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Neural Stem Cells: Developmental Insights with Potential Therapeutic Lessons Evan Snyder Harvard Medical School Incoming

Director and Professor, Program for Developmental & Regenerative Cell Biology Burnham Institute Incoming Director Basic Science Research, Division of Newborn Medicine, Department of Pediatrics University of California, San Diego

A series of reciprocal molecular communications between exogenous neural stem cells (NSCs) and their host environments -- in addition to cross-talk between NSCs -- have provided a basis for some appealing possibilities for CNS therapy in certain situations as well as providing a better understanding of the fundamental role of NSCs in development. First, abnormal hosts seem to alter the fate and behavior of immature, uncommitted NSCs. For example, during phases of active neurodegeneration, factors seem to be transiently elaborated to which NSCs may respond by migrating (even long distances) to degenerating regions & differentiating specifically towards replacement of dying neural cells. NSCs may "attempt" to emulate in the brain what hematopoietic stem cells do in the periphery: repopulation & reconstitution of ablated regions. These "repair mechanism" may reflect the re-expression of basic developmental principles (particularly during particular temporal "windows" following injury) that may be harnessed for therapeutic ends. In addition, NSCs in their native state (even without specific genetic engineering) appear to alter host tissue such that a more favorable milieu is established for the protection of imperiled host cells and/or the activation of intrinsic regenerative processes. Gene Therapy (2002) 9, 613-624

Continued:
Some of these process may derive from cues that NSCs provide to each other as one cell in a clone interacts with, "instructs" the fate of, or "chaperones" its sister cells through molecular cues; host cells may be bystanders who benefit from this interaction. Many of these factors are expressed in a regulated fashion, quite different from the mode by which they might be expressed via a viral vector, nonbiological system, or even an alternative non-neural cell type. Interestingly, attempting to augment one "intrinsic" factor within the neural stem cell may actually alter an apparent delicate intra-cellular "balance" in unanticipated and sometimes undesirable ways. Therefore, a better understanding of how neural stem cells regulate their expression of various "therapeutic" molecules is also pivotal to understanding both development and repair. Taken together, and based on observations in various animal models of CNS injury & degeneration, NSCs may theoretically serve both as mediators of cell replacement and as vehicles for protein delivery (e.g., including the expression of factors that might enhance differentiation, neurite outgrowth, connectivity, & neuroprotection). When combined with certain synthetic biomaterials, NSCs may be even more effective in "engineering" the damaged CNS towards reconstitution by, once again, "tapping" into fundamental developmental processes.

Gene Therapy (2002) 9, 613-624

Progenitor Cells in the Adult Substantia Nigra

The Salk Institute Dieter Chichung Lie Fred. H. Gage

In Parkinson's disease, progressive loss of dopaminergic neurons in the substantia nigra pars compacta (SN) leads to debilitating motor dysfunction. One current therapy aims at exogenous cellular replacement of dopaminergic function by transplanting dopamine producing cells into the striatum, the main projection area of the SN. However, results utilizing this approach have shown variable success. It has been proposed that cellular replacement by endogenous stem/progenitor cells may be useful for therapeutic interventions in neurodegenerative diseases, including Parkinson's Disease. Although it is widely accepted that progenitor cells are present in different areas of the adult central nervous system, it is unclear whether such cells reside in the adult SN and whether they have the potential to replace degenerating neurons. We have identified a population of actively dividing progenitor cells in the adult SN, which in situ give rise to new mature glial cells but not to neurons. However, when removed from the SN, progenitor cells display a broader neural potential and differentiate into all three major CNS lineages, including neurons. Transplantation of freshly isolated SN progenitor cells into the adult hippocampus showed that these cells also have a neuronal potential under in vivo conditions. Science 287:1433-1438

In summary, these results indicate that: Neural progenitor cells reside in the adult SN; Neural progenitor cells have an intrinsic potential to give rise to new neurons; The environment of the adult SN is not permissive for neuronal differentiation of intrinsic neural progenitor cells; This developmental potential of SN progenitor cells might be useful for future endogenous cell replacement strategies in Parkinson's disease.
Science 287:1433-1438

Selective Amplification of Stem Cells for Clinical Application

Jan W. M. Visser Vice President Stem Cell Research Viacell, Inc.

