Summary
National Heart, Lung, and Blood Institute
Working Group on
Tissuegenesis and Organogenesis for Heart, Lung, and Blood Applications

National Institutes of Health
Two Rockledge Centre
Bethesda, MD
August 13, 1999

TABLE OF CONTENTS

• Background
• Introduction
• Basic Science and Technology
• Clinical Problems
• Summary of Recommendations
• Agenda
• Roster

BACKGROUND

On August 13, 1999, an NHLBI Working Group Meeting on Tissuegenesis and Organogenesis for Heart, Lung, and Blood Applications was held at the National Institutes of Health, Rockledge Two Building. The one-day meeting, sponsored by the NHLBI Tissuegenesis/Organogenesis Interest Group (TOG), consisted of a series of discussions on five major topics as they related to advancing research toward the goal of growing tissues and organs for the repair or replacement of those lost or damaged due to injury or disease. The topics included: 1) Developmental Biology of Stem Cells, Tissues and Organs; 2) Gene Regulation in Tissues and Organs; 3) Structural and Functional Histoarchitecture; 4) Vascularization of Growing Tissues and Organs and; 5) Response to Injury. The Working Group Participants (see attached roster) addressed the state of the science and provided recommendations on ways to provide broader opportunities for research and development in this field to prepare for the future.

INTRODUCTION

Tissuegenesis and organogenesis are defined here as the formation of new tissues or organs to replace damaged or absent function. In one paradigm, progenitor cells or stem cells that will produce the major tissue-specific cell type (e.g., cardiac myocytes, lung epithelium) are seeded directly into the damaged site, or a temporary scaffold is placed in the site, to initiate a regeneration process, and supporting connective tissues (blood vessels, lymph, nerve, immune) are induced to grow in from surrounding tissue. For example, it is desirable to repair the infarct-induced damage to cardiac tissue rather than replace the entire heart by transplant. This might be achieved by implantation of fetal or neonatal cardiomyocytes or stem cells into the damaged tissue to restore contractility. In a second paradigm, tissue is grown in vitro for subsequent transplantation. This paradigm is used clinically in the hematopoietic system and is under development for others. In the case of cardiac repair, for example, a "patch" of tissue or tissue precursor might be grown in vitro and then grafted onto diseased tissue.

Heart, lung, blood, and vascular tissuegenesis/organogenesis share some common scientific challenges, and can all benefit from some common technological approaches. These include identifying appropriate sources of stem cells, leaning how to accomplish cell expansion and differentiation, and understanding the principles necessary for formation of complex multi-cellular structures, including vascular networks. At the same time, each application area also presents its own challenges that relate to specific clinical problems and the unique biology and physiology of the tissue. Research should thus proceed along two parallel fronts, cross-cutting basic science and technology, and focused approaches aimed at well-defined clinical problems.

BASIC SCIENCE AND TECHNOLOGY

Common themes include: (1) understanding how tissues develop during embryogenesis and how damaged tissue successfully heals itself (i.e. in the absence of fibrosis), and; (2) identifying both cellular elements (e.g., circulating or resident progenitor cells) and environmental elements (matrix, cytokines, growth factors) that are required for tissue healing. These will permit regeneration to be achieved reproducibly and cost-effectively in a clinical setting. Several specific topics are included in these two themes.

Progenitor Cell Biology

In one model of tissuegenesis, differentiated tissue would be generated from progenitor or stem cells either ex vivo, by recruitment to the site of interest, or used in vitro in combination with a scaffold to create new tissue. One critical area of fundamental investigation is in progenitor cell formation and differentiation. (In some cases this may rely upon stem cells/progenitor cells with capacity for self renewal). This requires: 1) development of cellular markers to distinguish such cells; 2) identification in the adult of where such cells reside; 3) understanding of factors and matrix needed to support their growth and morphogenesis and; 4) evaluation of methods to "erase" differentiation and thereby generate cells capable of becoming progenitor cells of other tissue. Regardless of whether stem cells, rather than more differentiated tissue-derived populations, are ultimately used in an application, the long-term function and maintenance of the tissue requires appropriate tissue kinetics and turnover. Thus progenitor cell biology is a foundation for tissuegenesis and organogenesis.

