By IRVING WEISSMAN with AMY ADAMS
In an effort to better understand and treat cancer or replenish healthy cells lost in cancer treatment, Stanford recently announced the formation of the new Institute for Cancer/Stem Cell Biology and Medicine. The important research focus of the new institute has been somewhat overlooked in the debate over one of the institute’s long-term goals, which involves developing new stem cell lines.
Much of the new institute’s work will involve adult stem cells, which have demonstrated great promise in treating disease. These cells exist in tissues such as the bone marrow, brain, muscle or liver and appear to be the only cells that regenerate these tissues when they become damaged. Adult stem cells are currently being used to treat cancers through bone marrow transplants, where blood-forming stem cells regenerate the blood of transplant recipients who receive otherwise lethal doses of chemotherapy. This work could eventually apply to treatments that allow doctors to give high doses of radiation to tissues such as brain or liver, then inject tissue-specific stem cells to replace radiation-damaged cells.
In addition to treating cancer, the study of adult stem cells could lead to insights into cancer cell biology. Recent studies indicate that cancers are continually replenished by a small population of cancer stem cells that are capable of self-renewal. By studying adult stem cells to learn more about the genes involved in self-renewal, it may be possible to identify new molecular targets for drug and immune therapies that destroy the self-renewing cancer stem cells.
The adult stem cells described above appear to be tissue-specific. However, other stem cells, called pluripotent stem cells, are not restricted to any particular tissue or organ and are capable of producing all cell types. These are sometimes referred to as embryonic stem cells because they exist only during an early stage of development. One of the institute’s many research goals will be to explore the potential of using pluripotent stem cells to better understand and treat disease.
Pluripotent stem cells come from an early stage of development called the blastocyst. A blastocyst is a ball of cells that forms after the fertilized egg undergoes seven to nine divisions. It is free-floating and cannot give rise to a developing embryo or fetus unless it is implanted in the uterus. About 17 years ago, scientists learned how to culture pluripotent cells from a mouse blastocyst so that they could divide continuously in a test tube and go on to form cells of all tissue types.
In mice, the creation of pluripotent stem cell lines carrying disease-causing mutations has greatly enhanced scientific and medical knowledge. The hope is that a similar knowledge explosion will take place by studying human pluripotent stem cell lines carrying mutations found in such genetic disorders as cancer, Parkinson’s disease, Alzheimer’s disease and Lou Gehrig’s disease. But the human pluripotent stem cell lines approved for use under U.S. federal funding do not carry the mutations that would make the cell lines useful for studying genetic diseases.
One goal of the institute is generating new pluripotent stem cell lines. Researchers at the institute will first test methods of creating the cell lines in mice, then apply the most successful technique to human cells. One possible method of creating pluripotent cell lines involves removing the nucleus from an existing pluripotent stem cell line and replacing it with a nucleus from an adult cell that carries genetic mutations implicated in human disease.
Another method is by transplanting an adult nucleus into an egg that has had its nucleus removed, stimulating the cell to divide as if the egg had been fertilized, and culturing the blastocyst-stage pluripotent cells. This process, called nuclear transplantation, has had limited success in mice, and has never been shown to be successful using human cells.
Producing human pluripotent stem cell lines by nuclear transplantation technology has special legal and ethical considerations. These have properly been the subject of inquiry by two panels assembled by the National Academies (National Academy of Sciences, the National Academy of Engineering, the Institute of Medicine of the National Academies, and the National Research Council). It was also debated by a specially convened panel by the State of California and by the President’s Council on Bioethics. All panels concerned with reproductive cloning voted unanimously to ban human reproductive cloning. Both National Academies’ panels and the California state panel voted that nuclear transplantation to produce human pluripotent stem cell lines was sufficiently important that it should not be banned and should be the subject of a broad debate.
In the fall of 2002, the State of California passed and Gov. Davis signed State Senate Bill 253(5), calling for research involving the derivation and use of human embryonic stem cells, human embryonic germ cells and human adult stem cells from any source, including somatic cell nuclear transplantation, with full consideration of the ethical and medical implication of this research, including a requirement for overview by an approved institutional review board.
