Presented by Douglas Melton, Ph.D.

Thomas Dudley Cabot Professor in the Natural Sciences at Harvard University
Investigator in the Howard Hughes Medical Institute
September 5, 2001

Good afternoon Chairman Kennedy, Senator Gregg and other distinguished members of the Committee. It is my pleasure to appear before you today to speak about human embryonic stem cells.

Mr. Chairman, before I begin my remarks on stem cells, I want to take this opportunity to thank you and the other members of this subcommittee for your leading role in supporting the NIH. I thank you on behalf of the nation's scientists who work to understand the basic principles of life and to cure human disease.

In the last three years, and increasingly so in the past few months, the potential of human embryonic stem cells has been widely debated in the public and rightly so. This subject forces us all to revisit the question of when life begins. We have to scrutinize the crossroads between scientific inquiry, our efforts to improve the human condition, and our moral and ethical responsibilities to preserve human dignity. Not surprisingly, a subject that combines the science of life's beginnings with politics and religion has captured the nation's attention. Indeed, this topic was recently the subject of President Bush's excellent speech on 9 August.

I am not here to testify on the moral, religious or political aspects of human embryonic stem cell research. I appear before you as a scientist and as the father of young boy with Type I or juvenile diabetes. I will furthermore not speak to you about the human burden of this disease, but simply say that I work on human embryonic stem cells with the aim of providing a cure for diabetes. My remarks today will be confined to the scientific potential of human embryonic stem cells and the implementation of the President's plan.

While I'm certain the committee is well aware of the potential uses for human embryonic stem cells, allow me to briefly put this research in context. In the last century, biologists showed that genes are the units of development and heredity, discovered that genes are made of DNA, and recently completed sequencing the DNA that comprises the human genome, that is, sequencing the DNA of all human genes. This monumental achievement will stand as one of the most important scientific triumphs from the last century. Knowing the sequence of DNA allows scientists to uncover the basis for development, heredity and disease and challenges us to understand how the code of life is read or interpreted. At the same time, this enduring achievement should not cause us to forget that the unit of life is not DNA nor the gene, but rather the unit of life is the cell. Cells are alive and reproduce and among cells, stem cells are unique. Embryonic stem cells are special because they can reproduce to make more of themselves and they have the remarkable capacity to make any kind of cell in the body. One might think of them as the fire hydrant of all cells, having the capacity to renew or replenish lost cells and tissues. Understanding how these cells can duplicate themselves and how they specialize to make all types of cells will undoubtedly reveal important insights into human biology and disease.

The ability of stem cells to specialize or differentiate into any kind of cell is what holds their enormous therapeutic promise. Many of the diseases that currently plague our society are diseases of cellular deficiency, diseases in which one particular cell type is missing or defective. These diseases include Parkinson's, Alzheimer's, osteoporosis, some cancers and the one that has my full attention, juvenile diabetes. It has been estimated that as many as one hundred million Americans are affected by these diseases. Stem cells have the potential to replace the missing or deficient cells and it follows that the nation's scientists and those suffering from diseases are anxious to aggressively pursue this research. I should like to note that while embryonic stem cells have a much broader potential for growth and differentiation than do adult stem cells, research on both adult and embryonic stem cells is warranted; it's too early to know which type of stem cell will be most useful. Whereas the last century of biology can be said to have focused on the gene and the sequence of DNA, I believe this century will see biologists come to understand and harness the unit of life, the cell, specifically stem cells.

President Bush's plan for sixty embryonic cell lines
President Bush has made clear his commitment to support research on human embryonic stem cells, highlighting the importance of this research. The President's plan provides the opportunity to advance embryonic stem cell research in the US, at least for a few years, and as such his plan marks an important commitment. The Honorable Tommy Thompson has worked diligently for this research and his continued leadership will be critical in moving forward with the President's plan.

For this field the date of the President's speech, 9 August 2001, is important because only stem cell lines in existence at that time, estimated to be about sixty, are eligible for federal support. This date was not chosen for scientific reasons and its arbitrary selection will have an effect on the progress of research. For example, it will not be possible for federally funded researchers to explore new ways to derive human embryonic stem cells nor work with cells that have been isolated without possible contamination from mouse or other supporting cells. Nevertheless, it is now possible for the nation's researchers to initiate studies on how embryonic stem (ES) cells differentiate and we can begin to explore their therapeutic potential.