The widespread clinical use of stem cells will depend on the ability to access and manufacture stem cells in large numbers with high quality. A selective amplification protocol was developed, which efficiently expands the hematopoietic stem cell compartment for transplantation while minimizing the content of differentiating and maturing cells. Using cord blood as a source of stem cells the average expansion of CD34+/CD38- is 40-fold in a 2 week period of selection and culture. This product is being tested in a clinical trial.

We are also exploring the plasticity of stem cells from cord blood in a rat stroke model. In this case the selectively amplified cord blood derived product had an effect when i.v. injected into a rat model for brain stroke, where it significantly enhanced functional recovery of rats which had received an infarct relative to control animals having received the same debilitating procedure. Manufactured stem cells from cord blood using selective amplification may provide a source of immunologically stem cells for use in this and other neural diseases. Additionally, in our hands stem and progenitor cells for pancreatic islets and beta-cells can also be cultured and expanded ex vivo for several months in an undifferentiated state. They produce islet-like structures when induced to differentiate. These cells are tested in animal models of type 1 diabetes. Although the frequency of expanded pancreatic stem cells is low (<1%) we intend to explore the use of our selective amplification system to increase the efficiency and purity of these culture systems. We are presently evaluating the utility of such amplification systems in the manufacture of pharmaceutical grade cellular compositions across these and other cell types.

Plasticity of Circulating Adult Bone Marrow Stem Cells

Tim Brazelton, Ph.D., Research Scientist Stanford University School of Medicine

Generally, it has been thought that only embryonic stem cells (ES) are pluripotent (capable of generating all or most cell types) while stem cells in the adult were considered to be restricted in their regenerative potential to the tissues in which they reside. However, observations from our laboratory and others have found that when adult bone marrow cells are administered intravascularly into adult recipients, that these cells home to various organs where they give rise to cells typical of that tissue, such as neurons, skeletal myofibers, liver hepatocytes, and intestinal and respiratory epithelium.

Continued:
Since our experimental methods take great care to reproduce physiological conditions (i.e., no intervening tissue culture, no tissue injury or disease in recipient, intravascular delivery) our results suggest that these "transdifferentiation" events are likely to occur in healthy adults from cells that normally circulate. While most reports have found that under physiological conditions (i.e., no overt injury) that "transdifferentiation" is a rare event, we've found that in some cases that bone marrow appears to be a robust source of tissue stem cells. For example, one year after bone marrow transplant and in the absence of injury, up to 10% of the myofibers in one skeletal muscle contain bone marrow derived nuclei. Our current efforts involve the establishment of novel in vivo and in vitro screens to identify the circulating progenitor cells and factors involved in these "transdifferentiation" events. Such knowledge will likely have enormous potential for the development of novel therapeutics which take advantage of the dramatic and inherent plasticity of circulating adult stem cells.

What is a stem cell? Classic definition is based on function and is still agreed upon by essentially all investigators: - Stem cells are cells capable of: proliferation self renewal production of a large number of differentiated progency regeneration of tissue after injury flexibility in the use of these options Additional characteristics classically associated with stem cells that may need to be re-evaluated given recent data: Tissue specific Undifferentiated (unspecialized) Linear, irreversible differentiation pathways A stem cell is a cell ( i.e., a discrete, identifiable entity)

What is a stem cell? (Revisited)


Tissue specific? -- No: Not limited to specific tissue Undifferentiated / unspecialized / primitive? -- Yes: Hard to identify; not many markers -- No: Some stem cells are differentiated:
- Bulge stem cells (skin) express keratin 5 and 11 - Multipotent neuronal stem cells ciliated cells, GFAP and nestins

They seem pretty specialized:


- Monitor environment & dynamic response to diverse signals * Plasticity requires active maintenance * NSC exist throughout brain generate progeny in only specific locations - Migrate throughout body - Generate diverse cell types

Linear, irreversible differentiation pathway?


--No: * Cloning; Forced cell fusion * Dedifferentiation

Stem cells are heterogeneous


-- Stem cells are different to isolate
* Purification protocols typically enrich; * Degree of enrichment balanced with the capture of stem cell capacity

A stem cell is a cell ( i.e., a discrete, identifiable entity)?


-- Since many types of cells from distinct tissues can be recruited to hehave as stem cells: -- We suggest that the concept of a stem cell most accurately refers to a cellular function that is recruitable in many cell types ( i.e., a cellular program like apoptosis) -- Cells classically identified as stem cells likely have the greatest propensity to act as stem cells but other cells may be recruited to function as stem cells if the need arises.

