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=Benefits=
=Benefits=
Due to the nature of maternal only inheritance of mitochondria between generations. Any offspring of an affected mother will inherit the same disposition to a mitochondrial disease. In the UK its estimated that 152 women per year are at risk of transmitting mtDNA diseases and 778 in the United States<ref><pubmed> 25629662 </pubmed></ref>.


PMID 25629662 '''Mitochondrial donation--how many women could benefit?'''<ref><pubmed> 25629662 </pubmed></ref>
PMID 25629662 '''Mitochondrial donation--how many women could benefit?'''<ref><pubmed> 25629662 </pubmed></ref>
This is a statistical analysis of the prevalence of women of child bearing age that have pathogenic mutation to their mitochondria that could benefit from mitochondrial donation in the UK. And the affects of the mitochondrial mutation on fertility as compared to background natural birth rate. They found no difference in fertility rates and 4% of women at risk of passing on symptomatic mitochondrial disease.


PMID 18674747 '''Pathogenic mitochondrial DNA mutations are common in the general population.'''<ref><pubmed> 18674747 </pubmed></ref>
PMID 18674747 '''Pathogenic mitochondrial DNA mutations are common in the general population.'''<ref><pubmed> 18674747 </pubmed></ref>
Another on the prevalence of mitochondrial mutations in the populous. This time via mtDNA sequencing from umbilical samples from live births, looking for ten specific mt-DNA mutations. It found a frequency rate of 0.54% for these mutations. Although they had limited data on the prevalence of these mutations maternally.
 


PMID: 24832374 '''Potential impact of human mitochondrial replacement on global policy regarding germline gene modification.'''<ref><pubmed> 24832374 </pubmed></ref>  
PMID: 24832374 '''Potential impact of human mitochondrial replacement on global policy regarding germline gene modification.'''<ref><pubmed> 24832374 </pubmed></ref>  

Revision as of 22:33, 7 October 2015

2015 Student Projects 
2015 Projects: Three Person Embryos | Ovarian Hyper-stimulation Syndrome | Polycystic Ovarian Syndrome | Male Infertility | Oncofertility | Preimplantation Genetic Diagnosis | Students
2015 Group Project Topic - Assisted Reproductive Technology
This page is an undergraduate science embryology student and may contain inaccuracies in either description or acknowledgements.

Three Person Embryos

(intro) Here is a good source for overview and status of 3 Person IVF. http://www.geneticsandsociety.org/article.php?id=6527

History

Timeline of Mitocondrial Donation

1990s

2000s

-2000
  • St Barnabas Hospital announces it has achieved live births from mitochondrial donation via Ooplasmic transfer [1]
-2008
  • 13th Nov The Human Fertilization and Embryology Act allows research into the techniques of three person IVF.

2010s

-2015
  • 29th October regulations to allow the open use of three person IVF in fertility clinics comes into affect in the UK.

Case of Alana Saarinen???

The girl with three biological parents

Benefits

Due to the nature of maternal only inheritance of mitochondria between generations. Any offspring of an affected mother will inherit the same disposition to a mitochondrial disease. In the UK its estimated that 152 women per year are at risk of transmitting mtDNA diseases and 778 in the United States[2].


PMID 25629662 Mitochondrial donation--how many women could benefit?[3]

PMID 18674747 Pathogenic mitochondrial DNA mutations are common in the general population.[4]


PMID: 24832374 Potential impact of human mitochondrial replacement on global policy regarding germline gene modification.[5]

Mitochondria

  • discovered in muscle by Kölliker in 1857
  • mitochondria are the "powerhouses" of the cell and the location where respiration occurs at the cellular level.
  • mitochondria contain their own DNA (mitochondrial DNA or mtDNA) that has been originally inherited only from the oocyte (maternal inheritance).
  • The spermatozoa (paternal) mitochondria- energy for fertilization motility but are generally destroyed during the first mitotic cell divisions.
  • This pattern of inheritance has important implications for a variety of mitochondrial associated diseases, usually occurring in tissues requiring lots of energy (muscle, brain).
Electron micrograph of mitochondria.

