The Lucky Years: How to Thrive in the Brave New World of Health (17 page)

Edward was a lucky one who enjoyed life through his teenage years and into young adulthood. He then experienced a steady weakening of his condition until he died from a cardiac arrest in 2011 following a year of chronic pain and severe muscular spasms caused by the chaotic, incurable disorder in his brain. Drugs could not help him.

Although people have criticized Sharon and Neil’s choices, accusing them of being selfish for wanting what they couldn’t have—biological children—their story now stands front and center of a debate about what medicine can finally offer such couples: a disease-free child. But there’s a catch: the child will have three parents—two mothers and a father—at least genetically speaking. For Sharon, it’s not so much her own suffering that has convinced her of the need to develop genetic therapies that would allow mitochondrial defects to become a thing of the past, or at least be remedied. It’s about the children’s suffering. And this breathtaking technology is taking flight.

The structure of the mitochondrion. These tiny “organelles” are the cell’s energy packers—they are responsible for creating more than 90 percent of the energy needed by the body to sustain life and support growth. Damage to these vital compartments can cause an array of disorders, from those of the musculature to serious neurological conditions. Mitochondrial diseases inflict the most damage to cells of the brain, heart, liver, skeletal muscles, kidney, and the endocrine and respiratory systems. The mitochondria have their own DNA coding for 37 genes, containing approximately 16,600 base pairs.

The mitochondria, sometimes referred to as the cells’ internal power plants, are tiny structures within our cells that have their own DNA separate from the DNA in the nucleus of the cell. They contain anywhere from five to ten copies of their DNA, whereas the nucleus of the cell contains only two copies of its DNA. Mitochondria are found
in all cells except red blood cells and generate energy in the form of a chemical called ATP (adenosine triphosphate). German doctor Carl Benda first identified them in 1897, noting that these particles looked like tiny threadlike grains. Hence the name
mitochondria
, derived from the Greek
mitos
, meaning “thread,” and
chondrin
, meaning “grain.”

In 1949 the mitochondria’s role as cellular powerhouses was finally explained by two American scientists, Eugene Kennedy and Albert Lehninger. Basically, mitochondria conduct chemical reactions that convert certain molecules and nutrients into the energy that powers most cell functions. It helps to think of mitochondria as cellular batteries. The energy-rich ATP they produce can be delivered throughout the cell as needed in the presence of specific enzymes. The cells in your brain, muscles, heart, kidney, and liver contain thousands of mitochondria each. And in some cells, mitochondria comprise up to 40 percent of the material.

The current thinking is that our mitochondria were once free-living bacterial organisms that eventually became part of our own cells, providing the benefit of producing energy. As a result, each single mitochondrion contains its own genome, but it doesn’t have all the genes it needs to function independently (it contains just 37 genes as opposed to the approximately 20,000 to 25,000 protein-coding genes found in the nucleus of cells). Like bacterial DNA, the DNA of the mitochondria is arranged in a circle, quite unlike the genetic material found within the nucleus of the cell. Also unlike our nuclear genome, which includes chromosomes from both parents, all of a person’s mitochondria originate from the thousands contained in the mother’s egg. In other words, it’s inherited solely from the female lineage. During reproduction, while the nuclear DNA of the sperm joins with that of the egg, the male’s mitochondria are excluded. This is the basis by which scientists use the term “Mitochondrial Eve,” referring to the first human mother from whom all humans have derived some of their mitochondrial DNA. She is thought to have lived some 170,000 years ago in East Africa when we
Homo sapiens
were evolving as a species separate from other hominids.

The mitochondrial genome is not nearly as stable as the nuclear genome. For reasons that science is still trying to figure out, mitochondrial
genes accrue random mutations about 1,000 times faster than nuclear DNA. As many as 1 in 5,000 children are born with diseases caused by these mutations, which affect cells that demand lots of energy, such as those in the brain and muscles. The proportion of diseased mitochondria that a mother passes on to her children determines the severity of the conditions.

Mitochondrial diseases include neurological, muscular, and metabolic disorders; diseases as diverse as diabetes, some forms of autism, Parkinson’s, Alzheimer’s, and even cancer have all been linked to mitochondrial problems.
⁴
So the question becomes: can we eradicate these mitochondrial defects? Enter someone like Douglass Turnbull.

Douglass Turnbull is a professor of neurology at Newcastle University in the United Kingdom, where he conducts research and is director of the Wellcome Trust Centre for Mitochondrial Research. After years of watching patients with untreatable and sometimes fatal mitochondrial diseases, including Sharon Bernardi and her children, he vowed to find a way to prevent mitochondrial disorders like Leigh’s disease from being passed on. He first got interested in mitochondrial diseases nearly forty years ago when he was working in a neurology ward and came across a member of the Royal Air Force who complained of severe muscle weakness on training runs. Although Turnbull was wrong to suspect a mitochondrial disease in this particular man, the subject nonetheless intrigued him. He then went on to earn an MD and a PhD, the latter of which focused on understanding the molecular mechanisms in mitochondrial disease. He’s devoted his career to understanding how these vital little structures, which have a life of their own inside cells, malfunction.

