Forbes and Fifth

Reprogenetics and the Use of Three Parent IVF to Prevent Genetic Diseases and Disorders

Reprogenetics and How It Affects Us Today 

In approaching the era benefitting from engineered bacteria and lab-generated tissues, advancements improving human health now surface. These improvements range from aesthetic selection to preventative care for genetic disorders and diseases. According to Genetics In Medicine, the average cost of treating a genetic disorder such as Tay-Sachs disease or cystic fibrosis can reach up to $375,000 over the course of one lifetimei. To curb medical costs related to genetic disorders, preventative procedures have recently become a hopeful endeavor for scientists and sufferers alike. Reprogenetics and preimplantation genetic diagnosis (PGD) are important stepping stones towards lower healthcare costs and diminishing rates of genetic diseases and disorders. Reprogenetics and PGD are umbrella terms encompassing methods and processes that test for and prevent possible genetic disorders before the mother’s egg matures into an embryo. Though, they are controversial procedures, as some claim that these procedures are against nature and leads to the genetic slippery slope of pre-programming our progenyii. The reprogenetics techniques discussed in this paper hold great potential for reducing health costs and providing a better quality of life for sufferers of genetic disorders as well as their children.

Three Parent IVF as an Effective Preventative Measure 

A specific application of reprogenetics prevents congenital mitochondrial disorders, such as mitochondrial myopathy, diabetes mellitus and deafness, Leber's hereditary optic neuropathy, and myoclonic epilepsy. These disorders are characterized by the epigenetic inheritance of abnormal mitochondria, the primary energy producer for the cell. Abnormal mitochondria result from a genetic mutation within the mitochondrial genome, creating dysfunctional proteins in place of the normal ones that are required for proper energy production. Abnormal mitochondria may reduce the quality of life for those who suffer from the myopathy. In addition, abnormal mitochondria have the potential to place a financial burden on patients’ families, with lifetime healthcare costs soaring to $306,332iii. Fortunately, there is a viable solution available today, where certain medical techniques, such as three parent in-vitro fertilization (IVF), eliminate the possibility of inherited mitochondrial disorders. Three-parent IVF is quite different from regular in-vitro fertilization, though. Regular IVF is ideal for couples who have physical infertility issues, such as sperm quality defects, poor egg quality, and blocked or damaged fallopian tubes. Three-parent IVF, in contrast, is not for infertility problems, but rather for couples who have a history of mitochondrial disorders and are likelier to pass it to their children. These couples may undergo two types of treatments: maternal spindle transfer or pronuclear transfer. Both of these processes require a third contribution of healthy mitochondria to replace the faulty mitochondria in the genetic mother’s egg cells. There have been multiple in-vitro clinical cycles of these processes, most of which have yielded successful outcomesiv.  

Maternal Spindle Transfer and Associated Procedures 

Although both processes are nearly identical, maternal spindle transfer is more widely-used in clinical practice due to higher success rates (75% versus 62% respectively)v. The area in the egg containing the dense collection of genetic information is known as the spindle fiber, hence the name of the procedure. In the maternal spindle transfer process, the egg is removed from the genetic mother’s ovary. In a parallel procedure, a donor egg with healthy mitochondria is obtained. All the genetic information from the original parent must be maintained through the process. The spindle is extracted from the mother’s egg. The maternal spindle is extracted using general nuclear extraction techniques, leaving the defective mitochondria behind. This procedure involves a vacuum pipette to hold the egg in place. A micropipette is used to pierce the Zona Pellucida (outer membrane) of the egg and retrieve the spindles inside. Once the spindles are extracted, the mother’s egg is no longer needed in the process and is disposed of accordingly. The same procedure is applied to the donor egg, ensuring that all DNA is removed. The donor’s DNA is subsequently discarded, as it is not needed. The maternal spindles are then inserted into the donor’s egg, which has the healthy mitochondria. This assembly ensures healthy mitochondria with the original mother’s genetic information. The egg may now undergo regular in-vitro fertilization procedures. The male parent’s sperm is combined with the new egg, and is implanted into the mother’s uterus to initiate pregnancy. 

