In the field of germline development in amniote vertebrates, primordial germ cell (PGC) specification in birds and reptiles remains controversial. Avians are believed to adopt a predetermination or maternal specification mode of PGC formation, contrary to an inductive mode employed by mammals and, supposedly, reptiles. Here, we revisit and review some key aspects of PGC development that channelled the current subdivision, and challenge the position of birds and reptiles as well as the ‘binary’ evolutionary model of PGC (...) development in vertebrates. We propose an alternative view on PGC specification where germ plasm plays a role in laying the foundation for the formation of PGC precursors (pPGC), but not necessarily of PGCs. Moreover, inductive mechanisms may be necessary for the transition from pPGCs to PGCs. Within this framework, the implementation of data from birds and reptiles could provide new insights on the evolution of PGC specification in amniotes. (shrink)

Like most bilaterian animals, the annelid Platynereis dumerilii generates the majority of its body axis in an anterior to posterior temporal progression with new segments added sequentially. This process relies on a posterior subterminal proliferative body region, known as the "segment addition zone" (SAZ). We explored some of the molecular and cellular aspects of posterior elongation in Platynereis, in particular to test the hypothesis that the SAZ contains a specific set of stem cells dedicated to posterior elongation.We cloned and characterized (...) the developmental expression patterns of orthologs of 17 genes known to be involved in the formation, behavior, or maintenance of stem cells in other metazoan models. These genes encode RNA-binding proteins(e.g., tudor, musashi, pumilio) or transcription factors(e.g., myc, id, runx) widely conserved in eumetazoans. Most of these genes are expressed both in the migrating primordial germ cells and in overlapping ring-like patterns in the SAZ, similar to some previously analyzed genes(piwi, vasa). The SAZ patterns are coincident with the expression of proliferation markers cyclin B and PCNA. EdU pulse and chase experiments suggest that new segments are produced through many rounds of divisions from small populations of teloblast-like posterior stem cells. The shared molecular signature between primordial germ cells and posterior stem cells in Platynereis thus corresponds to an ancestral "stemness" program. (shrink)

The mode and timing of germ-cell specification has been studied in diverse organisms, however, the molecular mechanism regulating germ-cell-fate determination remains to be elucidated. In some model organisms, maternal germ-cell determinants play a key role. In mouse embryos, some germ-line-specific gene products exist as maternal molecules and play critical roles in a pluripotential cell population at preimplantation stages. From those cells, primordial germ cells (PGCs) are specified by extracellular signaling mediated (...) by tissue, as well as cell–cell interaction during gastrulation. Thus, establishment of germ-cell lineage in mammalian embryos appears to be regulated by a multistep process, including formation and maintenance of a pluripotential cell population, as well as specification of PGCs. PGCs can be generated from pluripotential embryonic stem (ES) cells in a simple monolayer culture in which tissue interaction does not occur. This raises the possibility that ES cells, as well as, possibly, pluripotential cells in preimplantation embryos, are more closely related to the PGC precursors than pluripotential cells after implantation. BioEssays 27:136–143, 2005. © 2005 Wiley Periodicals, Inc. (shrink)

In gonad‐bearing animals gametogenesis can be divided into three main phases. During embryonic development the primordial gem cells move towards the gonadal primordia. A long, intra‐gonadal phase follows during which the germ cells grow and differentiate. Mature germ cells are finally released from the gonads and brought to the exterior. Thus, germ cells are successively motile, non‐motile and motile again. This complex life history is given here a simple evolutionary interpretation. The basic assumption is that primitive (...) Metazoa already had germ cells, but no gonads to harbour them. Higher animals acquired gonads, which sequestered the germ cells, thus creating the temporary confinement experienced by germ cells in most present‐day Metazoa. This evolutionalry scheme may explain why several steps of germ cell differentation are totally or partially independent of the gonads. These steps presumably existed in primitive, gonad‐free Metazoa, and conserved their autonomy in higher animals. (shrink)

Sexually reproducing metazoans establish a cell lineage during development that is ultimately dedicated to gamete production. Work in a variety of animals suggests that a group of conserved molecular determinants act in this germ line maintenance and function. The most universal of these genes are Vasa and Vasa‐like DEAD‐box RNA helicase genes. However, recent evidence indicates that Vasa genes also function in other cell types, distinct from the germ line. Here we evaluate our current understanding of (...) Vasa function and its regulation during development, addressing Vasa's emerging role in multipotent cells. We also explore the evolutionary diversification of the N‐terminal domain of this gene and how this impacts the association of Vasa with nuage‐like perinuclear structures. (shrink)

