You’ve probably heard the term “3 parent child” floating around in the news. In February of  2015 the UK Parliament approved the technology for use on humans, and later in 2015 a New York based Physician, Dr. John Zhang, implanted the first “3 parent” human embryo into a woman. The genetic modification of human embryos is still illegal in the US so the implantation took place in Mexico. In April of 2016 the first “3 parent” baby was born from this procedure, and Dr. Zhang has reported that the baby boy seems to be doing just fine. However, earlier this month the FDA published a firmly worded letter to Dr. Zhang instructing him to cease advertising the “3 parent child” procedures on his fertility clinic’s website as the technology has not been approved in the US.

Part of the public resistance to “3 parent children” technologies most likely stems from term “3 parent child” itself. This misleading title conjures images of some unnatural chimeric creation of science fiction. In truth, a “3 parent child” is hardly a 3 parent child at all, and the technology, called Mitochondrial Replacement Technology, serves to prevent the transmission of disease causing genetic mutations.  This article will attempt to dispel myths, clear up misunderstandings, explain the really cool science behind “3 parent children”.

The term “three parent child” is incredibly misleading yet not completely erroneous.  A child born from Mitochondrial Replacement Technologies does carry genetic components from 3 distinct people, but the child’s DNA is not split in the ⅓, ⅓, ⅓  distribution that the term implies. The “third parent” is only present in the 0.1% of DNA residing in mitochondria of the child’s cells – mitochondria that were only replaced to avoid transmitting disease causing genetic mutations carried in the mother’s mitochondrial DNA. In the following article we will start with the biological basics to explain the hows and whys behind this technology. What is the Mitochondria? What is Mitochondrial DNA? Why do we want to give children mitochondrial DNA from a third person? And HOW do we give a child a third person’s mitochondrial DNA?

What is the Mitochondria?

The mitochondria are somewhat spherical, double-membraned organelles (little organs) that float around in the cytoplasm of your cells. There are many mitochondria per cell, and their general purpose is cellular respiration: the process by which mitochondria break down glucose to produce energy. The mitochondria is the powerhouse of the cell!

Mitochondrial DNA and how it can go wrong

Mitochondrial DNA:

All cells with a nucleus (known as eukaryotic cells) have a mitochondria. The nucleus encapsulates the vast majority of your cells’ DNA. When someone tells you that you have 23 pairs of chromosomes or that half of your DNA comes from each of your biological parents, they are talking about your nuclear DNA. This DNA is the blueprint for making and maintaining you. However the mitochondria also carries a tiny bit of its own DNA. The 16,569 base pairs of DNA that live in each mitochondria may sound like a lot, but it’s nothing compared to the 3.3 billion base pairs that live in the nucleus. Mitochondrial DNA contains the instructions for producing a few of the proteins and RNA molecules required for cellular respiration.

Mitochondrial DNA inheritance:

Mitochondrial DNA is also unique in that you don’t inherit a part of it from each parent. All of your mitochondrial DNA comes from your mother. When fertilization occurs, the mitochondria in the sperm dissolves leaving the newly formed zygote (the single cell stage of you) with the mitochondria from only your mother’s egg. This means that a woman will pass down her mitochondrial DNA to 100% of her children. This maternal inheritance pattern has some pretty cool applications. For example, it is really easy to trace family history through the female line using mitochondrial DNA because the DNA sequence is conserved from generation to generation (barring mutations) as it is never mixed with fathers’ mitochondrial DNA.

In the genealogy tree below, you can follow the inheritance of mitochondrial DNA through the maternal line. Circles are female. Squares are male.

inhertitance

 

Mutations to Mitochondrial DNA:

There is also a downside to the maternal pattern of mitochondrial DNA inheritance. If all of a woman’s mitochondria carry a given mutation, she will pass it down to all of her offspring.

It is important to note, however, that is possible for only a fraction of a woman’s mitochondrial DNA to carry a given mutation (remember there are many mitochondria per cell and each mitochondria carries multiple copies of its DNA). In this scenario, called heteroplasmy, the higher the ratio of mutated mitochondrial DNA to wild type (normal) DNA, the greater the chance of passing on the mutation. A higher mutation load also increases the chance of a person experiencing the disease. Just because a disease causing mutation is inherited does not necessarily mean that there is a 100% chance the person will ever experience the disease. Genetic disease expression is controlled by genetic and environmental factors, and sometimes the genetic influence is stronger than others. The chances of mutation inheritance and expression can be better predicted by studying family history. In the case of the aforementioned Dr. Zhang, the mother he was helping had experienced several miscarriages and lost two children to a disease called Leigh’s Syndrome, a neurological disorder caused by mitochondrial mutation that results in loss of motor and mental abilities leading to early childhood death. Dr. Zhang’s patient also displayed a high mutation load. The chance of her losing another baby to Leigh’s Syndrome was extremely high.  

