November 12, 1998

Human Cells Revert to Embryo State, Scientists Assert


Venturing deep into uncharted realms of ethics and medicine, a small biotechnology company said Wednesday that its scientists had for the first time made human cells revert to the primordial, embryonic state from which all other cells develop, by fusing them with cow eggs and creating a hybrid cell.

The research comes from biologists who are well known in their field, but has yet to be confirmed or even published in a scientific journal. Their company, Advanced Cell Technology of Worcester, Mass., said the method could eventually be used to grow replacement body tissues of any kind from a patient's own cells, sidestepping the increasing scarcity of organs available for transplant and the problems of immune rejection.

The technique is likely to concern and perplex ethicists because it involves the creation of an embryonic cell that is part human and part cow, consisting of a human cell's nucleus inside a cow egg whose own nucleus has been removed. The company said the hybrid cell quickly became more human-like as the human nucleus took control and displaced cow proteins with human proteins. Creation of the embryonic cells is an important component of a strategy that in principle offers high medical benefits if it can overcome a doubtless high barrier to public acceptance.

The technique involves creating an embryo of uncertain moral status, and one that crosses the barrier between humans and other species. Even though the hybrid is in the form of cells, not a whole organism, the concept of half-human creatures arouses deeps anxiety, as is evident from the unfriendly powers ascribed to werewolves, centaurs, mermaids, Minotaurs and other characters of myth and folklore.

"Many people are going to be horrified by this scenario, others will say 'So what?' " said Thomas Murray, director of the center for biomedical ethics at Case Western Reserve University in Cleveland and a member of the National Bioethics Advisory Commission. "This is the sort of thing that makes me very uncomfortable. I think we are likely to get a very powerful reaction to it, and I would like for all of us to have a breathing space here to articulate our moral concerns."

Another serious uncertainty is the preliminary nature of the company's work. No article has yet been submitted for peer review and publication in a scientific journal, an essential touchstone of credibility. Scientists asked about the company's work said they would require much more proof before believing that human embryonic stem-like cells had been created as claimed, and some were skeptical the technique would work at all.

The company said it had achieved the feat announced Wednesday with one cell three years ago. Michael West, Advanced Cell Technology's chief executive officer, said he was announcing the work done to date in order to test its public acceptability He said the company, which is privately held, was not planning to go public or raise money at this time but needed to decide whether to commit investment to development of the technique.

Some scientists praised West's decision to make his work public but others are critical, saying he has invited an emotional public debate on a slender basis of fact.

West is the founder of Geron, a biotechnology company that has had two spectacular successes this year in its research on aging. In January, the company developed a method for "immortalizing" human cells grown in the laboratory by making them leap the supposedly immutable barrier at which cells usually lapse into senescence. Last week, two university teams financed by Geron said they had isolated and cultivated human embryonic stem cells, the all-purpose cells from which the fetus develops. West lay the foundations for these developments by financing leading scientists in the two fields.

Advanced Cell Technology, which West joined in October, has focused on cloning and genetically improving cows, a technology developed by James Robl and colleagues at the University of Massachusetts in Amherst. West said he hoped to use the technology to further the founding concept of Geron: delving into the mystery of human aging and sidestepping some of its processes.

The company said work with human cells was performed in 1996 by Jose Cibelli, a colleague of Robl at the University of Massachusetts. Using 52 of his own cells, some of them white blood cells and others scraped from the inside of his cheek, Cibelli fused each one with a cow egg whose own nucleus and DNA had first been removed, the company said. Most failed to thrive but one embryo grew and divided five times, generating cells resembling embryonic stem cells. Cibelli and West say the method can be made more efficient with present technology.

Considering this work was sufficient to describe an invention, Robl and Cibelli filed a patent application and then set the research aside to focus on the more immediately practical field of cow cloning. Only two others besides himself and Robl knew what had been done, Cibelli said. The patent has not yet been issued but West said he was confident of receiving "important intellectual property" in the field. He said he is making the hybrid cell technique public now "because I want to be very open and level with everyone. We need to get the ethicists to talk about it so as to encourage a rational response to these new technologies."