Development of the nematode Caenorhabditis elegans has been described completely on a cell‐by‐cell basis. In an invariant pattern five somatic founder cells and the primordial germ cell are generated within the first hour after the onset of cleavage. Using a laser microbeam for manipulation of individual blastomers several aspects of early embryogenesis have been investigated, including the expression of cellular polarity, the localization of lineage‐specific cleavage potential, the necessity for early cell–cell interaction, and (...) the control of differential cell‐cycle timing. The experiments demonstrate the central importance of a correct partitioning of cytoplasmic components during early embryogenesis and suggest a stepwise, binary segregation mechanism associated with the unequal cleavages in the germline. (shrink)

X chromosome centromeric drive may explain the prevalence of polycystic ovary syndrome and contribute to oocyte aneuploidy, menopause, and other conditions. The mammalian X chromosome may be vulnerable to meiotic drive because of X inactivation in the female germline. The human X pericentromeric region contains genes potentially involved in meiotic mechanisms, including multiple SPIN1 and ZXDC paralogs. This is consistent with a multigenic drive system comprising differential modification of the active and inactive X chromosome centromeres in female primordial (...) class='Hi'>germ cells and preferential segregation of the previously inactivated X chromosome centromere to the polar body at meiosis I. The drive mechanism may explain differences in X chromosome regulation in the female germlines of the human and mouse and, based on the functions encoded by the genes in the region, the transmission of X pericentromeric genetic or epigenetic variants to progeny could contribute to preeclampsia, autism, and differences in sexual differentiation. (shrink)

Germ cells are cross-roads of development and evolution. They define the origin of every new generation and, at the same time, represent the biological end-product of any mature organism. Germ cells are endowed with the following capacities: to store a self-descriptive program, to accumulate a protein-synthesizing machinery, and to incorporate enough nourishment to sustain embryonic development. To accomplish this goal, germ cells do not simply unfold a pre-determined program or realize a sole instructive role. On the contrary, (...) due to the complexity of their cytoarchitecture and the nature of the soma-to-germ interactions, they are heavily involved in processes of sign recognition and meaningful tissue exploration. At each stage of their inward migration, germ plasma membranes act as semiotic interfaces allowing cells to interact with the surrounding extracellular milieu and experience the compatibility of selected developmental sequences. The question of which signaling pathways are activated at each developmental stage does not result from a strictly predetermined program instructing germ cell stemness. Rather, each developmental sequence is an open-ended semiotic relationship explored and gradually defined during evolution by the context-dependency of specific cell-to-cell interactions. In this way, any structural and functional novelty that has emerged in the course of germ cell interactions may be interpreted as an exaptation fixed in the species genome in response to specific environmental constraints. (shrink)

