So What About Three-Person Embryos?


In 2013, Deiter Egli’s group at Harvard University successfully transferred chromosomes that were in the process of dividing and segregating (known as an incompletely assembled spindle-chromosome complex) from one human egg into another egg whose nucleus had been removed (Nature 493, 632–637 (31 January 2013) doi:10.1038/nature11800). They prevented the eggs from prematurely re-entering meiosis by cooling the chromosome/spindle complex to room temperature. This allowed normal polar body extrusion, efficient development to the blastocyst stage, and, eventually, the derivation of normal stem cells.

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Egli’s technique allows the genome of one egg to initiate development in the cytoplasm of another egg. Why is this significant? Because within out cells is a bean-shaped vesicle called a mitochondrion. Mitochondria make the energy for our cells. To do this, mitochondria use a variety of proteins encoded on genes found in the nuclear genome. However, mitochondria also have their own genome that encodes some crucial mitochondrial proteins and RNAs. The human mitochondrial genome is a small, circular DNA molecule that encodes 37 different genes.

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Mutations in genes encoded by the mitochondrial genome tend to have rather catastrophic consequences for the fertility of women. When the egg undergoes fertilization, the vast majority of the mitochondria of the sperm are degraded and their mitochondrial DNA is eliminated (Katsumi Kasashima, Yasumitsu Nagao, and Hitoshi Endo. Reprod Med Biol. 2014; 13(1): 11–20). Research has shown that the father’s mitochondrial genome can make some very small contribution to the embryo, a phenomenon known as “paternal leakage,” but it is usually pretty small (Kuijper B1, Lane N, Pomiankowski A. J Evol Biol. 2015 Feb;28(2):468-80). Therefore, if the mother carries a deleterious mutation in her mitochondrial DNA, her eggs will usually not be able to progress through fertilization successfully and support the growth and development of the embryo. Consequently, the mother will be infertile.

This new technique by Egli, however, allows mothers who are infertile because of mutations in their mitochondria DNA, to have children who are genetically related to them. All that is needed are eggs from a healthy donor, and a laboratory that has the know-how and will to do this procedure. The mother’s eggs are harvested by standard IVF technologies, fertilized by the father’s spermatozoa, and after fertilization has ended, the chromosome-spindle complex is lifted from the young embryos and transferred into enucleated donor eggs that contain mitochondria with normal genomes. Development will then ensue without a hitch. Right?

Well not so fast. As it turns out, this procedure has been carried out in several different animal species, and the results are decidedly mixed (see Reinhardt and others, Science 2013;341:1345).

If we begin with insects, we can move new mitochondrial genomes into embryos by standard genetic techniques. If we do so in the fruit fly, Drosophila melanogaster, such mitochondrial transfer produces fly embryos that develop normally, but the animals show altered juvenile viability, adult male animals show accelerated aging and reduced fertility. Genetically, it is clear that transferring new mitochondria into an egg messes up the expression of nuclear genes. Identical experiments in the seed beetle causes altered development and metabolic rates, reduced fertility in males and reduced survival in females. Similar studies in copepods (Tigriopus californicus) causes reduced juvenile viability, and reduced mitochondrial function and energy production in adults.

If mice are subjected to these same experiments, the animals develop normally and survive to adulthood, but these adult mice show reduced growth and exercise ability and reduced learning ability in males.

The above-mentioned experiments used standard genetic breeding techniques to generate animal strains that had a mismatch between the nuclear and mitochondrial genome.  Such techniques are demonstrably non-invasive.  However, the technology applied in Egli’s laboratory were invasive, and included removing chromosome/spindle complexes and transferring them to donor eggs that had been enucleated. Therefore, the effects of these invasive procedures had to be tested as well. If such invasive procedures were tested in cultured mouse cells, the hybrid cells showed altered cellular respiration and growth. In short, their mitochondria worked poorly inside their new homes.

If Egli’s technique was used in non-human primates, macaques in particular, the animals developed to the juvenile stage and appeared normal.

