With our insight into heredity growing and our ability to manipulate it becoming more sophisticated every day, one question is of increasing importance in family planning: How can you assess the genetic legacy that will shape your child’s life?
Today’s genetic counselors can advise prospective parents that they may be at risk of passing genetic conditions to their offspring. But some of these conditions aren’t “traditional” genetic diseases inherited through the X-shaped chromosomes of karyotypes and meiosis diagrams. Instead, they’re passed down in independent segments of DNA found in our cells’ energy centers: the mitochondria.
You might know mitochondria as the “powerhouses of the cell,” the factories that produce energy for our bodies. Each human cell contains a dynamic network of many mitochondria, which continuously fuse and break apart, die and grow, all the while metabolizing sugar derivatives into usable energy molecules. Mitochondria are deeply important and fascinating organelles, and they are unique in many ways—particularly in their relationship with DNA.
Most DNA lives in double-stranded, linear bundles—chromosomes—23 pairs of which live in the nucleus of almost every human cell. This nuclear DNA, or nDNA, is the primary “blueprint” from which each individual cell assembles and arranges materials like proteins, lipids, and nucleic acids into complicated networks of scaffolds, signaling pathways, repair machines, and more. These microscopic systems, working together in the trillions, ultimately sum up to a unique human body.
Unlike other human organelles, though, the blueprint to build a mitochondrion is not solely stored in stretches of DNA in our cells’ nuclear chromosomes. Much of it is encoded in double-stranded circular chromosomes, which reside inside mitochondria themselves instead of the cell nucleus. Curiously, this circular chromosome structure is also how single-celled bacteria package their DNA.
The similarity between mitochondrial and bacterial DNA storage can be explained by the endosymbiont theory: millions of years ago, the single-celled ancestor of all modern plants and animals probably swallowed (or “endocytosed”) an aerobic bacterium, but did not digest it. Instead, by serendipitous chance, a symbiotic relationship developed wherein the bacterium provided the cell with aerobic energy, and the cell gave the bacterium materials for growth and reproduction. That bacterium evolved into the mitochondrion, and that cell eventually multiplied and split off into billions of directions to form almost every eukaryote known today.
This evolutionary history explains why mitochondria have their own circular DNA and cellular machinery, but it doesn’t explain another crucial quirk of mitochondrial DNA, or mtDNA: maternal inheritance. In humans, mtDNA is only passed down from the female parent to a child, not from the male parent. This strange pattern is not just a subject of basic scientific interest—as you’ll see, mitochondrial matrilineage has deep implications for human health when mtDNA is somehow damaged or defective.
Not all mitochondria are created equal. Heteroplasmy—genomic heterogeneity among mitochondria in the same person, or even the same cell—means that individuals’ populations of mitochondria are generally diverse in health, to differing extents in different people. Consider an individual with a relatively high proportion of genetically unhealthy mitochondria. Even if that proportion isn’t high enough to cause noticeable problems, the individual risks producing and passing on an unlucky egg containing mostly or only defective mitochondria.
In this way, or through rare chance mutations, mtDNA-related mitochondrial defects can arise in children, even from mothers who do not display mitochondrial disease. Too many inefficient or unviable mitochondria simply cannot provide the energy that the cell needs to carry out all of its vital processes, leading to disease. Unhealthy populations of mitochondria are thought to be linked to numerous rare and common developmental and neurodegenerative disorders, including Leigh syndrome, dementia, and mitochondrial myopathy.
The major clinical importance of maternal mtDNA inheritance comes into play in a method called three-way in vitro fertilization (three-way IVF). IVF is a well-established fertility treatment for those who experience difficulty conceiving naturally. IVF is a simple concept: eggs are artificially inseminated outside of a human body in favourable fertilization conditions, forming zygotes that can then be transplanted into a womb for development.
