Morality of Stem Cells Wise Young, Ph.D., M.D. W. M. Keck Center for Collaborative Neuroscience Rutgers University, Piscataway, NJ 08854-8082 http://carecure.rutgers.edu, http://sciwire.org What a curious title for a lecture, you are probably asking yourself. How can a type of cells be moral or immoral? On the other hand, a casual observer reading some of the newspapers and internet expositions on the subject, might well conclude that many people do consider stem cells immoral, particularly stem cells obtained from human embryos. For example, President George W. Bush announced on August 9, 2001 that human embryonic stem cells are immoral, even when they come from frozen fertilized eggs that are being thrown away and will be destroyed anyway, but he is inexplicably allowing the federal government to use and study of cells obtained from these if they had been obtained before his announcement. For many scientists, the stem cell debate has been puzzling. It is difficult for many of us to comprehend the so-called “repugnance” that Leon Kass, a medical doctor cum philosopher that President Bush recently appointed to head the President’s ethics commission, says that American people feel about embryonic stem cells. Why, in a nation where both abortion and in vitro fertilization are not only legal and widely practiced for decades, is there so much angst over using some fertilized eggs that will be discarded, to obtain stem cells that could potentially save and benefit millions of lives? This lecture is a personal journey to try to understand the angst, an analysis of the consequences, and a proposed compromise. ,

Stem Cells Definition of stem cells Different kinds of stem cells Stem cells are “pluripotent” cells that can produce many different kinds of cells. A fertilized egg is “omnipotent”, i.e. can produce all cells. Different kinds of stem cells Embryonic stem cells come from embryos (<6 weeks). Stem cells from blastocysts (2 weeks) are virtually “immortal”. Fetal stem cells come from fetuses (> 6 weeks) Stem cells are present in some adult tissues, including brain, spinal cord, and bone marrow. Before we begin, it is important to define what stem cells are. A decade ago, the word stem cell was mostly used to refer to bone marrow cells that produce different types of blood cells. Biologists have of course long known that developing embryos have cells that can produce many different kinds of cells. The concept of stem cells, however, attract much attention until they were discovered in adult brains in the late 1990’s. The concept that stem cells can produce replacement cells in the brain, the single organ that everybody agrees to be incapable of regeneration may now be capable of repair. By definition, stem cells can produce many kinds of cells or are pluripotent. A fertilized egg is an omnipotent cell, capable to producing all cells. Embryonic stem cells, however, is a misnomer because they do not necessarily come from embryos. An embryo is between 2 to 6 weeks old. Before 2 weeks of age, the fertilized egg is a blastocyst, a round hollow ball of cells that has not yet developed any recognizable organ or orientation. Located on the inside surface of blastocysts, embryonic stem cells are the most pluripotent and proliferative of stem cells. Beyond 6 weeks, the embryo becomes a fetus. Fetal stem cells are less pluripotent and have limited capabilities for reproduction. Adult stem cells are even more limited.

Embryonic vs. Adult Stem Cells Embryonic stem cells Embryonic cells are pluripotent and virtually immortal. Embryonic stem cells can form tumors called teratomas. Several methods are now available to control growth of embryonic stem cells. Adult stem cells Adult stem cells also have the capacity to produce many different cell types, including neurons. A person’s own stem cells should be the best source of cells for transplantation Adult stem cells will eventually substitute for embryonic stem cells. Embryonic stem cells are often said to be “immortal”. In culture, they appear to be able to grow and divide indefinitely. Obviously, they are not immortal in the sense of being unable to die. All cells degrade over time, due to free radicals and other damage of DNA. Embryonic stem cells appear to be missing the natural aging mechanisms that differentiated cells show in culture. When implanted into brain or spinal cord, embryonic stem cells can produce tumors called teratomas. Fortunately, several methods are available to control the growth of embryonic stem cells. Adult stem cells also can produce many different cell types, including neurons. For example, mesenchymal stem cells situated in bone marrow, will produce neurons if they are placed in the brain. Adult stem cells have limited growth potential compared to embryonic stem cells and this may reduce the risk of stem-cell derived tumors such as teratomas. Adult stem cells are particularly attractive from a therapeutic point of view because they can be obtained from the person. Such cells when transplanted to another place of the body would be autografts, not unlike transplanting skin from area of the body to another.

