International Assessment of Research and Development in Physical Sciences

and Engineering Advances in Life Sciences and Oncology (APHELION)

Sponsors Meeting

NSF Stafford II Room 585

January 18, 2012

Briefing Book

World Technology Evaluation Center, Inc. 4600 N. Fairfax Drive #104

Arlington, VA 22203

International Assessment of Physical Sciences and Engineering Advances in Life Sciences and Oncology (APHELION)

Sponsors Meeting, January 18, 2012 NSF, 4201 Wilson Blvd, Arlington VA, Room II-585

AGENDA

11:00 AM Introductions 11:15 AM Overview of a WTEC Study with Process: scope, schedule, objectives 11:30 AM Major Topics/Themes for Study 12:00 PM Working lunch

• Discussion of agency interests • Scope modifications to SOW plan • Prospective sponsors to invite to kick-off meeting • Resource issues • Geographic scope • Timelines of Study • Bibliometric study

1:00 PM Adjourn

NCI-NSF IAA SOW APHELION DRAFT Dated 01-04-12 1

INTER-AGENCY AGREEMENT BETWEEN DEPARTMENT OF HEALTH AND HUMAN SERVICES

NATIONAL INSTITUTES OF HEALTH NATIONAL CANCER INSTITUTE

AND THE NATIONAL SCIENCE FOUNDATION

STATEMENT OF WORK

Assessment of PHysical sciences and Engineering advances

in LIfe sciences and ONcology (APHELION)

PROJECT SUMMARY This document describes a plan for the National Cancer Institute (NCI) Office of Physical Sciences – Oncology (OPSO) to participate in and co-sponsor a study led by the National Science Foundation (NSF) to conduct an international Assessment of PHysical sciences and Engineering advances in LIfe sciences and ONcology (APHELION). The APHELION is aimed at determining the status and trends of research and development whereby physical sciences and engineering principles are being applied to cancer research and oncology in leading laboratories and organizations via an on-site peer review process in Europe and Asia. The NSF has an existing contract with the World Technology Evaluation Center (WTEC), Inc. under which the study will be conducted. The mission of the NCI is to conduct and foster cancer research; reviewing and approving grant-in-aid applications to support promising research projects on the causes, prevention, diagnosis, and treatment of cancer; collecting, analyzing, and disseminating the results of cancer research conducted in the United States and in other countries; and providing training and instruction in the diagnosis and treatment of cancer. Over the years, NCI has evolved into the world's pre-eminent cancer research organization. Under the leadership of the NCI Deputy Director, the Center for Strategic Scientific Initiatives (CSSI) coordinates several efforts both within and outside of NCI to carry-out its function of supporting timely execution and implementation of activities that have trans-NCI benefit. Within the NCI, the CSSI houses (1) The Cancer Genome Atlas (TCGA) Program Office; (2) Office of Cancer Nanotechnology Research; (3) Office of Cancer Clinical Proteomics Research; (4) Office of Physical Sciences-Oncology; (5) Office of Biorepositories and Biospecimen Research; (6) Office of Cancer Genomics; (7) Knowledge Management and Special Projects Branch; (8) Center for Global Cancer Health Research. These offices support extramural research programs and lead standards and policy development initiatives with the goal of accelerating advances in biomedical technology and furthering the vision of personalized medicine. The NCI Office of Physical Sciences-Oncology (OPSO) (1) serves as a nexus for the development and implementation of physical science-based initiatives to enable progress in cancer research for NCI and its integration across trans-NCI, trans-NIH, and inter-agency

NCI-NSF IAA SOW APHELION DRAFT Dated 01-04-12 2

activities; (2) enables the development of discoveries and new fields of study based on the application of aspects of the physical sciences approaches to cancer research; (3) and facilitates the exploration of novel and innovative approaches to advance our understanding of the physical laws and principles that shape and govern the emergence and behavior of cancer at all scales. The NSF has long had a role in maintaining the general health of science and education across a range of universities and other organizations and has been deeply involved in funding research in engineering and the physical sciences. Recently, the NSF and the NCI have collaborated on a funding opportunity titled Physical and Engineering Sciences in Oncology (PESO) Awards [also known as the Physical and Life Sciences Early Research (PLIER) Awards]. The rationale for the NCI OPSO participation in the APHELION with NSF is based on the premise that significant advances may be expected as the result of continued investments in inter- and multi-disciplinary research at the intersection of the engineering/physical sciences and the life sciences. The field of cancer biology is one that has been dominated, historically, by researchers with classical training in the basic and clinical life sciences. More recently, the field has expanded to include physical and engineering scientists, whose background and expertise are complementary to those possessed by life scientists, leading to the recognition that significant advancements in the fundamental understanding of cancer diseases are possible through multidisciplinary research that involves experts in chemistry, physics, materials science, and manifold engineering disciplines. Emerging and burgeoning opportunities for collaborative research at the intersection of the physical/engineering sciences and the life sciences have been identified through several NSF workshops over the past few years. Furthermore, the NCI launched a program to bring new perspectives from the physical sciences to cancer biology and oncology in 2009. The Physical Sciences – Oncology Centers (PS-OCs) Program is in its third year of implementation and the OPSO will use the study to help develop relevant and novel funding concepts to further the mission of the NCI. Specifically, the OPSO seek novel research concepts at the interface of engineering/physical sciences and the life sciences with a focus on advancing the fundamental understanding of cancer biology to underpin translational research that promotes the prevention, detection, and treatment of cancer diseases. PROJECT BACKGROUND