Conclusions:
Dramatic plasticity exists within adult bone marrow-derived cells Cell fate transitions are physiological events Cell fate transitions are often rate but can be increased -- inhibition of local regeneration populations -- increased need for tissue regeneration Stem cell function may not be limited to stem cells

Cell Expansion in the AastromReplicell(tm) Cell Production System: Automated Single Pass Perfusion for Cell Expansion

Steven N. Wolff, M.D. Vice President Medical Research Aastrom Biosciences, Inc.

Cell therapy is currently used for hematologic restoration, immunologic vaccination and tissue regeneration with further promise due to broad transdifferentiation of adult marrow derived stem cells. Aastrom has developed a fully automated, GMP compliant, computer directed, closed system for the growth of these human cells. The presentation will highlight the production, cell characterization, pre-clinical and clinical studies of various cells grown in the ARS/CPS platform by addressing these specific goals:
1. To demonstrate the ARS/CPS platform and single pass perfusion 2. To show laboratory and clinical studies of hematopoietic cell expansion 3. To show substantial expansion of mesenchymal stem cells 4. To demonstrate the automated production of antigen loaded dendritic cells 5. To demonstrate the automated production of antigen specific T-cells 6. To discuss the capability of the ARS/CPS to grow and expand other cell types

An "Identity Crisis" For Stem Cells

Naohiro Terada, M.D., Ph.D Associate Professor University of Florida

Over the past few years, a traditional cell lineage dogma has been challenged by a group of studies showing plasticity in various types of adult-derived stem cells. Traditionally, stem cells in the adult body were thought to be limited in potential, such that a hematopoietic stem cell in the bone marrow, for instance, could only become a blood cell. However, recent reports have demonstrated that transplantation of hematopoietic stem cells, for example, can lead to production of muscle cells, liver cell types, cells of the brain, and other cell types. This research has caused much excitement over what is called 'transdifferentiation,' or the ability to acquire broadened differentiation potential. Work focusing on the ability of adult stem cells to become a variety of other cell types has been a hot topic, making implications for plasticity in tissuespecific adult stem cells. Decidedly, this work has inferred that these various adult cells could have the same multi-potency as embryonic stem (ES) cells. The ability to avoid using ES cells for clinical use is attractive, as it would avert much of the current political and ethical controversy over use of fertilized human eggs in research.

In article recently published, however, we demonstrated that cell fusion could be an alternative explanation for apparently "transdifferentiated" cells. A major question remains to be answered: does transdifferentiation truly occur in committed adult cells in our body? Continued work is necessary for a complete understanding of the exciting but unclear process of transdifferentiation.

First Products of Stem Cells from Stem Cell Technology: A Progress Report

Allan Robins, Ph.D. Chief Scientific Officer Bresagen

Prospective cell types for treatment of neurlogical disease in including Parkinson's have reached the rodent testing stage. We take a forward look at the challenges concerned with moving products into clinic.

PANEL: STEM CELLS: PATENTS, LICENSING AND INTELLECTUAL PROPERTY


MODERATOR:
Elizabeth R. Donley Legal Counsel WARF/WiCell

PANELISTS:
David Earp, J.D., Ph.D. Vice President, Intellectual Property Geron Corporation Kurt G. Briscoe, J.D. Partner Norris McLaughlin & Marcus, P.A Kevin Noonan, Ph.D., Partner McDonnell Boehnen Hulbert & Berghoff Bill Warren Partner Sutherland Asbill & Brennan LLP

As interest in adult and embryonic stem cells has grown, issues of intellectual property in, and licensing of rights to, the cells have been at the forefront of many discussions. The panelists addressed these issues and the audiences have opportunities to put questions to the panel for discussion.

Regenerative Medicine for Brain and Spinal Cord Repair

Annemarie Moseley, Ph.D., M.D. Acting CEO Layton BioScience, Inc.

