Seventh Annual Public Interest Organization Meeting

Stem cell technology is a fast-growing and controversial field of research. The participants at the meeting had an opportunity to attend two sessions during which NHLBI staff described the advances and promise of this research. In two other sessions, the participants had an opportunity to learn about the NIH grants process, priority setting, and strategic planning, and about NHLBI cohort studies and gene research. Each session included a question-and-answer period.

The State of Stem Cell Technology Today: Potential and Progress

NIH 101: The Grants Process, Priority Setting, and Strategic Planning

Stem Cells, Tissue Engineering, and Bioengineering for Therapy: "Oh Wow!" Science from a Clinician's Perspective

NHLBI Cohort Studies and Genetic Research: What Can We Learn and How Much Do We Want to Know?

Drs. John Thomas and Traci Heath Mondoro, Health Science Administrators, Division of Blood Diseases and Resources, NHLBI, spoke about stem cell technology. Dr. Thomas focused on the potential of stem cells—the types, sources, and applications of stem cells and challenges in using stem cells. Dr. Mondoro summarized the progress made in manufacturing a stem cell product-one specific type of regulatory T cells—and the opportunities for using these cells therapeutically. The NHLBI actively supports stem cell research related to heart, lung, and blood diseases and resources.

The Potential of Stem Cells

• stem cells, through self-renewal, can give rise to more stem cells and
• stem cells can differentiate into other cells (for example, transplanted blood stem cells can give rise to all other blood cells).

Having these properties, stem cells are potentially useful in cell therapy for restoring tissues damaged by injury or disease. These cells have a tremendous ability to amplify—that is, produce a large number of cells. The three types of stems cells are:

• Embryonic—blastocyst cells established during the first week of gestation
• Somatic—any "body" cell that is not a reproductive (germ) cell
• Adult—any general non-embryonic or non-germ (e.g., somatic) cell.

Scientists have found stem cells in a range of tissues, including nerve, cornea, mouth, fat, skin, and gut tissues. The NHLBI supports research to identify possible stem cells in blood, lung, and heart tissues. Scientists derived and successfully cultured the first stem cells, which were embryonic stem cells from mice, 25 years ago. Publication of this achievement in 1981 was followed by a 1998 report on the successful derivation of human embryonic stem cells and establishment of stem cell lines from the isolated blastocysts.

Dr. Thomas noted that stem cells may have three levels of potential. Some may be multipotent (e.g., blood stem cells), giving rise to all cells within a tissue or organ. Others may be pluripotent (e.g., embryonic stem cells), giving rise to all cells within the body. And, some may be totipotent (e.g., cells from a fertilized egg), giving rise to all cells within the body and the placenta and other supporting tissues. Scientists have particular interest in pluripotent cells because of their great promise. These cells may be derived from either blastocysts or fetal tissue. Dr. Thomas noted that the process of culturing pluripotent stem cells is difficult, time-consuming, and not always successful.

Stem cells potentially could be used in cell therapy for treating cancers of the blood (e.g., leukemia, lymphoma), other cancers (by stimulating the immune system), genetic diseases (e.g., Fanconi's anemia, sickle cell disease), and tissue damage (e.g., injury to the heart or blood vessels). To treat heart damage, stem cells could be used to replace heart muscle cells, grow new blood vessels, and deliver cell growth factors. Stem cells also could be used to replace damaged or atherosclerotic blood vessels.

Dr. Thomas emphasized that many challenges must be met before stem cells can be widely applied in cell therapy for patients. Considerable basic and preclinical research is still needed. The main research challenges are as follows:

For use of autologous stem cells (i.e., those derived from the patient)—scientists need to determine the best source of these cells within the body, find ways to better identify and obtain the cells, and establish whether the cells can be expanded and differentiated into the cell type needed. In addition, it is not clear whether stem cells or only differentiated cells should be used, how the cells should be delivered, and which factors encourage long-term engrafting and functional integration of the cells into tissue.

For use of allogeneic stem cells (i.e., donor cells)—two questions are paramount: Are the donor cells free of pathogens, genetic disease, and malignant cells? Will the immune system tolerate or reject the donor cells?

