ES Cells and the definition of an embryo

- Richard M. Lebovitz

Virginia, USA

Eubios Journal of Asian and International Bioethics 12 (2002), 151-153.
"When I use a word," Humpty Dumpty said, in a rather scornful tone, "it means just what I chose it to mean ― neither more nor less." "The question is," said Alice, "whether you can make words mean so many different things." "The question is," said Humpty Dumpty, "which is to be master ― that's all." From Through the Looking Glass and What Alice Found There by Lewis Carroll (1872).

Like Lewis Carroll's Humpty Dumpty, politicians want to believe that they are masters of the words they use, and that words can be defined to suit their whims. This strategy appears to have driven the U.S. President George Bush's announcement on August 6, 2001 that the U.S. federal government would fund work on human embryonic stem (ES) cells (1), despite a legislative ban on human embryo research. Because the law prohibits federally-funded scientists from experimenting with embryos, the only way stem cell research could go forward with federal funding would have been to define embryonic stem cell in such a way that it would not be considered an embryo under the research prohibition, or to change the law to plainly exclude them. The President has no power to rescind a law without Congressional action, but he could, and did, avoid it altogether by adopting a definition of embryo that excluded embryonic stem cells (2). Whether this was scientifically correct or simply political wordplay was ignored in the debates that have since surrounded the President's decision. What's troubling is that the Bush policy ignores research that embryonic stem cells from other mammals can under the appropriate conditions form fully viable embryos, capable of being born, making it difficult to accept the Bush Administration's logic that human ES cells are not human embryos.

Embryonic stem cells attracted international attention shortly after scientists announced the creation in 1998 of the first human embryo stem cell line (3). Embryonic stem cell lines are established cell lines, derived from an embryo, which can be maintained in vitro in a tissue culture dish for many generations, and which, under the appropriate conditions, are able to differentiate into all three tissue types found in a normal embryo. This ability is referred to as "pluripotency." Because of their close relationship to human embryos, controversy soon erupted all over the world on the question of whether experimentation on human ES cells was equivalent to permitting research on humans.

In the United States, a federal government funding law prohibited the spending of federal funds on human embryo research. Under Public Law (e.g., 105-277 and 106-554), federal funds may not be used "for the creation of a human embryo or embryos for research purposes; or research in which a human embryo or embryos are destroyed, discarded or knowingly subjected to risk of injury or death." Since in the course of carrying out stem cell research, it is almost unavoidable that human stem cells will be destroyed or discarded, it was critical to establish whether they fell within the statutory definition of embryo. If they did, the government's research agency, the National Institutes of Health (NIH), could not fund the work. The Bush administration had no power to repeal the law, but they could, and did, adopt a definition of it that permitted stem cell research to go on.

Concerned that the restriction on human embryo research under the federal funding ban would stifle human stem cell research, NIH asked the Department and Health and Human Services (DHHS) to clarify whether the use of human embryonic stem cells would violate the existing ban. In a January 15, 1999 opinion letter by Harriet S. Rabb, of the Office of the General Counsel of DHHS, to Dr. Harold Varmus, former NIH Director, it was concluded that federal funding to support human ES research would not violate the human embryo ban (4).

The DHHS opinion focused on a dictionary definition of embryo, defining it as an organism "constituted to carry out all life functions." According to Rabb, "Pluripotent stem cells are not organisms and do not have the capacity to develop into an organism that could performs all the life functions of a human being ― in this sense they are not even precursors to human organisms. … Moreover, a human embryo, as that term is virtually universally understood, has the potential to develop in the normal course of events into a living human being. … Pluripotent stem cells do not have the capacity to develop into a human being, even if transferred to a uterus." In making her point, Rabb cited, among others, concurring testimony by Dr. Michael West of Geron, the company who initially funded work that led to the creation of ES cell lines.

The linchpin of the DHHS argument was that embryonic stem cells are incapable of forming embryos that can be gestated inside a woman and born. For this reason, DHHS concluded, they are not embryos within the meaning of the statutory prohibition, opening the door for stem cell research funding. A key question, ignored in the public frenzy that surrounded the funding controversy, is whether the DHHS conclusion, and the Bush administration's adoption of it, was a correct assessment of stem cell biology. In fact, do biologists really know whether human stem cells can be turned into a human being that can achieve all the normal life functions? Given the Bush Administration's decision, the answer to the question may be surprising: At the present time, experiments have not being performed on human stem cells which could answer this question affirmatively for humans, but experiments on mice have been performed, and for them, the answer is yes. As explained in more detail below, mouse ES cells can be used to create wholly functional mice, providing basis for a reasonable scientific belief that such results could be obtained with other mammals, including humans. In short, the reasoning relied upon by the DHHS is flawed, ignores scientific facts, and is sure to come to public attention when scientists with the help of federal funds realize the potentiality of human ES cells and create the first human stem cell baby.