In lieu of an abstract, here is a brief excerpt of the content:Kennedy Institute of Ethics Journal 12.1 (2002) 95-102 [Access article in PDF] Bioethics Inside the Beltway Some Initial Reflections on NBAC Eric M. Meslin and Harold T. Shapiro On 3 October 2001, Executive Order 12975 expired, and with it so too did the National Bioethics Advisory Commission (NBAC). Established by President Bill Clinton in 1995, NBAC was the fifth national committee since 1974 created to advise the U.S. government (...) on bioethics policy. In the long political tradition in this country that national bioethics policy advice should use temporary rather than permanent bodies, NBAC followed in the footsteps of the National Commission for the Protection of Human Subjects of Biomedical and Behavioral Research (1974-78); the President's Commission for the Study of Ethical Problems in Medicine and Biomedical and Behavioral Research (1980-83); the Ethics Advisory Board (1978-80); and the Biomedical Ethics Advisory Committee (1988-89). Arguably, other distinguished panels could lay claim to recognition as a "national bioethics committee" including the Advisory Committee on Human Radiation Experiments (ACHRE) (1994-95); the Fetal Tissue Transplantation Research Panel (1988); the Human Embryo Research Panel (1994); and the National Institutes of Health (NIH) Recombinant DNA Advisory Committee (RAC), which continues to function.These committees and commissions form a kind of a continuum, albeit occasionally interrupted by periods during which no such bodies existed. Each arose from a particular confluence of events and circumstances. NBAC was no different; its history can be traced both to a series of discussions within the White House Office of Science and Technology Policy beginning in 1993 (NBAC 1998a, p. 3), and to a specific recommendation from ACHRE that called for a national committee to address ethical issues in human subjects research (ACHRE 1995, p. 817). Nbac's Impact In his useful comparison of the accomplishments of the National Commission and the President's Commission, Brad Gray concluded that seven lessons were learned, the sixth of which was that "nothing substitutes for having a perceptible impact on either policy or practice" (Gray 1995, p. 304). Assessing NBAC's [End Page 95] impact on "policy or practice" is difficult, particularly given the fact that it so recently completed its work. More time may be needed before a full assessment can be undertaken of the impact of its six reports (and their total of 120 recommendations). Instead, in this essay we offer some reflections on NBAC's initial impact, using some specific examples of how bioethics gets done Inside the Beltway. Eliciting Reaction If immediate reaction by the White House is any measure of impact, then Cloning Human Beings (NBAC 1997) had a significant one. The day after he received this report in a Rose Garden ceremony, President Clinton submitted a bill to Congress that would have extended the moratorium on federal funding to create a child using somatic cell nuclear transfer. This bill never passed, nor has any other bill emerged that has enjoyed the support of the House and the Senate. Five states have enacted legislation to date, but these vary in their permissibility from bans on all forms of cloning to bans similar to the one proposed by NBAC, which recommended a time-limited prohibition only on somatic cell transfer to create a child (reproductive cloning).If the Cloning report elicited speedy action from the White House, this paled in comparison to the reaction that led to and, in turn, was created by Ethical Issues in Human Stem Cell Research (NBAC 1999a). Those who believe that government moves slowly need only be reminded of the events of 8-14 November 1998 (and, as we shall mention below, the further events of 14 July 1999). Some will recall that early in the second week of November 1998, James Thomson and his colleagues published in Nature and John Gearhart and his colleagues published in the Proceedings of the National Academy of Sciences that they had isolated and cultured human primordial stem cells and germ cells respectively. Within days of these remarkable reports, Advanced Cell Technology (ACT) announced via an article written by Nicholas Wade in the... (shrink)

Germ cell segregation and gamete production are developmental problems that all sexually reproducing species must solve in order to survive. Many people are familiar with the complex social structures of some insect species, where specialised castes of adult insects perform specific tasks, one of which is usually to guard the sexually reproductive queen. The parasitic wasp Copidosoma floridanum adds another level of complexity to the caste system: a fertilised egg produces both sterile, short‐lived “soldier” larvae and “reproductive” larvae (...) that complete metamorphosis to produce sexually reproductive adults. How two morphologically and functionally distinct larval castes are produced by genetically identical groups of cells developing under the same environmental conditions is a baffling problem. A recent paper suggests that differential germ cell segregation during embryogenesis may be an event both necessary and sufficient for caste determination.1 BioEssays 26:1263–1267, 2004. © 2004 Wiley Periodicals, Inc. (shrink)

Acute starvation can have long-term consequences that are mediated through epigenetic change. Some of these changes are affected by the activity of AMP-activated protein kinase, a master regulator of cellular energy homeostasis. In Caenorhabditis elegans, the absence of AMPK during a period of starvation in an early larval stage results in developmental defects following their recovery on food, while many of them become sterile. Moreover, the loss of AMPK during this quiescent period results in transgenerational phenotypes that can become progressively (...) worse with each successive generation. Our recent data describe a chromatin-based mechanism of how AMPK mediates adjustment to acute starvation in the germ cells, however, the heritable aspect of this AMPK mutant phenotype remains unresolved. Here, we explore how AMPK might affect this process and speculate how the initial transcription that occurs in the germ cells may adversely affect subsequent germline gene expression and/or genomic integrity. AMPK protects germ cell integrity during acute starvation by blocking inappropriate transcription. How these aberrant transcripts cause transgenerational defects is unclear. AMPK likely regulates germline integrity at multiple levels through several targets. The authors speculate here how AMPK disruption during starvation could result in the observed defects seen at each generation. (shrink)

