The biology of infertility: research advances and clinical challenges Martin M Matzuk and Dolores J Lamb Departments of Pathology, Molecular and Cellular Biology, Molecular and Human Genetics, and Scott Department of Urology, Baylor College of Medicine, One Baylor Plaza, Houston, Texas 77030, USA Abstract Reproduction is essential for the survival of all mammals, and thousands of essential 'sex' genes are conserved through evolution. Basic research helps define these genes and the mechanisms responsible for the development, function, and regulation of the male and female reproductive systems. However, many infertile couples are still labeled with idiopathic infertility or given descriptive diagnoses that do not provide a cause for their defect. For individuals with a known etiology, effective cures are lacking, although their infertility is often bypassed with assisted reproductive technologies (ART), some accompanied by safety or ethical concerns. Progress in the field of reproduction has been realized in the 21st century with advances in understanding the regulation of fertility, with the production of over 400 mutant mouse models with a reproductive phenotype and the promise of regenerative gonadal stem cells. The past six years have witnessed a virtual explosion in the identification of gene mutations or polymorphisms that cause or are linked to human infertility. Translation of these findings to the clinic remains slow, as do new methods to diagnose and treat infertile couples. New approaches to contraception remain elusive. Nevertheless, the basic and clinical advances in the understanding of the molecular controls of reproduction are impressive and will ultimately improve patient care. The propagation of all vertebrate species requires the interaction of a sperm and an oocyte to form a zygote, the first step in the development of the embryo. The beginnings of the reproductive process are laid down weeks (in mice) to years (in humans) earlier during the development of the germline lineage in the embryo and the formation of the future gonads and genital tracts. Germ cells arise and propagate in an autocrine, paracrine, juxtracrine, and endocrine environment that includes factors within the gonads and beyond. It is obvious from mouse and human genetics and microarray technology that coordination of thousands of gene products throughout the body is necessary for reproductive success. Understanding the process is even more complicated than just knowing the functions of genes because of the discovery of thousands of small noncoding RNAs that have roles in mRNA stability, protein translation, protein modification, and protection of the germline. When these highly regulated processes go awry, infertility can occur. Defects in any step required for fertility will profoundly influence a couple's life plan and their vision together for a family. Although the development of ART has allowed otherwise hopelessly infertile couples to experience the joy of parenthood, these technologies also traverse the natural barriers preventing the transmission of genetic defects. Despite the increasing knowledge of the genetic causes of infertility, advances in theThe biology of infertility: research advances and clinical challenges Martin M Matzuk and Dolores J Lamb Departments of Pathology, Molecular and Cellular Biology, Molecular and Human Genetics, and Scott Department of Urology, Baylor College of Medicine, One Baylor Plaza, Houston, Texas 77030, USA Abstract Reproduction is essential for the survival of all mammals, and thousands of essential 'sex' genes are conserved through evolution. Basic research helps define these genes and the mechanisms responsible for the development, function, and regulation of the male and female reproductive systems. However, many infertile couples are still labeled with idiopathic infertility or given descriptive diagnoses that do not provide a cause for their defect. For individuals with a known etiology, effective cures are lacking, although their infertility is often bypassed with assisted reproductive technologies (ART), some accompanied by safety or ethical concerns. Progress in the field of reproduction has been realized in the 21st century with advances in understanding the regulation of fertility, with the production of over 400 mutant mouse models with a reproductive phenotype and the promise of regenerative gonadal stem cells. The past six years have witnessed a virtual explosion in the identification of gene mutations or polymorphisms that cause or are linked to human infertility. Translation of these findings to the clinic remains slow, as do new methods to diagnose and treat infertile couples. New approaches to contraception remain elusive. Nevertheless, the basic and clinical advances in the understanding of the molecular controls of reproduction are impressive and will ultimately improve patient care. The propagation of all vertebrate species requires the interaction of a sperm and an oocyte to form a zygote, the first step in the development of the embryo. The beginnings of the reproductive process are laid down weeks (in mice) to years (in humans) earlier during the development of the germline lineage in the embryo and the formation of the future gonads and genital tracts. Germ cells arise and propagate in an autocrine, paracrine, juxtracrine, and endocrine environment that includes factors within the gonads and beyond. It is obvious from mouse and human genetics and microarray technology that coordination of thousands of gene products throughout the body is necessary for reproductive success. Understanding the process is even more complicated than just knowing the functions of genes because of the discovery of thousands of small noncoding RNAs that have roles in mRNA stability, protein translation, protein modification, and protection of the germline. When these highly regulated processes go awry, infertility can occur. Defects in any step required for fertility will profoundly influence a couple's life plan and their vision together for a family. Although the development of ART has allowed otherwise hopelessly infertile couples to experience the joy of parenthood, these technologies also traverse the natural barriers preventing the transmission of genetic defects. Despite the increasing knowledge of the genetic causes of infertility, advances in the