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Stanford Report, January 22, 2003

A Message from the Director of the Institute of Cancer/Stem Cell Biology and Medicine at Stanford

By IRVING WEISSMAN, MD

Cancer is a cellular disease. Normally the body produces cells that can mature to replace dead or dying cells at a rate that allows for the orderly regeneration of tissues and organs. Cancer cells are the result of a long process within a cell and its produced progeny cells wherein the normal regulations on new cell production, cell maturation, and cell death are altered. Cancer cells reproduce themselves at a poorly regulated rate, cancer cells mature poorly, and cancer cells fail to die at a rate that limits their numbers. The events that lead a normal cell to become a cancer cell are called cancer progression, and these progressions result from particular kinds of genes within these cells being altered in their form or expression. Each step in the cancer progression occurs infrequently, and so in almost every cancer, only a single cancer cell emerges at a time. All of the daughter cells from a single cell are called it’s clonal progeny, and so each cancer as it emerges is a collection of the clonal progeny of the first cancer cell. As these cancers grow within a tissue or organ, they begin to invade adjacent regions and displace normal tissues. Later, cancer cells can invade the immune tissues (called lymph nodes) that drain the normal tissues, and they could also invade the blood vessels leading to and from the organ or tissue where the cancer started. When that happens, cancer cells can spread unpredictably throughout the body, and seed other tissues and organs such as liver, lung, brain, and bone. If cancer is diagnosed when it is local, surgery and/or local irradiation can remove the cancer and cure the patient. Removal and/or radiation ablation of the local organ and the draining lymph nodes can cure locally advancing cancers. But when cancer cells spread unpredictably throughout the body, chemotherapy or immunotherapy can be tried to eliminate those cancer cells. Each successful cancer chemotherapy drug either damages dividing cancer cells and dividing normal cells, or targets the products of genes that were altered in the cancer progression. Because we don’t start treatment until we know we have cancer, there are usually in excess of 10 billion cancer cells that must be destroyed to save the patient. The use of any single drug or any single kind of immune therapy might kill more than 99% of cancer cells, but rare cancer cells by that time have emerged that are resistant to that particular therapy because they have spontaneously altered the target molecules of that therapy. We need, usually, more than 3 independent targets in cancer cells to kill most, or all residual cancer cells in the body, and thus multidrug or multi-immune therapies are required. A major goal in cancer biology at the Institute is to identify the best targets for drug and for immune therapies for each kind of cancer.

Within normal tissues and organs it is believed that a special kind of cell called a stem cell is responsible for regenerating that organ or tissue. Stem cells are unique in that they can make more stem cells as well as progeny cells that mature to replace that organ or tissue. Making more cells of the same kind is called self-renewal, and within any tissue or organ, for the most part, only stem cells for that tissue or organ can self-renew. Stem cells are rare; in the blood-forming system, blood=forming stem cells represent about 1 in 20,000 cells. But although they are rare, it appears that they are the only cells in blood-forming tissues that regenerate these tissues for life. Blood-forming stem cells are the only critical cells that regenerate blood following chemotherapy and irradiation, and these stem cells can be eliminated when very high doses of therapies are used. Bone marrow transplants really work because the blood-forming stem cells in the transplant regenerate the blood of patients who receive otherwise lethal doses of chemotherapy in an attempt to kill all cancer cells in the body. Purified blood-forming stem cells are free from any cancer cells that contaminate bone marrow and blood while the cancer cells are spreading throughout the body, and Stanford was the first institution in the US to use purified blood-forming stem cells for this regenerative therapy. A major goal of the Institute is to discover and isolate other kinds of tissue and organ specific stem cells to regenerate other tissues and organs that might be irreversibly damaged by therapies.