In 1971 President Nixon declared war on cancer, and much effort has been invested in learning more about this complex system of diseases, and in developing treatments. However, despite considerable progress in treatment of certain forms of cancer, progress in reducing its mortality by conventional biomedical approaches is disappointing. Thus, in addition to new biomedical approaches, such as those based on the human genome, some researchers are using concepts from the physical sciences. In the U.S. much of the research that applies physical sciences and engineering concepts to cancer biology and oncology is supported by the Office of Physical Sciences – Oncology (OPSO) at the National Cancer Institute. The OPSO is exploring innovative new approaches to better understand and control cancer by encouraging the convergence of the physical sciences with cancer biology and oncology. Building on stunning progress in the molecular sciences, it supports new research themes based on the application of physical sciences concepts and approaches to the major barriers in cancer research. Examples of concepts being explored by the OPSO through its Physical Sciences – Oncology Centers (PS-OCs) Program are: (1) Applying physics and engineering laws and principles to cancer by defining the role of thermodynamics and mechanics in metastasis and determining

NCI-NSF IAA SOW APHELION DRAFT Dated 01-04-12 3

how this knowledge might be employed in new intervention strategies; (2) Applying evolution and evolutionary theory to cancer by developing a comprehensive theoretical inclusive construct that would provide a foundation for understanding and predicting cancer heterogeneity; (3) Applying information theory to cancer by pursuing theoretical and supportive experimental approaches that define what information is and how it is decoded and managed in terms of cell signaling and contextual information translation in cancer; and (4) Deconvoluting cancer’s complexity by pursuing theoretical and experimental approaches from the physical sciences to cancer complexity that will inform a new fundamental level of understanding of cancer that may facilitate prediction of viable pathways to develop novel interventions. The NSF currently has an umbrella contract awarded to the World Technology Evaluation Center (WTEC), Inc. to facilitate the assessment of research in engineering and science worldwide with the aim of maintaining U.S. leadership in these areas. WTEC is a non-profit research institute, which conducts international research assessment studies for the NSF, NIH, DOD, and other Federal agencies--more than 60 to date. Recent related studies include Nanotechnology Research Directions for Societal Needs in 2020, Brain-Computer Interfaces, Catalysis by Nanostructured Materials, Simulation-Based Engineering and Science, Rapid Vaccines Manufacturing, Tissue Engineering, and Systems Biology. PURPOSE

The objective of this joint study with the NCI OPSO and the NSF is to utilize an expert panel consisting of prominent scientists in the field of applying physical sciences and engineering perspectives/principles to oncology and other biomedical areas to conduct site visits at overseas institutions to conduct an international Assessment of PHysical sciences and Engineering advances in LIfe sciences and ONcology (APHELION). The findings of the APHELION will result in briefings to the sponsors, public workshops and a final report that will collectively provide a comprehensive, peer-reviewed set of evaluations of physical sciences-oncology research overseas in comparison to research being conducted in the United States. AUTHORITY This agreement is entered into under the authority of the National Science Foundation Act of 1950 as amended (42 USC 1861 et seq, specifically 1873(f) and section 241A and 301 of the Public Health Services Act, as amended. These authorizations for these agencies, together with the internal policies and procedures of each agency, define the authority of the agencies to enter Into this agreement and to manage this joint program focused on physical, mathematical, and engineering sciences or some combination of such the biological sciences. SCOPE OF WORK WTEC shall conduct the international assessment of the current status and the trends of the application of physical sciences and engineering concepts to cancer biology, oncology and other biomedical areas. The objectives of an international assessment would be to:

• Guide and justify U.S. research investments • Look for good ideas abroad (technology transfer, improving U.S. programs) • Look for opportunities for cooperation and collaboration

NCI-NSF IAA SOW APHELION DRAFT Dated 01-04-12 4

• Compare U.S. R&D with that abroad The study panel, under the guidance of the sponsors, will be instrumental in helping to develop a definitive scope of the study. Among these objectives related to the proposed study are:

• Information Transfer in Cancer and other Biomedical research areas through an Evolutionary Lens

o Can novel therapeutic strategies be developed based on increasing the genetic load of mutations in cancer cell population that will lead to extinction of this population?

o What genetic and epigenetic features define a cancer stem cell? o Do oncogenic mutations confer self-renewal to cells? o What is a gene and how is it regulated in time and space?

• Time Domain of Cancer Metastasis and other Diseases with Therapy o Is the fluid phase biopsy of solid tumors an accurate real-time representation of

the disease over the course of the patient’s lifetime? o How does the heterogeneity of a tumor or other diseased tissue impact drug

response? • Mechanics in Health and Disease

o Is Mechano-therapy of cancer possible? o “Follow the genes” is the dominant paradigm. Can we develop a complementary

“follow the physics” approach? o What is role of forces in cancer metastasis? o Can lessons learned from the roles that cell and tissue mechanics play in

developmental biology be applied to cancer and other diseases? • Physical Parameters of the Tumor Cells, Microenvironment, and Host

o How does a tumor cell change its genetic, epigenomic and metabolomic signature, as it becomes "successful" i.e. invasive, metastatic?

o Is the transport oncophysics of the microenvironment what really matters? o What is the energy budget of a cancer cell compared to a developing cell and a

mature normal cell? • Understanding Physical Emergent Properties: What is Cancer?

o How can we change the physical microenvironment (selective pressures) to prevent cancer?

o Is cancer curable? Can it be controlled through manipulation of the microenvironment?

o Why do tumors ultimately make a phase transition to a metastatic phenotype? The above list of topics will be refined by the panel members in consultation with the sponsors at the study kick-off meeting. TASKS Task 1 WTEC, in consultation with study sponsors, shall select a panel of six (6) U.S. experts (including the panel chair) in the field, who are familiar with international activities in the field. The panel chair shall have sufficient stature in this field to command respect in recruitment of panelists, and make presentations of results to peers. The chair also will have the necessary skills at leading a panel to efficiently conduct the study.