A key bottleneck in the development of stem cell-based therapies is the relative paucity of markers for stem cells and lineage progression, particularly for systems other than the hematopoietic system. Development of markers is hindered by the time-consuming nature of assays for differentiation, or the frank absence of reliable assays in some tissue systems. Methods for rapid identification of putative markers on candidate cell populations are also relatively poorly developed. Resources directed to both these areas would greatly enhance research in tissuegenesis of all systems, including those of interest to the NHLBI.

Relatively few tissues have been characterized as having highly accessible progenitor cells; the presence of highly plastic and accessible stem cells from other compartments, especially the circulation or bone marrow, would expand the possible applications. Harvesting stem cells from lung, for example, may be excruciatingly complex, while harvest from peripheral blood is relatively straightforward. Emerging data suggest there are stem cells which are highly plastic, and this fact has enormous implications for tissuegenesis.

Little is known about the environmental effects leading to stem cell self-renewal, replication and differentiation. To address this, better assays are needed to follow the fate of transplanted stem cells in vivo; such studies could go hand in hand with research in stem cell-based gene therapy. It will likely be desirable to expand stem cell populations in vitro. To accomplish this, rapid/high-throughput in vitro assays are needed to systematically investigate effects of environment (e.g., growth factors and cytokines) on cell differentiation, proliferation, and mobilization.

Obtaining stem cells by isolation from natural sources in the body may ultimately prove to be unfeasible, or too cumbersome for routine clinical use. One alternative approach to generate cells capable of appropriate differentiation may be to "erase" the differentiation of somatic cells through approaches such as altering DNA methylation. This could potentially increase the availability of cells and allow patient-specific tissues to be generated on a wider basis. A second approach is use of embryonic stem cells; this approach requires methods for reproducible, controlled differentiation of these cells, a goal far from being met.

Angiogenesis

With few exceptions, tissues in the heart, lung, and blood system contain dense capillary networks which are richly perfused. For metabolically active tissues like heart and marrow, parenchymal cells are generally within a few tens of microns from a capillary. This limits oxygen diffusion in such highly cellular and active tissue to about 150 microns. Tissue vascularization is thus a key, and a limiting, process for tissuegenesis and organogenesis.

For cells implanted directly into a site, angiogenesis would have to be derived from surrounding tissues. Despite the identification of many regulating molecules, and despite examples of angiogenesis in response to a single growth factor, many key issues regarding mechanisms of angiogenesis remain. In experimental systems in vivo, it is not clear that vessels induced by a single molecule are functionally equivalent to normal vessels. This is not surprising, as normal physiological vessel growth is regulated by multiple signals working in a concerted fashion. In addition, the capillary beds of tissues are highly specialized to meet the needs of the tissues, including such specializations as blood brain barrier and fenestrated endothelium. Yet, the integrated signals which lead to the specific architectures in tissues such as lung are not well-understood. In humans, the results of growth factor/gene trials are mixed, and there is a strong need for well-controlled clinical trials with functional endpoints. Little is known about the temporal regulation of molecular players already identified and about hierarchies of signaling during development of vascular networks in healing tissues. Mechanisms of vessel regression are also relatively poorly understood. In this regard, the role of endothelial cell-pericyte interactions in regulating microvascular growth, function, and stability has not been well characterized.

For tissues grown in vitro, moving beyond the dimensions of a few hundred microns will require creation of a vascular network capable of anastomosing with vessels at the site of implantation. This is a complex problem requiring multiple advances in science and technology, as tissues of any reasonable size must include vessels ranging from capillary beds to arteries/veins and true perfused capillary beds have not yet been demonstrated in vitro. Formation of larger vessels in vitro must also include understanding of cell-interactions in formation and maintenance of tissue structure, and the role of mechanical forces. Vessels grown in vitro must be tested with appropriate functional assays, such as demonstration of non-thrombogenicity.

