Biotech Hobbyist Magazine.
Pushing the frontiers of biology closer to the central mystery of life, scientists have for the first time picked out and cultivated the primordial human cells from which an entire individual is created. The cells, derived from fertilized human eggs just before they would have been implanted in the uterus, have the power to develop into many of the 210 different types of cell in the body -- and probably all of them. Because they can divide indefinitely when grown outside the body without signs of age that afflict other cells, biologists refer to them as immortal. Eventually, researchers hope to use the cells to grow tissue for human transplants and introduce genes into the body to remedy inherited disease. But there is a thicket of ethical and legal issues, as well as technical problems, to be tackled. The cells are obtained from embryos created at in-vitro fertilization clinics and so far do not seem definably different from the handful of primordial cells from which an entire individual is created. Though the scientists involved in the work consider use of the cells justified because they come from embryos that would otherwise have been discarded, other believe the cells have a special status in that they retain the potential to develop into an individual, and that the use of the cells may draw criticism if this status is not taken into account. The new cells, known as human embryonic stem cells, have eluded capture until now because they exist in this state only fleetingly before turning into more specialized cells, and need special ingredients to be kept alive outside the body. The cells have many possible uses, of which the most promising is to grow new tissue, of any kind, for transplant into a patient's body. The cells may also offer effective routes to human cloning, although both the researchers and their sponsor deny any interest in this application. Another likely use is in gene therapy, the insertion of new or modified genes into body tissue. Two forms of human embryonic cells have been developed, one by a team under Dr. James A. Thomson of the University of Wisconsin in Madison, the other by Dr. John Gearhart and colleagues at the Johns Hopkins University School of Medicine in Baltimore, Md. Dr. Thomson's work is reported in this week's issue of Science, Dr. Gearhart's in the Proceedings of the National Academy of Sciences. Congress in 1995 banned Federal financing of research on fetal cells, including those derived from embryos, and the university researchers whose work was announced today were funded by the Geron Corporation of Menlo Park, Calif., a biotechnology company that specializes in anti-aging research. The research "has potential health benefits which I think are extremely promising, and I am sorry that the law prevented us from supporting it," said Dr. Harold Varmus, director of the National Institutes of Health. Cells Are Specialized as They Develop After an egg is fertilized, it divides several times and forms a blastocyst, a hollow sphere with a blob of 15 to 20 cells, known as the inner cell mass, piled up against one wall. It is from these cells that the embryo develops. Dr. Thomson grew his embryonic stem cells from the inner cell mass of blastocysts that had been left over from fertility treatments and were due to be discarded. The donors of the blastocysts granted permission for them to be used in research. As an embryo grows and develops, its cells become irreversibly committed to their fates as specialized components of the body's organs. A pocket of cells, known as embryonic germ cells, is protected from the commitment process so as to create the next generation of eggs and sperm. Dr. Gearhart's group has developed embryonic stem cells from the germ cells of aborted fetuses. The cells developed by the two groups may well be equivalent but this has yet to be proved. If researchers are able to use the cells to grow new tissues, the work could alleviate the shortage of livers and other organs for transplant. Cultures of the cells in the laboratory could be nudged down different developmental pathways to become heart or bone marrow or pancreatic cells. Before reaching their final stages, the about-to-become heart cells, for example, could be injected into a patient's ailing heart. Guided then by the body's own internal regulatory signals, the cells would develop into new, young heart tissue, supplementing or replacing the heart cells already there. The same approach should in principle work with any tissue of the body. Human embryonic stem cells would thus serve as a universal spare parts system. Because the cells grow and divide indefinitely in the laboratory, very few blastocysts would be needed. Many technical problems remain to be resolved. The art of directing embryonic stem cells down specific pathways is in its infancy. But heart muscle cells have been grown from mouse embryonic stem cells and successfully integrated with the heart tissue of a living mouse. Dr. Thomson in 1995 isolated the embryonic stem cells of a monkey, and Geron intends to do pilot experiments in these cells. Another problem lies in making grafted cells compatible with the patient's immune system. Dr. Thomas B. Okarma, Geron's vice president for research, said Geron would explore several ways of doing this. One, the least preferred, would be to set up a bank with enough different human embryonic cells that most patients could be matched. Another would be to suppress the self-recognition genes that make the stem cells appear foreign to the patient's immune system or, more elegantly, to replace them with copies of the patient's own self-recognition genes. A third approach would be to convert one of the patient's own body cells back to embryonic form by fusing it with a human embryonic stem cell whose own nucleus had been removed. Embryonic cells may have the power, not yet understood, to rescue an adult cell's nucleus from its specialized state by flicking all the switches on its DNA back to default mode. This reprogramming of DNA is presumably what happened when mice were cloned in July from adult cells. Ethical Concerns Prevent Some Tests The ethical status of the cells is also likely to be a matter of discussion. They cannot become a fetus, as their blastocyst no longer exists, yet they are very similar, if not identical, to the 20 or so primordial cells from which the embryo develops. Both research groups refer to their cells as "pluripotent" because, when injected into a mouse with no immune system, the cells develop into many of the major tissues of the body. The tissues are disorganized and do not develop into a normal embryo. The cells may also be "totipotent," meaning they can form every one of the body's cell types. The test for totipotency, developed with mouse embryonic stem cells, is to inject stem cells into another blastocyst. A normal mouse will usually develop, but it is composed of a patchwork of cells, some from the blastocyst and some from the injected embryonic stem cells, proving the stem cells retain all their powers. It would be unethical to perform such an experiment on people, but if it could be done, it seems likely that the human embryonic cells cultured by the researchers would also prove to be totipotent. If so, they may be capable in principle of contributing to the generation of a new individual. But ethicists say great care must be taken in work involving human