Gene therapy

A technique intended to eliminate mitochondrial diseases would result in people with three genetic parents

Is it possible for a child to have three parents? That is the question raised by a paper just published in Nature by Shoukhrat Mitalipov and his colleagues at Oregon Health and Science University. And the answer seems to be “yes”, for this study paves the way for the birth of children who, genetically, have one father, but two mothers.

The reason this is possible is that a mother’s genetic contribution to her offspring comes in two separable pieces. By far the largest is packed into the 23 chromosomes in the nucleus of an unfertilised egg. In that, she is just like the child’s father, who provides another 23 through his sperm. But the mother also contributes what is known as mitochondrial DNA.

Mitochondria are a cell’s power-packs. They convert the energy in sugar into a form usable by the cell’s molecular machinery. And because mitochondria descend from a bacterium that, about 2 billion years ago, became symbiotic with the cell from which animals and plants are descended, they have their own, small chromosomes. In people, these chromosomes carry only 37 genes, compared with the 20,000 or so of the nucleus. But all of the mitochondria in a human body are descended from those in the egg from which it grew. The sperm contributes none. And it is that fact which has allowed doctors to conceive of the idea of people with two mothers: one providing the nuclear DNA and one the mitochondrial sort.

The reason for doing this is that mutations in mitochondrial DNA, like those in the nuclear genes, can cause disease. These diseases especially affect organs such as the brain and the muscles, which have high energy requirements. Each particular mitochondrial disease is rare. But there are lots of them. All told, there is about one chance in 5,000 that a child will develop such an inherited disease. That rate is similar, for example, to the rate of fragile-X syndrome, which is the second-most-common type of congenital learning difficulty after Down’s syndrome. Mitochondrial disease is thus not a huge problem, but it is not negligible, either.

New batteries, please

To find out whether mitochondrial transplantation could work in people (it has already been demonstrated in other species of mammal) Dr Mitalipov collected eggs from the ovaries of women with mutated mitochondria and others from donors with healthy mitochondria. He then removed the nuclei of both. Those from the healthy cells, he discarded. Those from the diseased cells, he transplanted into the healthy cells. He then fertilised the result with sperm and allowed the fertilised eggs to start dividing and thus begin taking the first steps on the journey that might ultimately lead to them becoming full-fledged human beings.

Nearly all of the experimental eggs survived the replacement of their nuclei, and three-quarters were successfully fertilised. However, just over half of the resulting zygotes—as the balls of cells that form from a fertilised egg’s early division are known—displayed abnormalities. That compared with an abnormality rate of just an eighth in control zygotes grown from untransplanted, healthy eggs.

This discrepancy surprised—and worried—Dr Mitalipov. The abnormality rate he observed was much higher than those seen when the procedure is carried out on other species. That, though, could be because this is the first time it has been attempted with human eggs. Each species has its quirks, and if mitochondrial transplants were to become routine, the quirks of humans would, no doubt, quickly become apparent. With tweaks, they could be fixed, Dr Mitalipov predicts.

However, turning this experiment into a medical procedure would be a long road, and not just scientifically. Dr Mitalipov has little doubt that his zygotes could be brought to term if they were transplanted into a woman’s womb. That experiment, though, is illegal—and, in the view of some, rightly so. But the fact that it now looks possible will surely stimulate debate about whether the law should be changed.

Two kinds of question arise. One kind is pragmatic: would the process usually work and, if it did, would it always lead to a healthy baby who would have a normal chance of growing into a healthy adult? The second kind of question is moral, for what is being proposed is, in essence, genetic engineering. Not, perhaps, as classically conceived because no DNA is artificially modified. But it is engineering nevertheless. And that might worry some people.

On the first kind of question, the auspices are good. When Dr Mitalipov tested his zygotes, he could find no trace of mutated mitochondrial DNA in them, so the purpose of the procedure seems to have been achieved. And an experiment on monkeys that he began three years ago has produced four healthy offspring that are not apparently different from any other young monkey of their age. These are preliminary results, but they are encouraging.