On the strength (or weakness) of these experiments, some reproductive specialists in countries where such techniques can be performed without fear of prosecution have used mitochondrial transfer in human embryos. Again the results are quite mixed. Healthy children have been born by this procedure, but several others have not. Helen Pearson reported in Nature News on the 14th of October, 2005 about two Chinese babies that were made with mitochondrial transfer that died in utero at 24 and 29 weeks. Other outcomes include a miscarriage, an abortion of a fetus that had Turner Syndrome, at least two children with mixed mitochondria that studies linked with cognitive dysfunction and obesity, and a child born with a severe developmental disorder. I do not call these hopeful results.

Another experiment that gives me pause was published in the journal Cell Reports in June of 2014 by Joerg Patrick Burgstaller and others. This paper showed that even small amounts of diseased mitochondrial DNA in an embryo would spread throughout the organism. The amount of spread is wide and varied, but even small amounts of variant mitochondrial DNA did spread. This significance of this is stark for this debate. You see, Egli’s original paper in Nature showed that very small amounts of the original mitochondrial DNA are transferred to the donor egg. Granted it below 1% of the total mitochondrial DNA in the embryo, but it is still detectable. Burgstaller and others have shown that even with this small amount of mitochondrial DNA, it will still spread throughout the developing baby and given them a body with some cells that have most the diseased mitochondrial DNA, and others that have the normal mitochondrial DNA, and other cells that have a mixture of the two. Therefore, Egli’s technique is NOT a cure for conditions linked to mitochondrial DNA mutations. Let me repeat this for every one – Egli’s technique is NOT a cure for conditions linked to mitochondrial DNA mutations.

No vertebrates have yet been studied who have gone through mitochondrial replacement and survived to reproductive age. Given the decidedly mixed record of this technology in a variety of animal models and the paucity of data so far, this technology is clearly not ready for use in humans.

However, that has not stopped scientists and politicians in the United Kingdom from pushing this technology forward as a fertility treatment for infertile women who harbor mitochondrial DNA mutations.  Some in the scientific community warned about the potential dangers of this technology.  Their concerns were largely ignored and in many cases severely criticized.  Even worse, some thought that three-person embryos could grease the slippery slope in which this technology or similar ones like cloning would be applied as generalized treatments for infertility.  That concern was labeled ridiculous. No longer.

Science magazine reported that cloning magnate Shoukhrat Mitalipov has formed a partnership with disgraced fraudster Woo Suk Hwang.  The two are teaming up to form a joint commercial venture to use Mitalipov’s cloning techniques as a way to treat infertility and perhaps other diseases.  Mitalipov’s commercial venture Mitogenome Therapuetics and Hwang along with the company BoyaLife, which will reportedly put up more than $90 million into the effort.  Mitalipov has also generated news reports by asking FDA approval to use so-called 3-person IVF “mitochondrial transfer” technology, which shares some technical elements with cloning, to treat infertility. This surprised some in the UK, including members of Parliament who were hoodwinked into voting to approve the three-person embryo procedure by being told that this technology would only be used to treat mitochondrial diseases.

The slippery slope is real and unless citizens rise up and make noise, we are going to be dragged where angels fear to tread by over-zealous scientists who are willing to sacrifice young children for the sake of their own fame and success.  This technology is not ready for use in humans.  The approval of this technology in the UK is a very bad idea.  It will also spread to the use of cloning in general as a treatment for diseases, and we will then move to fetus farming.  May God give us the strength to say enough is enough.

The United States FDA’s Cellular, Tissue and Gene Therapies Advisory Committee will be holding a public hearing to “discuss considerations for the design of early-phase clinical trials of cellular and gene therapy products” including the three-parent IVF method. The public has until October 15 to send in written comments. If you are interested in making your views known, go here.

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mburatov

Professor of Biochemistry at Spring Arbor University (SAU) in Spring Arbor, MI. Have been at SAU since 1999. Author of The Stem Cell Epistles. Before that I was a postdoctoral research fellow at the University of Pennsylvania in Philadelphia, PA (1997-1999), and Sussex University, Falmer, UK (1994-1997). I studied Cell and Developmental Biology at UC Irvine (PhD 1994), and Microbiology at UC Davis (MA 1986, BS 1984).