Eukaryotic mitochondrial genomes

  • double stranded circular DNA (mitoDNA. mtDNA)
  • 1981 complete human sequence (16,569 nucleotides)
    • 37 genes
    • encodes 13 polypeptides involved in oxidative phosphorylation
  • remaining genes transfer RNA (tRNA) and ribosomal RNA (rRNA)
  • multiple copies within the matrix
  • maternally inherited
  • remainder encoded by nuclear DNA
  • proteins made in cytosol and imported into mitochondria

Mitochondria Disease

link to Embryology website Mitochondria

Technical Progression

Three-person in-vitro fertilization is the process where gene replacement exerted to prevent mitochondrial disease passing through generations. Main aproaches to achieve this goal involve the replacement of mitochondrial genome between gametes or embryos [6] [7].

  • The first proposed treatment is cytoplasmic transfer, which transfers a small part of ooplasm from one oocyte to another. however, this approach were then considered to be inadequate to prevent the inheritance of diseased mitochondrial. because it adds in donor mitochondria without removing the mutated mtDNA, which will then generate a 'heteroplasmic oocyte' with both mitochondria haplotypes.
  • New emerged approaches of mitochondrial transmission are pronuclear transfer(PNT), spindle transfer (ST) and Polar body transfer (PBT). however, none of this techniques have been proved on generating healthy human offspring due to the technical difficulty, as well as the ethics issues being recognized worldwide [8].
  • Major breakthroughs of these techniques rely on the practice on animal models (mice and primate) [9], early stage human embryo and stem cell studies [10].


Image Source: http://www.popsci.com.au/science/medicine/what-3parent-babies-mean-for-the-future-of-reproductive-medicine,400376

Cytoplasmic transfer

Simplified Cell Structure

Egg repair by Cytoplasmic transfer Embryo repair by Cytoplasmic transfer

The girl with three biological parents


Human Model

Alana Saarinen is one of only 30 to 50 people in the world who have some mitochondria, and therefore a bit of DNA, from a third person. She was conceived through a pioneering infertility treatment in the USA which was later banned.

[NEWS]

Spindle-chromosome transfer

Transfer of the metaphase II spindle from the unfertilized oocyte of an affected woman to an enucleated donor oocyte, spindle transfer between human oocytes, resulting in blastocyst development and embryonic stem cell derivation, with very low levels of heteroplasmy.

(need to reproduce the diagram)

Primate model

Swapping mitochondrial DNA mammalian oocytes.jpg

Spindle-chromosome transfer in primates supports normal development to adults and low mtDNA carryover.[11]

Cases

PMID 23103867 Towards germline gene therapy of inherited mitochondrial diseases. [12] the authur investigates the spindle-chromosomal (ST) complex transfer on human oocytes. they concluded that the mtDNA can be efficiently replaced in human oocytes, although some ST oocytes displayed abnormal fertilization.

PMID 25973765 Extreme-Depth Re-sequencing of Mitochondrial DNA Finds No Evidence of Paternal Transmission in Humans[13] Extreme-high depth mtDNA re-sequencing up to ~1.2 million-fold coverage, the author has proved the dogma that mammalian mitochondrial DNA (mtDNA) is strictly maternally inherited. It also indicated that an active mechanism eliminates paternal mtDNA which likely acts at the molecular level.

PMID 19710649 Mitochondrial gene has been efficiently replaced by spindle-chromosomal complex transfer one egg to an enucleated, mitochondrial-replete egg in primate offspring and embryonic stem cells. (Here are copy right and permission issues regarding reuse)

Pronuclear transfer

the nuclear genome from the pronuclear stage zygote of an affected woman is transferred to an enucleated donor zygote Pronuclear transfer is associated with high levels of mtDNA carryover in mice but low levels in human embryos, carries ethical issues secondary to donor embryo destruction [14] PMID 25377180

(Need to reproduce the graph)

Diagram of Pronuclear transfer [1] What 3-Parent Babies Mean For The Future Of Reproductive Medicine

Human Embryo Model

PMID 20393463 Pronuclear transfer in human embryos to prevent transmission of mitochondrial DNA disease[15] As the name suggest this paper looks at pronuclear transfer as way to remove donor mitochondria measured by mt-DNA. And it effectiveness in doing so. And the processes that occur in the oocyte when this method is used

other Cases

Polar body transfer

Polar bodies are small cells formed during the meiotic reductive division of the oocyte. they contains complementary choromosomes (to the mature oocyte) and small amount of cytoplasmic segregation. Polar body 1 is formed and released during ovulation. it contains a diploid set of chromosomes. while Polar body 2 is formed during fertilization and can be identified in the zygote. it contains a haploit set of chromosomes. and both polar bodies are unable to be fertilized and disintegrate eventually. PMID 24949971

Mice Model

Polar body transfer in mice is coupled with PN or ST. It may increase the yield of reconstructed embryos with low mtDNA carryover. [16]

Cases

PMID 24949971 Polar body genome transfer for preventing the transmission of inherited mitochondrial diseases [17] The authur adopts polar body transfer to prevent the transmission of mtDNA variants. they also compare the effects of different types of germline genome transfer, including spindle-chromosome transfer, pronuclear transfer, and first and second polar body transfer, in mice. Their pre-clinical model indicate that polar body transfer has better potential in preventing the inheritance of mitochondrial diseases.