Local Environment – Analysis of Matrix & Growth Factor Interactions

Lung tissue can regenerate after an acute injury in some patients. Heart is not reported to generate new myocytes in the adult, even after injury. Two major research areas important for tissuegenesis/organogenesis arise out of these observations. First, what environmental cues attract the cells that ultimately lead to repopulation? Are there circulating stem cells which are drawn to sites of injury, and if so, what are the signals that induce them to colonize a specific site? Second, what are the factors that prevent regeneration of injured structures? Many physiological factors represent the net outcome of positive and negative factors acting together; understanding both types of signals is necessary to achieve the desired balance.

Classically, these signals are thought of as matrix (fixed molecules) and growth factors (diffusible molecules), with particular molecules assigned to one category or the other. In regeneration processes, matrix is being degraded and soluble fragments, as well as bound growth factors, are being released. Further, with the accumulating data indicating overlapping signaling pathways between adhesion receptors and growth factor receptors, and with examples of membrane-bound juxtacrine systems such as notch/delta, the lines of distinction between adhesion molecules, growth factor ligands, and growth factor receptors are blurred.

Identification of molecules present is thus only one component of understanding the process in a way it can be harnessed for tissuegenesis. There is a need for engineering analysis and models of how signals are presented physically and temporally, and how the cells integrate these multiple overlapping signals to generate a response. Such quantitative analysis and modeling is essential to provide a design basis for manipulation of the environment to achieve tissuegenesis. For example, it has been observed that epidermal growth factor (EGF) inhibits cell migration in some assays, and stimulates cell migration in others. When the effects of EGF are considered in the context of ECM adhesion and a biophysical analysis of cell migration, these results are not contradictory. The process of cell migration depends in a biphasic manner on the cell-substrate adhesion strength, exhibiting a maximum at intermediate levels of matrix adhesion, and EGF serves to decrease cell adhesion. Thus, when cells are plated on an intermediate density of matrix, EGF may decrease cell adhesion to the point that cells can barely get a grip on the substrate (migration inhibition). On the other hand, if the same cells are plated on a high matrix density, the decrease in adhesion induced by EGF may stimulate cell migration. Additional insights into the control of cell growth and differentiation, and how to manipulate these processes for use in tissuegenesis, might come from the field of cancer biology.

Local Environment – Scaffold Fabrication & Control of Cell Behavior

Generation of functional tissue or organ structure requires a scaffold to guide the overall shape and three dimensional organization of multiple cell types; i.e, a 3D physical set of cues. At one extreme, this may be the existing tissue structure (e.g., in repopulation of marrow with infused stem cells and in the proposed regeneration of heart muscle by introduction of stem cells). The existing tissue structure may not provide a conducive environment, though, if severely damaged and/or replaced by fibrous tissues, and thus synthetic alternatives must be considered. The field of biomaterials is only at the beginning stages of providing synthetic degradable materials that can mimic key aspects of ECM; indeed, the design rules for what is needed are only now being elucidated. Techniques for creating scaffolds with complex architecture and chemistry – e.g., to provide a template for a branching vascular network – are also relatively nascent and must be developed significantly beyond current stages to address the needs of vascularized tissues.

Although there remains much potential in the use of growth factors and cytokines, alone or in conjunction with matrix, technical and scientific barriers to clinical success are still significant. Tissuegenesis overall requires the orchestrated unfolding of a series of processes arranged in both temporal and spatial hierarchies, and each of the individual processes, such as angiogenesis, is likewise governed by an array of interlocking steps. Delivery of cytokines or other factors in a physiologically relevant context remains a technical challenge; drug delivery techniques allow sustained delivery, but not necessarily controlled on the time scale or length scale necessary for tissue-genesis. It is also becoming more apparent that few processes can be effectively stimulated by a single factor, and thus reliance on exogenously added factors becomes even more technically challenging.

CLINICAL PROBLEMS

Clinical challenges in heart, lung, blood, and vascular tissue engineering are wide ranging and at different stages of development. Methods for regenerating the hematopoietic system are by far the most well-developed, yet clinical demands for new therapies are still pushing advances. The complexity of lung structure places it among the most challenging of tissue and the one that has been pursued least by tissue engineering approaches.

