The United States should ban human reproductive cloning aimed at creating a child, says a new National Academies' report that considers only the scientific and medical aspects of this issue, plus ethical issues that pertain to human-subjects research. Based on experience with reproductive cloning in animals, the report concludes that human reproductive cloning would be dangerous for the woman, fetus, and newborn, and is likely to fail. The study panel did not address the issue of whether human reproductive cloning, even if it were found to be medically safe, would be -- or would not be -- acceptable to individuals or society.
"Data on the reproductive cloning of animals demonstrate that only a small percentage of attempts are successful, many of the clones die during all stages of gestation, newborn clones often are abnormal or die, and the procedures may carry serious risks for the mother," said Irving L. Weissman, chair of the panel that wrote the report and professor of pathology, cancer biology, and developmental biology, Stanford University, Stanford, Calif. "The proposed ban on human cloning should be reviewed within five years, but it should be reconsidered only if a new scientific review indicates that the procedures are likely to be safe and effective, and if a broad national dialogue on societal, religious, and ethical issues suggests that reconsideration is warranted."
Enacting a legally enforceable ban that carries substantial penalties would be the best way to discourage human reproductive cloning experiments in both the public and private sectors, the report says. A voluntary measure probably would not be effective because many of the technologies needed to accomplish human reproductive cloning are widely accessible in private fertility clinics and other organizations that are not subject to federal regulations.
What Does Cloning Entail?
Human reproductive cloning is an assisted reproductive technology that would be carried out with the goal of creating a newborn genetically identical to another human being. The method used to initiate the reproductive cloning procedure is called either nuclear transplantation or somatic cell nuclear transfer.
The initial step involves removing the nucleus of an egg cell and replacing it with the nucleus of a cell from an adult. The reconstructed egg is then stimulated to begin dividing. If the procedure is successful, the cell will divide several times to produce a pre-implantation embryo -- "blastocyst" -- that is composed of about 150 cells.
If the blastocyst is placed in a uterus, it can implant and form a fetus, which then may develop further and result in a newborn. Individuals created in this way would have the same nuclear genes as the original adult cells, but they would not be exact copies of the adults because of different prenatal and postnatal environments, as well as experiences.
There is a related but different procedure, which the panel denotes as nuclear transplantation to produce stem cells -- but which also has been called nonreproductive cloning, therapeutic cloning, research cloning, or somatic cell nuclear transfer to produce stem cells -- whose aim is the creation of embryonic stem cells for clinical and research purposes. Unlike reproductive cloning, the creation of embryonic stem cells by nuclear transplantation does not involve implantation of a blastocyst in a uterus.
Instead, cells are isolated from a blastocyst about five days after the nuclear transplantation procedure and used to make stem cell lines for further study and clinical applications. Such stem cells are unspecialized cells that can renew themselves indefinitely and, under the right conditions, develop into more mature cells with specialized functions. Stem cells derived from a cell nucleus of a patient could be powerful tools for medical research and improved therapies for treating disease.
Implications for Stem Cell Research
The panel concluded that the scientific and medical considerations that justify a ban on human reproductive cloning at this time are not applicable to nuclear transplantation to produce stem cells. Because of the considerable potential for developing new medical therapies to treat life-threatening diseases and advancing biomedical knowledge, the panel supported the conclusion of a previous National Academies' report -- Stem Cells and the Future of Regenerative Medicine -- that recommends that biomedical research using nuclear transplantation to produce stem cells be permitted.
The panel also encouraged a broad national dialogue on the societal, religious, and ethical issues concerning this matter.
Human Reproductive Cloning Would Be Risky
To date, five mammalian species -- sheep, cattle, pigs, goats, and mice -- have been used extensively in reproductive cloning studies. Data from these experiments clearly illustrate the problems involved and are quite compelling, the report says. Typically, very few cloning attempts are successful. Many clones die in utero -- even at late stages or soon after birth -- and those that survive frequently exhibit severe birth defects. In addition, female animals carrying cloned fetuses may face serious risks, including death from cloning-related complications. Human reproductive cloning is likely to have similar negative outcomes.
Because many eggs are needed for human reproductive cloning attempts, human experimentation could subject more women to adverse health effects -- either from high levels of hormones used to stimulate egg production or because more women overall would be sought to donate eggs, which involves surgery with its own inherent risks, the panel noted.
Some proponents of human reproductive cloning have argued that voluntary, informed consent would give people the option of making their own decisions about participating in research. But when critical information is lacking, as it would be in this case, fully informing patients of potential health effects is difficult or impossible. Moreover, the cloned offspring -- who would face the greatest risks of abnormality and death -- would not be in a position to offer consent. These circumstances provide additional reasons to exercise caution, the report says.
Consideration of Ethical Issues
The panel stressed that all concerned segments of society should examine and debate the broad societal, religious, and ethical issues associated with human reproductive cloning, as well as those associated with nuclear transplantation to produce stem cells. Although this report focuses on the scientific and medical aspects of these areas, it should help to inform this broader consideration by society.
