Stem Cell Science: The Foundation of Future Cures

Testimony

Statement by
Elias A. Zerhouni, M.D.,
Director

on
Stem Cell Science: The Foundation of Future Cures

before
Committee on Energy and Commerce
Subcommittee on Health
U.S. House of Representatives

Thursday, May 08, 2008

Good morning, Mr. Chairman, Ranking Member Deal and Members of the Subcommittee. I am Elias Zerhouni, the Director of the National Institutes of Health (NIH), an agency of the U.S. Department of Health and Human Services (HHS), and I am pleased to appear before you today to testify about the science of stem cell research. I look forward to discussing ongoing federal support of both embryonic and non-embryonic stem cell research and scientific progress, including the recently published findings on induced pluripotent stem cells and other updates provided during the NIH Symposium on Cell-Based Therapies, which we hosted just two days ago.

Stem cell research has the potential to lead to therapies for injuries and illnesses that could not even have been imagined when I first began studying medicine. As this new field of discovery advances, nothing we have learned has dissuaded us from the belief that these cells, representing the building blocks of life itself, offer the possibility of becoming a renewable source of replacement cells and tissues to treat such common diseases and disorders as Parkinson’s disease, spinal cord injury, stroke, burns, heart disease, diabetes, osteoarthritis, and rheumatoid arthritis.

A great deal of progress has already occurred. When I first became the Director of NIH, scientists were still struggling with learning how to grow embryonic stem cell lines. Since then, experiments have occurred in animals where embryonic stem cells actually replaced damaged cells and tissues. But we have a very long way to go.

The Need for Research to Explore the Potential of Human Stem Cells

Stem cells can multiply without changing – that is, self-renew – or can differentiate to produce specialized cell types. This ability to renew and eventually replace damaged cells and tissues fuels the excitement of stem cell researchers across the world. But all stem cells do not come from the same source; they have different characteristics and are difficult to harness and grow. Stem cells have been derived from both embryonic and non-embryonic tissues, and these cell types have different properties. Both pluripotent and nonpluripotent types show potential for developing treatments for human diseases and injuries, and there are many ways in which they might be used in basic and clinical research. We are still early in the learning process. This is an exciting but new field of discovery, and additional research is needed to realize the potential of stem cells and their uses. Before we reach the promised land of stem cell therapies, scientists must learn to reliably manipulate the cells so that they possess the necessary characteristics for successful differentiation, transplantation, and engraftment.

To be useful for transplant purposes, differentiated stem cells must:

Proliferate extensively and generate sufficient quantities of specialized cells;
Differentiate into the desired cell type(s);
Survive in the recipient after transplant;
Integrate into the surrounding tissue after transplant;
Function appropriately for extended periods of time; and
Avoid harming the recipient.

As this field of research advances, stem cells will yield still unknown information about the complex events that occur during the initial stages of human development. At present, a primary goal of this research is to identify the molecular mechanisms that allow undifferentiated stem cells to differentiate into one of the several hundred different cell types that make up the human body. Scientists have learned that turning genes on and off is central to this process. But we do not yet fully understand the signals that turn specific genes on and off to influence the differentiation of the stem cell into a specialized cell with a specific function, such as a nerve cell. This knowledge will not only offer the opportunity to learn how to control stem cells from both embryonic and non-embryonic sources, but also provide better understanding of the causes of a number of serious diseases, including those that affect infants and children, which in turn could lead to new and more effective intervention strategies and treatments.

Human stem cells are also being used to speed the development of new drugs. Initially testing thousands of potential drugs on cells in cell culture is typically far more efficient and informative than testing drugs in live animals. In vitro systems are useful in predicting in vivo responses and provide the benefits of requiring fewer animals, requiring less test material, and enabling higher throughput. New medications can be tested for safety on the specific types of human cells that are affected in disease by deriving these cells from human stem cell lines. Other kinds of cell lines are similarly used in this way. Cancer cell lines, for example, are used to screen potential anti-tumor drugs. The availability of useful stem cell lines would allow drug testing in a wider range of cell types. Potentially, stem cell research will result in a more efficient, effective, safer and faster way of developing drug treatments for a vast array of illnesses, but not until we produce the fundamental discoveries that will pave the way for the widespread use of stem cells in this manner.

