Saved from Your Genes

Fertility specialists have made a breakthrough that could eradicate a rare deadly disease. So why isn’t the world celebrating?

After several miscarriages and the deaths of two children at an early age, a Jordanian woman finally gave birth to a healthy boy this summer. A cause for private celebration? Undoubtedly. But this boy has already made headlines around the world.

The media have hailed him as the first “three-parent baby.” And this is where his story gets complicated.

The Jordanian woman carries a rare genetic disease known as Leigh Syndrome, which causes children to progressively lose control over their movements and mental faculties. They usually die before the age of three from respiratory failure. Both of her pervious children died from the illness.

The woman and her husband sought the help of Dr. John Zhang, the medical director of the New Hope Fertility Center in New York. His team attempted to cure the genetic disease by using a revolutionary form of in vitro fertilization (IVF), an umbrella term for techniques in which eggs are fertilized outside the body, leaving the mutated DNA behind.

The specialists combined genetic material from the mother, father, and a third person, who donated mitochondria – tiny compartments in cells that generate their energy from food. As the disease was contained in the Jordanian woman’s mitochondria, the donation was supposed to eradicate the condition.

The announcement of the successful procedure last month hasn’t received the kind of universal praise you might expect.

Reheated Franken-fears

First of all, Dr. Zhang has hardly helped his own cause. The procedure he used has not yet been approved in the U.S., so he carried out the procedure in Mexico. He later told the New Scientist that he went to Mexico because “there are no rules.”

Dr. David King, Director of the U.K.-based watchdog group Human Genetics Alert, criticized the research as irresponsible. “It is outrageous that they simply ignored the cautious approach of U.S. regulators,” he told the BBC.

Mitochondrial transfer has been denounced by public interest groups on religious and moral grounds. They say it’s the first step on a slippery slope towards genetically engineered babies, as it could enable a legal framework that allows for broadly modifying embryos, which is currently illegal.

Again, Dr. Zhang hardly dampened the zeal of these objectors, stating that the success of the Jordanian couple was “just the start.”  On the whole, though, scientists remain optimistic. “Much depends on whether the baby stays healthy, which we all hope!” says Dr. Jörg Burgstaller, a specialist working on mitochondrial DNA at the University of Veterinary Medicine in Vienna.

The cautious reaction of public interest groups reflects broader attitudes towards IVF, which continues to attract critical comment. Just this year, Austrian filmmaker Maria Arlamovsky released Future Baby, a documentary broadly critical of the changing face of reproduction.

The film tells stories that only a generation ago would have sounded like science fiction: women without a uterus having happy, healthy babies; sperm donors from South Africa matched online with surrogate mothers in India; doctors screening out potentially lethal diseases in embryos.

All this may well terrify critics of IVF. IVF is fast becoming the  go-to solution for infertile couples and those at greater risk of some severe birth defects.

The first IVF baby, Louise Brown, was born in the U.K. in 1978. Today, the European Society of Human Reproduction and Embryology (ESHRE) estimates that five million IVF babies have been born – equivalent to the population of Norway.

Today, there is still no treatment for Leigh Syndrome, or for any other mitochondrial disease, making the mitochondrial donation technique performed by Dr. Zhang an attractive option.  Such a treatment might be able to help around 50 couples each year in Austria alone.

Life in a cell

So far, mitochondrial transfers have only been made legal in the U.K., where they were approved in 2015 for the prevention of rare mitochondrial diseases including Leigh Syndrome.

“We have made significant strides in the diagnosis of mitochondrial diseases in the past few years but almost nothing in terms of treatment,” says Prof. Wolfgang Sperl, a pediatrician at the Center for the Diagnosis of Mitochondrial Disorders in Salzburg. “The diseases are extremely complex.”

Leigh Syndrome can be caused by mutations on the nuclei of cells, where most DNA is found, or on the mitochondria, where only a tiny proportion of genetic material is stored.

During fertilization, the embryo inherits nuclear DNA from both the mother and the father. But 100 percent of the mitochondrial DNA is passed down from the mother.

Importantly, mitochondrial genes tend to be less stable than our nuclear genome. According to the National Institute of Health in the U.S., as many as one in 5,000 children are born with mutations in their mitochondrial genes. Those children will have less energy to power parts of the body like the brain and muscles, leading to a wide range of diseases.

About 20 percent of Leigh Syndrome sufferers have a mutation in their mitochondrial DNA. In these cases, exchanging the mutated genetic material could be a way to stop the disease. That is exactly the trick scientists are now using. Here’s how it works:

The Jordanian couple’s child was born using a technique called “maternal spindle transfer,” in which the chromosomes of the unfertilized egg are physically removed from the cell, leaving the mutant mitochondria behind. These chromosomes are then transferred to an unfertilized donor egg with healthy mitochondria that has had its own chromosomes removed.

genetic modification
Illustration: Karin Dreher

This egg now has the genetic material of the mother, and the healthy mitochondria of the donor. Doctors then fertilize the egg with the father’s sperm, et voilà: After nine months, you have a baby with the genetic material of three people.

“The work being done on mitochondrial donation has real potential to improve the lives of children affected with these debilitating conditions,” says Prof. Sperl. “There is a strong and active community of parents in Austria and Germany whose children are affected by mitochondrial conditions who are watching the development of this story with great interest.”

The spindle transfer method tends to be preferred over techniques, known as pronuclear transfer, that involve fertilizing eggs from both the donor and the mother.

“Both methods aim at preventing the inheritance of the disease from the mother to the child,  ideally with 100 percent change of the mitochondrial DNA,” says Dr. Jörg Burgstaller. “This makes this therapy extremely attractive.”

The old three-parent trick

Although the “first three-parent baby” is a nice headline, it is not technically true.

In 1997, Dr. Jacques Cohen performed the first successful “cytoplasmic transfer,” a technique to revitalize eggs from women who were experiencing infertility because of their age. Dr. Cohen exchanged a portion of their egg’s cytoplasm with cytoplasm from a younger woman’s egg, and mitochondria may have been transferred along with it.

It is estimated that more than 20 children have been born using this technique, which may or may not have meant using genetic material from the donor. Dr. Cohen’s research, just like Dr. Zhang’s, caused quite an uproar, and currently the technique is banned in the U.S.

But it is important to take the controversies over mitochondrial donation with a pinch of salt. While nuclear DNA stores the information for the estimated 20,000 protein-coding genes in your body, mitochondrial DNA codes for just 37 genes. Mitochondrial genes do not affect someone’s appearance or personality, they just provide the energy.

“I like to think of it as an organ transplant,” says Prof. Sperl. “If you get a heart transplant, you also have the genetic material from another person inside of you, but that does not change who you are.” As the professor says, mitochondria are putting the wind into your sails: “It gives the driving power but that does not change the ship.”

Lanay Griessner
Lanay Griessner is a scientist and freelance journalist living in Vienna. She has a PhD in molecular biology from the Medical University of Vienna and is currently working in the biotech industry.

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