embryonic cells. "Any time you take a cell off a blastocyst, that cell could be used itself to create a human being, so some groups in our society believe in making it transplantable you have derailed it into becoming a kidney or some other tissue," Dr. Lori Andrews, an expert on the laws governing reproductive technology at the Chicago Kent College of Law, said. "Some researchers say, 'It's just a bunch of cells, why should people care?' But that totally avoids the fact that some people do care, and I'm concerned that if the researchers don't take into consideration the variety of viewpoints about embryos, they might ultimately end up with more restrictive regulations." Geron, which has exclusive licenses to use the cells, under patents held by the researchers' universities, says it regards them as qualitatively different from other cells used in research. "Because these cells are derived from human blastocysts there is a moral authority here, so we take these cells seriously," Dr. Okarma, of Geron, said. Dr. Okarma said he believes that use of the cells is justified because they are something less than a living embryo, and life-saving treatments may be derived from them. "We are not saying the ends justify the means, but that given that the moral authority of these cells is subordinate to that of the embryo, the work we contemplate with them is appropriate," he said. But Dr. Gearhart said he did not consider the cells that he and Dr. Thomson have isolated to have a special moral status because "they cannot form a fetus -- you cannot take one of these cells and form a being out of it." Still, Dr. Gearhart said he would not argue with the view of Dr. Okarma at Geron that the cells had a different standing from ordinary cells. Dr. Johnson, too, said that they were "special cells." Dr. Kevin T. Fitzgerald, a geneticist and Jesuit priest at Loyola University Medical School, said that if the human embryonic stem cells are totipotent, "then you are disrupting the viability of life and we are back to the question of how to justify destroying life for the purposes of scientific advancement." The new cells may well reawaken fears of human cloning, although many ethicists have now come around to believing that the public's fears, despite science fiction writers' portrayal of clonal armies of frenzied despots, are largely beside the point. Many experts now predict human cloning is more likely to end up as a rare treatment offered in fertility clinics, no different from others like in-vitro fertilization and egg donation in that they were first bitterly denounced and are now regarded as routine. "Human cloning will likely also be accepted once it becomes a reality. Most of today's ethical arguments against it were previously used against in-vitro fertilization and turned out to be false," writes Dorothy C. Wertz, a bioethicist at the Shriver Center, in the current issue of Gene Letter. The availability of human embryonic stem cells suggests a quite different possibility to biologists, who are well aware of how mouse embryonic stem cells have long been used to generate genetically altered mice. The belief that humans can now be modified like the mouse "will be the kneejerk reaction of the academic community," Dr. Thomson said. He said human embryonic stem cells were unlikely to be used in this way because there were more promising approaches for gene therapy in people. For one thing, the mouse method requires the creation of many embryos in order to obtain the few in which new genes integrate in exactly the correct position, as well as the breeding of a male and female mouse that have been genetically altered. In its present form, the technique is evidently inapplicable to humans. Federal Law Shifts Research to Industry The National Institutes of Health and the university scientists it funds often play a leading role in reviewing new biomedical technologies. But because of the Federal funding ban, university scientists cannot get Government support to study human embryonic stem cells. But industry can do whatever research it pleases, without necessarily obtaining government approval. Academic biologists believe this asymmetry is unfortunate and that the new technique would receive better and more detached review if the agency and its scientists could take part in the discussion. Dr. Varmus said that an expert panel on human embryo research had recommended to the health institutes that attempts to derive stem cells from human embryos should be permitted, but Federal efforts along this line were thwarted in 1995, with the Congressional funding ban. Dr. Varmus said he believed the public "will see how important the benefits of this research might be." A Senate bill to ban human cloning was defeated in February this year, the principal argument of its opponents being that its overly broad language would prohibit promising research on human embryonic stem cells. In any event, any ultimate use of human embryonic stem cells may face legal hurdles in the nine states that have outright bans on research on human fetal tissues, Dr. Andrews said. Some laws also prohibit payment for embryos, a restriction that might extend to cells and tissues derived from embryos. A Possibility of Eternal Cells The technique reported today reaches to the central mysteries of life and death. As biologists have recently begun to understand, the body's cells are not inherently mortal. They become mortal only when committed to developing into one or another of the body's mature cell types. These specialized cells have mostly lost the ability to grow and divide, but a few, typically those of the skin and intestinal lining, can divide in culture about 50 times and then die. In January this year, biologists at Geron learned how to manipulate the section of DNA that marks off the 50 or so permissible divisions. By reversing the changes in this section of DNA, called the telomere, they created lines of cells that divided well beyond the usual limit and are still going strong, while retaining their youthful vigor and appearance. Biologists refer to these cultured cells as immortal because they are expected to grow and divide indefinitely. Embyronic stem cells are also immortal because, until they become committed to specialized fates, their telomeres are renewed each time they divide. Unlike ordinary cells, they grow indefinitely in culture. In the lineage of living organisms, they cycle indefinitely from the embryo to the germ line to a new embryo, forever avoiding specialization into the mortal cell types that comprise the body. Geron biologists believe they can manipulate the telomeres of the human embryonic stem cells so that the cells stay immortal even as they turn into specialized tissues. Can the mortal body therefore be repaired with new, tissues that remain youthful indefinitely? "Exactly," Dr. Okarma said. Critics have said it would be folly to tamper with the telomere division-counting system because it probably arose in evolution as the body's last-ditch defense against any runaway cell likely to become a cancer. Dr. Okarma said that new experiments had largely laid this concern to rest by showing that telomerised cells are no more likely to become malignant than are normal cells. These grand schemes may or may not come to pass, but the techniques now at hand for manipulating human embryonic stem cells will at least allow them to be seriously attempted. November 6, 1998