Heart

An estimated 4.6 million Americans suffer from symptomatic heart failure. At end stage heart failure, transplantation is the only therapy. However, transplantation is limited by donor availability to 2600 per year. Thus, many patients die awaiting a transplant. Common causes of heart failure include coronary artery disease, cardiomyopathy, congenital abnormalities, and hypertensive heart disease. In principle, cell engineering and transplant procedures might be achieved to treat heart failure due to these underlying diseases. For example, after a myocardial infarct, scar might be replaced with muscle. This could be from cardiac cells (fetal, neonatal, or engineered adult cells) or perhaps stem cells that are injected directly into the scar area using either direct visualization or percutaneous technology. Another interesting concept would be to grow a beating patch that could be applied to the scarred tissue or sewn into the heart after removal of the scarred tissue. Another possibility is total heart replacement with a tissue engineered heart. However, with the current state of the art in tissue engineering, including the fact that generation of a perfused capillary network in vitro has not yet been demonstrated, the goal of creating an entire new organ for transplant remains distant. It is thus prudent to focus on addressing substantial clinical problems that rely on solving single steps. One such clinical problem is the need to repair and improve contractile function of the failing heart by local cell implantation or surgical addition of a myocardial patch.

Another promising area of cardiovascular tissue engineering involves cardiac valves. Congenital and acquired diseases of the heart valves and great arteries are leading causes of morbidity and mortality. Current prosthetic or bioprosthetic replacement devises are imperfect due to one or more ongoing risks including thrombosis, limited durability, infection, and the need for re-operations due to lack of growth. Through a tissue-engineering approach, progress could be made in producing more physiological valve replacements.

Vasculature

To date, whereas clinical experience with large diameter vascular grafts (e.g., for aortic aneurysm) has been generally favorable, no good substitutes exist for small vessels of less than 6 mm diameter. Small diameter vascular grafts are critical for the treatment of peripheral vascular and coronary artery disease. Grafts currently in use for bypass surgery are obtained either from the patients' own vessels or are constructed of synthetic materials. In either case, problems with vessel availability and high rates of failure due to thrombosis and occlusion make the use of these grafts less than optimal. Efforts to develop tissue-engineered vascular grafts with improved long-term patency have been undertaken. and there have been some promising developments particularly with the addition of physiologically relevant mechanical stress to the growing tissue. Long term performance of such grafts is pending and human performance data are not yet available.

Blood

A number of important opportunities for clinical application exist. Although bone marrow, peripheral blood stem cell, and cord blood stem cell transplants are being carried out in increasing numbers, the very high rate of morbidity and mortality signal the need for modification of existing conditions as well as development of new approaches. An overview of research needs necessary for optimal clinical applications is as follows. First, the properties of stem cells predictive of successful engraftment are undefined. Correlation between in vitro assays and in vivo results must be improved to provide better predictors of clinical outcome. A serious complication following stem cell transplantation is graft-versus-host disease (GvHD). GvHD might be reduced if not eliminated by development of methods to tolerize the recipient with allochimerism. It is also clear that less toxic conditioning regimens are badly needed. Graft rejection occurs frequently, yet ways to predict rejection and avoid it are poorly described. Collection of inadequate numbers of engraftable cells from peripheral blood or umbilical cords continues to be a problem. Although some modest success in expansion in culture has been reported, it remains very difficult to produce adequate numbers of totipotent stem cells without differentiation into unengraftable progenitors. Much research remains to be done so that adequate numbers of engraftable stem cells can be produced ex vivo. New approaches may emanate from recent reports of production of hematopoietic stem cells from neural cells. Indeed, the plasticity of stem cells exhibited by neural cell differentiation offers exciting opportunities to manipulate stem cells.

Opportunities for clinical application of these technologies is tremendous. For example, autoimmune disorders can be effectively treated by stem cell transplantation. However, wider application of such therapy is now limited by availability of antigenically compatible stem cells as well as toxicity of conditioning regimens. Future efforts in bone marrow transplantation should be directed at broader application. Efforts should be extended to make allogeneic transplantation more feasible. In particular, bone marrow transplantation needs to be more cost effective in order to be available to a wider range of patients. Application in older patients especially needs to be addressed, as the population grows older and health among older persons improves in general. Currently, bone marrow as well as heart, lung and liver transplantation are procedures which are restricted or discouraged in older patients or in patients with other underlying disease. These restrictions need to be reevaluated continually, and the limitations lifted as soon as possible.

