Current advances in artificial gametes

The birth of Louise Brown, the first IVF baby, in 1978 marked a breakthrough in infertility treatment. In recent decades, several important new techniques have been introduced. One limiting factor has been the requirement to use reproductive cells (gametes) for fertilization and for embryonic development. Somatic cell nuclear transfer (cloning) has been successful in mammals, opening a potential new approach for the treatment of human infertility. In addition, nuclear transfer to achieve embryo development starting from somatic cells instead of gametes, and the creation of artificial oocytes/spermatozoa has been attempted. The present paper reviews the various alternative approaches to haploidization of somatic cells. It has been observed that chromosome segregation (of the donor somatic nucleus) may take place; however, this process is largely random, thus leading to major cytogenetic abnormalities. An alternative approach is related to stem cell technology, to be further explored in the future. Culture conditions may be adjusted so that the totipotent embryonic stem cells will differentiate to specific gametes, sperm cells or egg cells. Injecting spermatozoa produced in this manner into recipient oocytes has led to pronuclear formation and early cleavage stages in some embryos. Finally, the birth of parthenogenetic mice indicates that some of these epigenetic problems can be overcome, and that some of the embryos may survive to birth.     

Mirror gametes donation

Candidate recipients of donor gametes have a moral obligation to make a contribution to the system from which they benefit by reciprocating. They can do this as a couple when the partner of the person who has no usable gametes donates and receives the mirror gametes in return. In an indirect exchange system, the couple receives bonus points for their donation so that their waiting time for the gametes is reduced or even fully canceled. A system of strict reciprocity is rejected as unfair because it excludes categories of people from access to donor gametes. Also candidate recipients who for medical or psychological reasons do not qualify as donors should have access to donor gametes on the basis of points collected on other criteria. Not only contribution but also need (the wish to have a child) should be taken into account when allocating donor gametes. The mirror exchange system can alleviate the shortage of both sperm and egg donation in an ethically acceptable way.     

Mirror gametes donation

Candidate recipients of donor gametes have a moral obligation to make a contribution to the system from which they benefit by reciprocating. They can do this as a couple when the partner of the person who has no usable gametes donates and receives the mirror gametes in return. In an indirect exchange system, the couple receives bonus points for their donation so that their waiting time for the gametes is reduced or even fully canceled. A system of strict reciprocity is rejected as unfair because it excludes categories of people from access to donor gametes. Also candidate recipients who for medical or psychological reasons do not qualify as donors should have access to donor gametes on the basis of points collected on other criteria. Not only contribution but also need (the wish to have a child) should be taken into account when allocating donor gametes. The mirror exchange system can alleviate the shortage of both sperm and egg donation in an ethically acceptable way.     

Genetics of gametes and embryos

Chromosome analysis of oocytes, sperm and embryos has mainly relied on fluorescent in situ hybridisation (FISH) and karyotyping. FISH studies have been performed on sperm from fertile and infertile men as well as men carrying known chromosomal translocations. Molecular DNA analyses has aided in the identification and treatment of men with Y chromosome deletions. In oocytes FISH and karyotyping have identified non-disjunction of univalents and predivision of chromatids. Analysis of the chromosomes from human embryos has shown that a high proportion of embryos are mosaic or chaotic, in addition to embryos beings uniformly and abnormal. FISH and PCR have also been used clinically for preimplantation genetic diagnosis (PGD). For patients at risk of transmitting a specific genetic or chromosomal abnormality, 1-2 blastomeres are biopsied from embryos and specific genes or chromosomes analysed. Normal embryos are then transferred to the uterus.     

Disclosure of medical errors involving gametes and embryos

Medical providers have an ethical duty to immediately disclose clinical errors involving gametes or embryos; clinics should have written policies in place for reducing and disclosing errors. This document was reviewed and affirmed in 2011 and replaces the earlier document of the same name.     

Immunogenesis of preeclampsia: lessons from donor gametes

Background: Preeclampsia remains an important complication of pregnancy. It is associated with mortality and morbidity for both maternal and fetal/newborn patients. Although major inroads have been made in understanding the pathophysiology of preeclampsia in recent decades, the initial primary cause of its occurrence in some women and not others has escaped clarification.

Review: There have been a number of clinical clues pointing to an immune genesis of this disease, including most recently the use of donor gametes in assisted reproductive technology (ART). Despite a number of confounding variables, most studies investigating the addition of donor ova to the ART environment point in the direction of an immune genesis due to the burden of an increasingly foreign fetal allograft on the maternal host. A review of a selection of these studies and a contemporary review of our own Maternal Fetal Medicine practice observations in this regard was completed.