Choices for women with a disease causing mitochondrial mutation are limited. Adoption or using donated eggs are viable options for preventing mitochondrial mutation inheritance, but these are options that will not allow women to have their own biological children.

The purpose of creating three parent children is to allow these women to have biological offspring without passing on mitochondrial mutations. The general concept is that the mutated DNA carried in the mitochondria of the intended mother’s egg can be replaced with wild type mitochondrial DNA from the egg of a donor.

Mitochondrial Replacement Technology by Nuclear Transfer: “Creating a 3 parent child” (AKA the really cool part)

Ok thanks for bearing with us through all the background info. This is the cool part:

As stated above, the purpose of creating a three parent child is to allow a woman with a mitochondrial mutation to have a baby that carries her and the biological father’s nuclear DNA without passing on any mitochondrial mutations. This is done by replacing the mutated mitochondria from the biological mother’s egg with the wild type (normal) mitochondrial DNA from a donor egg.

But how is it done!?

The creation of a “3 parent child” is executed through a procedure called nuclear transfer. Its called nuclear transfer because, well…, the nucleus of the intended mother’s egg  is transferred from the intended mother’s egg into the enucleated egg (egg with nucleus removed) of the donor. The nucleus is transferred instead of the mitochondria, because mitochondria are just too tiny and too numerous. It is much easier to transplant the nucleus.

Let’s break it down step-by-step by following my nifty diagram (below).

  1. The three biological contributors of the “three parent child” are as follows:
    • An egg donor contributes an egg containing mitochondria with no disease causing mutations
    • The intended mother contributes an egg containing her nuclear DNA.
    • The biological father contributes sperm.
  2. Both eggs are enucleated. The nucleus is removed by suction with a pipette. The cytoplasm of the egg donor’s enucleated egg contains a bunch of wild type mitochondria.
  3. The egg donor’s nucleus is discarded and the intended mother’s enucleated egg is discarded.
  4. The intended mother’s nucleus is inserted into the enucleated donor egg.
  5. The complete egg is then fertilized with the biological father’s sperm via in vitro (in lab) fertilization.  The result is a viable zygote complete with intended mother and biological father’s nuclear DNA (99.9% of total DNA) and the egg donor’s mutation free mitochondria (containing 0.1% of total DNA).
  6. The zygote / embryo is allowed to develop in vitro (in the lab) for a short time.
  7. The embryo is implanted in the intended mother’s uterus or into a surrogate if the intended mother can not carry children.
  8. A “three parent child” is born.

nuclear transfer visual

That’s the science!

A few parting words

What do you think? Are “three parent children” really three parent children? The term “Three parent child” can misleading, and the language we choose can have unforeseen consequences. As explained, the only contribution of the “third parent” is a small amount of mitochondrial DNA. As important as that contribution may be, referring to the resulting child as a “three parent child” perpetuates misunderstanding and powers public resistance to the procedure. Let’s call it what it is. Children born from Artificial Reproductive Technologies (in vitro fertilization, preimplantation genetic diagnosis…) are commonly referred to as ART Babies. So, if we must label these children born from Mitochondrial Replacement Technologies, let’s call them MRT Babies. Further research should be conducted cautiously and with full understanding of its potential. MRT may one day soon be capable of  helping many women have their own biological children without passing on mitochondrial mutations.

 

Sources:

Chial, H. & Craig, J. (2008) mtDNA and mitochondrial diseases. Nature Education 1(1):217 https://www.nature.com/scitable/topicpage/mtdna-and-mitochondrial-diseases-903#

Ruhoy, I. S., & Saneto, R. P. (2014). The genetics of Leigh syndrome and its implications for clinical practice and risk management. The Application of Clinical Genetics, 7, 221–234. http://doi.org/10.2147/TACG.S46176

Zhang, J. et al. (2017) Live birth derived from oocyte spindle transfer to prevent mitochondrial disease. Reproductive BioMedicine Online, 34(4), 361-368. http://dx.doi.org/10.1016/j.rbmo.2017.01.013