NCI-NSF IAA SOW APHELION DRAFT Dated 01-04-12 5

Task 2 The Contractor shall organize a sponsor meeting to be held in the Washington, DC metro area in January/February 2012 at which interested sponsors will attend along with the panel chair if they are available. Task 3 After the sponsor meeting, the Contractor shall organize a kick-off meeting to be held in the Washington, DC metro area in February 2012 at which the expert panel, any scientific advisors, and interested sponsors will attend. At the kick-off meeting, the chair will define the scope of the study (with guidance from all of the agency sponsors) and assign each panelist a section of the final report. During the preliminary study, WTEC shall assist the panelists by conducting electronic literature searches. Password protected and public Web sites will be maintained by the WTEC during the study to facilitate the work of the panel. Task 4 WTEC shall organize a fact-finding trip to Europe for the panel to visit centers of excellence in physical sciences and engineering for oncology and other biomedical areas. The sites will include sponsoring organizations, as well as top labs. Government observers will accompany the expert panel, to assist and gather information first hand. Task 5 WTEC shall provide template site visit reports for each site visited to the study panel members and obtain draft site visit reports from the panel by July 2012. Task 6 WTEC shall organize a workshop in the Washington, DC area for the presentation of the results in a timely fashion such that the final report may be produced in August 2012. Approximately 50 key participants from government and the private sector would be expected to attend a one-day discussion of the results. Each panelist will make a 30-minute presentation with visual aids, and the chair will give an overall summary. The workshop will be webcast to broaden its dissemination, including posting of the video for at least three years. Task 7 WTEC shall provide a template analytical report to the study panel members and obtain a comprehensive draft analytical report from the panel by the beginning of August 2012. Task 8 WTEC shall produce a final written report in August 2012, print and distribute 100 B&W bound hardcopies to study participants, hosts, and sponsors, and post the full report in color on the WTEC website. Task 9 If sufficient funds are available to conduct a subsequent study in another continent, WTEC shall organize a fact-finding trip to Asia in the spring or early summer of 2013 with a second final written report that shall be produced no later than August 2013.

NCI-NSF IAA SOW APHELION DRAFT Dated 01-04-12 6

DELIVERABLES The schedule for the study will be determined at the kick-off meeting by mutual agreement of the sponsors, the WTEC staff, and the panel members. However, the first phase of the timeline shall be driven by a report deadline of August 1, 2012 for study that will be conducted in Europe. Deliverable Deadline Task 1: Selection of chair, panel members, and scientific advisors January 2012 Task 2: Sponsor Meeting February 2012 Task 3: Kick-off Meeting March 2012 Task 4: Fact-finding trip to Europe June 2012 Task 5: Draft site reports from study in Europe July 2012 Task 6: Final workshop phase 1 July 2012 Task 7: Draft analytical report from study in Europe August 2012 Task 8: Final written report from study in Europe August 2012 Task 9: Fact-finding trip to Asia (if sufficient funds allow) May 2013 Draft site reports from study in Asia June 2013

Final workshop phase 2 July 2013 Draft analytical report from study in Asia July 2013

Final written report from study in Asia August 2013 DURATION, AMENDMENT, AND TERMINATION This IAA is in effect for FY 2012 – FY 2013 and may be amended by signed written agreement between the NCI/NIH and NSF. The NCI/NIH or NSF may terminate this agreement by signed written notice provided, at least ninety days in advance. The IAA may be terminated immediately by the signed written agreement of all parties. RESOLUTION OF DISAGREEMENTS Should disagreement arise under this agreement, or amendments and/or revisions thereto, which cannot be resolved at the Assistant Director (NSF/ENG) and Deputy Director (NCI) level, the area(s) of disagreement shall be slated in writing by each Party and presented to the other Party at the Director or equivalent level for consideration.

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Sharon GerechtAssistant Professor

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Office: MD 116Phone: (410) 516-2846 Email: gerecht@jhu.eduCurriculum Vitae

Research Interests

Our research is focused on employing engineering fundamentals to study basic questions in stemcell biology and applying these for tissue repair and regeneration.

Specifically, we study the interactions between stem cells (SCs) and their microenvironment w ith thelong term goal to engineer artificial SC microenvironments capable of guiding vascular differentiation,delivery and regeneration. Our research program is based on the integrated and advanced use oftissue engineering system components and is grounded in fundamentals of interfacial science andengineering and SC biology.

Publications

Gerecht-Nir S, Dazard J-E, Golan-Mashiach M, Osenberg S, Botvinnik A, Amariglio N, Domany E, RechaviG, Givol D and Itskovitz-Eldor J. Vascular gene expression and phenotypic correlation duringdifferentiation of human embryonic stem cells. Dev Dyn 2005; 232:488-498.

Gerecht S, Burdick JA, Ferreira LS, Townsend SA, Langer R, and Vunjak-Novakovic G. Hyaluronic acidhydrogel for controlled self-renewal and differentiation of human embryonic stem cells. Proc Natl Acad SciU S A. 2007; 104:11298-11303.

Gerecht S*, Bettinger* CJ, Zhang Z, Borenstein J, Vunjak-Novakovic G, Langer R. The effect of actindisrupting agents on contact guidance of human embryonic stem cells. Biomaterials. 2007; 28:4068-4077.

Figallo E*, Cannizzaro C*, Gerecht S*,Burdick JA, Langer R, Elvassor N, Vunjak-Novakovic G.Microbioreactor arrays for controlling cellular microenvironments. Lab Chip. Special issue on Cell andTissue Engineering in Microsystems. 2007; 7: 710 - 719

Gerecht S, Townsend SA, Pressler H, Zhu H, Nijst C.L.E, Broggeman J, Nichol J, Langer R. A porousphotocurable bioelastomer for cell encapsulation and culture. Biomaterials.doi:10.1016/j.biomaterials.2007.07.039.