It is on the moral questions that things may stumble. There is no consensus. Some people oppose such genetic tinkering in principle. Some worry about the consequences of a third adult being involved in the traditionally two-person process of parenthood—though the mitochondrial contribution is restricted to genes for energy-processing proteins and is unlikely to have wider ramifications on, say, family resemblance. Some worry that three-parented individuals may themselves be worried by knowledge of their origin. But until recently such questions have been hypothetical. Now they are real. In September, for example, Britain’s Human Fertilisation and Embryology Authority, which deals with such matters, launched a public consultation to discuss the ethics of creating three-parent offspring of the sort Dr Mitalipov proposes. This consultation runs till December 7th and the results will be given to the government in the spring.

In the end, whether three-parent children are permitted will probably depend on the public “uggh!” factor. There was once opposition to in vitro fertilisation, with pejorative terms like “test-tube baby” being bandied about. Now, IVF is routine, and it is routine because it is successful. In the case of mitochondrial transplants what will probably happen is that one country breaks ranks, permits the procedure, and the world will then see the consequences. If they are good, you will never find anyone who will admit to having opposed the transplants in the first place. If they are bad, the phrase “I told you so” will ring from the rafters.

First published in The Economist. Also available in audio hereThis article also had an editorial that ran with it.

This story was mentioned on the cover page of the print issue and made it to the front page of  Reddit and Digg, receiving over 250,000 views in two days.

Image credit: The Economist

Genetic medicine

A new technique to help cure mitochondrial diseases should be permitted by the law

In September Britain’s Human Fertilisation and Embryology Authority launched a public consultation on what sounds like a crackpot idea: to create children with three genetic parents. Yet this could be a way to eliminate a set of rare but nasty diseases caused by problems with pieces of cellular machinery called mitochondria. According to research published this week (see article), the basic technique of substituting problem-free mitochondria has now been tested in a laboratory and the researchers seem confident that, given the green light, they could bring a healthy child into the world.

Most of a child’s genes would come from the couple it would learn to call mum and dad. A tiny fraction of the DNA, however, would come from a female donor who would provide part of the egg from which the child grew. At present the law in Britain, like that in most other places, prohibits any genetic modification of embryos. It should be changed.

An in-gene-ious idea

Mitochondria turn the energy in sugar into a form a cell can use, so if they go wrong the consequences are dire. The brain, the nerves and the muscles, all huge consumers of energy, are the organs that suffer most. Mitochondria are also special, because they contain their own genes, completely separate from those in the cell nucleus, which are thus transmitted from mother to child in the egg.

Some mitochondrial disease is caused by mutations in these genes and is thus also inherited solely from the mother. Such diseases affect one person in 5,000 during his or her lifetime. But the separateness of mitochondrial genes means that by moving the nucleus from an afflicted egg into a healthy one, the mutated, disease-causing genes can be left behind. In effect, the nucleus would receive a mitochondrial transplant.

This incorporation of the DNA of two women might be seen by the nervous as a step down the slippery slope towards the genetic engineering of people. But that is unlikely.

The principal worry about genetic engineering is that it will lead to “designer babies” with customised DNA. But mitochondrial transplants involve no tinkering with the DNA itself. Though on a microscopic scale, the process is quite like a heart, liver or kidney transplant, with the caveat that the transplant will be passed on to the recipient’s children, if she is female. Any organ transplant introduces new genes into the body. Mitochondrial genes are ubiquitous, it is true, but this difference is one of degree, not kind.

Another reason not to worry is that the mitochondria carry only 37 genes, compared with about 20,000 in the cell nucleus, and these genes are exclusively concerned with energy metabolism. Pushy parents will not be picking mitochondrial donors on the basis of looks, personality or intelligence.

Non-biological objections are sometimes raised as well. Some worry, for instance, that a person with three genetic parents might suffer an identity crisis. But that seems less likely than in the case of people conceived by in vitro fertilisation using sperm donated by strangers who have contributed half of their offspring’s genes, not a paltry three dozen. And for that reason mitochondrial donors are even less likely than sperm donors to want to be involved with bringing up children in whom they have but a fractional genetic interest.

But is the process safe? Doing the experiment is the only way of finding out. It should be preceded by a lot of tests in Petri dishes and laboratory animals. But in the end, you just have to try it and see.

First published as a Leader in The Economist. Also available in audio hereThis editorial also had an accompanying article with it.

Free image from here.