Mission Statement
To develop and commercialize cell therapy products for repair of disorders of the central nervous system, such as stroke, Parkinsons disease, Huntingtons disease and spinal cord injury

Large Unmet Need


As the population ages, diseases of the central nervous system have an increasing impact on society Incidence of stroke increasing and one third of all strokes are left with debilitating effects which require assisted living There are no medical products available which can repair the nervous system and it cant repair itslef Challenge: decrease functional loss and introduce repair of the brain and spinal cord

LBS-NeuronsTM: Proprietary Cell Product


Differentiated, human neural progenitors Highly characterized: * Form functional synapses * Secrete neurotransmitters Non-tumorigenic Reproducible manufacturing process, produced under GMP on-site at Layton

LBS-NeuronsTM: Preclinical Studies in Stroke Long-term engraftment of LBS-Neurons in rats and primates No abnormal growth or differentiation No migration from site of implantation Functional improvement in animals receiving LBS-Neuron implants compared to controls No tumorigenicity

LBS-NeuronsTM: Phase 1 Trail in Stroke

Safty and feasibility confirmed in 12 patients with chronic stroke Seven of twelve patients had clinically significant improvement in motor function Positive PET scans correlated with improved motor function

LBS-NeuronsTM: Phase 2 Trail in Stroke


Dose escalation safety study * 18 patients * 5 and 10 million cell dose and control groups Two clinical centers: * University of Pittsburgh * Stanford University Enrollment completed Early data suggests that potential cognitive and sensory changes as well as motor changes

Summary
The promise of neural cell therapy lies in the reestablishment of neural connections or of the replacement of the milieu needed by regenerating neurons. Layton has led the field of neuronal cell implantation by providing a reproducible GMP neuronal cell product as an alternative to fetal cell transplants. Layton has patented the process for producing large quantities of pure cultures of LBS-Neurons from NT2/D1 cells. Early data demonstrated that LBS-Neurons could polarize, form functional synapses and undergo site-specific differentiation. Layton has now completed more than 2 year followup in the Phase 1 trial of implantation of LBS-Neurons into the basal ganglia region of the brain of chronic stroke patients.

Summary (Cont.)
The company has recently completed treatment of all patients in a Phase 2 clinical trial in chronic stroke patients with higher doses of the cells. In addition to PET scans, and motor function testing, cognitive studies have been performed in these chronic stroke patients. Recent data have additionally suggested an impact of the neurons in acute cortical stroke. The company anticipates entering clinical studies to further evaluate the implantation of LBS-Neurons in Huntington's disease patients and chronic spinal cord injury patients.

Overcoming the Supply Issue: Cell and Organ-Based Therapeutics

David Ayares, Ph.D. VP, Technology PPL Therapeutics

The primary bottleneck in the development of lifesaving therapies for such diseases as diabetes, parkinson's, alzheimers, and whole organ failure (heart, kidney, lung, pancreas), is the limited supply of appropriate donor cells and organs for transplantation. Xenografts from alpha 1,3 gal knockout pigs, in combination with tolerance regimes, provide the promise of an unlimited supply of cells and organs, which can be applied to humans without risk of rejection. Cloned pigs with knockout of alpha 1,3 galactosyl transferase gene are now available to begin the pivotal pig-to-primate preclinical experiments. In addition, significant progress has been made in the differentiation of embryonic stem cells into a variety of therapeutic cell types, which brings the promise of cures (not just therapies) for a number of debilitating diseases. This presentation addressed recent progress in xenotransplantation, as well as, new methods of generating and differentiating pluripotent stem cells.

Tissue Engineering Using Stem Cells: Current Applications and Future Potential

Andreas Kern, Ph.D. Principal Scientist Advanced Tissue Sciences, Inc.

Introduction
Tissue Engineering has the potential to become a major source for Regenerative Medicine. The combination of stem cells and scaffold technology may allow for the generation of transplantable materials for, among others, cardiovascular and musculoskeletal applications. However, several obstacles remain for the acceptance of such transplants. These challenges include the use of embryonic versus adult stem cells, an understanding of pathways to direct differentiation into specialized tissues, and the issue of alloreactivity.

