title: Artificial gametes: a systematic review of biological progress towards clinical application.
abstract: BACKGROUND
  Recent progress in the formation of artificial gametes, i.e. gametes generated by manipulation of their progenitors or of somatic cells, has led to scientific and societal discussion about their use in medically assisted reproduction (MAR). Artificial gametes could potentially help infertile men and women but also post-menopausal women and gay couples conceive genetically related children. This systematic review aimed to provide insight in the progress of biological research towards clinical application of artificial gametes.
  
  
  METHODS
  The electronic database 'Medline/Pubmed' was systematically searched with medical subject heading (MesH) terms, and reference lists of eligible studies were hand searched. Studies in English between January 1970 and December 2013 were selected based on meeting a priori defined starting- and end-points of gamete development, including gamete formation, fertilization and the birth of offspring. For each biologically plausible method to form artificial gametes, data were extracted on the potential to generate artificial gametes that might be used to achieve fertilization and to result in the birth of offspring in animals and humans.
  
  
  RESULTS
  The systematic search yielded 2424 articles, and 70 studies were included after screening. In animals, artificial sperm and artificial oocytes generated from germline stem cells (GSCs), embryonic stem cells (ESCs) and induced pluripotent stem cells (iPSCs) have resulted in the birth of viable offspring. Also in animals, artificial sperm and artificial oocytes have been generated from somatic cells directly, i.e. without documentation of intermediate stages of stem- or germ cell development or (epi)genetic status. Finally, although the subsequent embryos showed hampered development, haploidization by transplantation of a somatic cell nucleus into an enucleated donor oocyte has led to fertilized artificial oocytes. In humans, artificial sperm has been generated from ESCs and iPSCs. Artificial human oocytes have been generated from GSCs, ESCs and somatic cells (without documentation of intermediate stages of stem- or germ cell development). Fertilization of a human artificial oocyte after haploidization by transplantation of a somatic cell nucleus into an enucleated donor oocyte was also reported. Normal developmental potential, epigenetic and genetic stability and birth of children has not been reported following the use of human artificial gametes. In animals, artificial oocytes from a male have been created and fertilized and artificial sperm from a female has been fertilized and has resulted in the birth of viable offspring. In humans, artificial sperm has been generated from female iPSCs. To date, no study has reported the birth of human offspring from artificial gametes.
  
  
  CONCLUSIONS
  Our systematic review of the literature indicated that in animals live births have already been achieved using artificial gametes of varying (cell type) sources. Although experimental biological research is progressing steadily towards future clinical application, data on functionality, safety and efficiency of (human) artificial gametes are still preliminary. Although defining artificial gametes by start- and end-points limited the number of included studies, the search resulted in a clear overview of the subject. Clinical use of artificial gametes would expand the treatment possibilities of MAR and would have implications for society. Before potential clinical use, the societal and ethical implications of artificial gametes should be reflected on.
authors.affiliation: Center for Reproductive Medicine, Women's and Children's Hospital, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands.
authors.forename: Saskia
authors.initials: S
authors.lastname: Hendriks
authors.affiliation: Center for Reproductive Medicine, Women's and Children's Hospital, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands Leuven University Fertility Centre, Leuven University Hospital, Leuven, Belgium.
authors.forename: Eline A F
authors.initials: EA
authors.lastname: Dancet
authors.affiliation: Center for Reproductive Medicine, Women's and Children's Hospital, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands.
authors.forename: Ans M M
authors.initials: AM
authors.lastname: van Pelt
authors.affiliation: Center for Reproductive Medicine, Women's and Children's Hospital, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands.
authors.forename: Geert
authors.initials: G
authors.lastname: Hamer
authors.affiliation: Center for Reproductive Medicine, Women's and Children's Hospital, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands s.repping@amc.uva.nl.
authors.forename: Sjoerd
authors.initials: S
authors.lastname: Repping
mesh_terms: D000818:Animals; D002454:Cell Differentiation; D002467:Cell Nucleus / Q000502:physiology; D053595:Embryonic Stem Cells / Q000166:cytology*; D005260:Female; D005306:Fertilization; D005818:Genetic Engineering / Q000379:methods*; D006801:Humans; D007246:Infertility / Q000628:therapy*; D008297:Male; D053652:Nuclear Transfer Techniques; D009865:Oocytes / Q000166:cytology* / Q000378:metabolism; D039904:Pluripotent Stem Cells / Q000166:cytology; D027724:Reproductive Techniques, Assisted; D013094:Spermatozoa / Q000166:cytology* / Q000378:metabolism; D014019:Tissue Donors
keywords: artificial gametes; assisted reproductive technologies; gametogenesis