There is an interesting and important similarity between stem cells and the cells within a cancer that are expanding without maturing—they both are self-renewing cell populations. In fact, recent studies indicate that the self-renewing cells within at least some cancers represent only 1-10% of the cancer, and are called cancer stem cells. Self-renewal of normal cells is potentially dangerous and must be regulated, or else these normal cells will be like cancer cells. Self-renewal is therefore mainly limited to rare stem cells in a tissue or organ. Self-renewal of stem cells is the result of the concerted activation of some genes and inactivation of others. At Stanford recently many of the genes used for the self-renewal of blood-forming stem cells have been identified. In some mouse models of a cancer of the blood-forming system—leukemias---the leukemia stem cells have been identified and express many of the genes found in self-renewing blood-forming stem cells. It seems likely that these cancer stem cells have acquired the property of self-renewal by appropriating the gene expression pathways of normal stem cells. A major goal of the Institute is to learn much more about self-renewal gene expression programs in normal stem cells of other tissues, and of cancer stem cells from those tissues, with the hope of identifying their relationship to known cancer genes and for identifying new molecular targets for drug and immune therapies.

The stem cells I have described so far are called adult stem cells because they are developed and maintained throughout life. So far, these appear to be tissue-specific, and so brain stem cells are different from blood stem cells are different from skin stem cells, etc. At the earliest stages of development there are a class of stem cells that are not restricted to any particular tissue or organ, and are capable of producing all cell types of the body; these are called pluripotent stem cells, because they have the potency to produce the plurality of tissues in the body. While there is one published experiment that indicates that one can find and culture pluripotent stem cells from adult mice, for the most part pluripotency is lost after the blastocyst stage of early development. In normal development, the fertilized egg undergoes 7-9 cell divisions to make the blastocyst, a ball of cells that has minimal specialization. The outer cells of the blastocyst are designed to implant into the uterus to form the placenta, while the inner cell mass of the blastocyst contains the pluripotent stem cells to make the embryo. About 17 years ago scientists found out how to culture mouse blastocyst inner cells to produce pluripotent stem cell lines, popularly known as embryonic stem cell lines or ES cells. In the last 3 years this was accomplished using human blastocyst sources to produce human pluripotent stem cell lines. These cultured mouse and human pluripotent stem cell lines can produce cells of all tissue types in a disorganized fashion in the test tube. Many mouse stem cell lines have been prepared with mutations in genes found in some human diseases, and the study of these cell lines and their progeny cells has led to an explosion of scientific and medical knowledge. It is hoped that human pluripotent stem cell lines will also lead to a knowledge explosion. But the current list of human pluripotent stem cell lines approved for use under US federal funding represent the genetic diversity of the blastocysts, which all came from in vitro fertilization clinics, not diseased patients. In a recent and remarkable set of experiments with mouse cells, it has been possible to produce (with low efficiency) new pluripotent stem cell lines by transplanting the nucleus from an adult body cell into a mouse egg that had it’s own chromosomes removed, stimulating the cells to divide, and culturing the blastocyst-stage inner cells. If the body nucleus had been taken from a mouse that was mutant for a gene that is required to form immune system lymphocytes, the pluripotent stem cell line produced by nuclear transplantation also could not make immune system lymphocytes, unless the mutant gene was corrected in these test tube cultures. Remarkably, when the gene-corrected pluripotent stem cells were directed to make blood-forming stem cells in a test tube, these blood-forming stem cells could be transplanted into the immunodeficient mice and help cure the immunodeficiency. This and other experiments opens the door to produce by nuclear transplantation mouse and eventually human pluripotent stem cell lines using nuclei from patients with known genetic diseases such as adult and type 1 (juvenile onset) diabetes, amyotrophic lateral sclerosis (Lou Gehrig’s Disease), other neurodegenerative diseases, most cardiovascular diseases with a strong genetic component, all autoimmune diseases such as lupus or rheumatoid arthritis, allergies, etc. One might even try to use cancer stem cell nuclei to produce pluripotent stem cell lines to study how the genetic alterations in the progression to the cancer operate developmentally to recreate cancer cells from normal cells. The distribution of such pluripotent stem cell lines to physician-scientists and basic scientists would allow them to test hypotheses of how these diseases developed, and what can be done to treat them. But nuclear transplantation involves a number of poorly understood events, has never been efficient in mice, and in the few cases tried, never published as successful using human cells. In essence, for a nucleus transferred to an egg or another cell such as an already established pluripotent cell line to become pluripotent, it must shut down the expression of those genes that made it a skin cell, or muscle cell, or blood cell, and turn on those genes that make an inner cell mass cell.(The results from the Human Genome Project give us a hint of hhow complex this is; each cell has over 25,000 distinct genes, and for the cell to be , say, a blood-forming stem cell, it must share the state of activation, repression, readiness to be activated and readiness to be repressed of each of these genes with every other blood-forming stem cell. No other cell in the body has the same activation program. Pluripotent stem cells have a completely different gene expression program. No two different cell types could have arrived at their gene expression program randomly. This is an amazing and exquisitely controlled process.) This process of converting the expressed gene repertoire of say a skin cell to a pluripotent stem cell is called nuclear reprogramming,and is at the center of current pluripotent stem cell research. A major goal of the Institute is to establish a research base on nuclear reprogramming and nuclear transplantation research, first using mouse cells, with the eventual goal of producing new human pluripotent stem cell lines from genetic disease or cancer stem cell nuclei.

