node and Center educational/instructional plans formalized.

54 Months

• Centers become self sustaining through user fees and/or external grants.
• Nodes become self sustaining through federal funding.
• 100th publication from METACyt-supported investigations.