Pluripotent Cells for Tissue Engineering


Adult origin
- Bone marrow derived (Pittenger et al., 1999) * chondrocytic differentiation * osteocytic differentiation * adipocytic differentiation - Adipose tissue derived (Zuk et al., 2001) - Brain derived (Uchida et al., 2000) - Skin derived (Toma et al., 2001)

Embryonic stem (ES) cells - Derivatives of three germinal layers (Thompson et al., 1998) - Cardiomyocytes (L. Field, A. Wobus, Kehat et al., 2001)

Cardiomyocyte Summary
ES cells as potential source for large quantities of cardiomyocytes Challenges:
1) Yield of cardiomyocytes 2) Source of precursor cells 3) Novel perfusion bioreactor technology for tissue survival 4) Synchronized beating

Summary Allogeneic Rejection


Expression of rejection-related molecules may be modulated by ECM and differentiation Human fibroblasts with similar expression pattern do not exhibit acute rejection ES-derived tissues may have a similar potential

Tissue Engineering and Pluripotent Cells


Examples
- Embryonic cardiomyocytes within polymeric sheets (Shimizu et al., 2002) - Osteocytic development in rat (Gao et al., 2001)

Opportunities of cell-scaffold technology


- In vitro growth, matrix deposition and tissue formation - Cryopreservation - Off-the-shelf availability

Challenges:
- Adult vs embryonic cells - Immunology - Perfusion

The Road to Longevity: The Synergy of Centenarians and Stem Cells in Regenerative Medicine

Doros Platika, M.D., Ph.D. President and CEO Centagenetix

Longevity is a heritable human trait, much like height, weight, and susceptibility to diseases such as breast cancer. This was the conclusion of the New England Centenarian Study which, when looking at the characteristics of individuals surviving to very old age, noted that centenarians: tend to cluster in families (both horizontally within a generation as siblings and vertically through generations); delay the onset of the effects of ageing (i.e. are markedly more youthful than their same-age cohorts throughout their lives); escape catastrophic disease throughout their life; and, delay the onset of or escape the diseases associated with ageing (e.g. Alzheimers Disease)

Our primary research and development goal for the next five years is to gain an understanding of the genetic basis for longevity, whether in the negative as the absence of genes conferring susceptibility to particular diseases, or in the positive as beneficial or protective genes directly related to longevity. There is accumulating evidence that not all gene variants (alleles) are created equally the specific gene variant an individual inherits affects susceptibility to a wide range of ailments including diabetes, vascular disease, and dementia. Because the ability to survive to an extremely old age requires evading such calamities, it is expected that centenarians have a relative paucity of these disease alleles. We hypothesizes that a second class of genetic variants affects health and longevity more broadly, and conceptually these may be thought of as disease resistance or longevity promoting genes. For example, genetic differences among enzymes responsible for DNA and cellular repair may account for some of the heritable component of longevity. An individual fortunate enough to possess an extremely effective repair facility may be able to partially negate the detrimental effects of both nature (the environment) and nurture (detrimental genes they may inherit).

Centagenetix plans to gain understanding of the genetic basis for longevity using association studies comparing centenarians to various control and disease populations. Such population genetics studies are an extremely powerful approach to drug target discovery. The reason is simple: association studies seek the genetic basis of disease susceptibility and therefore tend to identify causes over effects. In contrast, other target screens, such as gene expression analysis, confound cause and effect its difficult or impossible to determine whether a change in mRNA expression is an effect, a cause, or coincident with a process being studied. The Holy Grail for investigators doing gene expression analysis would be computational methods which could reconstruct pathways from the massive amount of data these studies generate. This has proven hopeless, and the same will be true for the coming wave of proteomics platforms. With genetic variation this is not an issue: disease alleles promote disease not the converse.

The critical point is that, contrary to industry experience to date, gene targets generated through these types of association studies will be of very high quality, dramatically reducing the number of false positive targets carried through for further study. This will have profound effect in reducing the time and cost associated with target validation, a significant current bottleneck in the drug development process.

Therapeutic Cloning and Alternative Strategies for the Production of Autologous Totipotent Stem Cells

Michael D. West, Ph.D. President and CEO Advanced Cell Technologies

Advanced Cell Technologys (ACT) cell therapy programs are built upon a new class of cells able to form virtually every cell type in the body. This technology platform therefore has unusually broad applications in medicine. These primordial stem cells include Embryonic Stem (ES) cells and other cells from the Inner Cell Mass (ICM) of preimplantation embryos. The biotechnology industry hopes to produce many new therapies from these cells, for instance, neurons for the treatment of Parkinsons disease and spinal cord injury, heart muscle cells for heart failure, cartilage for arthritis, pancreatic cells for diabetes, as well as many others.

As promising as ES cell technology may seem, it does not solve the critical problem of histocompatibility. Human ES cells obtained from embryos derived during in vitro fertilization procedures, or from fetal sources, are essentially cells from another individual (allogeneic). This means that they, or any cells made from them, would be at risk of being rejected if transplanted into a human being. To solve this problem, ACT is performing research on three means to manufacture embryonic cells identical to a human adult, this is to say, autologous embryonic cells.

