Current Genetics Update: Mitochondrial DNA transfer (“three-parent” IVF) regulations being drafted in Britain

pgEd was delighted to have Hadley Stevens Smith as an intern this summer.  Hadley’s guest post about mitochondrial DNA transfer for Current Genetics Update is below.  Thank you Hadley for this detailed overview of the scientific and ethical issues!

 

The UK government’s health department is drafting regulations that would cover an ethically controversial new in vitro fertilization procedure. The treatment has the goal of eliminating incurable mitochondrial diseases passed down from mother to child. Publicized as “three-parent” IVF, the resulting embryo carries DNA from three people – nuclear DNA from the mother and the father, and mitochondrial DNA from a donor egg. (See the Reuters article here.) Labeling the embryo as one with three parents is thus granting the title of “parent” to a mitochondrial donor. Parliament, however, is not expected to legally recognize the donor as such.

The mitochondria are often referred to as the “powerhouse” of the cell, as they are responsible for generating cellular energy. The number of mitochondria varies with cell and tissue type according to energy needs. Mitochondrial DNA (mtDNA) only contains 37 genes, all of which are thought to be associated only with the production of cellular energy. Mutations in these genes can have serious health consequences if the mitochondria are not able to produce an adequate amount of energy to meet the demands of cells or tissues. Therefore, mitochondrial mutations can have a serious effect on organs that require a lot of energy, like the heart, brain, kidneys, and major muscle groups. There is no cure for diseases that result from mutated mitochondria, and often the symptoms cannot be treated. (More about mitochondrial diseases can be found here.) Either the cell can produce energy or it cannot. Thus, the scientific consensus is that mitochondrial genes do not have a physical effect beyond health or ill-health; they only govern features related to cellular energy production.

The nuclear DNA (nDNA) contribution of the two parents – about 25,000 genes – to the embryo is much larger and accounts for the characteristics typically thought of as being “in the family.” Mitochondria are maternally inherited; the sperm does not contribute any mitochondria to the embryo. The mutation rate of mtDNA is about 10 times higher that of nDNA, and the number of mutated mitochondria (the “mutant load”) can vary from cell to cell, meaning that health problems caused by mutated mitochondria are not straight forward. Females with some mutated mitochondria can produce eggs with a high mutant load, resulting in stillbirth or serious disease in the child. Employing this technology would therefore give a woman at risk of passing on mutated mitochondria an option to have a child that is both genetically related to her and healthy because each cell of the child would be populated with mitochondria from the donor egg capable of producing cellular energy.

Researchers are investigating two different techniques known as pronuclear transfer (PNT) and maternal spindle transfer (MST), both of which result in the embryo carrying healthy mitochondria from a donor egg instead of the dysfunctional mitochondria originally present in the mother’s egg. There is a nice illustration of the science in the BBC News article here.

The techniques are currently unlawful in the UK, but they could be voted in by Parliament under the existing Human Fertilisation and Embryology Act. Similar research is also being done in the US, which could mean that we also will be faced with important policy decisions in the next few years.

A working group of the Nuffield Council on Bioethics published a review of the ethical issues related to this technology prior to regulatory considerations by Parliament. The report is lengthy, but it provides an in-depth look at the science as well as ethical concerns. You can download the full report or just the summary and conclusions from here. The Working Group concluded that it would be ethical for families to use these techniques if they are proved to be safe and effective. There is popular support for the technology in Britain, but it does raise some ethical concerns. Among those discussed in the report are:

  • Implications for identity: the child would have genes from 3 people
  • Germline therapies: implications for future persons
  • Introduction of novel techniques and follow-up of children: new procedures would need a lot of oversight
  • Parentage of the child: could the mitochondrial donor be considered a legal parent?
  • The status of the mitochondrial donor: should she have the same status as other egg donors?
  • Implications for wider society and future generations: should male embryos, but not females, be selected so that they will not pass on the “new” mitochondria to their own children?

 

This article from BBC News, written following the decision of the Working Group, brings up some of the ethical concerns. Because the techniques involve cell reconstruction, they can be seen as more ethically troubling than procedures like prenatal genetic diagnostics (PGD) that involve the selection of embryos but do not modify them in any way. Therapies with germline effects (i.e. those that alter the genetic content of the egg or sperm) are also extremely controversial because they result in changes to the genetic inheritance of future persons. People disagree about whether PNT and MST should be regarded as a form of germline therapy. Every cell of the child for which the procedure was performed would contain the donor’s mitochondria, including sperm or egg cells. So, a female child would pass on the donor’s mitochondria to future generations. Some scientists define germline therapy in a narrow way, referring only to the modification of genes in the nuclear genome (not the mitochondrial genome). Therefore, they do not consider the procedure germline therapy. They point out that no genome is being modified, but rather whole mitochondria – with their genome intact – are being replaced. It is seen as a side effect that the healthy mitochondria will happen to remain in place for subsequent generations. Those who view the procedure as a germline therapy argue that without the procedure the embryo would have had a different genetic makeup – regardless of whether it is the nuclear or mitochondrial genome that is affected – and thus a different germline. They also see it as the first step down a slippery slope toward nDNA modification and “designer babies.” PNT and MST have some technical similarity to the somatic cell nuclear transfer technique used for cloning, which also raises concerns for some people.

There are certainly lots of ethical, social, and legal implications surrounding this procedure, and it will be interesting to see how things in the UK and beyond develop from both policy and ethical perspectives.