Germ-line gene therapy: making the case for embryonic mitochondrial modification

May 24, 2015

The British parliament has voted to pave the way for clinicians in the United Kingdom to be the first in the world to perform germ-line gene therapy. The precedent that has been set may constitute a guideline for the United States and other nations as they consider this groundbreaking technique and its implications.

What it is, and what it isn't

Germ-line gene therapy will involve performing modifications on embryos in an attempt to forestall incurable diseases which arise from abnormal mitochondria. Mitochondria are organelles in the fluid of a cell (cytoplasm) which act as the powerhouses of the cell. They have their own DNA, which mutates more than 100 times faster than the DNA within the nucleus, and therefore causes disease in about one in 6,000 children. Mitochondrial diseases are carried only in the woman's eggs and are passed on to all of her offspring. Depending on the percent of mutated mitochondria and the particular mutation, affected children show varying degrees of clinical problems, usually involving the heart, eyes, and/or muscles, which range from mild to fatal. The diseases can burden families for generations, and there are no cures. Reliable prenatal testing options for mitochondrial diseases are limited due to the complexity of accurate diagnoses.

The regulatory body which governs fertility treatments in the U.K, the Human Fertilisation and Embryonic Authority (HFEA), will oversee new genetic therapy for women who carry mitochondrial diseases, so that they may attempt to have children who are unaffected by these often devastating diseases. The success of this process, technically known as spindle transfer (ST), was advanced recently in the United States by an Oregon Health and Science University team lead by Shoukhrat Mitalipov, PhD, and it has now been replicated by several other researchers around the world. With this technique, a donated egg cell will contribute its healthy cytoplasm and mitochondria, but the nuclear DNA will come from the mother's egg and will thus express the mother's family traits. The ability to successfully replace a part of an egg cell will likely prove to be one of the most significant advances in modern medical history.

As is often the case with novel, complex medical advances, the terminology has been oversimplified in public discussion. Unfortunately, the adoption of the term “three-parent” IVF is unhelpful at best and grossly misleading in any case. An egg which was knowingly donated for this purpose from a well-informed donor does not a parent make. The mitochondrial DNA from the donor's egg contains only 1/1000th of the total genetic contribution of an individual and is not responsible for the transmission of traits or family-related personal features. The term mitochondrial replacement is more accurate and descriptive, and does not convey the unwarranted “Brave New World” associations.

Evaluating arguments against it

Opponents of the mitochondrial replacement technique speak out with a number of objections. One reflexive objection is that this technique will lead directly to human reproductive cloning and eugenics. This slippery-slope argument emerges in response to nearly every advance in the field of genetics, and it is baseless and unfounded. I would urge anyone who subscribes to the scare-tactic cliché of the door being opened to designer babies to think about the experience of a parent who has suffered through the loss of a young child from genetic disease, rather than dismiss a technique that could prevent such tragedies because of a trumped-up concern that will never be a reality.

Other objections to mitochondrial replacement are much more reasonable, and they deserve to be thoughtfully addressed. Some skeptics object that we do not have enough information to move this into human trials. Concerns exist regarding limited outcome data on offspring, as most data thus far come from human embryos which have only been grown to day 5 (known as blastocysts) and from non-human primates which have not lived to breed offspring. Other concerns involve more technical issues, such as unknowns regarding the interactions of the nuclear DNA and mitochondrial DNA.

These are fair issues. However, it is important to realize that a treatment similar to germ-line modification has been completed on humans. More than a decade ago, a team headed by Jacques Cohen at Saint Barnabas Medical Center in New Jersey injected tiny amounts of donor egg cytoplasm (containing mitochondria) into the eggs cells of infertile women. This experiment led to the birth of 17 babies who are now teenagers. The U.S. Food and Drug Administration stopped the procedure in 2001, stating that more research was needed. The team has now embarked on a long-term follow-up study of the health of children, which would contribute significantly to our knowledge.

In anticipation of the first case

The weight of the published evidence that tips the scales from basic science experiments to clinical human trials certainly warrants a long and informed discussion, best held by those who work in the field and comprehensively understand the science. As with the very first in vitro fertilization (IVF) treatment in 1978, which culminated in the birth of Louise Brown in England, there must be, at some point, a first case, even in the presence of controversy about the science and the ethics. That one initial pregnancy has now evolved into the birth of more than five million children around the world from IVF.

The utilization of mitochondrial replacement has the potential to eliminate incurable diseases in children and improve human life. It is also possible that, if it proves to be safe and effective, in the future ST-enabled advancements using mitochondrial replacement could improve egg quality in older women and restore fertility.

The British approach to the novel implementation of mitochondrial replacement therapy, with extensive public involvement and careful, measured scientific review, may serve as an example for the United States and rest of the world. • Brandon J. Bankowski, MD, MPH, is a board certified specialist in reproductive endocrinology and infertility who has practiced at Oregon Reproductive Medicine in Portland, Oregon, since 2005. Disclosure: ORM is a for-profit business that plans to offer human mitochondrial replacement therapy if and when it is approved for clinical practice.

Brandon J. Bankowski, MD, MPH, is a board-certified specialist in reproductive endocrinology and infertility who has practiced at Oregon Reproductive Medicine in Portland, Oregon, since 2005. Disclosure: ORM is a for-profit business that plans to offer human mitochondrial replacement therapy if and when it is approved for clinical practice.