BREAKING DOWN THE SCIENCE & SCRUTINY

“World’s First Three-Parent Baby” made headlines in publications ranging from Nature to CNN last week. This human interest story is of a baby boy born in Mexico with genetic material from three different parents, achieved by a technique known as three-parent in vitro fertilization (TPIVF). In this issue, we will explain why TPIVF is used and examine the science—and scrutiny—surrounding this controversial baby-making method.

REPLACING MITOCHONDRIAL DNA IN IVF

The rationale behind TPIVF lies with mitochondria—what many of us remember from high school biology as the “powerhouse” of a cell. Recall mitochondria are the organelles that convert glucose into the energy our cells use to do work. What you may not remember is mitochondria have their own DNA that is inherited maternally. When an egg is fertilized, the mitochondria from the egg get passed on in subsequent rounds of cell division, becoming a part of every cell in the developing baby. A woman with defective mitochondrial DNA passes this trait onto her child. However, with the advent of TPIVF, these mutations can be weeded out of a family’s genetic landscape.

During TPIVF the nuclear DNA is removed from the egg of the afflicted mother. This nuclear DNA is transferred into a donor egg whose own nuclear DNA has been removed, but whose mitochondrial DNA remains intact. The resulting donor egg is implanted into the prospective mother, and with fingers crossed, that donor egg (once fertilized with a sperm) develops into a healthy baby. The resulting child has DNA from two different women and one man.

LEIGH SYNDROME IS THE REASON

The three-parent boy’s parents sought out the TPIVF technique because they had already lost two children to a rare, mitochondrial DNA-linked disease called Leigh syndrome. Referred to as a “neurometabolic disorder,” Leigh syndrome affects the central nervous system. Symptoms usually begin within a year of birth and include failure to thrive, low muscle strength, and lack of control over movements. Death by cardiac or respiratory failure usually occurs within a few years.

CYTOPLASMIC TRANSFER STARTED IT ALL

TPIVF has some precedent in a procedure known as cytoplasmic transfer. In the late 1990s, this experimental procedure was used to help women, whose fertility had declined, to conceive.

The prospective mother’s egg was injected with a small amount of cytoplasm from another woman’s egg before fertilization. Cytoplasm is the liquid portion of a cell outside of the nucleus that also happens to contain mitochondria. The exact mechanism by which cytoplasmic transfer enables pregnancy is not clearly defined, but many doctors suspect some cases of infertility are caused by damaged mitochondria.

Twenty-four women achieved pregnancy via cytoplasmic transfer two decades ago. However, the FDA had safety concerns, and the practice was abandoned when fertility clinics were required to file an IND to continue the procedure. Cytoplasmic transfer is still not approved by the FDA, and this policy is credited with creating a market for reproductive tourism abroad.

EXAMINING GERMLINE MODIFICATION

TPIVF has the potential to become a routine medical procedure, but not without some scrutiny involving germline modification. In more simple terms, germline modification is the genetic changes made to sperm or egg cells. Any genetic changes made to these sex cells will be passed down to all resulting generations, which may have unforeseen risks and consequences.

The world’s first “three-parent baby” was born in Mexico to Jordanian parents with assistance from a New York City-based fertility doctor. Why not the United States? Because the FDA has yet to officially approve the technique. In February 2016, a U.S. National Academies of Science panel recommended approving the method with the restriction that it be limited (at least initially) to male offspring because men cannot pass down mitochondrial DNA. The panel also recommended following any children born of this technique for several years and sharing data with the public. The procedure was approved in the UK in 2015 without restriction.

COCKTAIL FODDER: ONLY 37 GENES

Although it is correct to say that a baby conceived by TPIVF has genetic material from three different parents, the vast majority (~99.9%) of that baby’s genetic material will come from the nuclear DNA of the original egg and sperm. Mitochondrial DNA codes for only 37 genes, whereas nuclear DNA codes for ~21,000 genes.

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