Other approaches

germinal vesicle nuclear transfer

Ethics

1.PMID 26239841 The ethical challenges of the clinical introduction of mitochondrial replacement techniques. [18] The first part of the paper evaluates the three concerns about the safety of mitochondrial replacement techniques including whether it is ethical; persons with three genetic contributors and the trust of society. And then, two recommendations are made.

2.PMID 21059727 Ethics of mitochondrial gene replacement: from bench to bedside. [19] Both of the risks and benefits are accessed in this paper after the briefly introduction of mitochondrial replacement techniques. And then the question of when are enough safeguards made to justify introducing mitochondrial gene replacement into the clinic is discussed.

3.PMID 25888328 Mitochondrial replacement to prevent the transmission of mitochondrial DNA disease. [20] This paper discussed about the ethics and feasibility of mitochondrial replacement techniques. The possibility of preventing the transmission of mtDNA disease by MRT is first discussed. Moreover, the four big challenges mainly ethics are discussed.

Legal Status

Laws on three person embryos by country

Country/Territory Treatment Research Restricted Notes

Albania

test1 test2 test3 test4

Australia

test1 test2 test3 test4

England

Aproved for clinical trails under licence as of October 2015 Test 2 test3 usefull: http://www.legislation.gov.uk/uksi/2015/572/contents/made http://www.nature.com/news/world-hails-uk-vote-on-three-person-embryos-1.16894

USA

test1 test2 test3 test4
Country/Territory Treatment Research Restricted Notes

Further Reading

useful publications:

PMID 23608245 The ethics of creating children with three genetic parents. [21]

PMID 24382342 Three-Parent IVF: Gene Replacement for the Prevention of Inherited Mitochondrial Diseases.[22]

PMID 20933103 Mitochondrial function in the human oocyte and embryo and their role in developmental competence.[23]

PMID 26020522 Mitochondrial reshaping accompanies neural differentiation in the developing spinal cord.[24]

PMID 25421171 The impact of mitochondrial function/dysfunction on IVF and new treatment possibilities for infertility.[25]

PMID 25807984 Risks inherent to mitochondrial replacement.[26]

Glossary

Maternal Spindle Transfer: The transfer of nuclear DNA from a patient egg into a donor egg with its nuclear DNA removed, which is then fertilized and implanted via standard IVF.

Ooplasmic Transfer: The injection of ooplasm from a donor egg into a patient egg. Leads to mitochondrial heteroplasmy.

Pronuclear Transfer: The pre-fertilized nuclear DNA form a patient is transferred into a donor egg with its nuclear DNA removed, which is then fertilized and implanted via standard IVF.

References

  1. <pubmed> 1128222 </pubmed>
  2. <pubmed> 25629662 </pubmed>
  3. <pubmed> 25629662 </pubmed>
  4. <pubmed> 18674747 </pubmed>
  5. <pubmed> 24832374 </pubmed>
  6. <pubmed> 24382342</pubmed>
  7. <pubmed> 25573721 </pubmed>
  8. <pubmed>24373414</pubmed>
  9. <pubmed> 25229667 </pubmed>
  10. <pubmed> 23103869 </pubmed>
  11. <pubmed> 25573721 </pubmed>
  12. <pubmed> 23103867</pubmed>
  13. <pubmed> 25973765 </pubmed>
  14. <pubmed> 25573721 </pubmed>
  15. <pubmed> 20393463 </pubmed>
  16. <pubmed> 25573721 </pubmed>
  17. <pubmed> 24949971 </pubmed>
  18. <pubmed>26239841</pubmed>
  19. <pubmed>21059727</pubmed>
  20. <pubmed>25888328</pubmed>
  21. <pubmed> 23608245</pubmed>
  22. <pubmed> 24382342</pubmed>
  23. <pubmed> 20933103 </pubmed>
  24. <pubmed> 26020522 </pubmed>
  25. <pubmed> 25421171</pubmed>
  26. <pubmed> 25807984</pubmed>

External Links