Mighty mitochondria and reproductive technology

November 18, 2013

Mitochondria have made the news recently. Moves toward three-parent IVF have been motivated by mitochondrial issues, and new IVF embryo screening methods assess the health of the embryos’ mitochondria to select the embryo that is more likely to implant. Both of these news items raise important bioethics issues, but unless you have had a recent refresher on cellular biology, what mitochondria actually do might be a little hazy. Let’s review the inner workings of the mitochondria and how it relates to assisted reproductive technology.

 

What are mitochondria?

In high school biology we learn that mitochondria are the “power plant of the cell.” Cells are like factories, and their organelles are like different sections of the factory that perform specific tasks. Mitochondria’s task is oxidative metabolism, which provides the cell with the energy it needs to conduct its tasks. Mitochondria take carbohydrates, fats, and amino acids and break them down into simple molecules, like CO2 and H2O. This process releases energy for the cell to use to survive.

An important fact about mitochondria for understanding bioethics issues is that it contains DNA. Most of the cell’s DNA is found in the nucleus, but a very small portion is found in the mitochondria.  Mitochondrial DNA codes for the proteins needed to perform oxidative metabolism, as well as other functions associated with the mitochondria. It has some unique features compared to nuclear DNA: 1) It is more susceptible to mutations, 2) it is circular in shape, and 3) it is passed down only from the mother. Some diseases occur as a result of mutations within the mitochondrial DNA. These mutations can be passed down from the mother, or – less commonly – they may be due to environmental factors. See here for a link to the United Mitochondrial Disease Foundation and here for a Nature SciTable article on mitochondrial disease. Both provide excellent information on the various forms of mitochondrial disease.

 

Assisted Reproductive Technology

Mitochondrial disease is typically passed down from the mother. The mitochondrial DNA that will be passed to the child comes from the egg, while the sperm cell’s mitochondria are destroyed in the fertilization process. Both the egg cell and the sperm cell contribute to the embryo’s nuclear DNA.

This is where “three-parent” IVF comes in. If the intended mother happens to have a known mitochondrial mutation and does not want to pass this down to her child, it is possible to remove the nucleus of her egg (oocyte) and place it in another woman’s enucleated oocyte. The newly formed oocyte would have nuclear DNA from the intended mother and mitochondrial DNA from the female egg donor, and would then be fertilized by a sperm cell.  This means there would be three genetic contributors to a single embryo, although more than 99% of the DNA would be from the original mother and father, and only a small fraction from the egg donor. Britain has approved the use of three-parent IVF, and the U.S. is currently discussing whether to approve it or not.

Another option is to screen an already-created embryo’s mitochondrial DNA to ensure that it did not inherit a particular mutation or genetic marker for mitochondrial disease. If a couple creates several embryos through in vitro fertilization, doctors can select the embryo that has the “healthiest” mitochondria.

Recently, scientists reported that mitochondria might be helpful for selecting healthy embryos in any IVF situation. A new study showed some indications that embryos with lower numbers of mitochondria tended to implant more successfully than other embryos. Even embryos that appeared healthy under a microscope were less likely to implant if their mitochondrial count was above a certain threshold. Scientists speculate that a high mitochondrial count might be related to “stress” signals in the embryo.

 

Bioethics Issues:

A number of scientists and ethicists have voiced concern over the safety of three-parent IVF. While scientists saw success in monkey models, human reproduction is typically more complicated than trials involving animal models. Moreover, mitochondrial DNA codes for some of the proteins that will be used in the mitochondria, but not all of them. Some nuclear DNA codes for proteins that are transported to the mitochondria, which raises questions about compatibility and long-term effects. If the couple has a daughter and something goes wrong as a result of the technique, that daughter will pass the defective mitochondria to her offspring.

A child with three genetic contributors also raises some legal concerns. There will be three “biological parents,” although the vast majority of genetic contribution comes from the egg nucleus and sperm. To put numbers to it: in a cell the nuclear DNA has 3.3 billion DNA base pairs, while mitochondrial DNA only has 16,569 DNA base pairs. (Note: Although there are several mitochondria in a cell, they will all have the same DNA sequence.) In states where the biological parents are required to sign the birth certificate, will laws have to be amended to indicate that “biological parents” include only the primary genetic contributors? Will we have to set genetic boundaries for who counts as a biological parent?

Three-parent embryos bring up unique social concerns. Ancestral lines are often determined through mitochondrial DNA. Because mitochondrial DNA is preserved through the maternal line, many ancestral studies use mitochondria to trace family lineage. If scientists create embryos in which the mitochondria have been changed from the primary maternal genetic contributor, then ancestral studies can no longer be done for this individual.

Additionally, this technique of replacing the nucleus of one oocyte with another may fall into the category of “germ-line intervention” under UNESCO’s Universal Declaration on the Human Genome and Human Rights. Many members of the Council of Europe signed a petition saying that this type of intervention is contrary to human dignity and should not be allowed in Britain.

Mitochondrial screening, while not as potentially dicey as mitochondrial transplants, has issues of its own. According to Dr. Dagan Wells, co-author of the mitochondrial screening study cited above, “The mitochondrial screen could potentially be a free add-on on top of chromosomal screening … Once you’ve got those cells, you might as well do as much as you can with them.” This is the pervasive attitude towards screening: More information is better. But this assumes that we are reliably able to interpret the information correctly. Mitochondrial screening of embryos brings, along with its prospective benefits, the prospective risk of wrongly rejecting certain embryos based on preconceived notions or theories of what is “normal” or “healthy.” As with many forms of embryonic screening, there is a need for caution against subtly eugenic attitudes in which a person’s or society’s definition of “normal” excludes certain other persons.

As mentioned in a prior bioethics.com post, one of the problems with genetic screening is how to interpret the information. Having a genetic marker for a disease usually does not mean that the child will definitely develop the disease. In many cases, the mere presence of a gene is not enough. It also must be activated. Whether or not a gene is activated depends on many factors, including environment, lifestyle, and epigenetics.

Finally, we need to consider the potential for the destruction of embryos. While the technology used for mitochondrial screening does not destroy the embryo, the purpose behind screening is to accept healthy embryos and reject unhealthy ones. The unhealthy embryos are discarded based on an assumption about the correlation between the amount of mitochondria in a cell and the health of an embryo.

Additionally, the technique for creating a three-parent embryo does not necessarily result in the destruction of an embryo. However, current IVF technology typically results in a 30% success rate, and usually involves screening for healthy embryos.  In regards to the fate of certain embryos, the three-parent IVF technique involves many of the same concerns as traditional IVF, particularly those that include third-party donors.

Mitochondrial disease can be devastating, and finding cures to diseases caused by mutations in mitochondrial DNA is certainly a worthy pursuit. Wanting to cure mitochondrial disease is not ethically problematic. But we must be careful to distinguish between curing people with a disease and curing the disease by getting rid of (or preventing the existence of) people who have it, as in the case of mitochondrial screening.

Additionally, we must consider the means by which we cure diseases – including those that afflict us at the genetic level. Three-parent IVF may have unforeseen consequences that would affect the child and may be passed down to later generations through the maternal line. We do not know the long-term effects three-parent IVF will have on the embryo, and must balance the cost of potentially getting mitochondrial disease with the cost of harm or defects due to the three-parent IVF technique. The gamble is that mitochondrial disease causes more harm than three-parent IVF, but we do not know this for certain unless an embryo is grown to term, which constitutes a dicey case of human experimentation.

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