Progress Made: Regulatory T Cells

Dr. Mondoro noted that scientists have been able to manufacture only a relatively small amount of stem cells. To scale up production and to ensure the safety of stem-cell products, cell processing centers are needed with both specialized skills and quality control.

Dr. Mondoro described one study supported by the NHLBI to produce large quantities of pure CD4+/CD25+ regulatory T cells, which are derived from hematopoietic stem cells. She explained that T cells are a subset of white blood cells whose final stages of development occur in the thymus. There are three types of T cells: cytotoxic (which destroy infected cells), helper (which proliferate and produce cytokines to "help" other immune cells), and regulatory (which suppress activation of the immune system).

Dr. Mondoro focused on regulatory T cells. She noted that the exact mechanism of their suppressive effects is not known and, yet, their failure to perform can result in autoimmune disease. CD4+ and CD25+ T cells are a small subset of T cells that regulate the function of other immune cells. Dr. Mondoro described the manufacturing process used to extract and culture quantities of pure CD4+ and CD25+ cells from donor blood.

In the NHLBI study, the CD4+ and CD25+ cells are being developed for use in bone marrow transplantation, during which large numbers of these regulatory cells are needed at critical times to balance the dynamics between graft-versus-host and graft-versus-tumor effects. For example, as proposed for a clinical study at the University of Minnesota Cancer Center, regulatory T cells would be infused as adjunctive therapy during stem cell transplantation for patients with a hematologic malignancy and an available matched sibling donor. Dr. Mondoro noted that the CD4+ and CD25+ regulatory T cells also may be useful for replenishing T cell populations needed in patients with diabetes and for suppressing autoreactive myelin-specific T cells in patients with multiple sclerosis.

Dr. Mondoro concluded by noting that the NHLBI currently provides support to three stem cell production centers. Participating in the NHLBI-sponsored Production Assistance for Cellular Therapies (PACT) Group, the centers are located at Baylor College of Medicine, University of Pittsburgh Medical Center, and University of Minnesota. The EMMES Corporation, in Rockville, Maryland, is the coordinating administrative center. The goal of PACT is to provide clinical-grade stem cells to researchers.

Dr. Roth briefly discussed the organizational structure of the NIH, highlighting the NHLBI and the Center for Scientific Review (CSR), which is responsible for reviewing and scoring applications that are submitted to the NIH for research funding. He noted that although the NIH components have separate budgets and individual approaches to allocating funds among various activities, all ICs have similar organizational structures and procedures for funding grants and setting research priorities.

NHLBI Budget

Extramural research—which constituted 91.3 percent of the FY  2005 budget. The funds are awarded as grants and contracts to researchers at universities, medical centers, and private companies. They support investigator-initiated research (amounting to approximately 68.2 percent of the extramural funds), institute-initiated research (approximately 28.5 percent), and training (approximately 3.3 percent). Investigator-initiated grant applications are submitted by researchers who select the research topic. Institute initiatives, in contrast, solicit applications and proposals that address topics selected by the NHLBI.

Intramural research—which constituted 5.7 percent of the FY 2005 budget. The funds are used to support intramural researchers in laboratories on the NIH campus.

Research management and support—which constituted 3.1 percent of the FY 2005 budget. The funds cover employee salaries and overhead, education and outreach programs, and activities such as the annual PIO meeting.

The Grants Process

Dr. Roth summarized the NIH process for peer review of research grant applications. This process differs for investigator-initiated applications and institute-initiated research. He also commented on the review process for research training awards.

Investigator-Initiated Applications

The NIH uses a standardized process for evaluating and selecting investigator-initiated grant applications for funding. The CSR receives all applications and, based on the topic area of the application and on established referral guidelines, assigns each application to a CSR study section and the appropriate IC. The CSR study sections, which are composed of scientific experts in a particular field, meet three times a year to review grant applications. The study sections give each application a score that, when expressed as a percentile, reflects the application's scientific merit relative to other applications they review.

