Scientists have been working on techniques to treat mitochondrial diseases, and one strategy is to create “3 parent” babies, where the mother’s defective mitochondria are replaced or supplemented in her gametes with mitochondria from another woman, and the gamete is then fertilized with sperm from the father. It works!
In September, reproductive endocrinologist John Zhang and his team at the New Hope Fertility Center in New York City captured the world’s attention when they announced the birth of a child to a mother carrying a fatal genetic defect.
Using a technique called mitochondrial replacement therapy, the researchers combined DNA from two women and one man to bypass the defect and produce a healthy baby boy — one with, quite literally, three genetic parents.
There is, however, a significant possibility of failure.
Earlier this month, a study published in Nature by Shoukhrat Mitalipov, head of the Center for Embryonic Cell and Gene Therapy at the Oregon Health and Science University in Portland, suggested that in roughly 15 percent of cases, the mitochondrial replacement could fail and allow fatal defects to return, or even increase a child’s vulnerability to new ailments.
The findings confirmed the suspicions of many researchers, and the conclusions drawn by Mitalipov and his team were unequivocal: The potential for conflicts between transplanted and original mitochondrial genomes is real, and more sophisticated matching of donor and recipient eggs — pairing mothers whose mitochondria share genetic similarities, for example — is needed to avoid potential tragedies.
This is not at all surprising, and shouldn’t be used as a reason to stop the research. This was expected. Anyone who has studied mitochondrial genetics — and I’m sure this is the case for these researchers as well — knows about dominant negative effects. There are known alleles in mitochondria that are negative, that is they are deleterious to the organelle, and are also dominant, that is, one copy of the of the allele can suppress healthy mitochondria in the same cell. We also know that mitochondria replicate independently of the cell, and that in some cases the defective mitochondria can outcompete and replace the healthy mitochondria. This is the case in, for instance, poky mutants in Neurospora, and petite mutants in yeast.
So, old news. It seems to make the popular press only when it looks like it might affect human beings, though, which is too bad, because awareness of the problem arose from basic cell biology, and will be best solved by experimental work in non-human organisms. Let’s see more funding for yeast and Neurospora and fruit fly and zebrafish research!
Science News listed this in their Top Ten stories for 2016. IIRC, the work that showed the potential for failure was done in mice. The Zhang team chose to go ahead with the human MRT experiment anyway.
I hope things go well for the kid, and the others who are sure to follow.
“petite mutants in yeast” is the name of my experimental yet-to-be-formed band
I don’t get this. If all the cytoplasm is from the donated ovum, why would there be any of the original defective mitochondria left? And what does “matching” of mitochondrial DNA have to do with anything? Something is missing or inaccurate in this story.
Maybe they should just go with a donor egg…
@ cervantes
short version. 99%+ of the cytoplasm is from the donated ovum but that less than 1% still contains a few mitochondria. What this and other investigators have found is that in some combinations of donor and recipient, following fertilization of the ovum and growth of the embryo, that less than 1% can increase until it represents >90% of the mitochondria in the cells. The goal presumably is to identify the combinations of donor and recipient for which this won’t happen, hence the reference to ‘matching of mitochondrial DNA’.
Still not getting the “matching” issue. What’s needed is that the donor mitochondria have high r, regardless of the mother’s, right? Also, is it really impractical to eliminate all mitochondria from the implanted nucleus? It seems to me that ought to be possible, e.g. using ubiquitin, which would mark them as paternal?
@ cervantes
Think of mitochondrial donation like blood donation. If you were to transfuse one random person with blood from a random donor, it might work fine or disaster might ensure depending upon whether the blood types were compatible. What this paper and others like it showed is that like blood transfusion, not all donors and recipients may be compatible and as of now there is no way to predict compatibility.
As far as eliminating all mitochondria from the implanted nucleus, yes it is impractical, in large part because the more manipulations you perform on the nucleus the less likely the resultant embryo is to develop normally.
I’m still confused about one thing. If female #1 is carrying defective mitochondria that would cause a fatal condition in her baby, why is this woman still alive? Shouldn’t the mitochondria defect have killed her as a baby or fetus?
@8
I mean, I’m not sure about the specific case, but it’s possible to be a carrier for genes that only become deleterious when crossed with certain other genes.
Like, in middle-school simple cross terms, let’s say the defect is a recessive trait, so it only expresses itself if the gene in question is “dd”, rather than “Dd” or “DD”.
The mother could be a carrier, in which case they have the genotype “Dd”. This means that they have the potential to pass on the defect if they cross with another carrier, but are not themselves affected by the defect.
A little off-topic, but …
RE: “anyone who has studied mitochondrial genetics”
Look up: Alexander Tzagoloff. (Columbia U.)
OOOPS
TSagoloff. S, not z.
Or adopt.
Nick Lane’s The Vital Question* is a good read on this subject. It’s not the main focus of the book, but I was quite shocked (!) to find out what sneaky little bastards mitochondria are.
They’re the Machiavelli’s of sub-cellular organelles.
* There may be better books from him, this is the one I have read.
@8 gAytheist
The problem is something called heteroplasmy. Because each cell has hundreds to thousands of mitochondria many women who are carrying defective mitochondria don’t have disease because their level of defective mitochondria is low. However that won’t necessarily be the case for their children and prenatal diagnosis doesn’t help because the ratio of defective to functional mitochondria can vary in different tissues and prenatal diagnosis only samples a few cells.
Egg donation or adoption is always a choice but I have a certain amount of sympathy for people for whom having biological children is important.
Blattafrax@13,
Having read four of Lane’s books (Oxygen: The Molecule that Made the World, <Life Ascending: The Ten Great Inventions of Evolution, Power, Sex, Suicide and The Vital Question, I’d recommend them all (and the one I haven’t read, Origins of Life. How Life Began. Abiogenesis, Astrobiology). However The Vital Question probably covers most of the ground of Oxygen… and Power…, and is more up-to-date. I’d actually say mitochondria are absolutely central to the second half of the book, which deals with the origin and evolution of eukaryotes (the first half is on abiogenesis): Lane hypothesises that many of the most profound and puzzling features of eukaryotes are the result of selection on nuclear and mitochondrial genes pulling in different directions.
blf @12 — Hear, hear!