The Department of Chemical and Biomolecular Engineering, Johns Hopkins University221Maryland Hall 3400 North Charles Street, Baltmore, MD 21218 410-516-7170 (phone) | 410-516-5510 (fax) | chembe@jhu.edu

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PAUL JANMEY, PH.D.Professor of Physiology

Institute for Medicine and Engineering1010 Vagelos Laboratories

3340 Smith WalkPhiladelphia, PA 19104

janmey@mail.med.upenn.edu

Phone: (215) 573-7380Fax: (215) 573-68151

Other Perelman School of Medicine AffiliationsCell and Molecular Biology Graduate GroupPennsylvania Muscle Institute

DegreesPh.D., University of Wisconsin, 1982A.B., Oberlin College, 1976

HonorsRotschild-Yvette Mayent Award, Institut Curie, 1999

Professional AffiliationsAmerican Society for Cell BiologyBiophysical Society

Research Description Our lab studies several aspects of cell mechanics. In oneproject, we produce soft materials, usually hydrogels, towhich cell adhesion proteins are linked to study how thestiffness of surfaces alters cell structure, function, andgrowth. Endothelial cells, fibroblasts, neurons andastrocytes each show unique dependence on substratestiffness, and we seek to understand how they sense andrespond to this mechanical cue. In related work we measurethe structure and viscoelasticity of cytoskeletal polymernetworks using a variety of imaging, scattering, andrheologic methods. Further studies examine how changes incell membrane structure mediated by inositol phospholipidslead to production of signals that remodel the cytoskeleton.?

Representative PublicationsFlanagan, L. A., Ju, Y. E., Marg, B., Osterfield, M., andJanmey, P. A. (2002). Neurite branching on deformablesubstrates. Neuroreport 13, 2411-5

Yin, H.L., and P.A. Janmey. 2003. Phosphoinositideregulation of the actin cytoskeleton. Annu Rev Physiol.65:761-89

Bucki, R., Pastore, J.J., Giraud, F., Sulpice, J.C. andJanmey, P.A. 2003. Flavonoid inhibition of plateletprocoagulant activity and phosphoinositide synthesis. JThromb Haemost 1:1820-8.

Wong, G. C. L., Lijn, A., Tang, J. X., Li, Y., Janmey, P. andSafinya, C. R. (2003). Lamellar Phase of Stacked Two-Dimensional Rafts of Actin Filaments. Phys. Rev. Lett. 91,018103.

Click here for a full list of publications (searches the National Library of Medicine's PubMeddatabase.)

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Parag Mallick

Assistant Adjunct Professor of Biochemistry

B.S., Washington University, St. Louis; Ph.D, Chemistry & Biochemistry, UCLA

Mallick Lab Page | Current Research | Representative Publications | Lab MembersPhone: (310) 423-7600 Fax: (310) 423-1998 E-mail:mallick@chem.ucla.edu

UCLA Department of Chemistry & BiochemistryBox 951569 (post)607 Charles E. Young Drive East (courier)Los Angeles, CA 90095-1569

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Biochemistry Home | Department of Chemistry & Biochemistry Home | MBI Home

Current Research InterestsMolecularly-targeted therapy holds great promise as a new paradigm for treatment. The primary research interests of my lab centreon developing and applying systems approaches to quantitatively describe organisms' physiologic states towards the goal ofenabling personalized, predictive medicine. We are currently developing experimental techniques and computational methods forquantitative proteomic profiling and pattern discovery in order to identify prognostic fingerprints. To validate fingerprints, rapidlyclassify samples, and better understand the chemical processes underlying proteomic technologies, we are developingcomputational and experimental tools for the discovery and application of proteotypic peptides. In addition, we are developingtools to integrate genomic information with proteomic information so as to better elucidate the genome and to develop moredetailed models of regulation. Our general hope is to apply systems biology's complimentary computational and experimentalmethods in hopes that experimental results motivate large-scale computational studies, which initiate new experimentalexplorations. We hope this synergistic combination will provide insight into the relationship between molecular phenomena andorganismic phenomena.

Background

The knowledge of the complete gene set of a species is providing the opportunity to systematically study the organization andexpression of genes and their products. We are now able to interpret DNA and protein sequences in terms of structure,biochemical function, cellular networks and cellular control systems. Organismic states, both healthy and diseased, arehypothesized to arise from the alteration of systems' normal network structures through a combination of genetic modifications andenvironmental agents. Whole cell, and whole organism, genome-wide analysis of gene expression, protein expression, proteinstate (e.g. glycosylation, phosphorylation) and related differential analyses in differentially perturbed systems have been widelyapplied to study biological processes and disease states. Consequently, genome- and proteome-based techniques are rapidlypermitting the examination of cellular processes and their relationship to physiologic effects in a greater detail than previouslypossible, enabling better characterizations of pathologic states, such as cancer.

Quantitative differential proteomics, defined as the comparison of relative protein changes in different samples, an importantcomponent of the emerging sciences of systems biology and functional genomics, provides accurate and comprehensivequantitation of the components of differentially-perturbed cell systems. The technology is expected to facilitate the detection andidentification of diagnostic or prognostic markers, to identify proteins for use as therapeutic targets and to provide insights intobiological processes.

Differential genomic and proteomic analyses assume that specific alteration in the molecular composition and/or organizations ofconstituent molecules distinguish cells or organisms in different states; alterations consequential to a specific state, may serve asdiagnostic markers. For instance, protein markers like PSA for prostate cancer, progesterone receptors for breast cancer andalpha-fetoprotein for testicular cancers. On the other hand, alterations causal to the induction of a specific state reveal fundamentalbiological control mechanisms and relationships between cellular and physiologic processes identifying potential therapeutictargets. Examples include the Ras oncogene targeted by inhibitors of farnesyltransferase and the transmembrane tyrosine kinaseHer-2/neu, a target of antibody-based therapies.