Pronuclear Transfer and Associated Procedures 

Except for fertilization, pronuclear transfer is nearly identical to the maternal spindle transfer. In maternal spindle transfer, the egg is fertilized after the genetic material is transferred to the donor egg. However, the first step in pronuclear transfer involves fertilizing the genetic mother’s egg with the father’s sperm in-vitro. Doing this results in a pronucleus, which is a cell complex that develops right after fertilization. This pronucleus, containing the genetic material of both parents, is then transferred to the donor egg. Like maternal spindle transfer, all the DNA is removed from the donor egg before the transfer takes place. Although pronuclear transfer has been tested on many human zygotes (fertilized egg cells) vii, there is a slightly greater chance that the pronucleus does not develop properly when compared to post-procedural fertilization in the maternal spindle process. This discrepancy occurs because it is difficult to determine the correct time when the pronucleus is ready for extraction. This is not a problem with maternal spindle transfer, as the spindle can be extracted at any time during the life of the egg cell. 

FIGURE 1 vi 

Maternal Spindle Transfer 

Figure 1 shows the mother’s genetic information being removed from the egg and transferred to an egg with healthy mitochondria, and the new egg is subsequently fertilized.

FIGURE 2 

Figure 2 depicts pronuclear transfer. The only major difference is in step 1, wherein the egg is already fertilized before extraction of the genetic material.  

Why Should Engineers Focus on Three-parent IVF? 

According to the US Department of Health and Human Services, “health expenses doubled between 1996 and 2006, and are predicted to reach one-fourth of the gross domestic product by 2025”viii. As government officials and politicians struggle to find a solution to burgeoning costs of healthcare, engineers may offer cost-effective treatments and procedures. The National Institutes of Health states that genetic testing and treatment for genetic disorders costs around $5,000 per person, which leads to an estimated diagnostic and prognostic national cost of $2 billion for genetic disordersix. Three-parent IVF will contribute towards lowering this overall cost of treatment, especially for families suffering from mitochondrial disorders. Not only are maternal spindle transfers and pronuclear transfers financially beneficial for sufferers and their families, but they also provide relief from lifelong suffering and inconvenience.

With the rise of career-focused lifestyles, the window for conceiving a child becomes limited. The chances of genetic and chromosomal aberrations increase when women reach 40, leading to difficult decisions regarding planned parenthoodx. Three-parent IVF can provide the gateway into more involved preimplantation genetic diagnosis and treatment of any possible mitochondrial complications that arise from late planned parenthood. Through these advancements in genetics, women obtain greater control over their planned parenthood and may conceive at a later age without the risk of abnormalities. 

Ethical Concerns for Treating Mitochondrial Disorders 

Both maternal spindle transfer and pronuclear transfer have gained positive, widespread recognition and success rates for preventing mitochondrial disorders. However, opponents still consider them as genetic engineering. A survey done on one thousand people conducted by the Human Fertilisation and Embryology Authority, “over half of the public are ‘very’ or ‘fairly’ positive about mitochondrial donation,” while the rest are opposed to any type of genetic engineering and/or modification. First and foremost, opponents of genetic engineering state that three-parent IVF could be the “slippery slope towards allowing other techniques, such as nuclear genetic modification, which could be used to create ‘designer babies’”xi. However, the processes for treating mitochondrial disorders do not involve changing any of the genetic information, but rather involve the transfer of the genetic material to a new medium. Since DNA is being transferred, it does not affect the offspring in any physical or psychological way.

Other opponents of three-parent IVF state that there are truly three parents involved in the development of the offspring, which they claim “opposes the laws of nature”xii. 99.9% of genetic material within a cell is contained within the dense area of the nucleusxiii, while the other 0.1% of the genetic information is stored in the mitochondria, which have DNA of their own. The DNA contained in mitochondria, however, only serve to allow the mitochondria to function properly, and do not contribute to the physical and mental development of the offspring. Thus, the mitochondrial donor only contributes that 0.1%, which does not contribute to the baby’s physical appearance and development, thereby weakening the argument that three parents are involved in the development of the child. Evidently, mitochondrial donation procedures provide unprecedented relief for families of sufferers. It is important to note the distinction between genetic modification and genetic enhancement. Three-parent IVFs are genetic modifications which do not enhance the offspring at all, but rather offer a preventative approach to dealing with genetically inherited diseases and disorders. Neither procedure, in any way, results in a physically, mentally, or psychologically advantaged offspringxiv

Conclusion 

Three-parent IVF has seen great success in the UKxv, and can be the primary solution for lowered healthcare costs for many families in the United States as well. Increased responsibility should not be accompanied by even greater risks for women who wish to start a family later in life. Since egg cells age along with somatic cells, three-parent IVF eliminates the increased risk of genetic abnormality in children associated with conceiving at a later age. Even if a woman decides to have children later in life, she can be provided with a healthy, young egg. 