Embryonic Stem Cells Adapted from the New York Times 18 December 2001 The word embryo is used almost ubiquitously to describe an organism developing from an egg and before birth. However, scientists define a human embryo as the stage of development after the primitive streak (the precursor to the midline) appears but before recognizable organs appear. The streak appears at about two weeks. Before that time, it is called a blastocyst, a simple fluid-filled ball of cells with a collection of stem cells on one side of the inner surface. By 6 weeks, in the human embryo, the primitive streak develops into the notochord, the precursor to the spinal cord and various organs such as the head, limb buds, and guts become apparent. At this stage, the embryo becomes a fetus. The so-called embryonic stem cells are obtained from blastocysts at 1-2 weeks after fertilization. The cells are extracted and placed into tissue culture media containing fibroblast growth factor (FGF) or epidermal growth factor (EGF). These two growth factors stimulate the stem cells to divide and produce more cells. If serum (extracts of blood with the cells removed) is placed in the culture, the cells begin differentiating into other cells. However, if the cells are grown in the presence of FGF or EGF in serum-free media, the cells continue to divide, producing more stem cells. Adapted from the New York Times 18 December 2001

Fetal Stem Cells Neurosphere from rat brain Nestin stain BRDU stain

The Stem Cell Debate On August 9, 2001, President George Bush announced that NIH will fund human embryonic stem cell (HESC) research for the first time. The research will be restricted to 72 cell lines derived from surplus fertilized embryos before August 9. Both opponents and supporters of HESC research are unhappy with the ruling. Opponents believe that federal funding of human ESC research will open a Pandora’s box leading to baby and organ factories. Supporters believe that the restrictions will hold back crucial research that will benefit millions of people. Researchers have recently found that they can create cloned embryos. Stem cells derived from such embryos have the same genes and are an ideal source of stem cells for transplantation. Congress, however, is considering a bill that would outlaw making of cloned embryonic stem cells.

Importance of Stem Cells Studies of human embryonic stem cells will lead to major advances in human biology Embryonic stem cell research will provide critical insights into mechanisms of cell differentiation, growth, and death. Understanding stem cells may provide keys to why people age. Limitations on the study of human embryonic stem cell research will hold back biomedical research. Human embryonic stem cell therapies can save lives and restore function of people Human embryonic stem cell can replace damaged or lost cells These include diabetes, degenerative neurological diseases, demyelinative diseases, brain & spinal cord injury. These conditions are the most common and costly causes of disability in the United States.

Opposition to HESC Research Killing human embryos is unacceptable Use and study of human embryonic stem cells will require destruction of human embryos. Killing human embryos is unacceptable, no matter how much good such research will bring about. The facts that embryos will die anyway and that many people would benefit from the therapies do not justify killing embryos. The end does not justify the means. Embryonic stem cell therapies are not necessary Adult and other sources of stem cells, i.e. umbilical blood or bone marrow stem cells can be used. Many studies suggest that stem cells from these sources are beneficial in animal disease models Embryonic stem cells may form tumors whereas adult stem cells have limited growth potential and are less likely to produce cancers.

Common Misconceptions Human embryonic stem cell research encourages abortions. The proposed NIH research will use frozen fertilized eggs, not aborted fetuses. The fertilized eggs are used with permission of the parents who would otherwise discard them. Availability of human embryonic stem cells should reduce the current need for and use of human fetal tissues to treat Parkinson’s disease and other conditions. The research will increase killing of human embryos. The proposed NIH research will not create or clone human embryos. Only fertilized eggs that were already been created for the purposes of in vitro fertilization are used. Availability of this source of stem cells should reduce current unrestricted creation and destruction of human embryos for their stem cells.

More Misconceptions Embryonic stem cells come from embryos that can become adults Thousands of fertilized eggs are being discarded from fertility and not being used for research or therapy Many fertilized eggs have been stored beyond the time when they are suitable for producing embryos. Many parents do not want their eggs to be “adopted” by others. Embryonic stem cells come from embryos with recognizable body parts Embryonic stem cells come from blastocysts (2 weeks), little round balls of cells with no discernible organs or body parts. The blastocysts are never implanted into a uterus. Embryos form only after the notochord appears at about 2 weeks. Embryos become fetuses at 6 weeks.