After the December announcement of the Institute for Cancer/Stem Cell Biology there was some confusion about the true research goals of the institute. This confusion arose, in part, from the terminology used to describe the work, particularly the words "embryo" and "cloning." In scientific terms, all stages of development from fertilization through organ development constitute the embryonic period. However, most people asked to draw an embryo instead draw a fetus, with head, limbs, eyes and other identifiably human traits. Likewise, scientists use the word "cloning" every day to describe how they isolate genes; how cancer cells develop from a single cancer stem cell; or to characterize the progeny of a single blood-forming stem cell, or bacterium or virus. But to most people the word "cloning" conjures up images of mad scientists producing fully grown human clones or slaves.
The issues surrounding nuclear transplantation to produce human pluripotent stem cell lines are real and need to be debated and reviewed for what they are, not for the images the words "embryo" and "cloning" conjure up. For that reason, both National Academies’ panels chose to use the language that accurately and dispassionately describes the nuclear transplantation technique rather than use the terms "therapeutic cloning," "research cloning" or "cloning for biomedical research," as other groups have chosen to do. This language was supported in a Science article written by the presidents of the National Academies of Science and of the Institute of Medicine.
For religious and ethical reasons, many consider the nuclear transplant blastocyst to be fully human. That issue about when personhood develops in an individual cannot at this time be settled scientifically, and so it will remain the subject of controversy and debate. For many physician-scientists, the blastocyst is a ball of cells and it would be a violation of their medical oaths not to use these cells to gain valuable medical knowledge that could translate to therapies.
In the end, physicians and scientists have the obligation to pursue the best medical therapies, making sure to do no harm, by translating today’s science into tomorrow’s treatments. That devotion to discovery and to translation is the overriding goal of the Institute for Cancer/Stem Cell Biology at Stanford.
Irving Weissman, MD, is the Karel and Avice Beekhuis professor of cancer biology and the director of the Institute for Cancer/Stem Cell Biology and Medicine. Amy Adams is a science writer in the Office of Communication & Public Affairs.
ON THE WEB
A Message from the Director of the Institute of Cancer/Stem Cell Biology and Medicine at Stanford, by Irving Weissman
Vision statement for the Institute of Cancer/Stem Cell Biology and Medicine at Stanford, by Irving Weissman
National Research Council, Stem Cells and the Future of Regenerative Medicine (National Academy Press, Washington, DC, 2001). Bert Vogelstein, chair.
National Research Council, Scientific and Medical Aspects of Human Reproductive Cloning (National Academy Press, Washington, DC, 2002). Irving Weissman, chair.
Executive Summary from the President’s Council on Bioethics
Report on Human Cloning and Human Dignity: An Ethical Inquiry
Editorial by the minority on the President’s Council on Bioethics regarding stem cell research
Rowley, JD, Blackburn, E, Gazzaniga, MS, Foster, DW. (2002). Harmful Moratorium on Stem Cell Research. Science 297:1957.
Report of the California Advisory Committee on Human Cloning
California Senate Bill 253
Support for dispassionate language to describe nuclear transfer by the presidents of the National Academies of Science and of the Institute of Medicine along with Dr. Bert Vogelstein
Vogelstein, B., Alberts, B., Shine, K. (2002) Please Don’t call it cloning. Science 295(5558):1237
Stanford School of Medicine graduation address by Irving Weissman
Review of stem cell biology and political issues, by Irving Weissman
Weissman, I.L. (2002) Stem Cells – Scientific, Medical, and Political Issues. NEJM 346(20):1576-1579
Opinion piece on the new Institute of Cancer/Stem Cell Biology and Medicine by Philip Pizzo, dean of the school of medicine
For a list of related links and background information on stem cells, please scroll down to "On the Web" at the bottom of this document.
Stanford Report, January 22, 2003