Advances in Stem Cell Research

Over the past year, scientists have made remarkable discoveries about the potential of stem cells. For example, NIH-funded scientists have developed a method to coax human embryonic stem cells (hESCs) into becoming cells that resemble lung epithelial cells. The scientists engineered a virus (modified to eliminate its disease-transmitting function) to infect cells with two genes simultaneously, one that drives them into becoming a specialized type of lung cell and another that enables them to resist being killed by a drug (neomycin). Only those cells that express the two genes survived when the scientists treated the culture dish with neomycin. In this way, they were able to generate a pure population of lung-like cells, with no contaminating cells. The surviving cells had the appearance and shape of lung-lining cells called alveolar type 2 cells, which help maximize air exchange, remove fluid from the lungs, serve as a pool of repair cells, and fight airborne diseases. (Proceedings of the National Academy of Sciences of the USA 104(11):4449–4454, laboratory of R.A. Wetsel. 2007 March.)

In another experiment, NIH-funded investigators developed a new technique to generate large numbers of pure cardiomyocytes (heart muscle cells) from hESCs. They also formulated a “prosurvival” cocktail (PSC) of factors designed to overcome several known causes of transplanted cell death. The scientists then induced heart attacks in rats and injected the rat hearts with either hESC-derived human cardiomyocytes plus PSC (treatment group) or one of several control preparations. Four weeks later, the scientists identified human cardiomyocytes being supported by rat blood vessels in the treated rat hearts. The treated rat hearts also demonstrated an improved ability to pump blood. The control animals presented no improvement in heart function. This work demonstrates that hESC-derived cardiomyocytes can survive and improve function in damaged rat hearts. Scientists now hope to learn how the human cells improved the rat hearts, and eventually to test this method to treat human heart disease. (Nature Biotechnology 25(9):1015–1024, laboratory of CE Murry. 2007 Sept.)

In a significant advance, Japanese scientists and a team of NIH-supported scientists reported that they each succeeded at reprogramming adult human skin cells to behave like hESCs. The Japanese team forced adult skin cells to express the proteins Oct3/4, Sox2, Klf4, and c-Myc, while the NIH-supported team forced adult skin cells to express OCT4, SOX2, NANOG, and LIN28. The genes were all chosen for their known importance in maintaining the so-called “stemness” properties of stem cells. In both reports, the adult skin cells are thus reprogrammed into human induced pluripotent stem (iPS) cells that demonstrate important characteristics of pluripotency. The techniques reported by these research teams will enable scientists to generate patient-specific and disease-specific human stem cell lines for laboratory study, and to test potential drugs on human cells in culture. However, these human iPS cells are not yet suitable for use in transplantation medicine. The current techniques use viruses that could generate tumors or other undesirable mutations in cells derived from iPS cells. Scientists are now working to accomplish reprogramming in adult human cells without using potentially dangerous viruses. (Cell 131:861–72, laboratory of S. Yamanaka, 2007 Nov 30; Science 318:1917–1920, laboratory of J. Thomson, 2007 Dec 21

Researchers from Japan were the first to successfully generate germ cells (the cells that give rise to sperm or eggs) from mouse iPS cells, and their results were verified and extended by another independent laboratory (Rudolf Jaenisch) in the United States. Recent publications from the same Japanese scientists, a team of NIH-supported scientists from University of Wisconsin-Madison, and the Harvard Stem Cell Institute report that they have each succeeded at reprogramming adult human skin cells to become human iPS cells.

There is no doubt that this finding is a remarkable scientific achievement, providing non-embryonic sources of pluripotent cells. Human ESCs and iPS cells are excellent tools to study differentiation, reversal of differentiation, and re-differentiation. In addition, both types of pluripotent cells may be useful for studying the cell biologic changes that accompany human disease. However, from a purely scientific view, it is essential to pursue all types of stem cell research simultaneously, including hESC research, since we cannot predict which type of stem cell will lead to the best possible therapeutic application.