Cibelli said he regarded any embryos obtained in this way as "not a separate individual, just a de-differentiated cell from a patient." Differentiation is the process whereby the all-purpose cells of the very early embryo, known as human embryonic stem cells, become committed to their roles as the various specialized tissues of the body. The process is irreversible in nature but egg cells apparently have the ability to de-differentiate, or reset to default mode, the settings in a specialized cell's nucleus. This is presumably what happened in the experiment reported in July when mice were cloned by transferring the nucleus of an adult mouse cell into another mouse's egg cell.

Cibelli, who trained as a veterinary doctor in Argentina, said he believed that he and his colleagues "were the first to de-differentiate a human cell by nuclear transfer."

Asked if he was concerned about destroying, in principle, 52 potential twins of himself, he said, "I never thought about it, it's a good question. But if you use your own cells to treat a disease you may have, you are not taking cells from another person selfishly."

West and Cibelli said they had no intention of transferring the embryos to a uterus, a step they consider unethical and unsafe for it. The embryos would be created solely for the purpose of tissue culture. "Any technology can be abused but once the public understands how these cells can be used to treat any disease caused by loss or malfunction of cells, from Parkinson's to diabetes to heart disease, the concerns will be overshadowed," West said.

Whether or not West's prediction will be borne out depends on two major sets of factors, the scientific validity of the proposed method and the ethical and legal questions that related work has already raised.

From discussions with scientists, ethicists and lawyers in the past few days, several concerns have emerged.

Scientists are particularly critical of the lack of supporting evidence accompanying Advanced Cell Technology's announcement, saying in essence the claim could be true but there was no compelling reason yet to accept it. Even if the claim is valid, biologists note a serious uncertainty relating to an important part of the cells known as the mitochondria, components that produce the energy the cell needs and that are, in essence, the cell's batteries. If the bovine mitochondria should prove incompatible with their humanized environment the cells will not be viable.

Ethicists believe the mixing of species is likely to trouble the public severely, at least at first. Lawyers who specialize in issues of human reproduction note that the moral and legal status of the human embryo is undecided in American law, a fact pointed up by the isolation of the human embryonic stem cells announced last week. The new entity adds further complexity.

If Advanced Cell Technology can produce viable hybrid cells, those cells will offer a new route to grow tissue for transplant. This is the same goal held by the scientists who announced last week they had grown human embryonic stem cells in the laboratory. It is widely accepted in principle that embryonic stem cells can be directed to develop into any desired tissue, with enormous potential for medicine, even though this has yet to be achieved in practice.

West said the advantage of the Advanced Cell Technology method was that embryonic cells derived from the patient being treated would generate entirely compatible tissues. The two methods reported last week, by James Thomson of the University of Wisconsin and John Gearhart of Johns Hopkins University, derive stem cells from human embryos or fetuses. Tissues made from these cells would be incompatible with the patient, a problem that has yet to be resolved.

In support of its claim, Advanced Cell Technology supplied a patent application and a photograph taken of its embryonic cells under a microscope. The patent application describes how the cells are made but provides no proof that they possess the properties to be expected of human embryonic stem cells. Robl said his laboratory was not set up to perform the required tests at the time the hybrid cells were made.

Shown the photograph of the hybrid cells, John Gearhart of Johns Hopkins University, author of one of the two methods reported last week, said that "they certainly could be embryonic stem cells" but that no scientific journal would publish the result without further proof. "It's not that I don't believe this biologically. I just think they could have given a little bit more assurance as to what was done here."

Roger Pedersen of the University of California at San Francisco, who also works on human embryonic stem cells, said he doubted the hybrid cells would last long enough to develop into useful tissue because of their cow-derived mitochondria.