The issue of producing human pluripotent stem cell lines by nuclear transplantation technology has special legal and ethical issues that could arise. If one learns from nuclear reprogramming research how to do successful nuclear transfer without the use of eggs, but for example, already-established but modified pluripotent cell lines as the recipient of the transferred nuclei, there will be no legal or ethical issue. If the method of obtaining pluripotent stem cell lines from adults can be generalized from mice to humans, and especially using cells from humans with genetic disorders, then there will be no legal or ethical issue, although this method could not be used to generate human pluripotent stem cell lines from human cancer nuclei. It is only when human nuclear transplantation into human enucleated eggs is the method used to produce human pluripotent stem cell lines that large legal and ethical (and political and religious) issues arise. These issues have properly been the subject of a medical and scientific and human participants in medical research inquiry by one panel of the National Academies (National Academy of Sciences, Institute of Medicine of the National Academies, National Institute of Engineering, and the National Research Council) called Scientific and Medical Aspects of Human Reproductive Cloning(1). Stem cell research and its ethical implications were independently addressed by another panel of the National Academies, called Stem Cells and the Future of Regenerative Medicine(2), by a specially convened panel by the State of California(3)_, and the entire issue was taken up also by the President’s Council on Bioethics(4). These panels considered at least two distinct issues; human reproductive cloning, and the use of nuclear transplantation technology to produce human pluripotent stem cell lines. Human reproductive cloning would involve the deliberate production of born humans by implantation into the uterus of prepared subjects a blastocyst produced by nuclear transfer from a pre-defined donor. By considering the scientific, medical, and human subjects issues alone, the first panel voted unanimously that human reproductive cloning was medically dangerous and should be legally banned, but 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. The other National Academies Panel also called for nuclear transplantation research to produce human pluripotent stem cell lines. The California panel called for a ban on human reproductive cloning but encouraged human pluripotent stem cell line research with careful local and state regulations. The President’s Bioethics Panel unanimously called for a ban on human reproductive cloning, but a majority called for a moratorium on what they called "cloning for biomedical research", while a minority called for approval for such research with clear regulations. In the fall of 2002 the State of California passed and the Governor 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 implications of this research, including a requirement for review by an approved institutional review board. I append the website addresses for those who wish to view the documents more completely.