Genetic disorders are unique, in that they do not just affect the sufferer, but also potentially their progeny as well. For this reason, reprogenetics and preimplantation genetic diagnosis is in a strategic position to attack these diseases. Three-parent IVF is the first step in providing these families relief, and could be the necessary antecedent to further genetic testing to prevent other genetic maladies outside mitochondrial disordersxvi

Meta-Analysis

In a study conducted by Dr. Masahito Tachibana, 106 human oocytes (egg cells) were subjected to maternal spindle transfer. 52% had abnormal fertilization (using unipronuclear or tripronuclear zygotes instead of two-pronuclear zygotes that are normally used for in-vitro fertility) following the procedure, but 73% of all zygotes, including the abnormally fertilized, had continued development into blastocysts (slightly differentiated cells that arise from embryonic cells)xvii. Another study conducted by Dr. Lyndsey Craven subjected 80 zygotes to pronuclear transfer and 50% of the pronucleated zygotes underwent abnormal fertilization. 22.7% of the zygotes advanced to blastocysts. In both procedures, minimal retention of mitochondrial DNA was observed, with figures less than 1% for maternal spindle transfer and less than 2% for pronuclear transferxviii

Table 1

This table shows various statistics from clinical human trials of both the maternal spindle transfer procedure and the pronuclear transfer procedure.

Bibliography

(2014). “Mitochondrial donation: an introductory briefing note.” Human Fertilisation and Embryology Authority. (online government report). http://www.hfea.gov.uk/docs/2014-10-01_Mitochondrial_donation__an_introd...

A. Kuliev. (2003). “The role of preimplantation genetic diagnosis in women of advanced reproductive age.” Obstetrics and Gynecology. (online report). http://journals.lww.com/co-obgyn/Abstract/2003/06000/The_role_of_preimpl...

B. Hodes-Wertz. (2011). “Retrospective analysis of outcomes following transfer of previously cryopreserved oocytes, pronuclear zygotes and supernumerary blastocysts.” Reproductive BioMedicine Online (Reproductive Healthcare Limited). (online report). http://web.a.ebscohost.com/ehost/pdfviewer/pdfviewer?sid=fd5cfa9c-d9fb-4...

C. Lyndsey. (2010). “Pronuclear transfer in human embryos to prevent transmission of mitochondrial DNA disease.” Nature. (online report). http://search.ebscohost.com/login.aspx?direct=true&AuthType=ip,uid&db=ap...

H. Liu. (2015). “The In Vitro Development of Human Zygote Reconstructed by Pronuclear Transfer.” Fertility & Sterility. (online report). http://search.ebscohost.com/login.aspx?direct=true&AuthType=ip,uid&db=ap...

H. Smeets. (2013). “Preventing the transmission of mitochondrial DNA disorders: Selecting the good guys or kicking out the bad guys.” Reproductive BioMedicine Online (Elsevier Science). (online report). http://search.ebscohost.com/login.aspx?direct=true&AuthType=ip,uid&db=ap...

K. van Gool. (2012). “Understanding the costs of care for cystic fibrosis: an analysis by age and health state.” National Center for Biotechnology Information. (online report). http://www.ncbi.nlm.nih.gov/pubmed/23538187

Kim, Y.J., Lee, E.J., et. al. “Maternal Age-specific Rates of Fetal Chromosomal Abnormalities in Korean Pregnant Women of Advanced Maternal Age.” Obstetrics & Gynecology Science. Korean Society of Obstetrics and Gynecology; Korean Society of Contraception and Reproductive Health; Korean Society of Gynecologic Endocrinology; Korean Society of Gynecologic Endoscopy and Minimal Invasive Surgery; Korean Society of Maternal Fetal Medicine; Korean Society of Ultrasound in Obstetrics and Gynecology, May 2013. Web. 12 Nov. 2016.

R. Coco. (2013). “Reprogenetics: Preimplantational genetics diagnosis.” National Center for Biotechnology Information. (online report). http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3983589/

R. Ramanathan. (2012). “Translational Medicine: Taking Medicine from Bench to Bedside.” Pharma Magazine (Print Article). November/December 2012.