Discovering Serum Markers Using Glycopeptide Enrichment

Quantitative proteomic analysis of blood serum seeks to detect and identify prognostic and diagnostic markers. Blood serum ishighly accessible and contains enormous information about organismic physiologic state; when blood circulates through the body,proteins secreted from cells, shed from cell surfaces and released from dead cells are deposited to the blood serum. Thephysiologic state, the genetic background of the individual and pathological changes in organs, such as cancer, can affect serumprotein composition. Blood serum is also readily-accessible for diagnostic purposes. A key problem with the proteomic analysisof serum and many other body fluids is the highly skewed composition of blood serum, which is dominated by a few highly-abundantproteins; albumin alone represents over 50% of total serum protein content. Enrichment methods are typically employed, as therange of abundance of serum proteins is approximately 12 orders of magnitude, whereas the dynamic range of a massspectrometry is only 4 orders of magnitude.

Our strategy for serum marker discovery is outlined here: First, serum from annotated patients is enriched for glycopeptides.

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Owen J.T. McCartyE-mail: mccartyo@ohsu.eduPhone: 503-418-9307Fax: 503-418-9311Alt Phone: 503-418-9350

Current AppointmentsAssociate Professor, Department of Biomedical Engineering Associate Professor, Department of Cell & Development Biology

OfficeCenter for Health and Healing3303 SW Bond Avenue Mail code: CH13B

Rm #13033Education

BS, Chemical Engineering, State University of New York at Buffalo, 1997Ph.D, Chemical & Biomolecular Engineering, Johns Hopkins University, 2002

Department(s)Biomedical Engineering

BiographyDr. McCarty received his Ph.D in Chemical & Biomolecular Engineering from Johns Hopkins Universitywith dissertation work focused on the role of platelets in cancer metastasis and thrombosis. As aWellcome Trust Postdoctoral Fellow, he continued his research in the area of thrombosis, examiningthe signaling pathways governing platelet cytoskeletal reorganization, at the Department ofPharmacology, Oxford University and Centre for Cardiovascular Sciences, University of Birmingham,UK.

Research InterestsDr. McCarty's research is focused on understanding the interplay between cell biology and fluidmechanics in the cardiovascular system. In particular, his research into the balance betweenhydrodynamic shear forces and chemical adhesive interactions has great relevance to underlyingprocesses of cancer, cardiovascular disease, and inflammation.

Research Project(s)Thrombosis and Hemostasis

Research Group(s)Cardiovascular and Blood ResearchVascular Biology and Vascular Tissue Engineering

Selected Publications

1. McCarty OJ, Mousa SA, Bray PF, Konstantopoulos K. Immobilized platelets support human coloncarcinoma cell tethering, rolling and firm adhesion under dynamic flow conditions. Blood 2000 Sep;96(5): 1789-1797

2. Abulencia JP, Tien N, McCarty OJ, Plymire D, Mousa SA, Konstantopoulos K. Comparativeantiplatelet efficacy of a novel nonpeptide GPIIb/IIIa antagonist (XV454) and abciximab (c7E3) in flowmodels of thrombosis. Arteriosclerosis Thrombosis & Vascular Biology. 2001 Jan; 21(1): 149-156

3. Burdick MM, McCarty OJ, Jadhav S, Konstantopoulos K. Cell-cell interactions in inflammation andcancer metastasis. IEEE Engineering in Medicine and Biology 2001 May; 20(3): 86-91

4. Mousa SA, Abulencia JP, McCarty OJ, Turner NA, Konstantopoulos K. Comparative efficacy betweenthe GPIIb/IIIa antagonists, roxifiban and orbofiban, in inhibiting platelet function in flow models ofthrombosis. Journal of Cardiovascular Pharmacology 2002 Apr; 39(4): 552-5560

5. McCarty OJ, Jadhav S, Burdick MM, Bell WR, Konstantopoulos K. Fluid shear regulates the kineticsand molecular mechanisms of activation-dependent platelet binding to colon carcinoma cells.Biophysical Journal 2002 Aug; 83(2): 836-48

6. McCarty OJ, Tien N, Bochner BS, Konstantopoulos K. Exogenous eosinophil activation convertsPSGL-1-dependent binding to CD18-dependent stable adhesion to Platelets in shear flow. AmericanJournal of Physiology: Cell Physiology 2003 May; 284(5): C1223-34

7. Hanley W†, McCarty OJ†, Jadhav S, Tseng Y, Wirtz D, Konstantopoulos K. Single-moleculecharacterization of P-selectin/ligand binding. Journal of Biological Chemistry 2003 Mar; 278(12):10556-61. †equally contributing first authors

8. McCarty OJ, Abulencia JP, Mousa SA, Konstantopoulos K. Evaluation of platelet antagonists in in-vitro flow models of thrombosis. Methods of Molecular Medicine 2004 Aug; 93: 21-34

9. McCarty OJ, Zhao Y, Andrew N, Machesky LM, Staunton D, Frampton J, Watson SP. Evaluation of therole of platelet integrins in fibronectin-dependent spreading and adhesion. Journal of Thrombosis

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Munn LabResearch topics include: leukocyte mechanics andtumor physiology

OVERVIEW GROUP MEMBERS PUBLICATIONS CONTACT

PROGRAM AFFILIATIONS

Radiation Oncology Research

Edwin L. Steele Laboratory forTumor Biology

Lance L. Munn, PhDAssociate Professor of Radiation OncologyHarvard Medical School

Associate BiologistEdwin L. Steele Laboratory for Tumor Biology

Research Summary

As part of the Edwin L. Steele Laboratory for Tumor Biology, research at the Munn Laboratory focuses on blood vessel structureand function in normal and pathological conditions. Within this broad area, I have projects that address:

Leukocyte Trafficking and Blood Dynamics

A physiological inflammatory response requires margination, adhesion and extravasation of leukocytes which then migrate tothe region of insult. Some aspects of this process occur in tumors, but in general, the immune response is ineffective. Usingmathematical modeling validated by experiments, we have characterized the physical mechanisms that encourage leukocyteadhesion in normal vasculature. These mechanisms are inefficient in tumor vessels due to the abnormal flow conditions andnetwork topology. We are investigating the possibility of altering the fluid dynamics in tumors to encourage infiltration of blood-borne immune cells. Because our tools for studying blood dynamics are fundamentally robust, we can also use them toanalyze thrombosis, sickle cells and the mechanics of atherosclerosis.