Finally, increasingly sophisticated medical therapy is increasing the need for transfusable blood components. Production of blood components ex vivo has the potential to minimize reliance on voluntary blood donation to meet these increasing needs. In the area of red cell replacement, there is still no alternative for transfusion. However, it is likely that in the next few years, new oxygen carrying solutions will be developed which can alleviate up to two-thirds of current transfusions of red blood cells in the U.S. These products are acellular and therefore have plasma persistence times measured in days, not weeks. However, there are no plans to provide alternatives for the other 1/3 of red cell transfusions which are in patients with chronic disease, or bone marrow failure who require regular transfusions. Long-term culture of human red blood cells is a possible alternative to allogeneic red cell transfusion, but presently is limited by inability to maintain long-term cultures or for prolonged storage of cells produced in vitro. Beyond improvements in culture conditions and requirements, attention needs to be directed at massive scale-up. In this regard, industry needs to be recruited to apply methods which traditional academic researchers are not familiar with. In addition, platelet usage in the U.S. continues to increase as cancer treatments intensify and new surgical procedures become available to more patients. At present there are no promising alternatives to the use of human platelets in surgical patients who have been significantly hemodiluted or in other thrombocytopenias. Efforts for in vitro culture of such cells on large scale, by commercially- viable methods should be encouraged.

Lung

Lung disease often progresses far beyond local tissue damage and involves the whole organ. For several lung diseases including emphysema, pulmonary fibrosis, and primary pulmonary hypertension transplantation is the only current therapy for end stage lung disease. However, transplantation is constrained by donor availability and, consequently many patients die awaiting a lung transplant. Therefore, a grave clinical need to seek alternatives to lung transplantation exists. The lung, however, probably represents the greatest challenge to tissuegenesis and organogenesis. It is comprised of a wide variety of highly differentiated cell types organized in a uniquely complicated architecture. For instance, lung parenchyma, airways, and the pulmonary vasculature consist of over 40 different cell types. Moreover, ventilation-perfusion matching is an imperative for function. Restoration of complex vascular networks must accompany tissue repair.

From lung injury during infancy that results in bronchopulmonary dysplasia to idiopathic pulmonary fibrosis that occurs in middle and later years of life, the lung represents an organ whose function cannot be permanently replaced by any mechanical device as might occur with mechanical assist devices for heart, such as pacemakers and valves, or for kidneys, such as routine dialysis. Major disease categories accounting for replacement needs include pulmonary fibrosis, chronic obstructive pulmonary disease, cystic fibrosis, pulmonary hypertension and others.

New insights into tissuegenesis of the lung will likely emerge from an improved understanding of injury and repair. Options for repair are likely to surface as studies on developmental mechanisms in the lung continue, particularly in the area of systems engineering, i. e. matching vascularization with structural replacement. In order to take advantage of opportunities for intervention, study of normal lung growth and development, as well as those on repair and regeneration must continue to determine whether common mechanisms are involved in these processes. Since early developmental events may be determinative of lung sequelae later in life, information on fetal lung development as well as post-natal events such as alveolar septation mechanisms is required. Comparison of differences between factors elaborated during lung development with those which can be identified as active during post-pneumonectomy lung growth should provide a guide to deciphering the link between regeneration and growth of the collateral circulation. Recent work has shown that pulmonary vascular development requires crosstalk with the developing epithelium for normal development. Markers of early vasculogenesis in the developing lung have indicated that endothelial precursor cells are associated with pulmonary epithelial cells as soon as the lung primordial buds evaginate from the foregut endoderm. These data indicate that the initiation of lung epithelial morphogenesis and lung vasculogenesis are synchronized and appear to be co-dependent processes. It is highly likely that a similar signaling gradient exists among cell types participating in repair.