The advisory council of the assigned IC conducts a secondary review of the grant applications assigned to the IC. At the NHLBI, the NHLBAC consists of 12 health research experts and 6 public interest members who meet four times a year. The NHLBI makes the final decision on whether to fund a particular grant based on the CSR percentile score, the NHLBAC recommendation, and budgetary considerations.

Institute-Initiated Research

Ideas for institute-initiated research come from a variety of sources, including NHBLI program staff and scientific experts who participate in Institute-sponsored workshops and task forces. NHLBI staff present proposed initiatives to the NHLBI Board of Extramural Advisors (BEA) for detailed discussion. The BEA, a group of experts representing scientific areas in the Institute's purview, ranks the initiatives. The director of the appropriate NHLBI extramural division and the NHLBI director review the rankings. The NHLBAC provides a final review.

The NHLBI selects initiatives to announce to the scientific community based on the BEA and NHLBAC recommendations and on budgetary considerations. NHLBI staff members then prepare RFAs, PAs, and RFPs to invite researchers to apply for funding.

Like investigator-initiated grant applications, grant applications received in response to RFAs and PAs are reviewed and awarded based on scientific merit. CSR study sections review applications received in response to PAs, and special emphasis panels convened by the NHLBI review applications received in response to RFAs and RFPs.

Research Training

The NIH funds research training through National Research Service Awards (NRSAs) to institutions, who then select their own trainees, as well as through NRSAs to individuals (fellowships). All applications for training awards undergo a competitive review process to determine which applications will be funded.

NHLBI Management of Grants and Contracts

• Division of Heart and Vascular Diseases
• Division of Lung Diseases
• Division of Blood Diseases and Resources
• Division of Epidemiology and Clinical Applications
• Division of Extramural Affairs.

Discussion

Budget Constraints and Research Funding

Dr. Roth noted that current budget constraints may reduce the number of awards the NHLBI is able to fund.

Criteria for Funding Decisions

Decisions about the allocation of NHLBI funds to various research areas develop differently for investigator- and institute-initiated research. Dr. Roth emphasized that decisions about the funding of investigator-initiated research occur virtually independent of the research area and topic of the grant application. The decisions are based on scientific merit, as judged during the review process. Institute-initiated research grants and contracts also are awarded based on scientific merit, but the NHLBI chooses the topic areas to fund based on scientific needs and opportunities and on whether the particular area is sufficiently represented by grants in NHLBI's investigator-initiated research portfolio.

Coordination of NIH Research on Diseases Affecting Multiple Organ Systems

Dr. Roth commented that ICs with an interest in the same research area or disease often issue joint initiatives.

Dr. Alice M. Mascette, Director, Clinical and Molecular Medicine Program, Division of Heart and Vascular Diseases, NHLBI, presented a cardiology clinician's perspective of the possibilities of high-tech science for everyday use in the heart clinic. She summarized the status of clinical research on stem cells, tissue engineering, and bioengineering, asking "What's around the corner for patients in my clinic?"

Stem Cells for Cardiovascular Therapy

Dr. Mascette said that cell-based therapies for cardiovascular diseases are in their infancy. The concept of such treatments arose during the past decade, and the two main contemplated applications are for repair of diffuse heart muscle problems and repair of tissue damaged in heart attacks.

Researchers are focusing on three major types of stem cells—blood, bone marrow, and skeletal muscle. Other possibilities include fat cells and embryonic stem cells. The possible avenues for delivering these cells to the heart include infusion through the coronary arteries, catheter-based needle injection into the heart muscle, and direct injection into the heart muscle during surgery. Dr. Mascette noted that many steps are involved in getting the cells to stay, engage, and grow in the heart muscle. She also noted that the injected stem cells potentially could differentiate into different cell types. For example, injected stem cells might differentiate into blood vessel cells and grow new blood vessel that would restore blood flow to damaged heart tissue. Currently, although researchers do not know whether, or if, the cells that are delivered would eventually become blood vessel cells, they have a better understanding of how to grow blood vessels (e.g., through angiogenesis), than they have of how to grow heart muscle. Being able to replace heart muscle cells (e.g., in patients with cardiomyopathy) and treat heart muscle before it is scarred are two main goals.