Transvascular Transport

Heterogenous permeability of tumor vasculature makes it difficult to deliver drugs via systemic injection to all cells in a tumor.The goal of this project is to determine the mechanisms of spatial and organ-specific dependence of vascular leakage intumors. A better understanding of the mechanisms of barrier modulation will allow the development of strategies for improvingdrug delivery to all regions of solid tumors.

Cell and Vessel Morphogenesis During Angiogenesis

In many normal physiological responses, endothelial cells and the blood vessel networks they form undergo dramaticchanges in morphology and function. Examples include angiogenesis in wound healing, vessel dilation/hyperpermeability ininflammation, and endometrial angiogenesis in the female reproductive cycle. Endothelial cells, in cooperation with otherstromal cells, have to accomplish these diverse changes by responding to a limited number of growth factors including VEGF,PlGF and bFGF. We are using a systems biology approach to understand how the various growth factors and cells cooperateto produce these seemingly diverse functions. Because tumor angiogenesis relies on many of these same growth factors andcellular mechanisms (but in an abnormal, poorly controlled way), these studies will allow a better understanding of tumorangiogenesis and anti-angiogenic therapy.

Cancer Cell Intravasation

During the initial stage of metastasis, cancer cells must breach the vessel wall and enter the circulation. Despite intenseresearch in this area, the cellular mechanisms by which this occurs are poorly understood. Some tumors seem tometastasize as single rogue cells, while others travel in groups or clusters; some seem to actively migrate into the vessel,while others may be passively pushed. Using gene array analysis and carefully designed coculture systems, we areassessing the mechanical and cellular determinants of the initiation of metastasis.

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Cynthia A. Reinhart-KingDept: Biomedical Engineering

Title: Assistant Professor

Address: 302 Weill Hall

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email: CAK57@cornell.edu

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CYNTHIA A. REINHART-KINGBiography

Cynthia Reinhart-King is an Assistant Professor in theDepartment of Biomedical Engineering at CornellUniversity, and a member of the graduate faculty inMechanical and Aerospace Engineering and the CornellNanobiotechnology Center. She obtained undergraduatedegrees in chemical engineering and biology at MIT.While there, she was awarded the Randolph G. WeiAward for "research at the interface of the life sciencesand engineering." As a graduate student at theUniversity of Pennsylvania in the Department ofBioengineering, she received a Whitaker FoundationGraduate Fellowship to support her thesis work onendothelial cell mechanobiology. She then completedpostdoctoral training as an Individual NIH NRSApostdoctoral fellow in the Cardiovascular ResearchInstitute at the University of Rochester. Dr. Reinhart-King's current research interests are in the areas ofcell-biomaterial interactions, cell mechanics, cancermetastasis and vascular cell signaling. Her lab uses amultidisciplinary approach, drawing from cell andmolecular biology, biophysics, and biomechanics toquantitatively examine the mechanisms of tissueformation and disease progression. Her lab is funded bythe National Institutes of Health, the National Scienceof Foundation, the American Heart Association, and theAmerican Federation for Aging Research. Additionally,she is a project leader in the NIH-funded U54 CornellCenter on the Microenvironment and Metastasis. Shehas received the Rita Schaffer Young InvestigatorAward, the Biomedical Engineering Society's highest recognition for a young faculty member,and the 2010 Sonny Yau '72 Excellence in Teaching Award from the Cornell College ofEngineering.

Research Interests

The research conducted by Cynthia Reinhart-King focuses on elucidating the basic principles ofcell adhesion and cell-biomaterial interactions for applications relating primarily to thecardiovascular system. The central mission of this work is to understand the mechanisms thatdrive tissue formation. This work uses a multidisciplinary approach involving principles from cellbiology, biophysics, biomaterials and biomechanics to guide the development of materials fortissue engineering applications and the development of novel therapeutics. Of particularinterest are the physiology of blood vessel formation and the pathophysiology of vasculardisease.

At a molecular level, this work involves characterizing the role of intracellular structural andsignaling proteins in governing cell adhesion and tissue development specifically as it pertains toblood vessel formation. At the cellular level, the properties of the extracellular matrixenvironment, both chemical and mechanical, are manipulated and exploited to controlendothelial cell behaviors such as growth, adhesion and migration. At the tissue level, this workincludes elucidating the properties of the extracellular matrix that foster healthy tissueformation from individual cell populations. Biophysical and biochemical techniques are exploitedto quantitatively characterize cell behavior in both normal and diseased states. Using TractionForce Microscopy, our group was the first to quantify the forces exerted by endothelial cells ontheir substrate in response to both chemical and mechanical cues during cell spreading andadhesion, providing key insights into the molecular mechanisms of cell-biomaterial interactions.The ultimate goal is to determine governing parameters that can used to predict and controlcell behavior in order to form new tissues. Knowledge gained in these areas will provide insight

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WTEC Highlights

Duane Shelton

January, 2012

August 27, 2008

Acknowledgements

…and over 400 expert panelists, thousands of foreign hosts

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WTEC Past

• WTEC is a non-profit that leads in international R&D t b iR&D assessments by peer review

• Funded by peer-reviewed ENG awards• Studies are jointly funded by several agencies• ITRI is the small business subsidiary of WTEC• Both were spun off from Loyola University

Maryland in 2001Maryland in 2001

Related Studies (Sponsors)

• Systems Biology (NSF, DARPA, DOE, EPA, NASA, NCI, NIST)

• Brain-Computer Interfaces (TATRC, NSF, NIBIB, NINDS, 2 foundations)