In addition, reprogramming adult human cells would not have been possible without years of prior research studying the properties of hESCs. Two fundamental factors critical to the development of human iPS cells are based upon the knowledge gained from studying hESCs: knowledge of “stemness” genes whose expression or repression is essential to maintain pluripotency; and hESC culture conditions. NIH is proud of the role it has played in supporting this work since 2001 and advancing non-embryonic sources of pluripotent cells.

Scientists must now focus on understanding the mechanism by which retroviral transduction and consequent expression of “stemness” genes induce pluripotency in somatic cells. The consequences of using retroviral vectors to induce pluripotentiality for normal cell functions are unclear, and because the retroviral vectors integrate into the genome of the somatic cell, it can cause the cell to function abnormally. Scientists are now looking for safer methods to reprogram adult cells to a pluripotent state that do not disrupt the genome.

NIH Stem Cell Symposium on Cell-Based Therapies

Two days ago, on May 6, the NIH hosted a symposium entitled “Challenges and Promise of Cell-Based Therapies.” Notable stem cell researcher Dr. Stuart Orkin opened the symposium by explaining how 25 years of active research using blood stem cells has led to their successful use in the treatment of blood cancers and other blood disorders. He described the critical characteristics of blood-forming stem cells that have enabled their use in therapies, and how this knowledge will help scientists understand ways to use these and other types of stem cells for treating human diseases. Prominent scientists then discussed how they are developing stem cells as therapies for diseases of the nervous system, heart, muscle and bone, and metabolic disorders. The scientists shared their research results, the technical hurdles they must overcome, and what they ultimately hope to achieve with stem cells. Dr. George Daley of the Harvard Stem Cell Institute gave the final presentation on patient-specific pluripotent stem cells, also known as induced pluripotent stem cells.

Federal Funding of Stem Cell Research

NIH has acted quickly and aggressively to provide support for this research in accordance with the President’s 2001 stem cell policy. Since 2001, NIH has invested approximately $3.7 billion on all types of stem cell research. Within this total, NIH has funded: more than $174 million in research studying human embryonic stem cells; more than $1.3 billion on research using human non-embryonic stem cells; more than $628 million on nonhuman embryonic stem cells; and more than $1.5 billion on nonhuman non-embryonic stem cells.

Additionally, in FY 2009, it is projected that NIH will spend approximately $41 million on human embryonic stem cell research and about $203 million on human non-embryonic stem cell research, while also investing approximately $105 million on nonhuman embryonic stem cell research and nearly $306 million on nonhuman non-embryonic stem cell research.

In addition, NIH is conducting activities under the President’s July 2007 directive in Executive Order 13435, which directs HHS and NIH to ensure that the human pluripotent stem cell lines on research that it conducts or supports are derived without creating a human embryo for research purposes or destroying, discarding, or subjecting to harm a human embryo or fetus. The order expands the NIH Embryonic Stem Cell registry to include all types of ethically produced human pluripotent stem cells, and renames the registry as the Human Pluripotent Stem Cell Registry. The order invites scientists to work with the NIH, so we can add new ethically derived stem cell lines to the list of those eligible for federal funding.

Further, NIH has encouraged stem cell research through the establishment of an NIH Stem Cell Task Force, a Stem Cell Information Web Site, an Embryonic Stem Cell Characterization Unit, training courses in the culturing of human embryonic stem cells, support for multidisciplinary teams of stem cell investigators, and a National Stem Cell Bank and Centers of Excellence in Translational Human Stem Cell Research, as well as through extensive investigator initiated research. NIH determined that obtaining access to hESC lines listed on the Human Pluripotent Stem Cell Registry and the lack of trained scientists with the ability to culture hESCs were obstacles to moving this field of research forward. To remove these potential barriers, the National Stem Cell Bank and the providers on the Human Pluripotent Stem Cell Registry together have currently made over 1400 shipments of the hESC cell lines that are eligible for federal funding, as posted on the Human Pluripotent Stem Cell Registry web site. In addition, the NIH-supported hESC training courses have taught several hundred scientists the techniques necessary to culture these cells. We plan to continue to aggressively fund this exciting area of science.

Thank you for the opportunity to present these exciting developments to you. I will be happy to try to answer any questions.

Last revised: December 24,2008