Somatic Cell Nuclear Transfer: In this technique, commonly designated Human Therapeutic Cloning a patients body cell is combined with an egg cell that has its DNA removed. As a result the body cells DNA is reprogrammed back to an embryonic state, and totipotent stem cells are produced identical to the patient. Parthenogenesis: In this technique a womans oocyte is directly activated without the removal of its DNA to begin development on its own, forming a preimplantation embryo from which totipotent stem cells are isolated. Ooplasmic Transfer: In the reverse of nuclear transfer, ooplasmic transfer involves the removal of the cytoplasm of an oocyte and transferring it into the body cell of a patient thereby transforming the patients cell into a primitive stem cell.

Studies on Organ(1) Regeneration in situ or in vitro


Xu, Rong-xiang, M.D. President of MEBO International

Introduction
This is a tremendous research project in series which started 14 years ago. Our purpose is to initiate and maintain the potential regenerative cells in tissues to proliferate and regenerate new cells to take places the flawed, worn-out, destroyed, or apoptosis cells in vivo and in situ, which assures the well-working structure and function of the tissues or organs. Based on this theory and the successful progresses we made in it, we established Regenerative Medicine.

Purpose and Method


Based on the classifications in Anatomy of Human Function, we divide the whole living human body into 206 functional tissue units. We set up different experiment models by culturing each of these units in vitro. Using these well-established modelswe are doing the research of seeking life regenerative substances(3) which are able to initiate, maintain cells to be alive, to proliferate and to regenerate. And then, we put these life substances back into organism to fulfill the organ regeneration or physiologically repair in vivo and in situ, which reaches our goals to cure the diseases and ensure organ healthiness.

Project Procedures
1Studies on seeking the tissue cells in situ of organ which have the potential to regenerate. 2Taking out these potential regenerative cells to culture in vitro, initiate the proliferation and differentiation of these cells in order to form tissues or organs as same as the ones in situ. 3Studies on seeking the Life Regenerative Substances which are able to initiate, maintain cells to be alive, to proliferate, to different, and to regenerate using the successful procedures and models in vitro. 4 Putting these life substances back into organism to fulfill the organ regeneration or physiologically repair in vivo and in situ.

Key Words
1Tissue Organ: The tissue unit which has the ability to carry out organism functions. 2Potential Regenerative Cell: The cells which have the potential ability of regeneration similar as stem cell but regularly exist in tissue/organ as normal cells. 3Life Regenerative substance: The substances which are able to initiate and maintain cell proliferation, differentiation, regeneration and to form tissue or organs eventually. 4In situThe positions where the cells, tissues or organs exist in organism.

Main contents of this report


1The dynamic study on Potential Regenerative Cell; 2The process of mouse gastrointestinal mucosa regeneration in situ or in vitro; 3Cultivation of mouse pancreas in vitro; 4Hair follicle regeneration in vitro; 5Human skin organ regeneration in situ; 6Clinical studies on tumor cells affected by life regenerative substances.

Results:
1) Establish the technology of normal tissue cell culture in vitro; 2) Fulfilled the human skin organ regeneration in vivo and in situ; 3) Achievements on clinical application of skin organ regeneration for 15 years; 3) Set up some functional tissue organ (such as gastrointestinal mucosa) regeneration models in vitro. 4) Successfully finished 21 life regenerative substances which can fulfill 21 types of functional organ regenerations.

PANEL: COMMERCIAL IMPLICATIONS OF STEM CELL RESEARCH FOR THE PHARMACEUTICAL AND BIOTECH INDUSTRIES
MODERATOR:
Linda Powers Managing Director TOUCAN CAPITAL

PANELISTS:
Sami Hamade V.P., Compass Group Guidant Corporation Rodney Altman Principal Piper Jaffray Ventures Joel F. Martin Partner Forward Ventures Robert Caffarata Director, Emerging Ventures Medtronic Vascular Miles Greenberg Principal A.M. Pappas and Associates

As the pharmaceutical industry prepares for potential involvement in medical breakthroughs afforded by stem cell research and regenerative medicine, venture capital and investment managers on this panel convened to discuss the commercial and financial aspects; both present and future.