Stem cell researchers working with mouse ES stems, the model on which human stem cells were based, routinely conduct experiments to determine the developmental potential of the cells. Developmental potential simply means the ability of a stem cell to form adult cell types, e.g., heart, brain, and pancreas. Since, by definition, an ES cell is capable of forming every single tissue type found in an embryo, researchers must have a way of assessing their competence. To make this determination, mouse embryonic stem cells are mixed with normal mouse embryo cells to form a cell aggregate, and then the aggregate is introduced into a mouse uterus where it implants and is carried to term. The resulting mouse that is born contains cells which originate from both the normal embryo and the ES cells. Such an animal is described as a "chimera" because it is composed of two genetically distinct tissues ― those derived from normal embryonic cells and those from the ES cell line. This kind of experiment would be prohibited under the federal appropriations law because it requires normal human embryo cells to make it work. Nonetheless, mouse ES stem cells, at least, are capable of contributing to the tissues of a whole, functional organism that can survive outside the uterus. An organism could result from such procedure that had, for instance, a brain of ES origin, but other tissues made from the normal cells. At least some of the ES cells are "precursors" to a part of a normal, living organism. Still, under the DHHS definition, it is correct that one individual stem cell in this type of experiment does not develop into a single organism that performs "all the life functions of a human being." (Emphasis added.) But there is more to story.

Since 1993, a number of scientific reports have appeared in the literature of mice derived entirely from embryonic mouse stem cells (5). In these studies, ES cells were mixed with normal embryo cells which had been genetically debilitated by making them have twice the normal number of chromosomes ("tetraploid cells"). The reason for compromising the normal embryo cells was to weaken and slow their growth, giving the ES stem cells the opportunity to populate all the tissues of the embryo. The faster growing, more robust, ES cells outgrew the tetraploid cells, and mice were eventually formed that were descended completely from them. While the tetraploid cells formed the extra-embryonic tissues, such as the placenta, ES cells became the exclusive progenitor of the fetal parts of the embryo (6). Initially, the frequency of live-born fertile animals produced by ES-tetraploid cell technology was very low, but recent discoveries have significantly increased it (7). By 2001, scientists had successfully genetically engineered the DNA of mouse ES stem cells, and produced live-born mice 100% derived from the engineered cells.

Together, these results establish that embryonic stem cells, at least from a mouse, do possess the ability to develop into an organism that can perform all its life functions outside the uterus. In other words, the DHHS conclusion, strictly speaking, is not correct. Embryonic stem cells have the capacity to develop into a completely functional organism when transferred to a female's uterus. There is no reason to believe that the same could not be achieved with human cells, if the experiment were ever performed. Under President's Bush decision, scientists have complete freedom to go ahead and try.

ES cells differ in the type of contributions made by gametes (sperm and egg) during fertilization and body cells in cloning experiments. In each of the latter, the cell provides a missing part that is subsequently subsumed by a next generation cell. In the case of the gamete, the sperm and egg are incorporated into the embryonic cell ― and in cloning, the nucleus and DNA of the body cell is included into the cytoplasm of the host cell which is missing its own DNA. Embryonic stem cells possess the true competence to completely colonize each and every tissue that forms a living fetus. As demonstrated with the ES-tetraploid cell technology, an ES cell can accurately be characterized as the precursor cell to the human embryo and subsequent fetus, rather than simply the precursor material as supplied by the gamete during fertilization and body cell in a cloning experiment. If Congress's intent was to prohibit experimentation with the cells that could become a human being, then the Bush administration's policy is at odds with it. As a direct result, there is no prohibition from using federal grant money to manipulate or engineer human ES cells into full-fledged human beings ― the exact result the embryo ban was designed to stop. Considering the fast pace at which paradigms in developmental biology have been invalidated, it is not unreasonable to expect a human stem cell baby very soon.

References and Notes

(1) Embryonic stem cell lines are established cell lines, derived from an embryo, which can be maintained in vitro in a tissue culture dish for many generations, and which, under the appropriate conditions, are able to differentiate into all three tissue types found in a normal embryo ("pluripotent"). The embryonic stem cells were created by culturing normal embryo cells under in vitro conditions until a cell line with the desired pluripotent properties was derived.

(2) Government administrative agencies control and execute the statutes created by the U.S. Congress. When a statute is ambiguous, it is the function of the agency to interpret it, and administer it in a way that is consistent with the intent of Congress in writing the statute. In this case, it was not clear from the plain language of the statute whether ES cell experimentation was within the scope of the embryo ban. As a government agency, it was NIH's job to construe the statute, and decide whether ES cell research could be funded under the federal law. The decision ultimately fell to the President as the chief policy maker. At the time his decision was made, Bush had not yet appointed a chief administrator to head NIH.

(3) Thomson et al., Science, 282:1145-1147, 1998; Shamblott et al., Proc. Natl. Acad. Sci., 95:13726-13731, 1998.

(4) Memorandum from Harriet S. Rabb to Harold Varmus, M.D., Director, NIH, January 15, 1999.

(5) Nagy et al., Proc. Natl. Acad. Sci., 90:8424-8428, 1993; Zang et al., Mech. Dev., 62:137-145, 1997. Similar experiments performed with cattle have not yet been so successful. Only chimeric cattle resulted, having both ES and tetraploid cells present in the fetal tissues. See, Iwasaki et al., Biology of Reproduction, 62:470-475, 2000.

(6) Cross, Proc. Natl. Acad. Sci., 98: 5949-5951, 2001.

(7) Eggan et al., Proc. Natl. Acad. Sci., 98: 6209-6214, 2001, found that ES stem cells from F1 hybrids, rather than inbred strains, increased the fraction of live-born births by 50-fold. See, also, Cross, Proc. Natl. Acad. Sci., 98: 5949-5951, 2001.

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