• Simulation-Based Engineering & Science(NSF, NASA, DOE, NIST, NIBIB)

• Nano2 (NSF, USDA)• Stem Cell Engineering (NSF, NCI, NIST)

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WTEC Future: New in FY2012

• Converging Technologies for Societal Benefit (ENG MPS SBE EPA t l ) 12/15/11(ENG, MPS, SBE; EPA, et al.) 12/15/11

• Physical Science for Oncology (NCI, NSF) 1/18/12

• Systems Engineering and Education for Manufacturing (4 ENG divisions) 1/19/12

• BioImaging R&D (NSF, NIH) 2/7/12g g ( , ) / /• Bidding on NNCO and NITRD contracts

Purposes of Study

Guide and justify U.S. research investments Look for good ideas abroad (tech transfer) Look for opportunities for cooperation and

collaboration Compare U.S. R&D programs and status with

those abroad

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WTEC Methods

Write grant proposals that can pass peer reviewreview

Establish a coalition of sponsors who have resources to make it happen

Recruit a great panel from sponsor nominations

Conduct the study effectively; sponsors participate in decisions—like where to go

Maintain good host relations, so we can return in future studies

Publish an outstanding report

Report Editing

Our reports are of academic quality with f ll it ti tfull citations, etc.

Analytical chapters written by experts Site reports are merely an appendix

They are edited several times We always have to extract chapters

from holdouts Published in 9 books; we now have

Springer series with 4 published Distribution by paper media pales in

comparison to Web downloads

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WTEC Staff for This Study

Frank Huband PhD VP for OperationsFrank Huband, PhD, VP for OperationsHassan Ali, MS, Project ManagerGrant Lewison, PhD, EU Advance

ContractorHaydon Rochester, PhD, Senior EditorHemant Sarin, MD, WTEC Science Policy

Fellow

More Information

Briefing books for this meeting Hassan Ali at 301-461-2109 or

hali@ScienceUS.org http://wtec.org http://wtec.org/private/aphelion/

(password available from Hassan)(password available from Hassan)

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Milestones for WTEC Milestones for WTEC International Studies

• Preliminary Phase• Study Tour Planning PhaseStudy Tour Planning Phase• Study Tour Phase• Working Reports Phase• Final Report Phase

Acknowledgments

…and over 400 expert panelists, thousands of foreign hosts

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Milestones for WTEC International Studies Preliminary Phase

• Fund raising – solicit resources necessary for the study, WTEC contacts program officers in the field of study to invite them to project p g y p jmeetings

• Sponsors’ meeting – potential sponsors discuss scope and Statement of Work (SOW) for project, determine if there is enough funding available to begin a study, and nominate panelists and panel chair

• Chair’s meeting – study chair presents benefits of study to potential sponsors, including draft scope of project, names of panelists and of other potential sponsors (sometimes addressed at Sponsor’s meeting)

• Kickoff meeting – introduce study panelists, update draft scope, ff g y p , p p ,assign technical topics to panelists, provide preliminary bibliometric study, decide if U.S. baseline workshop is necessary (if so, schedule workshop and speakers), choose U.S. research to be presented to foreign hosts, schedule foreign study tour and workshop dates, and define process for preparing a list of questions for foreign hosts; WTEC engages advance contractor(s), creates public and private websites for information exchange, and schedules monthly conference calls with panelists; study chair defines structure of final report; WTEC project manager assumes responsibilities, including serving as a general point of contact (POC)

Milestones for WTEC International Studies Study Tour Planning Phase

• Baseline workshop – study panelists (an approximately ten selected U.S. researchers) present the state of art in the U.S. or North America; draft

t f di i d li d t th k h d d t d t report of proceedings is delivered at the workshop and updated to serve as a quid pro quo for foreign hosts; WTEC reimburses speakers for travel and lodging

• Advance work – bibliometric study identifies sites with significant number of publications to supplement expert panel knowledge; panelists and sponsors introduce advance contractor to as many hosts as possible; advance contractor sends panelist bios and lists of questions to foreign hosts, schedules itinerary, and arranges travel and lodging (one or more conference calls provide coordination); advance contractor provides detailed itinerary one-week before departure; panelists make their own

l i f h i l i f h i htravel reservations from their own travel reservations from their home across the Atlantic or Pacific, but advance contractor makes arrangements in foreign locations

• Literature survey – in parallel with advance work, panelists survey recent literature, especially papers and websites of the sites to be visited; WTEC and advance contractor help provide information; to attract audience for the final workshop, WTEC publicizes workshop via online calendars and sends postcards to memebers of targeted professional society lists

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Milestones for WTEC International Studies Study Tour Phase

• Study tour week – panelists fly to a common arrival location (e.g., Frankfurt to Tokyo) on Friday/Saturday; on Sunday, panelists meet with Frankfurt to Tokyo) on Friday/Saturday; on Sunday, panelists meet with advance contractor to receive final itineraries; panelists usually divide into two groups; each group selects a head of delegation and a scribe for each site to be visited; head of delegation presents to foreign hosts the purpose of study, U.S. baseline information, and a brief bios of panelists; each site’s scribe records minutes of meeting, collects handout materials provided by hosts, and copies host’s electronic presentations on a memory stick; each group will be issued an international cell phone and a digital voice recorder; most delegations meet for breakfast daily to compare notes; the schedule is intense (panelists will be stressed but they will learn a lot)

• Closing meeting - after a week on tour, the panel reassembles on Friday i h d i h l l i i i h d l devening at the departure airport hotel; a closing meeting is scheduled on

Saturday morning:1. Scribes present as 5-minute review of main points of interests at each site

(takes 1-2 hours)2. Panelists list the most interesting preliminary findings of the week3. A schedule is determined for delivery of site reports to other panelists via

project manager4. Any changes to the workshop or report assignments are considered

