Wednesday, October 12, 2016

"Three parent" baby

A medical breakthrough was announced this week when scientists described the birth of a healthy baby boy who was born free of the mitochondrial disease that his mother carries. How did it happen?

Through a process called mitochondrial manipulation technology (MMT), a team of physicians isolated the nucleus from the mother's oocyte and transferred it to a donor oocyte that was then fertilized and implanted into the mother. The mother went on to have a normal pregnancy and delivered the boy 3 months ago, at 37 weeks gestation, according to an abstract published in Fertility and Sterility.

Here's a quick roundup of the most important things to know about this case.

1. The term "three-parent baby" is misleading.
While many news outlets ran headlines announcing that a "three-parent baby" had been born, the scientific facts make this not quite accurate. As Dr Richard J. Paulson, president-elect of the American Society for Reproductive Medicine, told the New York Times, "Mitochondria do not define who you are" because they don't carry the genes for traits.

2. Mitochondrial diseases are rare but devastating.
Mitochondrial mutations are maternally transmitted and can have fatal or debilitating consequences. The mother in this case carries a mitochondrial disease called Leigh syndrome. She previously had two children who were born with the disease and both died, one at age 6 and one at 8 months. The mitochondrial DNA inheritance pattern is unpredictable, so while a quarter of the mother's tested cells had mitochondrial mutations, the two deceased children had the mutation in over 95% of their mitochondria.

The team that performed the procedure tested several neonatal tissues, such as hair follicles and the umbilical cord, and reported that they contained about 1%-2% of the mother's mitochondrial DNA.

3. MMT is not available in the United States.
Although the ob/gyn who led the team, John Zhang, MD, PhD, is based in New York City, the nuclear transfer intervention was done in Mexico. A US Food and Drug Administration panel concluded in February 2015 that more data are needed before the procedure can be conducted in the United States.

This is in contrast to a decision by lawmakers in the United Kingdom, who voted last year to allow MMT to go forward and with a conclusion from the Institute of Medicine in February 2016 that MMT is "ethically permissible." 

4. Two approaches for MMT are possible.
Medscape Medical News reporter Ricki Lewis, PhD, describes the two approaches in a recent article. In one approach, known as pronuclear transfer, the father's sperm is used to fertilize two oocytes in vitro, one from the mother and another from a donor. The nucleus from the donor's fertilized ovum is removed and replaced with the nucleus from the mother's fertilized ovum. This process creates two ova and typically means that one of them is destroyed.

The second approach, which was used in this case, is called spindle nuclear transfer. It involves transferring the nucleus of the mother's oocyte to the enucleated donor oocyte. The oocyte is then fertilized with the father's sperm.

5. Options differ as to whether the technology is necessary.
In an interview with Medscape Medical News, Marcy Darnovsky, PhD, executive director of the Center for Genetics and Society, said "mitochondrial transfer is not medically necessary."

According to Dr Darnovsky, "it doesn't cure, treat, or prevent any existing person's disease. Nor is it necessary to have a child unaffected by mitochondrial DNA disease, since all people at risk of transmitting this condition can opt to use another person's egg."

Meanwhile, in a commentary published last year, Medscape's medical ethicist, Arthur L. Caplan, PhD, said the controversies surrounding the technology seem to be unfounded, as mitochondria do not carry genes related to behaviors or traits.

"Preventing parents who want to try to have a healthy child who can live does not seem to be the right place to say no to this form of genetic engineering," he concluded.



  1. J. Zhang, H. Liu, S. Luo, A. Chavez-Badiola, Z. Liu, m. yang, S. Munne, M. Konstantinidis, D. Wells, T. Huang. First live birth using human oocytes reconstituted by spindle nuclear transfer for mitochondrial DNA mutation causing Leigh syndrome. Fertility and Sterility.