The panel's work was sponsored by the National Academies, which comprise the National Research Council, National Academy of Sciences, National Academy of Engineering, and Institute of Medicine. They are private, nonprofit institutions that provide science, technology, and health policy advice under a congressional charter.
February 10, 2002 - Scientists prove mature adult cells can be cloned
Researchers from Rudolf Jaenisch's lab at the Whitehead Institute for Biomedical Research have taken a significant step toward answering a half century old question -- do clones, like Dolly, derived from adult cells develop from a fully mature adult cell or do they develop from rare stem cells found in adult tissues? The researchers have proved for the first time that fully differentiated adult cells can form clones, but they found the process is extremely inefficient. It is more likely that elusive adult stem cells, which exist in tiny numbers along with the mature adult cells, are actually the ones to form clones, says Jaenisch. The study was conducted by Konrad Hochedlinger, a student in the Jaenisch lab, and will appear in Nature online February 10, 2002. This study will affect the debate on the pros and cons of human cloning.
"This finding tells us something about the nature of the genome of adult cells -- these cells are not very labile and difficult to clone. This is important to know, if adult cells are going to be cloned for personalized cell therapy," says Jaenisch. Therapeutic cloning involves removing the nucleus, or the genetic command center, of an egg and replacing it with the nucleus from an adult donor cell. Ideally, the egg resets the developmental clock of the nucleus back to a state compatible with early embryonic growth. This ball of cells growing in culture gives rise to embryonic stem (ES) cells that genetically match the donor and have the potential to become any tissue in the body. In theory, these ES cells may be used to treat diseases, such as diabetes or spinal cord injury, without the complications of organ rejection.
Using Immune Cells to Clone Mice
Scientists have known for sometime that cloning using ES cells is much more efficient than using adult cells, probably 10 fold more efficient. This makes sense because ES cells are at the earliest developmental stage and have the potential to become all the cells that make up an organism. But researchers didn't know if cloning could set the clock back for mature adult cells, such as skin or mammary cells, which are committed to a specific function. Alternatively, researchers speculated that rare, adult stem cells, which are further along the developmental path than ES cells, but not yet committed to a specific function, were the ones creating the clones.
This was a difficult puzzle to solve since most adult cells don't have stable genetic markers, which can be tracked from the donor nucleus to the resulting clone. Immune cells called B cells and T cells are an exception -- when these cells reach maturity, special genes, called immunoglobulin genes, are permanently shuffled. This rearrangement process allows these immune cells to produce the many unique antibodies and receptors necessary to recognize and fight the plethora of pathogens we encounter from a limited number of genes.
The Jaenisch lab took advantage of these "unique gene signatures" and used nuclei from adult B cells and T cells to create clones. Where other groups had failed in creating clones from these immune cells, Hochedlinger succeeded by using a new two step cloning process.
They first created cloned mouse embryos by transferring the nucleus from either a B cell or a T cell into a mouse egg that was devoid of its own nucleus. Instead of implanting the cloned embryos into the womb of a surrogate mouse at this point, the embryos were grown in tissue culture to make ES cells. From the 1,000 nuclear transfers attempted, the researchers were able to establish only two ES cell lines -- one from a B cell and one from a T cell. Then in a second step, these ES cells were successfully used to create mouse clones. Instead of each successful nuclear transfer resulting in one implanted embryo, the two step process allowed the researchers to make multiple attempts at creating identical mouse clones from each ES cell line.
The resulting cloned mice had the unique gene rearrangement that was present in the original B cell or T cell from which they were derived in all the cells of their body. The mice could not rearrange their immune genes, so they were only able to make the one type of antibody or receptor they started out with. "This tells us that the original B cell and T cell were truly mature, functional cells waiting to get activated by a pathogen," explains Hochedlinger.
Implications on the pro's and cons of human cloning
"In normal cloning attempts, it would be too inefficient to use mature adult cells. We were able to produce clones from adult cells because we took the two step approach. I think this supports the suggestion that many clones are derived not from mature cells but rather from adult stem cells, but we haven't proven this," says Jaenisch. To test whether adult stem cells have a higher cloning efficiency, scientists need to compare the clone-forming potential of adult stem cells (precursors to B and T cells) to the mature B and T cells. "If adult stem cells are more easily reprogrammed, than one could argue that clones are actually derived from these rare cells," he adds. This next step will be challenging since adult stem cells are very difficult to identify and grow in culture.
This study also represents a proof of principle for a tool that can be used to distinguish between epigenetic and genetic changes occurring in adult cells, for example, during brain development or cancer. "You may be able to take a single neuron and make a cloned mouse with it. All the cells in the resulting mouse will be genetically identical to the original donor cell. The cloning technique amplifies what happens in a single cell into a whole animal. If changes in a cell are reversible -- epigenetic -- the mouse will be normal. However, genetic changes, no matter how subtle, are irreversible and observable, like the rearrangement of immunoglobulin genes in B cells and T cells," explains Jaenisch.