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Pregnancy Timeline by SemestersDevelopmental TimelineFertilizationFirst TrimesterSecond TrimesterThird TrimesterFirst Thin Layer of Skin AppearsEnd of Embryonic PeriodEnd of Embryonic PeriodFemale Reproductive SystemBeginning Cerebral HemispheresA Four Chambered HeartFirst Detectable Brain WavesThe Appearance of SomitesBasic Brain Structure in PlaceHeartbeat can be detectedHeartbeat can be detectedFinger and toe prints appearFinger and toe prints appearFetal sexual organs visibleBrown fat surrounds lymphatic systemBone marrow starts making blood cellsBone marrow starts making blood cellsInner Ear Bones HardenSensory brain waves begin to activateSensory brain waves begin to activateFetal liver is producing blood cellsBrain convolutions beginBrain convolutions beginImmune system beginningWhite fat begins to be madeHead may position into pelvisWhite fat begins to be madePeriod of rapid brain growthFull TermHead may position into pelvisImmune system beginningLungs begin to produce surfactant
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Mitochondrial DNA therapy still imperfect

Mitochondrial replacement therapy is a procedure showing promise for preventing inheritance of mitochondrial diseases. However, small amounts of damanaged mtDNA — mitochondrial DNA — are now found to hitch a ride with the transferred nucleus, and recreate mtDNA errors in the baby.

Mitochondria exist in the cytoplasm surrounding the nucleus to turn oxygen into energy via ATP (adenosine triphosphate). Mitochondrial DNA (mtDNA) is exclusively transmitted through a mother's egg cells — sperm make no contribution of mitochondria to a fertilized embryo.

Replacement therapy is a procedure to remove the nucleus of an egg in order to place it in a healthy donor egg previously enucleated. The healthy mitochondria in the cytoplasm of the donor egg then support the developing zygote created after fertilization by a sperm. Fertilization effectively creates a "three-parent" baby whose DNA is from the mother and father, but whose mitochondrial DNA (mtDNA) is from a donor woman's egg.

However, in a study publishing May 19 in Cell Stem Cell, it was revealed that even trace amounts of transferred mtDNA can override the healthy mitochondria of the donor egg. This revelation questions the beneficial effect of nuclear transfer to overcome damaged mtDNA.

Says senior study author Dieter Egli of the New York Stem Cell Foundation: "We identified a challenge to making mitochondrial replacement therapy safe and effective. We anticipate that the findings will inform decisions regarding when and how mitochondrial replacement in humans will be done clinically."

Mitochondria generate most of a cell's energy, so mitochondrial mutations can result in serious health problems including developmental delays.

Examples of mitochondrial disease include:

Mitochondrial myopathy or neuromuscular diseases
Diabetes mellitus and deafness (DAD)
Leber's hereditary optic neuropathy (LHON)
Leigh syndrome
Neuropathy, ataxia, retinitis pigmentosa, and ptosis (NARP)
Myoneurogenic gastrointestinal encephalopathy (MNGIE)
Myoclonic Epilepsy with Ragged Red Fibers (MERRF)
"Ragged Red Fibers" – clumps of diseased mitochondria appear as "Ragged Red Fibers" when muscle tissue is stained
short stature
hearing loss
lactic acidosis
exercise intolerance
Mitochondrial myopathy, encephalomyopathy, lactic acidosis, stroke-like symptoms (MELAS)
mtDNA depletion
mitochondrial neurogastrointestinal encephalomyopathy (MNGIE)

Although mitochondrial replacement therapy to prevent such conditions have not been approved in the United States, the procedure is approved in the United Kingdom. Recently, the National Academies of Sciences, Engineering, and Medicine has given permission for research to conduct clinical investigations of the procedure in the United States. In the new study, Egli and his collaborators wanted to know if they could reliably reproduce the nuclear transfer procedure.

For six months, researchers continuously measured the transferred mtDNA as it underwent genetic drift — or changes in gene variations. In most cases any transferred mtDNA vanished — it was completely replaced in its new cell environment.

But a few mtDNA cell colonies underwent complete reversion. Up to 100% of the donor recipient mtDNA now matched the (damaged) transferred DNA.

In future research, Egli's team will try to prevent mtDNA carrying over into the donor egg cell through the nuclear transfer procedure. Possible strategies include reducing the amount of cytoplasm transferred during the nuclear shuffle, or only selecting embryos without any detectable levels of "extra" mtDNA.

Egli: "We will also examine whether matching mitochondrial genotypes will be able to avoid mitochondrial genotype instability, and how precise this match needs to be. Whether it has to be of the same ethnic group, or even of the same maternal lineage, progress on either of these fronts should provide a path to therapeutic translation."

•Cryopreservation allows coordinated nuclear transfer in human oocytes
•Stem cell lines and derivatives show low-level carryover of transferred mtDNA
•Recipient mtDNA is functionally compatible with donor nuclear DNA
•Genetic drift can lead to restoration of the original donor mitochondrial genotype

Replacement of mitochondria through nuclear transfer between oocytes of two different women has emerged recently as a strategy for preventing inheritance of mtDNA diseases. Although experiments in human oocytes have shown effective replacement, the consequences of small amounts of mtDNA carryover have not been studied sufficiently. Using human mitochondrial replacement stem cell lines, we show that, even though the low levels of heteroplasmy introduced into human oocytes by mitochondrial carryover during nuclear transfer often vanish, they can sometimes instead result in mtDNA genotypic drift and reversion to the original genotype. Comparison of cells with identical oocyte-derived nuclear DNA but different mtDNA shows that either mtDNA genotype is compatible with the nucleus and that drift is independent of mitochondrial function. Thus, although functional replacement of the mitochondrial genome is possible, even low levels of heteroplasmy can affect the stability of the mtDNA genotype and compromise the efficacy of mitochondrial replacement.

This research was supported by the New York Stem Cell Foundation (NYSCF) and the Bernard and Anne Spitzer Fund. We thank Mr. Futoshi Inoue (Kitazato Corporation) for developing and supplying new oocyte freezing and thawing media. D.E. is a NYSCF-Robertson Investigator. We thank Salvatore DiMauro for comments on the manuscript.

Cell Stem Cell (@CellStemCell), published by Cell Press, is a monthly journal that publishes research reports describing novel results of unusual significance in all areas of stem cell research. Each issue also contains a wide variety of review and analysis articles covering topics relevant to stem cell research ranging from basic biological advances to ethical, policy, and funding issues. Visit: http://www.cell.com/cell-stem-cell. To receive Cell Press media alerts, contact press@cell.com.

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May 27, 2016   Fetal Timeline   Maternal Timeline   News   News Archive   

Researchers extract mtDNA from eggs with inherited mtDNA disease
and place the entire nucleus into a healthy donor egg without one.
Image Credit: Dieter Egli, New York Stem Cell Foundation



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