It is likely that relatively few cell types play a pivotal role in development and maintenance of the normal architecture of the lung. Functional activity of cell types and cell-cell interactions could provide important information on how the architecture of the lung is determined. For instance, studies on how specific cell types might propagate along the highly differentiated matrix of the lung and airways could provide a model to approach lung construction problems via utilization of endogenous scaffolding. Although a primordial stem cell may not exist as such in the lung, opportunities for de-differentiation and subsequent controlled functional differentiation do, indeed, appear to exist. Expanding knowledge in this area may permit identification of the most hospitable location for transfer of small patches to replace function in disease.

The importance of mechanical factors should not be ignored and the development of natural or synthetic materials for the manufacture of airway stents should not be overlooked. Likewise, the opportunity to implant tracheal rings that are vascularized and enervated for purposes of local repair should be explored. It is likely that the future holds much promise for a more functional approach to tissue and organ replacement through tissue engineering methodology. Progress in this area will depend upon the successful merger of molecular medicine and bio-engineering.

SUMMARY OF RECOMMENDATIONS

As a result of the Working Group Meeting, the following recommendations for basic science and technology development, and clinical areas to be addressed, have emerged.

1. Basic Science and Technology Common to Heart, Lung, and Blood

• Progenitor Cell Biology--Progenitor cell formation and differentiation including: 1) Development of cellular markers to distinguish progenitor cells; 2) Location of progenitor cells in the adult; 3) Understanding growth factors and matrix molecules needed to support their growth and morphogenesis and; 4) Evaluation of methods to "erase" differentiation and thereby generate cells capable of becoming progenitor cells of other tissue.

• Vascularization-- Research in two major areas is needed: 1) For cells or patches of tissue implanted directly into a site in vivo, knowledge of the temporal regulation of known molecular players and signaling hierarchies during development and regeneration of vascular networks, and mechanisms of vessel regression; 2) For tissues grown in vitro, ways to create vascular networks ranging from capillaries to arteries/veins that are capable of anastomosing with vessels at the site of implantation.
  
  
• Matrix and Growth Factor Interactions--1) Understanding what environmental cues, including growth factors and matrix molecules, attract the cells that ultimately lead to repopulation of sites of injury and identifying where such cells originate. 2) Understanding the factors that prevent regeneration of injured structures. 3) Developing quantitative analyses and modeling of how signals are presented physically and temporally, and how the cells integrate these multiple overlapping signals to generate a response which could provide a design basis for the manipulation of the environment to achieve tissuegenesis.
  
  
• Scaffold Fabrication and Control of Cell Behavior--Techniques for creating scaffolds with complex architecture and chemistry must be developed significantly beyond current stages to address the needs of vascularized and innervated tissues.
  
  2. Functional Applications of Science and Technology to Clinical Problems
  • Heart--1) Engineer cardiac cells, myocardial patches, or total hearts for implantation to restore, renew or replace the contractile function of the failing heart. 2) Tissue engineer valves to treat congenital or acquired diseases of the heart valves and great arteries. 3) Develop physiologic biomechanical environments to optimize development of engineered cardiac tissues.
    
    
• Vasculature–Further efforts to develop tissue-engineered vascular grafts with improved long-term patency need to be undertaken particularly with the addition of physiologically relevant mechanical forces to the growing tissue.
  
  
• Blood–1) Hematopoietic stem cells: assays for stem cell products that predict engraftment in patients, transplant regimens with reduced toxicity, regimens that induce tolerance, methods to identify, purify, and expand specific populations of lineage committed cells, and generation of "generic" stem cell populations from bone marrow (i.e., mesenchymal stem cells, muscle, liver, etc. 2) Transfusable blood components: culture-derived red blood cells and platelets (or their precursors), artificial oxygen carrying solutions, methods to prevent immunization by such cells or artificial blood components, and large scale production and storage methods are needed.
  
  
• Lung--1) Novel approaches such as using micro-patches of primordial lung tissue to replace gas exchange areas destroyed by dysfunctional tissue. 2) Effects of mechanical factors on function of newly generated or transplanted tissues will need to be assessed.