Tachibana, Masahito, et. al. “Towards Germline Gene Therapy of Inherited Mitochondrial Diseases.” Nature. U.S. National Library of Medicine, 31 Jan. 2013. Web. 12 Nov. 2016.

 Warren, Emma, MA, and Rob Anderson, PhD, MSc. “Cost-effectiveness of a School-based Tay-Sachs and Cystic Fibrosis Genetic Carrier Screening Program.” Genetics in Medicine 7.7 (2005): 484-94. Nature. American College of Medical Genetics. Web.

Endnotes

i Warren, Emma, MA, and Rob Anderson, PhD, MSc. "Cost-effectiveness of a School-based Tay-Sachs and Cystic Fibrosis Genetic Carrier Screening Program." Genetics in Medicine 7.7 (2005): 484-94. Nature. American College of Medical Genetics. Web.

ii B. Hodes-Wertz. (2011). “Retrospective analysis of outcomes following transfer of previously cryopreserved oocytes, pronuclear zygotes and supernumerary blastocysts.” Reproductive BioMedicine Online (Reproductive Healthcare Limited). (online report). http://web.a.ebscohost.com/ehost/pdfviewer/pdfviewer?sid=fd5cfa9c-d9fb-4...

iii C. Lyndsey. (2010). “Pronuclear transfer in human embryos to prevent transmission of mitochondrial DNA disease.” Nature. (online report). http://search.ebscohost.com/login.aspx?direct=true&AuthType=ip,uid&db=ap...

iv ibid

v Tachibana, Masahito, et. al. "Towards Germline Gene Therapy of Inherited Mitochondrial Diseases." Nature. U.S. National Library of Medicine, 31 Jan. 2013. Web. 12 Nov. 2016.

vi B. Hodes-Wertz. (2011). “Retrospective analysis of outcomes following transfer of previously cryopreserved oocytes, pronuclear zygotes and supernumerary blastocysts.” Reproductive BioMedicine Online (Reproductive Healthcare Limited). (online report). http://web.a.ebscohost.com/ehost/pdfviewer/pdfviewer?sid=fd5cfa9c-d9fb-4...

vii H. Liu. (2015). “The In Vitro Development of Human Zygote Reconstructed by Pronuclear Transfer.” Fertility & Sterility. (online report). http://search.ebscohost.com/login.aspx?direct=true&AuthType=ip,uid&db=ap...

viii ibid

ix R. Ramanathan. (2012). “Translational Medicine: Taking Medicine from Bench to Bedside.” Pharma Magazine (Print Article). November/December 2012.

x Kim, Y.J., Lee, E.J., et. al. "Maternal Age-specific Rates of Fetal Chromosomal Abnormalities in Korean Pregnant Women of Advanced Maternal Age." Obstetrics & Gynecology Science. Korean Society of Obstetrics and Gynecology; Korean Society of Contraception and Reproductive Health; Korean Society of Gynecologic Endocrinology; Korean Society of Gynecologic Endoscopy and Minimal Invasive Surgery; Korean Society of Maternal Fetal Medicine; Korean Society of Ultrasound in Obstetrics and Gynecology, May 2013. Web. 12 Nov. 2016.

xi H. Smeets. (2013). “Preventing the transmission of mitochondrial DNA disorders: Selecting the good guys or kicking out the bad guys.” Reproductive BioMedicine Online (Elsevier Science). (online report). http://search.ebscohost.com/login.aspx?direct=true&AuthType=ip,uid&db=ap...                            

xii ibid

xiii ibid

xiv ibid

xv ibid

xvi R. Coco. (2013). “Reprogenetics: Preimplantational genetics diagnosis.” National Center for Biotechnology Information. (online report). http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3983589/ 

xvii Tachibana, Masahito, et. al. "Towards Germline Gene Therapy of Inherited Mitochondrial Diseases." Nature. U.S. National Library of Medicine, 31 Jan. 2013. Web. 12 Nov. 2016.

xviii C. Lyndsey. (2010). “Pronuclear transfer in human embryos to prevent transmission of mitochondrial DNA disease.” Nature. (online report). http://search.ebscohost.com/login.aspx?direct=true&AuthType=ip,uid&db=ap...

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Volume 9, Fall 2016