    Mutations in mitochondrial (mt) DNA are maternally inherited and can cause fatal or debilitating disorders without effective treatments. The severity of clinical symptoms is often associated with the mtDNA mutation load in heteroplasmy. Experimental nuclear transfer in metaphase II (MII) spindle oocytes or in pronuclear (PN) zygotes, also called mitochondrial replacement therapy, has been shown to be a novel technology in minimizing mutated mtDNA transmission from oocytes to pre-implantation embryos. Here we report the first live birth of a boy following spindle nuclear transfer (SNT).

    Translational research.

    Materials and Methods
    The patient is a 36-year-old woman with 24.5% mtDNA displaying 8993T>G mutation in subunit 6 of the ATPase gene known to cause Leigh syndrome.6 She had 4 pregnancy losses and 2 deceased children at age 8 months and 6 years from Leigh syndrome as confirmed by >95% mutation load. She was seeking conception of a healthy baby and elected to have SNT over PN transfer for religious reasons. Under IRB-approved protocol with proper consent, the patient’s spindle nuclei were isolated and transferred into the perivitelline space of enucleated donor oocytes. The micro-manipulated complexes were then subjected to 1.4 kV/cm DC voltage for cell membrane fusion. The reconstituted oocytes were fertilized by intracytoplasmic sperm injection (ICSI). The developed blastocysts were biopsied for preimplantation genetic screening (PGS) by array comparative genetic hybridization and whole quantitative genomic mtDNA analysis by Next Generation Sequencing.

    Five MII oocytes with birefringent spindles were subjected to meiotic SNT. The 5 oocytes were successfully reconstituted and fertilized normally by ICSI. Four out of 5 fertilized oocytes developed into blastocysts. PGS showed that one blastocyst was euploid (46XY), while 3 embryos were aneuploid. The average transmission rate of maternal mtDNA in the biopsied euploid blastocyst was 5.10 ± 1.11% and the heteroplasmy level for 8993T>G was 5.73%. Transfer of the euploid embryo resulted in an uneventful pregnancy with delivery of a healthy boy at 37 weeks of gestation. The average level of transmitted mother’s mtDNA in several neonatal tissues including buccal epithelium, hair follicles, circumcised foreskin, urine precipitate, placenta, amnion, umbilical blood, and umbilical cord was less than 1.60 ± 0.92%. The baby is currently 3 months old and doing well.

    Human oocytes reconstituted by SNT are capable of producing a healthy live birth. SNT may provide a novel treatment option in minimizing pathogenic mtDNA transmission from mothers to their babies.

  2. Others say that if we do this, are we somehow creating a child who has three parents—the donor of the mitochondria and the couple who will make the biological child? Personally, I do not find this objection at all moving. We already have sperm donors. We already have egg donors. We even sometimes have embryo donors. Adoption technically leads to a child having more than two parents. I am not convinced that having three parents is going to destroy the American family.

    Moreover, even if we are concerned about putting three parents into the picture (or if you can put that to the side), in reality, I am not sure why a mitochondrial donor would have a parental claim anyway. If I owned a car with a good car battery and you had a car with a bad battery, and I decided that I did not want my car anymore and I gave you my car battery, am I now an owner of your car?

    Mitochondria, while vital for physiology, are trivial in terms of genetics. I do not believe that you become a parent by donating mitochondria. Thus, this whole notion of a three-parent baby has very little traction...

    The last worry is, are we starting down the road to eugenics? Some people worry that because mitochondria will be inherited, this will lead to transplanting not only the genes of the body but the germline genes, genes that will be passed on to future generations.

    I am not saying that we need not worry about people trying to make "superbabies," or smarter, faster, taller, stronger babies, but this technique of mitochondrial transplantation has nothing to do with that. First, mitochondrial transplants do not carry that kind of genetic material. Mitochondria do not carry information about our traits or behaviors. Even if one wanted to make a superbaby, mitochondrial transplant is a procedure that is all about cure. It is trying to prevent death, not make mightier, stronger, or somehow all-powerful children.

    There certainly is room to debate where we want genetic engineering to go. I would argue that mitochondrial transplant is the wrong place to draw the line. Preventing parents who want to try to have a healthy child who can live does not seem to be the right place to say no to this form of genetic engineering.