Dr. Mascette noted that research on catheter-based delivery of progenitor cells is in the early stages. In small early-use clinical trials, scientists have induced various types of cells to grow, injecting them into the hearts of patients with heart attacks and studying the results. The first publication of results of a clinical trial using stem cells in heart disease patients occurred in 2003. In this trial, scientists tested the effects of injecting cultured skeletal thigh muscle cells during coronary artery bypass surgery in patients with depressed heart muscle function. Dr. Mascette noted that the trial included only 10 patients, the implanted muscle cells did not form connections with native cells, and there was no control group. In one patient, myotubules did form in the heart—an exciting finding. The trial established the technical feasibility of the approach, but did not establish whether the approach favorably affects overall heart function or outcomes. A larger trial of 300 patients is now under way in Europe.

Scientists also are pursuing the use of more "primitive," undifferentiated, non-muscle progenitor stem cells-from bone marrow, blood, and embryos. Dr. Mascette outlined the many challenges facing researchers in the field, which include determining the type of cells to use, inducing proper differentiation in culture, scaling up production, establishing the dosing level of cells, and achieving cell survival and integration. In addition, the criteria for transdifferentiation—that is, defining when a heart muscle cell is a heart muscle cell—have not been established.

Cardiovascular Cell Therapy Research Network (CCTRN)

Dr. Mascette noted that the NHLBI is organizing a network of clinical research centers to promote and accelerate clinical research in the evaluation of novel cell therapy treatment strategies for individuals with cardiovascular disease. The CCTRN will include a data coordinating center, a data safety management board, and oversight by NHLBI. The clinical centers will have cell-processing capabilities and skill development cores.

Cardiovascular Tissue Engineering

• NIH Roadmap activities
• Multi-Agency Tissue Engineering Science (MATES)
• Bioengineering Consortium (BECON)
• Biomedical Information and Science Technology Initiative (BISTIC)
• Bioengineering Materials Applications (BEMA) Roundtable with the National Research Council (NRC) and Institute of Medicine (IOM).

Vascular Grafts

Blood vessel grafts are used in coronary artery bypass surgery and in hemodialysis. Dr. Mascette noted that approximately 500,000 bypass procedures are performed every year in the United States. For these operations, native arterial grafts are in short supply and, in many cases, suitable replacement vessels are not available. Development of stenosis within grafts is a major problem. Success with currently available artificial grafts is limited-for example, they are not sufficiently durable and are associated with thrombogenesis and intimal hyperplasia.

The NHLBI is funding a number of innovative research projects and has issued an RFA for innovative technologies for engineering small blood vessels. In a recent effort reported in the New York Times on November 16, 2005, NHLBI-supported scientists produced the first blood vessels cultured in a laboratory from patients' own skin tissue, and they are testing the vessels in dialysis patients.

Cardiac Patch

The NHLBI also is supporting research to develop patch replacements for heart muscle. Investigators are using cell scaffolds to build patches and have shown that electrical stimulation of cells on a scaffold results in better alignment of the cells, which is similar to that in heart muscle and necessary for efficient contraction of the muscle. Dr. Mascette noted that this research, which is still very basic, has great potential and could result in treatments for patients who have suffered a major heart attack or have poor heart contraction.

Heart Valves

Scientists are farther along in developing a completely biological tissue-engineered valve from cell-remodeled fibrin. "Growable" valves are especially needed for pediatric heart patients.

Lung Tissue

Dr. Mascette noted that the lungs are much more complex than the heart. An NHLBI-supported investigator is studying how tissue buds form, as a first step toward understanding disease processes in the lung and, ultimately, creating lung tissue.

Bioengineering: Mechanical Circulatory Assist

Since the beginning of the Artificial Heart Program, the NHLBI has actively supported the development of innovative ventricular assist systems. Third-generation devices, which are smaller and more durable and biocompatible than before, are now available. Two new research directions for the NHLBI are:

• Ventricular assist devices as a "destination" or permanent treatment-for patients who do not have access to a donor heart. One contract was awarded in 2005.
• Pediatric circulatory support systems. Five contracts were awarded in 2004.