Plant reproduction is vital for species survival, and is also central to the production of food for human consumption. Seeds result from the successful fertilization of male and female gametes, but our understanding of the development, differentiation of gamete lineages and fertilization processes in higher plants is limited. Germ cells in animals diverge from somatic cells early in embryo development, whereas plants have distinct vegetative and reproductive phases in which gametes are formed from somatic cells after the plant has (...) made the transition to flowering and the formation of the reproductive organs. Recently, novel insights into the molecular mechanisms underlying male germ‐line initiation and male gamete development in plants have been obtained. Transcriptional repression of male germ‐line genes in non‐male germ‐line cells have been identified as a key mechanism for spatial and temporal control of male germ‐line development. This review focuses on molecular events controlling male germ‐line development especially, on the nature and regulation of gene expression programs operating in male gametes of flowering plants. BioEssays 29:1124–1132, 2007. © 2007 Wiley Periodicals, Inc. (shrink)

Sex determination in the germ line may either rely on cell‐autonomous genetic information, or it may be imposed during development by inductive somatic signals. In Drosophila, both mechanisms contribute to ensure that germ cells are oogenic when differentiating in females and spermatogenic when differentiating in males. Some of the genes that are involved in germ line sex determination have been identified. In other species, including vertebrates, inductive signals are commonly used to determine the sex of (...) class='Hi'>germ cells. (shrink)

Many strands of research by different groups, starting from teratocarcinomas in the laboratory mouse, later moving the corresponding human tumors, contributed to the isolation and description of human pluripotent stem cells (PSCs). In this review, I highlight the contributions from my own research, particularly at the Wistar Institute during the 1980s, when with my colleagues we characterized one of the first clonal lines of pluripotent human embryonal carcinoma (EC) cells, the stem cells of teratocarcinomas, and identified key features including (...) class='Hi'>cell surface antigen markers that have since found a place in the study and exploitation of human PSC. Much of this research depended upon close teamwork with colleagues, many in other laboratories, who contributed different expertise and experience. It was also often driven by circumstance and chance rather than pursuit of a grand design. (shrink)

Egg or sperm? The mechanism of sexual fate decision in germ cells has been a long‐standing issue in biology. A recent analysis identified foxl3 as a gene that determines the sexual fate decision of germ cells in the teleost fish, medaka. foxl3/Foxl3 acts in female germline stem cells to repress commitment into male fate (spermatogenesis), indicating that the presence of mitotic germ cells in the female is critical for continuous sexual fate decision of germ cells in (...) medaka gonads. Interestingly, foxl3 is found in most vertebrate genomes except for mammals. This provides the interesting possibility that the sexual fate of germ cells in mammals is determined in a different way compared to foxl3‐possessing vertebrates. Considering the fact that germline stem cells are the cells where foxl3 begins to express and sexual fate decision initiates and mammalian ovary does not have typical germline stem cells, the mechanism in mammals may have been co‐evolved with germline stem cell loss in mammalian ovary. (shrink)

The haploid male germ cell differentiation program controls essential steps of male gametogenesis and relies partly on a significant number of sex chromosome‐linked genes. These genes need to escape chromosome‐wide transcriptional repression of sex chromosomes, which occurs during meiosis and is largely maintained in post‐meiotic cells. A newly discovered histone lysine modification, crotonylation (Kcr), marks X/Y‐linked genes that are active in post‐meiotic male germ cells. Histone Kcr, by conferring resistance to transcriptional repressors, could be a dominant element (...) in maintaining these genes active in the globally repressive environment of haploid cell sex chromosomes. Furthermore, the same mark was found associated with post‐meiotically activated genes on autosomes. Histone Kcr therefore appears to be an indicator of the male haploid cell gene expression program and a notable element of genome programming in the post‐meiotic phases of spermatogenesis. (shrink)

