Testimony before the Senate Appropriations Subcommittee on Labor, HHS, Education

Statement of
Elias Zerhouni, M.D.
Director,
National Institutes of Health
Department of Health and Human Services

Wednesday, September 25, 2002

Mr. Chairman, Senator Specter, and Members of the Subcommittee, I am pleased to appear before you today to testify about the role of NIH in advancing the field of stem cell research. Properly harnessed, adult and embryonic stem cells have the potential to replace cells that are damaged or diseased to restore vital functions of the human body. They offer the promise of curing disease and ending disabilities at some point in the future. So there are ample reasons for excitement about stem cell research, and high expectations for new treatments are understandable. But such expectations should be tempered by the enormous challenges that must be addressed before the research evolves into proven therapy.

These challenges involve both human embryonic stem cell research and adult stem cell research. Human embryonic stem cells and adult stem cells have potential as future therapies. I believe that NIH should continue to fund research on both types of cells.

We are at a very early stage of embryonic stem cell research, and have a great deal of basic research to conduct before we can unlock the potential of these cells and fulfill their promise. I will describe the pathway of discovery that I believe will unfold as the research evolves from stem cell lines to cell based therapy. In the basic research phase, which is the current focus of NIH-supported activities, we first need to build the scientific capacity. As is true for any area of research, progress depends on attracting outstanding scientists to design and perform the needed studies. NIH is providing opportunities for the scientific community to develop training courses for researchers to acquire the skills needed to culture embryonic stem cells, as well as opportunities to support stem cell research career pathways. NIH has already taken major steps to accomplish this goal by supporting infrastructure awards to expand cell lines, refine culture methods, and establish improved methods to select the most desirable embryonic stem cell populations.

There have been significant scientific discoveries in the past year involving embryonic and adult stem cells. Scientists have recently shown that human embryonic stem cells can be directed to develop into cells resembling nerve cells, cardiac muscle cells and insulin producing cells. These are the cells that might someday be used to treat Parkinson's disease, heart disease and type I diabetes.

In addition to the new research opportunity provided by the availability of human embryonic stem cells, NIH continues to aggressively support research on developing the therapeutic potential of adult stem cells. Scientists have recently discovered that adult stem cells in animals may be used to repair cartilage and bone damaged by injury and disease. In addition, research published this past summer showed that adult stem cells from the bone marrow of both rodents and humans can differentiate into multiple cell types, and can grow for long periods of time in culture. Understanding the molecular signals that direct adult stem cell differentiation may lead to new strategies for harnessing the power of a person's adult stem cells to replenish specialized cells destroyed by disease or aging. But it is clear that much more research needs to be done to explore the characteristics of adult stem cells, and to develop methods of expanding different populations of adult stem cells in the laboratory. In addition, for many types of adult stem cells, more research is needed to determine techniques to expand these cells in the laboratory, a capacity that will enable both basic and clinical studies using adult stem cells. NIH continues to believe that research on both embryonic stem cells and adult stem cells must be pursued simultaneously in order to learn as much as possible about the potential of these cells to treat human disease.

These findings are important, but I continue to emphasize that we are at a very early stage. Much more basic research needs to be done. Stem cell researchers have shown that these cells have long term viability, with no evidence for genetic changes. However, human embryonic stem cells tend to be unstable and must be closely monitored to maintain them in their undifferentiated state. Much more basic research needs to be done to validate the long term stability of human embryonic stem cells, both in culture and after transplantation. Embryonic stem cells have the remarkable capacity to continue to grow indefinitely in an unspecialized state. In research involving other cell types, much has been learned about key regulators of cell division. Additional research is needed to determine how to harness the molecular systems that control this process, so that once transplanted, the specialized cells developed from embryonic stem cells do not revert back to their embryonic state and grow in an uncontrolled fashion leading to tumors or other unwelcome outcomes.

If we are able to direct stem cells to develop into a specialized cell type, research will need to be done to determine that the specialized cells function appropriately in the context of an animal model system for human disease. NIH's long term commitment to developing such animal models for diseases such as diabetes, Parkinson's disease, and spinal cord injury will be an important factor in developing this aspect of embryonic stem cell research. As we proceed, NIH will also ensure that federal funds are used to support research that has scientific merit and demonstrates outstanding opportunities.

Such basic research is only the first phase of the journey along the pathway of embryonic stem cell research. There are many pre-clinical studies, which do not involve human subjects, that need to be performed before any new therapeutic modality advances to clinical trials on real patients. These studies include tests of the long term survival and fate of transplanted cells, cell dosing studies, as well as tests of the safety, toxicity, and effectiveness of the cells in treating animal models for disease.