It was Turnbull who found out that Sharon carried mutant mitochondria when he met her in the mid-1990s and had her undergo a muscle biopsy. He was surprised that Sharon looked so well, but he wasn’t surprised to hear that many of her family members had suffered major health challenges. Sharon herself began to have health issues at
the age of thirty-five. Her mother started to experience heart difficulties in her mid-fifties. Turnbull was determined to prevent kids from inheriting bad mitochondria.

Dr. Turnbull wasn’t the first to think about wiping out mutant mitochondria. In the 1980s, embryologists working with mice began exploring possible techniques for doing so. The procedure they discovered, sometimes called three-person in vitro fertilization (IVF), involves transferring the genetic material from the cell’s nucleus (the 23 pairs of chromosomes) from the egg of a woman with mutant mitochondria into another woman’s healthy egg. This eliminates defective mitochondria while preserving the biological mother’s chromosomal DNA. The procedure can be done in a couple of ways (see
page 110
).

Turnbull and other scientists have experimented with this technique in monkeys, mice, and human egg cells in culture. In 2009, at the Oregon Health & Science University in Beaverton, stem-cell and reproductive biologist Shoukhrat Mitalipov and his colleagues announced the birth of two healthy rhesus macaques whose nuclei and mitochondria had come from different egg cells. At their fifth birthdays, they were still as healthy as could be. Mitalipov and his team have also demonstrated their procedure in human eggs: they created embryos that developed into formed blastocysts—cellular masses of between 50 and 200 stem cells that have the potential to develop into any of the body’s different tissues. These blastocysts could be transplanted into a woman’s uterus. Now the team is eager to do just that and test their method out in humans.

The procedures do have their critics, and for obvious reasons. Could these techniques have unintended consequences? For example, could they trigger small changes at the molecular or genetic level that impact development or trigger health problems later in life? This is possible, if there are unforeseen incompatibilities between the mitochondrial and nuclear genomes in individuals conceived using such techniques. For the mitochondria to function properly, the mitochondrial genes need to be compatible with the individual’s own DNA. Genetic variations in both structures probably evolved together. Several studies have shown that replacing the mitochondria in mice, fruit flies, and other organisms can sometimes result in issues with breathing, fertility, and cognition. So how can we be sure the technique is safe for all involved? And does this technology place us on the top of a steep slope down which we can easily slide to creating “designer babies”?

This diagram demonstrates the two procedures capable of fusing a diseased egg with a healthy one to prevent rare but devastating mitochondrial diseases.

Compared to what’s going on in Britain, we’re far behind in talking about these developments and how to regulate them nationally and
globally. And yet the technology is already at our fingertips. It’s been here for much longer than anyone probably realizes, and even the FDA has had to play catch-up. Since 2001, the FDA has required researchers to gain permission for mitochondrial transfers. This came after a fertility clinic in New Jersey performed numerous procedures that transferred small amounts of cytoplasm—and some of their mitochondria—between human eggs to help women conceive. It happened in the mid-1990s, the same time Sharon Bernardi was grieving her deceased children, and her doctors were finally beginning to understand their demise. A fertility specialist named Jacques Cohen, then at Saint Barnabas Medical Center in Livingston, New Jersey, conducted an experiment that achieved mitochondrial replacement. At the time he was trying to treat a handful of women who were unable to conceive on their own. These women had eggs that were still young enough to produce healthy children, but the cytoplasm around their nuclei didn’t look good.

The cytoplasm of a cell is a thick, gel-like solution that encompasses the area around the nucleus and is enclosed by the cell membrane. It’s about 80 percent water and includes all of the material inside the cell and outside the nucleus, including the mitochondria. In Cohen’s infertile patients, the cytoplasm appeared fragmented and filled with debris, which led him to wonder what would happen if he added some cytoplasm from another woman’s healthy egg, thereby “rejuvenating” the egg.

After his first attempt in mice worked, he tested the technique in humans in 1997, rejuvenating the eggs of 33 infertile women with a careful squirt of cytoplasm from another woman’s egg. Nine months later, 17 babies were born as a result. Cohen knew that the transplanted cytoplasm likely contained the “cellular battery packs known as mitochondria” that would support embryo development. But he probably had no idea at the time that his team was actually changing each egg’s mitochondrial DNA, pioneering a way to tinker with a human’s genetic inheritance—and creating the world’s first genetically modified humans. In 2001, tests emerged that confirmed that at least two babies had mitochondria from two sources: the cytoplasm donor and their own biological mother.

What happened—and what
will
happen—to these children? We don’t know all the health implications. Studies in mice suggest that such mixed mitochondria can have unintended consequences. In mice, at least, it’s been documented that they can become hypertensive and obese in middle age, and have impaired cognition. Among Cohen’s new mothers, one of the babies born developed an autism spectrum disorder, and two of the fetuses, one of which was miscarried and the other aborted, had a serious genetic defect known as Turner’s syndrome. Whether or not these defects were a direct result of the procedure is yet to be known. The team stopped performing the procedure in 2001, when the FDA cracked down, saying that more research was required before it could be applied for human use.

These 17 children are now teenagers, and nobody has formally followed up with them. Cohen is currently the lab director of Reprogenetics, a preimplantation genetic diagnostics company in Livingston, and he’s on a hunt to see what happened to these children, if they are willing to be revealed and undergo further testing. He and his team hope their findings can further move the needle in this area of medicine and push the debate forward for the benefit of all of us.