Recent mutagenesis studies have demonstrated that the chemotherapeutic agent, chlorambucll (CHL), is highly mutagenic in male germ cells of the mouse. Post‐melotic germ cells, and especially early spermatids, are the most sensitive to the cytotoxic and mutagenic effects of this agent. Genetic, cytogenetic and molecular analyses of many induced mutations have shown that, in these germ‐cell stages, CHL induces predominantly chromosomal rearrangements (deletions and translocations), and mutation‐rate studies show that, in terms of tolerated doses, CHL is (...) perhaps five to ten times more efficient in inducing rearrangements than is radiation exposure. Appropriate breeding protocols, along with knowledge of the advantages and limitations associated with the use of CHL, can be used to expand the current resource of chromosomal rearrangements in the mouse and to provide new phenotype‐associated mutations amenable to positional‐cloning techniques. The analysis of CHL‐induced mutations has also contributed to understanding the factors that affect the yield and nature of chemically induced germline mutations in mammals. (shrink)

From stem cells to oocyte, Drosophila germ cells undergo a short, defined lineage. Molecular genetic analyses of a collection of female sterile mutations have indicated that a germ cell‐specific organelle called the fusome has a central role at several steps in this lineage. The fusome grows from a prominent spherical organelle to an elongated and branched structure that connects all mitotic sisters in a germ cell syncytium. The organelle is assembled from proteins normally found in (...) the membrane skeleton and, additionally, contains an extensive membranous reticulum, the probable product of differentiation‐dependent vesicle trafficking. This review briefly summarizes a current view of the processes that drive germ cell differentiation, particularly the various roles that the fusome might play in regulating the developmental events. Future efforts will consider to what extent an organelle assembly‐dependent model for differentiation is heuristic and whether the Drosophila fusome represents a homolog of a similar organelle in vertebrate lymphocytes. (shrink)

It is now clear that two prominent nuclear domains, interchromatin granule clusters (IGCs) and Cajal bodies (CBs), contribute to the highly ordered organization of the extrachromosomal space of the cell nucleus. These functional domains represent structurally stable but highly dynamic nuclear organelles enriched in factors that are required for different nuclear activities, especially RNA biogenesis. IGCs are considered to be the main sites for storage, assembly, and/or recycling of the essential spliceosome components. CBs are involved in the biogenesis of (...) several classes of small RNPs as well as the modification of newly assembled small nuclear RNA. We have summarized data on the molecular composition, structure, and functional roles of IGCs and CBs in the nuclei of mammalian somatic cells and oocytes of some animals with a special focus on insects. We have focused on similarities and differences between the IGCs and CBs of oocytes and the well‐studied CBs and IGCs of cultured mammalian somatic cells. We have shown the heterogeneous character of oocyte IGCs and CBs, both in structure and molecular content. We have also demonstrated the unique capacity of oocytes to form close structural interactions between IGC and CB components. We proposed to consider these joint structures as integrated entities, sharing the features of both IGCs and CBs. (shrink)

The teratogenic effect of ethanol on human and animal embryos is now well documented. Recent studies have clearly demonstrated that ethanol and related spindle‐acting agents may additionally interfere with normal meiotic chromosome segregation during oocyte maturation, leading to the production of aneuploid embryos. The mode of action, and potential hazard posed by these agents is considered.

Sex chromosomes are advantageous to mammals, allowing them to adopt a genetic rather than environmental sex determination system. However, sex chromosome evolution also carries a burden, because it results in an imbalance in gene dosage between females (XX) and males (XY). This imbalance is resolved by X dosage compensation, which comprises both X chromosome inactivation and X chromosome upregulation. X dosage compensation has been well characterized in the soma, but not in the germ line. Germ cells face a (...) special challenge, because genome wide reprogramming erases epigenetic marks responsible for maintaining the X dosage compensated state. Here we explain how evolution has influenced the gene content and germ line specialization of the mammalian sex chromosomes. We discuss new research uncovering unusual X dosage compensation states in germ cells, which we postulate influence sexual dimorphisms in germ line development and cause infertility in individuals with sex chromosome aneuploidy. (shrink)

Somatic cell gene therapy has yielded promising results. If germ cell gene therapy can be developed, the promise is even greater: hundreds of genetic diseases might be virtually eliminated. But some claim the procedure is morally unacceptable. We thoroughly and sympathetically examine several possible reasons for this claim but find them inadequate. There is no moral reason, then, not to develop and employ germ-line gene therapy. Taking the offensive, we argue next that medicine has a prima (...) facie moral obligation to do so. (shrink)