Mitochondria, former bacteria enslaved by cells eons ago, have their own genes but operate in close cooperation with genes from the cell's nucleus.

Pedersen cited a recent experiment showing that within the human-ape-monkey family, each species' mitochondria is subtly different, the more so the longer the evolutionary distance between the species in question. The mitochondria of chimpanzees and gorillas work well enough in human cells but those of primate species that diverged more than 10 million years ago from the human line, do not work.

Because cows and humans last shared an ancestor so long ago, cow mitochondria are very unlikely to work well with a human nucleus, in Pedersen's view, and as most of the mitochondria in the hybrid cells are contributed by the cow egg, the cells would probably not remain viable for long. "It's hard to say this is a total sham, but I smell a sham here," he said.

Citing the same data, Gearhart said the mitochondria in the hybrid cell had clearly carried it through its first few divisions but might not sustain it in further development, unless the few human mitochondria that were also present somehow took over.

Pedersen said Advanced Cell Technology should be held to a high standard of proof "because of what the implications are for upsetting people unnecessarily -- if you cry fire in a crowded auditorium you may be liable if it's a false alarm."

The human embryonic stem cells announced last week have already pushed against the frontiers of ethical acceptance. Experts in biomedical ethics say the public is likely to be alarmed by the new technique, particularly because of the mingling of species. Murray of Case Western Reserve University said that the hybrid embryo "escapes our usual categories." When biologists first learned to transfer genes from one species to another, "The idea of human-animal hybrids was often raised as the kind of monstrosity that no morally perceptive person would ever create," he said.

"Even if it's only to create tissue, the minute you start mixing species you raise all kinds of red flags in people's minds," said Barnie Steinboch, a moral philosopher at the State University of New York in Albany. But she noted that pig valves are now seen as acceptable replacements in human hearts.

Rebecca Dresser, a law professor at Washington University in St. Louis, noted, as did several biologists, that distinctions between humans and other animals are less clear in nature than they are in people's minds. "Biologically a lot of this research is showing us similarities and the upshot in a hundred years may be that the lines between humans and non-humans will be viewed as a little bit grayer," she said.

A perplexing feature of the hybrid embryo is that it starts off mostly bovine and then becomes mostly yet not entirely human. But some legal experts have no doubt that it should be regarded from the start as a human embryo. "It doesn't matter that the mitochondria come from a cow, it also has human mitochondria and so has all the potentials of a human embryo," said Lori Andrews of the Chicago-Kent College of Law in Chicago.

"Once it's gone through that first division it has gone from being a somatic cell to a thing with potential life," she said, referring to the ordinary specialized cells of the human body. If transferred to a woman's uterus the embryos may or may not come to term, "but under state laws it doesn't matter whether the fetus is going to be born or not - it doesn't make them less human."

The human body consists of 100 billion cells. Should embryos created from them by the cow egg method be regarded as having special status when they can be made so easily and plentifully? Ms. Andrews said that human embryos are not so hard to make the usual way, and the fact that an embryo is easily made, by whatever means, is irrelevant to arguments about its status.

The moral status of the human embryo "is not clearly established in U.S. law," Dresser said. The embryo can be regarded as mere property, as a person, or as something in between but deserving of special respect. Congress, in banning the use of federal funds for research on human embryos, has favored the view that they are in the category of people. But in custody battles over fertilized embryos, courts have favored the special respect status. Dresser said the hybrid cells could be seen as somewhere between the property and special-respect status.

The hybrid cells were made by Cibelli in Robl's laboratory in the University of Massachusetts at Amherst. Michael Weinberg, executive secretary of the university's human subjects committee, said the experiment was given administrative approval, without review by the committee or any major discussion. Cibelli was using his own cells, not experimenting on other people, and self-experimentation does not require special consent. "If someone wants to inoculate themselves they can do that," Weinberg said.

Copyright 1998 The New York Times Company