The announcement of the founding of the Institute of Cancer/Stem Cell Biology at Stanford was mainly followed by lay press articles claiming Stanford would launch a human embryo cloning project and the response to such columns and reports. This use of terminology was not the terminology used by any of the panels. I will here give my own account of the terms used, and the reasons that the term human embryonic cloning was not used by the various panels, but was embraced by some of the press. I was chair of the National Academies panel on human reproductive cloning, and testified before the other National Academies panel as well as before the Bioethics Council and the California Senate Committee concerned with the issue. At the outset my panel needed to use language that was scientifically and medically accurate, and had not been become inaccurate lay jargon. While classical embryologists describe the stages of (at least) vertebrate development following fertilization of an egg by a sperm as an embryo until organs and distinct body parts are just beginning to form as the embryonic phase (divided into a preimplantation stage from zygote to blastocyst, and a postimplantation stage), and from the initiation of organogenesis until birth as the fetal stage, that is not what the lay community understands. Most lay people asked to draw an embryo instead draw a fetus, with formed head, limbs etc. There would be no way to communicate the reality of the situation accurately and understandably if the term embryo was used. Technically, one should not use the term embryo to describe a blastocyst produced by nuclear transfer as an embryo, because it was not the product of sperm and egg, although I think that since the embryologists who coined the term embryo could not have known about nuclear transfer technology, it’s anyone’s guess what they might say now. The second term used by the press is cloning. As a scientist I use the term cloning everyday to describe how we isolate genes; or how cancer cells develop; or what are the progeny of a single blood forming stem cell, or single bacterium, or single virus, or even a single organism I study at Hopkin’s Marine Station at Stanford, a colonial tunicate. But if you ask the general community what cloning is or what clones are the general response comes from movies and novels, for example "Brave New World" or "Attack of the Clones". If you think I’m wrong, read the Congressional Record for the debate in the House of Representatives in July 2001 on this kind of research (the Weldon and Greenwood bills), and read about mad scientists, and producing fully grown human clones or slaves(6). So we couldn’t use that term alone without modifiers, and we didn’t use the word cloning. Many like to call nuclear transplantation to produce pluripotent stem cell lines "therapeutic cloning", but that jargon means producing one’s own pluripotent stem cell line from your own cell nuclei for the express purpose of transplanting the maturing cells back into yourself, and by no stretch of the imagination could the production of disease or cancer nucleus derived pluripotent cell lines be used therapeutically. We ended up using the language which accurately and dispassionately describes exactly what was done. The later decision of the Bioethics Council to call it ‘cloning for biomedical research’ does not in my view tell the reader what was done, and is just another jargon that requires explanation.

This is therefore not just about language, but is about the symbols various groups use to communicate much more complex, and usually confusing concepts. I question those who persist in debating only in a way that uses confused language and symbols that bring out wrong concepts and much emotion. 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 what images the languages conjure up. I was and am worried about the inefficiency of the process if human eggs are the only way to go, as there are many potentials for abuse and risk if institutional review boards are not used. I would hope we could discover ways to process ovaries as byproducts of human tissues from surgeries so that the tens of thousands of pre-oocytes could be made into useful targets of nuclear transplantation. I also understand that for religious and for ethical reasons many individuals consider the nuclear transplant blastocyst to be fully human in the sense it has rights usually assigned to sentient or nearly sentient persons. That issue about when personhood develops in an individual cannot at this time be settled scientifically, and so it will always be the subject of controversy and debate. In a pluralistic democratic society the concerns of those who object to this research on personal moral, religious and /or ethical grounds, as well as the concerns of patient advocacy groups must also be weighed in the debate; it was in the California legislature, and will be again by institutional review boards as well as the US legislative bodies. For many the blastocyst is a ball of cells like many other cell lines from other tissues, 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, I believe, physicians and physician scientists have the obligation to present and future patients to pursue the best medical therapies, making sure to do no harm, by translating current day science to tomorrow’s treatments(7,8). That devotion to discovery and to translation is the overriding major goal of the Institute for Cancer/Stem Cell Biology at Stanford.