Creating the stuff of life

Many of us believe the use of gene therapy to create 'saviour siblings' is morally wrong. But now scientists want to go even further. By Steve Connor debates medicine's most controversial new developments

The tragic case of the Hashmi family has reignited the debate over what is meant by "designer babies". Raj and Shahana Hashmi want to have a baby by in vitro fertilisation (IVF). Not only do they want the baby to be free of genetic disease; they also want it to be screened so that it will match the tissue of their six-year-old son Zain, who suffers from a rare blood disorder. If Zain does not receive a stem-cell transplant from his "saviour sibling", he'll almost certainly die. Their case is now being considered by the House of Lords.

The tragic case of the Hashmi family has reignited the debate over what is meant by "designer babies". Raj and Shahana Hashmi want to have a baby by in vitro fertilisation (IVF). Not only do they want the baby to be free of genetic disease; they also want it to be screened so that it will match the tissue of their six-year-old son Zain, who suffers from a rare blood disorder. If Zain does not receive a stem-cell transplant from his "saviour sibling", he'll almost certainly die. Their case is now being considered by the House of Lords.

The term "designer baby" has been widely used in the context of a range of difficult issues surrounding developments in reproductive medicine. Pre-natal genetic diagnosis (PGD) - when a single cell from an early IVF embryo is removed and genetically analysed - enables doctors to test for a range of inherited disorders, as well as carry out tissue typing.

In 2000, Lisa and Jack Nash of Denver, Colorado were the first couple to benefit from the idea of creating "saviour siblings" by PGD when their son Adam was born. The Nashes, both carriers of Fanconi anaemia, had a six-year-old daughter, Molly, who was born with the rare inherited bone-marrow disease. Scientists tested 15 of the Nashes' embryos for the presence of the diseased gene. They then went a step further to see which one also had the same tissue type as Molly. The result was Adam, who donated a stem-cell transplant that helped his sister to recover.

For some, the idea of creating a baby to order is anathema. For others, it is nothing more sinister than planning a family with the benefits of modern medicine. However, the tortuous ethical and legal arguments over designer babies such as Adam will seem relatively trivial compared to the impending debate over the technological developments in reproductive genetics that are now on the horizon.

Some scientists believe we are on the verge of being able to engineer the human gene-pool for the first time. They're not talking about straightforward gene therapy, but something called germline gene therapy, when the genes of future generations can be changed for ever. This would make today's "designer babies" appear decidedly low-tech compared with what might be possible in years to come.

We are, to some extent, already accustomed to the idea of tinkering with genes. Last week, doctors in London said they had successfully cured a second child of a fatal inherited condition with the help of gene therapy, a technique that replaces - or, more correctly, augments - a faulty gene with a normal, healthy version.

Gene therapy has had mixed results. Early experiments led to some disastrous outcomes. One of the most infamous was the case of Jesse Gelsinger, who died in 1999 after undergoing gene therapy that involved infecting him with a genetically engineered virus. The intention was that the virus would carry healthy genes into his liver. Instead, he suffered liver failure.

This sort of gene therapy targets only the tissues damaged by the faulty gene. Germline gene therapy involves tinkering with genes at the stage of the embryo, so that each and every cell of the resulting baby carries the newly inserted gene. This more radical modification would have far-reaching consequences because it would also include changing the sperm and eggs of the mature adult. It would mean that their children would also inherit the altered genes, which is why it's called "germline" gene therapy. Potentially, it has the power of changing the genetic make-up of the human species for good.

In Britain, germline gene therapy is not allowed under current legislation, but there may soon be calls to look again at the ban, especially in the light of recent work into artificial human chromosomes (HACs). The idea is to add an extra chromosome to the complement of 46 that normally reside in most cells of the body. Some scientists believe that many of the safety concerns about germline gene therapy can be addressed by refinements in the technology of making this putative "cousin 47" - the 47th human chromosome.

Proponents say HACs are inherently safer than other ways of introducing foreign genes into the body, because the DNA of the artificial chromosomes is not "naked" but enclosed in a structure that mimics the way human DNA is naturally stored in each of our 46 chromosomes. They believe HACs can be made to replicate faithfully each time cells divide, and it could be possible to turn their genes on or off at will. It might also be possible to include a self-destruct mechanism that prevents the HAC from being passed on to future generations if this is of concern.

The neurobiologists Gregory Stock and John Campbell of the University of California at Los Angeles have been at the forefront of promoting the idea of using HACs for human germline gene therapy. "In discussions of cloning and germline modifications of animals, it's easy to pretend that human manipulations can be ignored," they say. "But it seems virtually certain that, as these technologies evolve, their focus will swing back towards ourselves. The real question is not whether they will be applied to humans, but when, how and to what extent."

Artificial chromosomes have been used in genetics for years, notably those that mimic yeast chromosomes. Huntington Willard of the Case Research University School of Medicine in Cleveland, Ohio made the first artificial human chromosome in 1997. He put three types of DNA in a test tube, and the primitive "chromosome" self-assembled. It survived in the cells for six months, apparently retaining its integrity during cell division.

Chromosomes are complex structures, but there seem to be three crucial components necessary for them to replicate each time the cell divides. One is the centromere, a structure at the centre of the chromosome that plays a vital role in aligning the chromosome on the protein "spindles" involved in cell division. Then there are the telomeres at the end of the chromosome (like the plastic tips of shoelaces that prevent them from fraying). And there are the so-called origins of replication, the DNA sequences that initiate duplication of the chromosome during cell division.

Stock and Campbell believe it will soon be possible to consider radical therapies that involve inserting specially-designed HACs into human embryos. They suggest, for instance, that an HAC could be built containing genes that confer life-long resistance to HIV. Another idea is to introduce into male embryos an HAC containing a series of genetic switches that can, when turned on, trigger the destruction of prostate cancer cells.

If preventative treatments such as these are shown to work safely, it is not difficult to envisage an array of treatments delivered as a "gene cassette" on a single HAC. Perhaps anti-ageing genes could be added to every embryo's extra chromosome. "Two things will be necessary before human germline engineering can occur broadly," Stock and Campbell say. "A safe, reliable way of delivering genetic changes to a human embryo, and genetic modifications so compelling that large numbers of parents will want them."

They argue that both are nearer than many people believe because of recent developments in human artificial chromosomes. "The time to examine and discuss the realistic benefits and challenges these new reproductive technologies embody is now, while they are still nascent. And to keep such discussion focused on realistic possibilities rather than science fiction, it is imperative that active researchers in the field participate," they say.

One scenario that has been envisaged if germline gene therapy goes ahead is the idea of human society being divided between the "gene enriched" and the "naturals" - some people having the resources to exploit all aspects of the technology to improve the lives of themselves and their children, with others left to live and breed naturally. Princeton University's Lee Silver believes that although such a dystopia is not imminent, it is plausible and could eventually lead to two species of humans.

"If the accumulation of genetic knowledge and advances in genetic enhancement technology continue at the present rate," Silver says, "then by the end of the third millennium, the genrich class and the natural class will become the GenRich humans and the Natural humans - entirely separate species with no ability to cross-breed and with as much romantic interest in each other as a current human would have for a chimpanzee."