Overcoming mitochondrial diseases by having three parents

Whenever I hear about mitochondria, I think of midichlorians, “the force” of John Lucas’ Star Wars, the life energy that binds the universe by being part of every living thing, but especially concentrated in Jedi…and Sith. I don’t know if knowledge of mitochondria inspired Lucas, but there are strong parallels to midichlorians. Mitochondria are part of almost every animal (eukaryote). They are organelles, small organ-like components of the cell. In this case, mitochondria are the ‘power plants,’ their chief function being the transformation of sugars and other materials into adenosine triphosphate (ATP), the energy source (the force) of the living cell.

The thing about mitochondria is that they’re not native. They didn’t evolve from the primordial eukaryote. Mitochondria were incorporated or possibly implanted from bacteria. The mitochondria in our cells have their own DNA, limited to be sure, but still a complement of thirty-seven genes. They also have RNA and in some respects develop as if they were a separate cell or, shall I say, life form. That’s because they probably were. For now, most biologists believe today’s mitochondria are the evolutionary result of the primordial incorporation of a bacterium probably 1.7 to 2.0 billion years ago. Whether it was by incorporation, where the host cell took in the mitochondrial bacteria, the bacteria invaded the host cell, or some kind of symbiotic combination that simply joined and then evolved – is unknown.

However it happened, mitochondria are now part of almost every human cell (except red blood cells). They are essential to life as we know it, but, since they carry DNA and are involved in their own form of reproduction – they are subject to mutation, just like DNA in the cell nucleus. Likewise, when mitochondrial genes mutate or something amiss occurs within the mitochondrial genome, diseases can arise. There are many forms of mitochondrial disease, but all of them are rare. Rare in the sense that for most of them the rate of occurrence is about 1 in 4,000 (0.00025%). In the United States, that amounts to less than 5,000 cases a year – therefore rare, but significant since many of the diseases are severe or fatal.

In most species of animals, including human, only the mother’s mitochondrial DNA passes on to the children. In the human fertilization process, the mitochondria in the male sperm are marked with ubiquitin (a regulatory protein) for eventual destruction in the embryo. With recent advances in genomic analysis, it is possible to identify in the mother’s mitochondrial DNA many of the genes involved in mutations or mitochondrial diseases. That identification is the first step in a new procedure that can prevent passing mitochondrial disease to the next generation. The technique, dubbed “three-parent IVF,” is adapted from conventional in vitro fertilization (IVF). Here are the basic steps of the procedure:

1. The primary mother’s mitochondrial DNA is analyzed and known to carry genetic mutations or other genetic problems that may lead to mitochondrial disease.
2. A secondary mother is selected whose mitochondrial DNA is known to be free of mutations and genetic problems.
3. An oocyte (mother’s egg) is extracted from the primary mother, and the nucleus extracted (enucleated).
4. An oocyte is extracted from the secondary mother and the nucleus removed but mitochondrial DNA remains.
5. The nucleus from the primary mother is inserted into the egg of the secondary mother.
6. After the nucleus of the primary mother is bound to the egg of the secondary mother, a sperm from the father is inserted to fertilize the egg.
7. After fertilization, the egg is brought to term either by insertion in to uterus of the primary mother, or into a surrogate mother. (Standard IVF practice.)
8. Gestation and birthing is the same as for a fully natural birth.

You’ll notice this description says ‘primary mother,’ ‘secondary mother,’ and father. There is no reference to the relationship of these three participants. While there is a definite cultural pressure to have the father and primary mother be married, it has no biological necessity. In fact, this sort of fertilization process and gestation may often involve four parties, primary mother, secondary mother, father and surrogate mother.

If you’ve ever watched episodes of the television series Private Practice or the soaps, ER and similar medically oriented series, you’ll know that the more people involved in the procreation process, the more complicated – personally, ethically and legally – it becomes. A multi-parent fertilization sounds like a lawyer’s wet dream (pardon the expression). For example, since the secondary mother only contributes a small percentage of the total DNA, does that mean she has (a) no claim, (b) a full claim or (c) some claim based on percentage of DNA to the child? Or, what are the child’s rights to know who the secondary mother was? This can be even more complicated if a surrogate mother is part of the picture.

Stepping back a moment from the potential complications, it should be emphasized that so far no child has been born from this procedure. It has, however, been tried with monkeys. The results did not show anything unusual. The monkey babies were born with the same rate of success and did not have any apparent abnormalities.

Moving from monkeys to humans is something else. Researchers at the Oregon Health and Science University (Portland, Oregon USA) and the Boston University School of Medicine (Boston, Massachusetts USA) reported in the journal Nature on taking the mitochondrial transfer procedure up to the point of a fertilized human egg. Researchers selected 65 oocytes from seven volunteer women for mitochondrial genetic problems. Another group of 33 healthy oocytes remained unchanged as a control group.

The results were mostly positive: 98% of the “spindle transfers” (nucleus transfer) were successful and 44 out of 65 were successfully fertilized. This rate was the same as for the control group. Fertilization and original development of an embryo was normal for 21 out of 44 fertilized eggs; not the same as the control group but similar. In short, the researchers decided that “spindle nucleus transfer can be performed with high efficiency in human oocytes.” This means that within a few years – more testing with animals, in vitro human cells and finally in Phase I clinical trials – this technique may well be approved (on a medical basis).

Of course, at this point no one has any idea if there will be short-term or long-term complications for children born through mitochondrial replacement. All that can be said, is the experiment will happen, with or without official approval.

Given that the medical procedure is fundamentally safe and reasonably practical (that is, not outrageously expensive), and I think this is a viable assumption; then it is time to consider what the impact will be on society. Not only for this procedure, but the entire catalog of IVF procedures that now exist or are likely to exist within the next 10 to 20 years.

There is the potential in many of these procedure to abstract the procreation process from many kinds of human relationships (e.g. marriage, civil union) and involve total strangers in something that may benefit only one person (as parent) but have an economic attraction (payment) for the others involved. This combination of ingredients may have a profound effect on how we view parenthood, marriage, and family relations – or not. We don’t know yet, but it is arguably worth considering.

As with many procreation related procedures, most were developed to help people, usually couples, with fertility problems, medical conditions and other physical disabilities that prevented them from having a reasonable expectation of normal childbirth. That by no means limits the procedure to such altruistic situations. In the case of mitochondrial diseases and the desire for healthy children, this may only represent a very small number of cases. However, it is part of the legal, ethical and cultural picture of the future, where the impact of genetic modification [SciTechStory impact area] will be far greater than it is today.

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