Conclusions: This retrospective evidence suggests a highly likely association. A more basic understanding of the immune interactions at the maternal-fetal interface is required before a final solution to this problem will be at hand and targeted remedies can be formulated.     

Ethical dilemmas arising from the cryopreservation of gametes

An Ethics &; Policy Workshop was held with 20 invited UK stakeholders to consider whether embryo donors should be able to restrict the future use of human embryonic stem cells (hESCs) created from their embryos. Participants cited tensions between pure altruism and a more reciprocal basis for donation; and between basic research (in which genetic material would never form part of another living being) and treatment applications. Two restriction models were suggested to acknowledge specific ethical issues raised by hESCs' use in research and treatments: (1) a two tier system: hESCs with unrestricted consent could go to the UK Stem Cell Bank; those with restricted consent could be used in individual labs which could guarantee to honour the restrictions, and Bank deposit would not be required. (2) a three category system: restrictions could include (i) basic hESC research; (ii) hESC research and treatment; no gamete derivation (iii) ‘unrestricted’ hESC research and treatment.     

Klinefelter syndrome: spermatogenesis and quality of gametes

Klinefelter syndrome is defined by the presence of a supernumerary X chromosome in a phenotypic male. It is the most frequent gonosomic anomaly in infertile men with an incidence of 0.1 to 0.2% in newborn males. The presence of an additional X chromosome induces spermatogenic failure but when gametes are present, they are usually normal. The risk of transmission of the chromosomal anomaly remains low. In the literature, only one 47,XXY foetus resulting from more than a hundred births from fathers with Klinefelter syndrome, has been reported. One can estimate, that a TESE performed in half of the patients with non-mosaic 47,XXY will be positive and may enable IVF/ICSI to be achieved.     

Micromanipulation of gametes and pre-implantation mammalian embryos--a review

With the successful management of the in vitro fertilization and embryo transfer in humans and in several mammalians it became possible to introduce further methods of the cellbiology in the practice. One complex in this connection is hereby shown to be the micromanipulation on gametes and on preimplantative embryos. With this technique the way was opened for some procedures which are known as microfertilization, transplantation of the nucleus and gene transfer somatic gene therapy. With these experiments a broad field of possibilities would be opened although about these can be only speculated.     

Delivered by direct intrauterine transfer of gametes]

A nurse, 27, primary sterility for 5 years with normal pelvic findings. Hysterosalpingogram showed right tube not visualized, and impatent, left tube with slight enlargement at ampulla. Her last menstrual period was September 5, 1991. Ovaries hyperstimulated by clomiphene, HMG and hCG, and 8 ova taken through vaginal aspiration under B scanning on September 19, 1991. Ova and washed sperms were directly introduced into uterine cavity simultaneously. It turned out to be a successful clinical pregnancy, carried on smoothly up to 36(+1) weeks. She spontaneously delivered a healthy male infant weight 2250 grams on May 15, 1992.     

Filiation in assisted reproduction with donor gametes

Donor-assisted reproduction entails a definitive separation between biological and social filiation. In ovocyte donation, the dissociation remains partial, only genetic, because the pregnancy maintains a biological bond. On the contrary, in sperm donation, the break-off is complete. Should the circumstances of his/her conception be revealed to the child? Despite a long practice of artificial insemination by donor (AID) the issue is still a matter of controversy. The majority of couples undergoing AID prefer maintaining the secret. But this attitude goes against the right of the child to be aware of his/her origin     

Embryonic stem cells as a potential source of gametes

Embryonic stem cells (ESCs) have a remarkable capacity for pluripotency; that is, they are capable of differentiating into all types of cell lineages. Recent studies have reported that successful differentiation of mouse ESCs into primordial germ cells (PGCs) as well as into mature male and female gametes can be achieved in vitro and in vivo. In addition, human ESCs can be differentiated into PGCs. The differentiation of ESCs into germ cells of various stages appears to be a spontaneous and quick process, probably due to the nature of ESCs themselves and the microenvironment of the culture conditions that favor this process. Although the functionality of these ESC-derived gametes remains to be established, derivation of both male and female gametes from ESCs raises the possibility of using these gametes to gain a better understanding of basic reproductive biology and, in particular, in conjunction with nuclear transfer technology, to extend the potential for therapeutic cloning and the treatment for infertility. We review the current knowledge on the potential of ESCs to differentiate into both male and female gametes.