Dr. Mascette said that the NHLBI is very interested in developing a U.S.-made ventricular assist device for children with heart conditions. The challenges are many-for example, children have small hearts and blood vessels and their hearts grow. Affected children often have abnormal heart anatomy, right and bi-ventricular failure, and pulmonary disease. Dr. Mascette noted that research on these devices is still in the design phase. The use of advanced computational tools for measuring fluid dynamics and mechanics, as well as anatomic fit, is helping to move this research forward.

Dr. Christopher O'Donnell, Senior Advisor to the Director for Genomic Research, NHLBI, considered the lessons learned about risk factors, prevention, and treatment from cohort studies; the interest in genomics and genomic medicine; and the future of genomic medicine in clinical research.

Risk Factors—Lessons Learned

Dr. O'Donnell noted that although trends in cardiovascular disease deaths have declined over the past 50 years, cardiovascular disease is increasingly prevalent in the aging U.S. population and continues to be the leading cause of death in the Western world. To improve understanding of cardiovascular disease and its risk factors, the NHLBI has organized and supported several major cohort studies over the years. They include the famous Framingham Heart Study, as well as the Jackson Heart Study and the Coronary Artery Risk Development in Young Adults (CARDIA) study. All of these studies enrolled large numbers of individuals; together they address persons from diverse backgrounds and geographic locations.

The Framingham Heart Study, which began in 1948, included 5,209 men and women ages 28 to 62 years. In 1972, researchers began a second phase that included 5,124 offspring, ages 5 to 70 years, of the original cohort and recently third-generation study of the original cohort's grandchildren was launched.

The Framingham Heart Study has tracked the progression of cardiovascular disease from the appearance of risk factors to the experience of clinical events. The risk factors identified in the study include high blood pressure, high levels of low-density lipoprotein (LDL) cholesterol, low levels of high-density lipoprotein (HDL) cholesterol, diabetes mellitus, smoking, overweight and obesity, age, and gender. The findings indicate that risk factors frequently act synergistically to influence risk for disease. The risk algorithms developed by the researchers are now used as a basis for treatment decisions for patients (e.g., whether drug therapy should be initiated to reduce LDL cholesterol). Newer, proposed risk factors for cardiovascular disease include amount of abdominal fat, presence of metabolic syndrome, physical inactivity, and homocysteine level.

Genomics and Genomic Medicine

Dr. O'Donnell defined genomics as the study of all genes and their function and interaction. He noted that, in 2004, scientists completed the sequencing of the human genome—which consists of 46 chromosomes, 2.85 billion nucleotides, and the codes for approximately 20,000 to 25,000 genes. He noted further that researchers using newly developed gene chip technology can detect genetic mutations, or SNPs (single nucleotide polymorphisms)—up to 50,000 SNPs on a single silicon chip.

Dr. O'Donnell noted that the NHLBI supports research using this technology to determine how genes and gene mutations influence progression from normal health to subclinical and clinical cardiovascular disease. Currently, clinicians use imaging techniques to assess thickening of the coronary and carotid arteries due to atherosclerosis in patients with subclinical disease and offer treatments to halt or delay the progression of disease. The availability of chip technology will enable researchers and clinicians to correlate the progression of cardiovascular disease with genes and their mutations.

A challenge for the future is to develop capabilities to perform genome-wide scans in well-examined, population-based cohorts. Dr. O'Donnell mentioned that the Framingham Heart Study, for example, already has DNA samples from approximately 9,000 individuals across three generations and that genomic studies of this cohort could yield valuable information on the role of genetics in cardiovascular disease. Genomics will eventually be used in clinical practice for genetic testing, as a basis for decision-making, and for identification of drug targets.

Dr. O'Donnell emphasized the importance of recognizing that genetic information is personal, powerful, predictive, pedigree-sensitive, and permanent. He noted that such information could be used in prejudicial ways.

• Heart development and disease
• Vascular disease
• Lung diseases
• Airway diseases
• Blood diseases and resources
• Sleep and sleep disorders.

Dr. Nabel thanked the PIO representatives and the NHLBI staff for their contributions and participation.

The meeting was adjourned at 4:20 p.m.