Current Situation Current laws do not regulate embryo production or use by private companies Many companies produce stem cells from human embryos created for this purpose. Some private organizations are developing stem cells from aborted fetuses. Some companies are even cloning human embryos to develop stem cell lines. Most human embryonic stem lines belong to private companies. Companies therefore must develop their own lines if they want to do human stem cell research. A “public” source of human embryonic stem cells should significantly reduce the number of embryos that are created and destroyed for their stem cells.

Stem Cells vs non-Stem Cells Stem cell therapies will revolutionize medicine. The current generation of doctors will be the first to use stem cell transplants to repair and replace tissues. Genetically modified stem cells can deliver molecules. For example, insulin-secreting cells may replace life-time insulin injections. Stem cells are important class of transplantable cells because they are robust and produce many cell types. Non-stem cells may be better for some purposes Genetically modified fibroblasts, for example, have already been shown to deliver gene products Mixtures of progenitor cells that produce only one kind of cell may be more easy to control than stem cells. Some specialized cells may have advantages over stem cells. For example, Sertoli cells have anti-immune properties.

Slippery Slope Arguments Federal funding of HESC research may lead to a slide down a slippery slope. A oft-stated fear is that embryonic stem cell research will go the way of abortion. The United States went from a complete ban to abortions on demand. People feel that there are no safeguard against a similar slide towards a “Brave New World” with embryo farms and body parts for sale. Limited stem cell availability may lead to a slide down another slippery slope: The stem cell lines created before August 9 are not sufficiently available nor diverse for therapy HESC research will continue in the private sector and overseas where embryo use is not regulated. Embryos are being created for the purpose of stem cell production.

Human Cloning First human clone by placing human nucleus into a cow’s egg and growing it to 32-cell stage. Nov 1997 Scientific American article reporting the “first” cloned human embryo showing a fertilized cloned oocyte and cumulus cells. Advanced Cell Technology Nov 24, 2001 http://news.bbc.co.uk/hi/english/sci/tech/newsid_371000/371378.stm http://www.sciam.com/explorations/2001/112401ezzell/

Therapeutic Cloning Reproductive cloning Therapeutic cloning The process of creating an individual organism that is genetically identical. Current method requires somatic nuclear transfer (transfer of nucleus of a somatic cell to an oocyte) Therapeutic cloning The process of creating genetically identical cells for therapeutic purposes. Many methods can be used, including somatic nuclear transfer & parthenogenesis Clonaid claims also to have created first human clones and plans for reproductive cloning. - CNN, 27 Nov 2001 http://www.cnn.com/HEALTH/

Religious Positions Human embryonic stem cells are immoral The Catholic and Greek Orthodox Churches believe that embryos are potential humans. Even if embryos are being destroyed for other reasons, their use is immoral. Research and use of early embryos is not immoral The Synod (Protestant) believes that human embryonic research is not immoral if it occurs before implantation Islamic schools do not recognize early embryos as moral persons and have no difficulty with use and study of them. Life-saving research is a moral obligation The Jewish faith believes that saving human lives is a moral obligation and a divine mandate as long as care is taken to ensure that the process is fair to all parties involved.

Philosophical Positions The “wisdom of repugnance” argument Dr. Leon Kass applied this phrase to therapeutic cloning, meaning that we know, deep down, that it is immoral to create human embryos to use them. The “sanctity of life” argument Some philosophers have invoked the ”sanctity of life” as an argument against using embryonic stem cells. This reduces the question to our definition of life and a person. The “respect for the embryo” argument Human life demands respect. While it is not disrespectful to use an organ from a dead person, some argue that it is disrespectful to create an embryo and kill it for its stem cells

U.S. Government Positions In August 2000, NIH proposed to fund research on human embryonic stem cells obtained from excess fertilized human eggs that will be discarded by fertility clinics. These embryos were not produced for the purposes of research or therapy. If they are not used for research, they would be discarded. President Bush ruled that NIH can fund research on human embryonic stem cells but only cell lines derived from fertilized embryos before August 9, 2001 This compromise ensures that no federal funding will support destruction embryos for research or therapy President Bush strongly opposes human cloning or the creation and killing embryos for the purposes of research or therapy. NIH has since identified about 72 human embryonic cell lines created before August 9 and are eligible for study.

