MINIREVIEW SERIES FOR THE 50TH
VOLUME
Preface to minireviews
Innovations in assisted reproduction: a view of the future
Yasunori Yoshimura
Editor
Department of Obstetrics and Gynecology, School of Medicine, Keio University, Tokyo, Japan

It is now over 20 years since the birth of Louise
Brown and in the meanwhile there has been a dramaticincrease in the number of infertility clinics around theworld that can offer in vitro fertilization (IVF) andnewer, related assisted reproduction technologies. IVF
techniques have given embryologists the extraordinary
possibility of exploring the ﬁrst events which preside at
the beginning of a human life. There has been a gradualincrease in the success rates achieved using these techniques, but it is still necessary to make qualitative judgements about early embryos. The evaluation of embryo
viability in clinical IVF relies on morphological criteria
which are assessed by light microscopy. What should beconsidered normal and abnormal?
Blastomere number and size, cytoplasmic appearance, presence of fragments in the periviteline space,
and the cleavage rate in relation to the time frame ofdevelopment are the most non-invasive parameters toevaluate embryonic competence. However, what wedeﬁne as morphologically ‘abnormal’ may only represent different physiological aspects of oocyte and embryo development. Conversely, a ‘normal’ appearance
is not necessarily synonymous with viability. As a consequence, it is possible that the limited efﬁciency ofIVF techniques could be partially due to our poor ability
to identify a viable embryo.
Opportunities have now been opened to replace
human embryos at various stages into their mothers
in attempts to alleviate infertility. It is thus possible toplan the preimplantation diagnosis of genetic diseases
by excising a blastomere(s) at 4 cell to 8 cell stageembryos. Studies on outgrowths of embryonic cells fromblastocysts are also possible now. This would enable embryonic stem cells, or differentiating tissues, to be grownin vitro and used for study or, one day, for grafting into
sick adults.
The use of ovulation stimulation techniques to improve and simplify human IVF led to the recovery oflarge numbers of oocytes and consequently embryos. In
order to limit the risks of multiple pregnancies arisingfrom the transfer in utero of numerous embryos and to
avoid the wastage of supernumerary embryos, the development of embryo cryopreservation was initiated inhumans. Mammalian embryos have been successfully
frozen and stored since 1972. The human embryo
freezing spread rapidly in the world and became an indispensable extension of IVF, with the maintenance ofoptimized and simpliﬁed biological procedures.
Cryopreservation of immature oocytes, supposed tobe less sensitive to cryo-injury, could be an advantage
and could offer an opportunity to store the gametes ofyoung patients requiring anti-cancer therapy for whom
urgency of treatment may preclude the whole stimulation protocol used in mature oocyte collection. Numerous experimental studies on immature human oocytes
have been carried out according to the embryo freezing
procedure. Nevertheless, no advantage of immature
oocyte freezing could be drawn from these results, despite the birth of a normal female baby after cryopreservation of prophase I oocytes with subsequent in vitro
maturation. Improvements in the technique of oocytein vitro maturation should precede the extension of immature oocyte freezing to reach satisfactory results.
Intracytoplasmic sperm injection (ICSI) is a highly
effective therapeutic intervention used to assist fertilization with sperm from an infertile male, and its innovation offers a previously unavailable opportunity forcouples with male factor infertility to now produce
children. Its inception has revolutionized the management of male infertility. However, critics have suggested
that the use of ICSI for the treatment of male infertility
has the potential to negatively impact the genetic composition of the human population for future generations.
ICSI is a technique that bypasses the effective biologic
mechanisms of sperm selection that were set in place
during the evolution of the human reproductive process. The application of ICSI to human reproduction
has not been preceded by an extensive research trial inother mammals. Consequently, the human experience
with ICSI is the experimental record.

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The application of ICSI foregoes an understandingof the underlying etiology of the individual male’s infertility, which may be of a transmissible genetic basis.
The use of ICSI to alter the reproductive performanceof a male with infertility resulting from a speciﬁc genetic constitution or genotype changes the ﬁtness of hisgenotype. The application of ICSI in assisted reproductive technology provided the ability to dramatically
improve the ﬁtness of many mutant male genotypes andpotentially alter the genetic composition of a population. It is therefore essential to have an understandingof the genetic risks and possible consequences that areinherent when ICSI is used to assist fertilization in thepopulation of infertile males.
Genetic diagnostic testing of infertile males should
be strongly recommended when there is a signiﬁcantrisk of transmitting identiﬁable chromosomal abnormalities or genetic mutations to the conceptus that willseverely impact its future health and well being. All
couples in which a male has been identiﬁed as having
a chromosomal anomaly or a clinically signiﬁcant genetic mutation should be referred to a certiﬁed genetics
counselor and/or a clinical or prenatal geneticist forpreconception counseling and possible prenatal diagnostic evaluation.
With the Human Genome Project now almost com-Yasunori Y: Preface to minireviews

pleted, micro-array technology offers the potential toopen up a whole new vista in the ﬁeld of human reproduction. In the next 10–20 years, we will be able toscreen each human embryo simultaneously for all numerical chromosomal abnormalities and many genetic
diseases. In addition, genotyping micro-arrays will permit allele determination at hundreds of different locifrom the human genome. Applied to expression analysis, this approach will facilitate the measurement ofRNA levels for the complete set of transcripts of thehuman embryo. Arrays offer the ﬁrst great hope forsuch global views in reproduction by providing a systematic way to survey DNA and RNA variation. It is
still too early to predict what the ultimate impact of
micro-arrays (or similar but even more complex technology) will be on our understanding in clinical embryology.
DNA micro-arrays are tiny chips made of siliconglass a couple of centimetres across, dotted with thousands of DNA snippets of oligonucleotides from either
the coding region of a gene or its variants associatedwith a particular disease. The patterns of expression
will offer clues to the developmental potential of an individual oocyte or embryo. The analysis of a single cellin a cleavage stage embryo may eventually reveal thegenetic predisposition of each individual embryo.