WORKING GROUP ON
TISSUEGENESIS/ORGANOGENESIS
OF HEARTS, BLOOD VESSELS, LUNGS AND BLOOD

Location: Rockledge II, Conference Room 9116
Date: Friday, August 13, 1999
AGENDA

ROSTER
WORKING GROUP MEETING ON
TISSUEGENESIS/ORGANOGENESIS

Co-Chairs:
William J. Martin II, M.D.
Department of Medicine
Indiana University Medical Center
1001 West 10th Street, OPW 425
Indianapolis, IN 46202-2879
Telephone: (317) 630-8445
Fax: (317) 630-6386
Email: wjmartin@iupui.edu

Linda G. Griffith, Ph.D.
Div Bioeng & Envrnmt
Building 66, Room 466
77 Massachusetts Ave.
Cambridge, MA 02139
Telephone: (617) 253-0013
Fax: (617) 258-5042
Email: griff@mit.edu

Participants:
Ronald G. Crystal, M.D.
Cornell University Medical College
1300 York Avenue, Box 96
New York, New York 10021
Telephone: (212) 746-2258
Fax: (212) 746-8383
Email: rgcryst@mail.med.cornell.edu

Patricia A. D'Amore, Ph.D.
Schepens Eye Research Institute
20 Staniford Street
Boston, MA 02114
Telephone: (617) 912-2559
Fax: (617) 912-0128
Email: pdamore@vision.eri.harvard.edu

Mark C. Fishman, M.D.
Massachusetts General Hospital
Dept. of Medicine
149 13th St., 4th Floor
Charlestown, MA, 02129-2060
Telephone: (617) 726-3738
Fax: (617) 726-5806
Email: fishman@cvrc.mgh.harvard.edu

Robert Kloner, M.D.
Good Samaritan Hospital
Department Of Heart Institute/Research
1225 Wilshire Boulevard
Los Angeles, CA 90017
Telephone: (213) 977-4050
Fax: (213) 977-4107
Email: rkloner@goodsam.org

Gloria D. Massaro, M.D.
Georgetown University School of Medicine
Lung Biology Laboratory
Pre-Clinical Science Bldg. GM-12
3900 Resevoir Rd.
Washington, D.C. 20007
Telephone: (202) 687-4967
Fax: (202) 687-8538
Email: massarog@gusun.georgetown.edu

David J. Mooney, Ph.D.
Department of Biologic and
Materials Science
University of Michigan School of Dentistry
1011 North University Ave.
Ann Arbor, MI 48109-1078
Telephone: (734) 764-2560
Fax: (734) 647-2110
Email: mooneyd@umich.edu

Peter J. Quesenberry, M.D.
University of Massachusetts Medical Center
Cancer Center
373 Plantation Street
Suite 302, Biotech Two
Worcester, MA 01604
Telephone: (508) 856-6958
Fax: (508) 856-1310
Email: quesenbp@ummhc.org

Marlene Rabinovitch, M.D.
The Hospital for Sick Children
University of Toronto
555 University Avenue
Toronto, Ontario M5S 1X8
Canada
Telephone: (416) 813-5918
Fax: (416) 813-7480
Email: mr@sickkids.on.ca

Shahin Rafii, M.D.
Cornell University Medical College
Department of Hematology/Oncology
Room C-606
1300 York Avenue
New York, NY 10021
Telephone: 212-746-2070
Fax: 212-746-8866
Email: srafii@mail.med.cornell.edu

H. Steven Wiley, Ph.D.
University of Utah
Dept. of Pathology
50 North Medical Drive
Salt Lake City, UT 84132
Telephone: (801) 581-5967
Fax: (801) 581-4517
Email: wiley@path.med.utah.edu

Jeffrey A. Whitsett, M.D.
Children's Hospital Medical Center
Division of Pulmonary Biology
3333 Burnet Ave.
Cincinnati, OH 45229-3039
Telephone: (513) 636-4830
Fax: (513) 636-7868
Email: whitj0@chmcc.org

Robert M. Winslow, M.D.
Sangart, Inc.
11199 Sorrento Valley Rd.
San Diego, CA 92121
Telephone: (619) 455-0966
Fax: (619) 455-6993
Email: rwinslow@sangart.com

Last Updated April 2011