Trials using human subjects, the clinical research phase, will begin only after the basic and pre-clinical foundation has been laid. This foundation will minimize any chance of unpredictable harmful effects that stem cell based therapies might cause. These trials are usually phased, with the phase I trial focusing on safety, and phase II and III trials aimed at establishing optimal dose, providing additional assurance of safety, and determining efficacy. Only after these many important steps are taken will the promise of embryonic stem cells to treat disorders like diabetes, Parkinson's disease, spinal cord injury, and cardiac failure be realized.

Having provided you with a strategic vision for research using human embryonic stem cells, I want to explain to you how NIH is addressing two immediate major issues that are essential for stem cell research community to move forward:

Increasing the number of stem cell researchers.

As is the case at the beginning of any new field of discovery, there is a shortage of researchers with expertise in stem cell research. This dearth is currently a rate-limiting step in advancing the progress of embryonic stem cell research. Simply growing embryonic stem cells to the state where they can be used for experimentation requires substantial knowledge, training and experience. NIH will strive to make stem cell research as attractive as possible to our most talented research scientists, whose creativity in developing investigator-initiated research will move the research agenda forward. NIH is soliciting grant applications to support training courses to teach investigators how best to grow stem cells into useful lines.

Making human stem cells more available for research.

On November 7, NIH published a registry of derived stem cells that would be eligible for federal funding. The registry consists of 14 sources across the world. The cells are in various stages of characterization and preparation for research applications. There are many steps required to develop embryonic stem cells from when they are first removed from an embryo and put in culture into an established, well characterized embryonic stem cell line ready for distribution to the research community. After derivation, embryonic stem cells need to be expanded from a small cluster into hundreds of million of cells before they are ready for distribution. During the scaling up process, investigators need to repeatedly check that the cells maintain their ability to divide continuously and become all of the specialized cells required for research. This process of expanding a cell line requires time, resources, and expertise.

As a first step toward overcoming this challenge, NIH has announced five infrastructure grant awards, totaling $4.3 million, to five sources on the NIH Registry holding 23 of the eligible derivations. Two additional awards passed peer review and await final approval and funding within the next few weeks. These awards will fund the expansion, testing, quality assurance and distribution of cells.

We are also working with stem cell sources to address complex issues that might limit widespread availability of these eligible cells. In the past year, NIH has negotiated agreements with four stem cell providers to allow our intramural researchers access to their cells. These providers have also agreed to offer similar terms to our grantees, enabling them to obtain cells without developing their own agreements de novo. Under these four agreements, our intramural researchers are free to publish their findings and the NIH will own any inventions made in the course of its research. As a result of these agreements, six intramural laboratories have received stem cells and are pursuing research with them. The agreements commit the four providers to offering cells under similar terms to NIH's extramural investigators. In addition, the Wisconsin Alumni Research Foundation (WARF), which holds key patents on this technology, has agreed to provide a free license to non-profit researchers conducting academic research with cells from other providers. WARF has informed us that it has agreements in place with 111 researchers, and has shipped cells to 74 of them. The researchers represent 61 institutions, 12 of them in foreign countries. Another source, ESI, informs us that it currently has a supply of cells that far exceeds current demand. Meanwhile, NIH is in active discussions with other sources listed on the NIH Registry in pursuit of additional agreements.

NIH is beginning to receive investigator-initiated research grant applications from new investigators focusing on human embryonic stem cell research. So far, five new grants, totaling $4.2 million, have been awarded. Also, NIH has issued 32 administrative supplements to existing grant awards that will allow 30 researchers from 25 different institutions to rapidly incorporate research on human embryonic stem cells as part their ongoing federally-supported research. This means that currently funded laboratories are extending their work to include human embryonic stem cells, which is a way for them to develop their skills with these difficult cells and develop some preliminary data — both key steps to success in future research. All told, over 40 investigators are now funded by the NIH to work in this area.

Much progress has occurred in the past year, including new discoveries, identifying sources of stem cells, negotiating access agreements, and creating a friendly environment to attract researchers. However, these are only initial steps. To move us into the next phase, I have created a new stem cell task force at NIH, led by Dr. James Battey, the Director of the National Institute on Deafness and Other Communication Disorders. The task force will provide direction for the future in the form of recommendations for NIH-supported research initiatives. Currently, the task force is reviewing the state of the science for all stem cell research, with the goal of using NIH resources to enable the scientific community to capitalize on this new and challenging opportunity.

NIH would not be able to move forward in stem cell research, and for that matter, any other research, without the support of this Subcommittee. Thank you for your support. I look forward to working with you to advance this and all fields of biomedical research. I will be happy to answer any questions you might have.