U.S. Legislative Positions H.R.2747 Stem Cell Research for Patient Benefit Act of 2001. NIH research with human pluripotent stem cells, restricted to cell lines available before August 9. Also funds an Institute of Medicine study and establishes a Biomedical Advisory Commission. S.1349 Responsible Stem Cell Research Act (2001) $275 million for a National Stem Cell Donor Bank for qualified human stem cells: human placenta, umbilical cord blood, organs or tissues of adults, or unborn humans who died of natural causes HR2505 Cloning Prohibition Act of 2001 Criminalizes attempts, transport, or participation in human cloning with a penalty of 10 years in prison and $1 million fine. Cloning is defined as “human asexual reproduction, accomplished by introducing nuclear material from one or more human somatic cells into a fertilized or unfertilized oocyte”,

A Flawed Policy Encourages private creation and use of embryos Private use of human embryos is unregulated. Delays in stem cell therapies for people Available cell lines are not sufficient ly diverse for therapeutic purposes Non-cloned stem cells are not immunologically compatible Flight of research overseas Scientists and companies will move their research overseas to more supportive environments Banning of therapeutic cloning is not enforceable It is difficult to detect the origins of transplanted cells.

Extreme Positions Only consequences matter Unrestricted Prohibit all human embryonic stem cell or cloning Unrestricted human stem cell and cloning research • Risk Analyses • Consequences • Alternatives Ends do not justify means

Scientific Consequences Consequences of slowing HESC research Greater emphasis on adult stem cell technologies Limited human stem cell clinical trials for 3-5 years Flight of academic and commercial research to countries that are more supportive of HESC work Intensified HESC research overseas Consequences of federal funding of HESC research Availability of human stem cells for research and therapy Reduced creation and destruction of human and animal embryos and fetuses for research and therapy Replacement of embryonic stem cells by adult stem cell therapies in 3-5 years

Human Consequences Restricted federal funding and human stem cell lines is slowing progress in moving stem cell therapies to trial Millions of people are dying from progressive disease, I.e. Alzheimer’s, Parkinson’s & Huntington’s, amyotrophic lateral sclerosis. We cannot and should not ask people with progressive diseases and severe brain and spinal cord injuries to wait years for human stem cells to reach clinical trial. Limited availability of human stem cells is encouraging use of higher risk therapies. Genetically modified porcine (pig) stem cells are being transplanted into people to treat stroke, brain & spinal cord injury. Xenotransplants pose special risks of animal diseases passing to humans Human fetal tissues are being transplanted to people with Parkinson’s disease & spinal cord injury.

Risk Analyses Risks of slowing HESC research Alternatives are being applied (xenotransplants, fetal cell transplants) with higher risks to individuals and society Slowing down biological research crucial for understanding mechanisms of life, development, and death Delaying therapies for people who are dying and suffering from severe disability Unregulated private sector creation and destruction of embryos for stem cell production Risks of federal funding of HESC research Slide down the slippery slope of condoning embryonic use The research will encourage cloning, baby-organ “factories”

Some Alternatives Increase NIH funding of adult stem cell research This would strongly encourage scientists to develop alternatives to embryonic stem cells It will provide alternatives to embryonic stem cell therapies that will be developed overseas Prohibit reproductive cloning but allow therapeutic zygote cloning (<2 weeks) for stem cell production This allows federal regulation of stem cell production. This, however, will be opposed by anti-cloning groups. Do nothing Companies will continue to clone and make stem cells Adult stem cells will be preferred over embryonic stem cells

A Better Compromise Allow NIH to use stem cells derived from fertilized eggs under a strict guideline of demonstrated need. This provides sufficient diversity for therapy. It will reduce the embryos use by private companies. Ban implant of non-fertilized eggs into human uterus This ban on reproductive cloning is eminently enforceable. It would allow cloning of eggs for infertile women. Allow therapeutic cloning with a sunset clause This provides a temporary solution until adult stem cells and other alternatives can be developed It will prevent the flight of stem cell and cloning research overseas

Conclusions Both sides of the debate share the same goal: minimize creation and destruction of human embryos while accelerating stem cell therapies The current policy of limiting stem cells created before August 9, 2001 will encourage unregulated use of embryos while delaying stem cell therapies Proposed anti-cloning legislation banning therapeutic cloning is not enforceable, delays stem cell therapies, and will drive scientists and companies overseas A better policy would be to allow NIH to use new stem cell lines, ban reproductive cloning, and allow therapeutic cloning with a sunset clause