Panelists may depart for home on Saturday afternoon or Sunday

Milestones for WTEC International Studies Working Reports Phase

• Site reports drafted and distributed – two weeks after the end of the study tour; these reports serve as data for panelist to write about sites of the study tour; these reports serve as data for panelist to write about sites that they did no visit; a bonus is paid to scribes for timely delivery; WTEC final reports have standard site report formats that include : site visited, data of visit, names of U.S. visitors, names of host participants, background, funding sources and commercialization, R&D activities, and summary and conclusions; WTEC edits and sends site reports to individual hosts for review; as an interim product, WTEC usually points a bound booklet of draft site reports for sponsors

• Final workshop – approximately two months after the last site visits, a one day public meeting with a webcast that will be publicly broadcast is held at NSF from 8am 4pm Panelists will come the evening before for a held at NSF from 8am -4pm. Panelists will come the evening before for a working dinner to review consensus findings for the chair's exec summary presentation. Panelists will send a power point presentation a week before for the webcast files; WTEC will compile them into a conference proceedings and posts proceedings on public Web site (Missing presentations will be shown with a blank page with that person's name;) panelists can change their .ppt slides, as long as they don't insert additional ones. WTEC director of Publications assumes project responsibilities as POC for editing final report

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Milestones for WTEC International Studies Final Report Phase

• Each panelist drafts a chapter – technical chapters are due one month after the final workshop; study chair writes an executive one month after the final workshop; study chair writes an executive summary and introductory chapter on the study process; each panelist writes an analytical chapter on a subtopic of the field (the page quota is 10 pages, including figures and references); previous WTEC reports serve as style guides; figures should have source citations, usually from host presentations captures on memory sticks; panelists receive a bonus for timely delivery of chapters

• Draft analytical report completed – site reports are included in an appendix; WTEC edits and sends draft reports to sponsors and hosts sometimes to peer reviewers; study chair sponsors and hosts, sometimes to peer reviewers; study chair receives a bonus if the overall manuscript is compiled in a timely manner; WTEC posts the draft report on the private website for review and prints a paper draft for sponsors.

• Final report – WTEC edits to academic specifications, prints 100 paper copies, and posts report in PDF format on public Web site; if resources are available, WTEC will seek publication of final report by a commercial publisher

WTEC Project Management

• Frank Huband, Vice President for Operations, fhuband@scienceus.org, 202-290-5230, fax 703-527-4805

• Hassan Ali, Project Manager, hali@scienceus.org, office 301-461-2109. Hassan should be copied on all emails and should be able to give a status check on the project at any time

• Faith Wang, Panelist Contracts, fwang@scienceus.org, f 717-299-7130, fax 717-299-7131

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Travel Arrangements

From/To USPanelists may make their own travel arrangements with Panelists may make their own travel arrangements with Travelocity.com (or the like) and WTEC will reimburse them. If they use our agents, airline tickets are charged directly to WTEC. Our agents are: Kristin Friant, Frosch Travel: kristin.friant@frosch.com, 410-433-9300, and Joan Porte, Joan’s Travel Partners: Joanstravel@verizon.net, 703-533-2210 Coach class only

Travel In EuropeDr. Grant Lewison, Advance Contractor: grantlewison@aol.co.uk, 44-20-8878-5646. Grant usually grantlewison@aol.co.uk, 44 20 8878 5646. Grant usually performs bibliometric studies to provide metrics on which countries are ahead in the field; Grant helps identify the best people and places to visit abroad.

Travel in Asia Dr. David Kahaner, Advance contractor: kahaner@atip.or.jp

Travel Reimbursement

Reimbursement Formhttp://www.wtec.org/travel/2010AprWTECTravelReimbursementForm.xls

For timely reimbursement, please download form and submit the completed form via mail, fax, or email to:

WTEC, Inc.Att: Christopher McGee, cmcgee@scienceus.org1653 Lititz Pike #417Lancaster, PA 17601717-299-7131 (fax)

Travel Reimbursement PoliciesSee http://www.wtec.org/travel/

Sponsor Meeting Attendees. Jan. 18, 2012. NSF, Room II-585 U.S Government Agencies

Larry Nagahara NIH/NCI nagaharl@mail.nih.gov 301-594-9018 Nastaran Kuhn NIH/NCI nastaran.kuhn@nih.gov 301-451-2472 Nicole Moore NIH/NCI nicole.moore@nih.gov Semahat Demir NSF/ BES sdemir@nsf.gov 703-292-7950 Mike Roco NSF/ENG/OAD mroco@nsf.gov 703-292-7032 Ted Conway NSF/CBET tconway@nsf.gov 703-292-7091 Chris Kelley NIH/DHHS kelleyc@mail.nih.gov 301-451-4778 Martha Lundberg

NIH/NHLBI lundberm@nhlbi.nih.gov

Jerry Lee NIH/NCI leejerry@mail.nih.gov

Clark Cooper ENG/CMMI CCOOPER@nsf.gov

Sandra Laney U.S. Department of State

LaneySJ@state.gov 202-663-3244

Krastan Blagoev NSF/MPS/PHY kblagoev@nsf.gov 703-292-4666

Other Agencies

Nancy Sung Welcome Trust (NSF)

nsung@nsf.gov; nsung@bwfund.org

Panelists Paul Janmey (Chair)

School of Medicine, U. Pennsylvania

janmey@mail.med.upenn.edu

Expert Advisors

WTEC Duane Shelton WTEC shelton@scienceus.org 717-659-7714 Frank Huband WTEC fhuband@scienceus.org 202-290-5230 Hassan Ali WTEC hali@scienceus.org 301-461-2109 Hemant Sarin WTEC hemantsarin74@gmail.com Matt Henderson WTEC mhenderson@scienceus.org Grant Lewison Europe Adv. g.lewison@ucl.ac.uk 44-20-8878 5646