When a would-be biological mother is found to have a high enough proportion of unhealthy mitochondria to pose a risk to a future child, though, IVF can be harnessed in a unique way. The nuclear DNA of an egg from this mother is removed and transplanted into the egg of a donor with a healthy population of mitochondria, whose nucleus has been removed. This way, a hybrid egg is formed: the nDNA that acts as a blueprint for all of a child’s observable traits comes from the original mother, but the mtDNA that is responsible for producing healthy mitochondria comes from a healthier donor. Finally, a sperm cell can fertilize this hybrid egg, and an embryo can begin to develop normally.
Three-way IVF looks like an ingenious and scientifically sound way to avert mitochondrial disease. It’s even possible that it could improve fertility in mothers without mitochondrial concerns (though recent findings suggest that this may not be the case).
As promising as it is, though, this method raises a host of social concerns. Does a mitochondrial donor have any claim to a child produced with three-way IVF? Does that child have three biological parents, or only two? Is mitochondrial DNA donation equivalent to an organ transplant, or is it something more?
The onset of three-way IVF could be a solution to the inheritance of potentially devastating mtDNA-linked diseases, but it calls for careful re-examination of the concepts of parenthood and heredity. Intuitively, the encoding of visible and personality traits appears to be the most important part of inheritance; the nuclear genes inherited from the intended mother can continue to propagate throughout generations, and each generation will look and behave the same as they would otherwise —minus a high probability of mitochondrial disease. In that case, it seems like donating mitochondria is just like donating liver tissue or a kidney.
The issue is, that might not be true. Complicating matters further, we don’t understand the intricate genetic networks at work in our bodies deeply enough to say for sure that mtDNA has no effect on phenotype beyond the mitochondria. There is currently no way to comprehensively evaluate the effects of mitochondrial genotypes and resultant phenotypes on the rest of the cell, and there may never be. It’s not just a matter of not knowing the answers; we don’t even know all the questions.
Besides, unlike normal organ transplants, the mtDNA of a female product of three-way IVF can be passed on, affecting the health and cellular energy production of future generations. Even if it produces no noticeable change in phenotype beyond preventing disease (though especially if it does), could three-way IVF be considered a step toward designer babies—and is that a bad thing?
On a related note, when three-way IVF is available, is it ethical for a mother with a high risk of passing on mitochondrial disease to conceive naturally? Considering the blurred lines between disease and simple natural variation, what level of risk to a child justifies such an intervention? If it turns out to be feasible, should three-way IVF be used to improve fertility when mitochondrial disease is not a concern?
These issues are far from broadly resolved. In the United States, three-way IVF has been (controversially) banned because it is considered a genetic modification, which may have long-term impacts on future generations. At the same time, the United Kingdom has approved the technique, but only for preventing transmission of mitochondrial disease. Most countries don’t have clear legislation around three-way IVF.
It could be argued, on one hand, that the unknown consequences of mtDNA manipulations do call for a ban, pending further investigation; others might say that many health interventions have unknown effects, but a demonstrated ability to improve human health is worth it. Some proponents claim that a ban on three-way IVF constitutes a violation of the right to procreate; some detractors cite questions of informed consent and religious objections.
As the UK has implemented and as the USA’s National Academies of Science, Engineering and Medicine has proposed, a potential compromise could be the legalization of three-way IVF when hereditary mitochondrial disease is likely, but not in general infertility cases.
Ultimately, the questions raised by three-way IVF are part of a much larger set of ethical, social, legal, and scientific questions surrounding the manipulation of inheritance. Three-way IVF itself is also only one part of a new wave of genetic interventions that threaten to turn our notions of parenthood, legacy, and heredity on their heads.
Today’s world has to reckon with questions about the nature of our genetic legacies that were inconceivable one hundred, fifty, or even ten years ago. With legislative disputes and ethical debates ongoing and human health hanging in the balance, three-way IVF shows us that, just as it may shape the evolution of our species, the growing frontier of molecular genetic science holds the power to change the course of our society.
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