Reaching the limits of genetic medicine

Last week British MPs in the House of Commons voted to allow scientists to create so-called three parent babies. The procedure could eliminate the birth of babies who are genetically fated to carry mitochondrial diseases. Whether or not such a baby will actually be born in the next 12 months depends on the legislation being ratified in the House of Lords. And then the members of the Human Fertilisation and Embryo authority must decide whether they should issue a licence to individual clinics that would carry out the experimental procedure.

Despite the vote in Westminster and a decade’s worth of discussion about the basic research idea, the issue is far from settled. More needs to be said – and learned – as the concept edges toward clinical reality. As a bioethicist who has been part of this long discussion, here’s my take.

I was introduced to the issue in 1988 when I was working as a nurse while studying moral philosophy. One night a small, floppy, six-week-old baby was admitted. She had been seemingly healthy at birth, but when she caught her first cold she became feverish and too weak to suckle. Our high-tech neonatal intensive care unit was helpless to save her. The doctors were baffled until a resident came up with an obscure diagnosis: perhaps a new category of genetic disease – mitochondrial disorders – was responsible. Tests were carried out on the baby and her mother – who somebody noticed seemed “a little subdued”. Both carried the same diseased gene.

Mitochondrial disorders are not carried within the main genetic blueprint (the nucleus). Rather this gene was carried by mitochondria – thousands of tiny lozenge-shaped power stations within the cell that convert sugar into ATP, the molecule that drives chemical reactions in cells. With her faulty gene, the baby could not power the chemical reactions necessary to sustain her life.

According to some reports nearly 4,000 Americans are born each year with some variant of this disease. Some, like my patient, die in infancy but many, like her mother, live into adulthood with no symptoms except perhaps for appearing a little too placid. Mutations in mitochondrial genes are at the root of a wide range of disorders, often causing slow atrophy of the brain, nervous system and muscles. The new technique would fix these rare disorders by replacing the faulty mitochondria contained within the mother’s egg with healthy ones that come from a donated egg (see graphic). Mitochondria have their own set of 37 genes, which are separate from the 20,000 or so genes on a human’s 23 pairs of chromosomes found in a cell nucleus. In mitochondrial DNA transfer, these 20,000 genes will still come from the child’s father and mother. The donor will only contribute their mitochondrial DNA.

The technique makes use of the fact that the main DNA blueprint is nicely packaged up in a ball called the nucleus that floats in a soup called the cytoplasm. The cytoplasm also contains the mitochondria. The mother’s heathy nucleus is first fertilised by the father’s sperm, then scooped out of its unhealthy cytoplasmic soup, and popped inside the donor’s healthy egg whose own nucleus has been removed. In another variation of the technique, the sperm does not fertilise the egg until the graft is complete. Finally the hybrid embryo carrying the mother’s and father’s nuclear DNA, plus the DNA present in the mitochondria of the donor egg, would be implanted back in the mother using standard IVF techniques.

A chorus of scientists have given the House of Commons a hearty slap on the back for approving the approach. And women yearning for healthy children are, of course, delighted. Surely, finding a way to prevent disease is the most noble kind of medical research?

Yet the opposition has been virulent. It hinges on three arguments.

First, many are concerned about what the outcome might be in a human baby. The procedure represents a radical disruption of an intact cellular system. And we don’t know enough to predict how the new interactions will work out.

The exact techniques being proposed here have never been tried in humans but a somewhat similar technique was tried by private US fertility clinics between the late 1990s and 2001. Known as “cytoplasmic transfer”, it did not replace the mother’s faulty mitochondrial DNA. Rather her fertilised egg was boosted by an injection of mitochondrial soup from a healthy donor egg. Some 30 pregnancies resulted. Certainly some resulted in healthy children but there were also a few spontaneous abortions and abnormal foetuses that may or may not have had anything to do with the procedure. Expressing concerns about safety, the FDA tightened regulation which brought a halt to the procedure in 2001.

The second argument is that the procedure breaches a long-standing principle about the limits of genetic medicine.

In 1999, geneticists threw up a major moral challenge: they had the technical ability to alter genes in a fertilised animal egg, so-called germ-line genetic engineering. But should this procedure be allowed on humans who carry a genetic defect? Dare we tamper with our human genetic heritage?

The American Association for the Advancement of Science gathered in one room the geneticists who advocated the technique as well as ethicists, theologians from a wide variety of faiths, lawyers, human rights activists, patient advocates, and policymakers. They came up with a framework to regulate such research. Heritable genetic manipulation would be permitted only if the disease could be treated in no other way and if it were proven to be safe. In addition, good answers had to be found regarding the ethical limits of genetic research.

Full disclosure – I was on that committee. In general, we reasoned that when it came to an individual patient, allowing genetic therapy, even if risky, was permissible. But eliminating disease in all future generations was not. One reason was that our definition of disease changes. Homosexuality is a prime example.

The third argument is that medicine progresses at an ever more rapid rate. What if more straightforward cures can be found to heal disease? And isn’t that the real goal of medicine, rather than producing custom-made embryos?

It is the job of ethicists to raise questions, to notice the uncertainty, give voice to humility and to see every single person who might be touched by irrevocable changes. For this experiment will eliminate forever both the suffering baby and the mother who holds her in the dark.

I saw the devastation of mitochondrial disease first hand and I yearn for a cure for that terrible sort of death. If there were a way to alter the cells of a person who could consent, then genetic approaches would be a noble enterprise. But to create children with three types of DNA, who will carry this forward forever, when we are not at all sure to what complex consequence that may lead, is another matter. I believe this way of avoiding disease uses methods beyond our knowledge and our moral capacity, and that far more reflection needs to occur before it is used.