Looking ahead to how the plan will work, I turn to two issues: the quality of the sixty cell lines and their access or availability.

Quality of the human embryonic stem cell lines
Scientists are, by their nature, inquisitive and skeptical and we hold dear the practice of publishing results following an independent review by qualified experts. Moreover, by publishing results, scientists generally agree that the reagents reported, including cells, are available to be shared with the research community. In this way results can be independently verified and new directions and discoveries can be explored. In the present case, only a handful of the sixty+ embryonic cell lines have been published so it is not yet possible to evaluate or comment on the quality of cells. Nonetheless, legitimate scientific questions about the growth, differentiation potential, age, and purity of the lines must be considered. Decades of experience with mouse embryonic stem cells have shown that ES cells can lose their differentiation potential, become contaminated, accumulate mutations, and tend toward spontaneous or uncontrolled differentiation. The fact that mouse ES cells lose their full potential with increasing age or passage number is only one reason to believe that the sixty+ cell lines will not be sufficient for the years of research required to investigate therapies with these cells. Looking ahead to clinical applications, including transplantation and the problem of immunological rejection, there will certainly be a need for broader genetic diversity of cell lines. There may also be a need for cell lines that have been isolated without the use of mouse feeder layers.

I hasten to add that I am not criticizing the NIH nor the scientists who have reported the isolation of the sixty human embryonic stem cell lines. Indeed, the scientists have not published their work and they may well wish to further characterize the cells before doing so. It is therefore too early to tell how many of the sixty+ lines are truly useful embryonic stem cell lines. Preliminary indications from press reports do suggest that the final number will be significantly less than sixty. If the available lines have been grown extensively and have a high passage number that will further reduce their value.

Availability
A separate issue concerns whether the cell lines will be made available to federally funded researchers in a timely manner and without restrictions on their use for research. It is noteworthy that most of the entities that have isolated the sixty+ human embryonic stem cell lines are companies with proprietary and commercial interests. In addition, there are relevant patents on some of the cells that may further restrict their distribution and use. Experience shows that the negotiation of transfer from those who own a reagent to federally funded scientists can be slow, expensive, and sometimes accompanied by onerous restrictions on use. It is obvious that the legitimate interests of companies may not coincide with scientist's research plans or our nation's public health policy.

I believe this problem of access is likely to be quite serious. The NIH plan to create a registry of cells will leave it to individual investigators to negotiate for transfer of the cells. This places a heavy burden on researchers and one can anticipate, at a minimum, significant delays. In some cases the terms of the transfer may be too restrictive to allow scientists access to the material. Finally, I note that some of the potential suppliers have already indicated that they lack the resources and incentive to prepare their cells for distribution.

Create a federal repository for human stem cells
I would like to suggest a plan that addresses both of these issues. Specifically, I suggest that the NIH create a repository, not a registry, for the sixty+ embryonic cell lines. The NIH could collect the cell lines, determine their quality, and certify them for distribution to qualified researchers. Equally important, this plan would have the NIH negotiate favorable terms with the suppliers, set out in a Material Transfer Agreement, so that scientists could use the cells for research purposes. The Federal government and the NIH are in an immeasurably stronger position than are individual investigators to obtain the human embryonic stem cell lines from suppliers, verify their quality, and arrange for their distribution.

Summary
In conclusion, Mr. Chairman, I think that President Bush and Secretary Thompson have proposed a plan that will allow federally supported scientists to begin to explore the potential of human embryonic stem cells and work towards a cure for numerous diseases. This is a very important step forward. If my remarks today seem cautious, the reason is the uncertainty about the quality, availability and longevity of the cells. Assuming that some of the sixty cell lines are made available, federally supported scientists can work to understand how these cells can be directed to differentiate. As the studies progress to the point where clinical applications can begin, I expect the plan will have to be revisited because the viability or utility of the sixty+ cell lines will have been exhausted.

In closing, I thank you and Committee once again for the privilege of speaking to you about this important area of biology.