Human Embryos Carrying Altered Genes - New Scientist 19 July 1997

HUMAN embryos carrying altered genes could become a possibility sooner than anyone thought. For the first time, a biologist claims to have grown long-lived cultures of human embryonic cells that have the capacity to develop into a wide range of tissues. The cells could find important medical applications. However, in theory, they could also be used to create genetically engineered humans. In mice, similar cultures have allowed scientists to make genetically engineered animals with unprecedented precision. The key is that the cells are "pluripotent"-they can divide and differentiate to form any tissue type. Working with a culture of these "embryonic stem cells" held in an undifferentiated state, geneticists can target genetic manipulations with much greater precision than would be possible by the haphazard injection of genes into newly fertilised mouse eggs. They can then inject the genetically engineered stem cells into an early mouse embryo. This develops into a "chimeric" mouse in which a proportion of cells in most or all of its tissues carry the altered genes (see Figure). Because those tissues can include the cells that give rise to sperm and eggs, repeating these experiments in humans would break the biggest taboo in modern genetics: manipulating the human germline to induce genetic changes that can be passed down the generations. The researcher who created the human cell cultures, John Gearhart of Johns Hopkins University in Baltimore, Maryland, stresses that altering the germline is not his goal. He hopes that the cells will find a use in conventional gene therapy, in which the altered genes cannot be inherited, or in creating tissues that could be used for grafts without the need for drugs to combat rejection. "I believe what comes out will be extremely beneficial," he says. Last week, at the 13th International Congress of Developmental Biology in Snowbird, Utah, Gearhart revealed that he now has seven separate cell lines growing in culture. To create the cultures, Gearhart took cells from fetuses roughly eight weeks into gestation, which had been aborted at a clinic in Baltimore. The cells came from a structure called the gonadal ridge, which would have developed into reproductive organs. As such, they are different from most of the embryonic stem cells used by mouse geneticists, which usually come from earlier embryos. However, Gearhart believes his cells have many of the same properties. One possibility, however, is that Gearhart's cells grow in culture in an undifferentiated state not because they are pluripotent, but because they are cancerous. But Gearhart notes that "marker" proteins carried on the surface of his cells suggest that they are pluripotent. They can also form clumps of cells that, in mouse cell cultures, are precursors to further development.

The ultimate test of pluripotency would be to inject the cells into an early human embryo and show that a healthy human chimera develops-an experiment that few scientists would regard as ethical. In the absence of these data, however, other sci entists say they are inclined to believe Gearhart's claim. "The science is solid and the chromosomes look fine," says Peter Grass, a developmental biologist at the Max Planck Institute for Biophysical Chemistry in Gbttingen, Germany. Gearhart's cells could find applications in conventional gene therapy. Gruss says that experiments with mouse embryonic stem cells show that they can differ entiate into the tissues that give rise to blood cells. If the same is true for Gearhart's human cells, it may be possible to use them to treat people with genetic diseases of the blood. Gearhart's main goal is to create cells that could be grown to form tissues suitable for grafts. If the cells were manipulated to remove genes of the major histocompatibility complex, which play a central role in the recognition of foreign tissue by the immune system, this would help solve the problem of rejection. "These cells would be the best donors," he claims. But at the back of people's minds is the possibility that human embryonic cells could be used to manipulate the germline. This would raise serious ethical concerns, says David Shapiro of the Nuffield Council on Bioethics in London, as genetic changes would be passed down to future generations without their consent.

However, Anne McLaren of the Wellcome Cancer Research Campaign Institute in Cambridge, who attended the Utah meeting, questions whether anyone would attempt human germline manipulation. "No one in their right mind would want to do it," she says. McLaren notes that couples carrying genetic diseases can instead have their embryos screened through pre implantation diagnosis and select a healthy embryo to take to term. Mario Capecchi of the University of Utah in Salt Lake City, who pioneered the use of embryonic stem cells to create genetically engineered mice, says that using genetic manipulation to develop cells for trans plantation would be acceptable. "But as soon as you do it to create a human being, you've crossed the line." Steven Dickman


THREE cheers for John Gearhart, the American embryologist who believes that he has discovered how to create long-lasting cell cultures from aborted human fetuses. Few would have had the courage and gumption to bring such controversial results out into the open so early. Indeed, so fast has Gearhart moved that nobody is completely certain about the biological properties of these cells or what they might be used for. Starry-eyed researchers are talking about turning the cultures into an inexhaustible supply of replacement cells and tissues to graft into sick people. But all we know about the cells for sure is what has been learnt from similar work with mice. And here they are not used for grafting, they are used to transfer altered genes into embryos. They are the reason why making strains of mice with permanently altered genes that can be passed down the generations is so easy. This doesn't mean geneticists will be demanding to use Gearhart's cells for the same purpose in humans: this practice would be unacceptable or illegal in most countries. Besides, anyone attempting to follow the mouse recipe with humans would run into problems. In mice, the cells help to create "chimeric" animals with mixed genetics that are then bred to produce the pure transgenic strains. Human chimeras wouldn't necessarily be sick or abnormal, but it is hard to imagine any contemporary scientist wanting to produce them. Nor does the new research mean that designer babies and other clich6d creations of the genetic era are inevitable in the long run either. What it does mean is that we should demand an open debate about these cells and their potential applications. Some will still call this scaremongering: why worry at all if no researcher is pressing to extend to human fetuses what is routinely done in mice? The answer is that experiments that look abhorrent and far-fetched today may look very different tomorrow. Thirty years ago, people were appalled by the idea of geneficafly manipulated bacteria. Now we use them to make soap powder. And less than two decades ago test-tube babies still had the power to shock. We live in an age of rapidly changing perceptions about what is and what is not acceptable in biological research. Who knows, one day people may decide that germline genetic manipulation is not such a bad idea after all. It would be sad if we reached such a position through ignorance rather than a firm grasp of the science. That is why Gearhart has done the right thing. And why we need to keep everything out in the open. Andy Coghlan