Human induced pluripotent stem cells can be obtained from somatic cells, and their derivation does not require destruction of embryos, thus avoiding ethical problems arising from the destruction of human embryos. This type of stem cell may provide an important tool for stem cell therapy, but it also results in some ethical concerns. It is likely that abnormal reprogramming occurs in the induction of human induced pluripotent stem cells, and that the stem cells generate tumors in the process (...) of stem cell therapy. Human induced pluripotent stem cells should not be used to clone human beings, to produce human germ cells, nor to make human embryos. Informed consent should be obtained from patients in stem cell therapy. (shrink)

In 1982, the President's Commission produced its report on human gene therapy. One of that report's recommendations was to expand the Recombinant DNA Advisory Committee to the National Institutes of Health to include a subcommittee on human gene therapy. In 1984, the Human Gene Therapy Subcommittee was established, and in 1989 it produced a document—“Points to Consider for Protocols for the Transfer of Recombinant DNA into Human Subjects”—that stated the RAC's position on what sorts of protocols it would approve.In assessing (...) the impact of the President's Commission report, Alexander Capron wrote,[t]he line [the report] drew between somatic cell and germ-line therapies has shaped subsequent discussions and policy formulation. Its conclusion … that somatic cell therapy resembles medical treatment is the basic premise of the RAC subcommittee's “Points to Consider,” while the Commission's view that ethical as well as technical barriers preclude present attempts to alter germ cells continues to be generally accepted by scientists and nonscientists alike. (shrink)

Literature on maternal exposures and the risk of epigenetic changes or diseases in the offspring is growing. Paternal contributions are often not considered. However, some animal and epidemiologic studies on various contaminants, nutrition, and lifestyle‐related conditions suggest a paternal influence on the offspring's future health. The phenotypic outcomes may have been attributed to DNA damage or mutations, but increasing evidence shows that the inheritance of environmentally induced functional changes of the genome, and related disorders, are (also) driven by epigenetic components. (...) In this essay we suggest the existence of epigenetic windows of susceptibility to environmental insults during sperm development. Changes in DNA methylation, histone modification, and non‐coding RNAs are viable mechanistic candidates for a non‐genetic transfer of paternal environmental information, from maturing germ cell to zygote. Inclusion of paternal factors in future research will ultimately improve the understanding of transgenerational epigenetic plasticity and health‐related effects in future generations. (shrink)

Development and homeostasis of the haematopoietic system is dependent upon stem cells that have the unique ability to both self‐renew and to differentiate in all cell lineages of the blood. The crucial decision between haematopoietic stem cell (HSC) self‐renewal and differentiation must be tightly controlled. Ultimately, this choice is regulated by the integration of intrinsic signals together with extrinsic cues provided by an exclusive microenvironment, the so‐called haematopoietic niche. Although the haematopoietic system of vertebrates has been studied extensively (...) for many decades, the specification of the HSC niche and its signals involved are poorly understood. Much of our current knowledge of how niches regulate long‐term maintenance of stem cells is derived from studies on Drosophila germ cells. Now, two recently published studies by Mandal et al.1 and Krezmien et al.2 describe the Drosophila haematopoietic niche and signal transduction pathways that are involved in the maintenance of haematopoietic precursors. Both reports emphasize several features that are important for controlling stem cell behavior and show parallels to both the vertebrate haematopoietic niche as well as the Drosophila germline stem cell niches in ovary and testis. The findings of both papers shed new light on the specific interactions between haematopoietic progenitors and their microenvironment. BioEssays 29:713–716, 2007. © 2007 Wiley Periodicals, Inc. (shrink)

Programmed cell death (PCD) or apoptosis is a broadly conserved phenomenon in metazoans, whereby activation of canonical signal pathways induces an ordered dismantling and death of a cell. Paradoxically, the constituent proteins and pathways of PCD (most notably the metacaspase/caspase protease mediated signal pathways) have been demonstrated to retain non‐death functions across all phyla including yeast, nematodes, drosophila, and mammals. The ancient conservation of both death and non‐death functions of PCD proteins raises an interesting evolutionary conundrum: was the (...) primordial intent of these factors to induce cell death or to regulate other cellular adaptations? Here, we propose the hypothesis that apoptotic behavior of PCD proteins evolved or were co‐opted from core non‐death functions. (shrink)

In the seminiferous tubule of the mammalian testis, one type A1 spermatogonium (diploid, 2n) divides and differentiates into 256 spermatozoa (haploid, n) during spermatogenesis. To complete spermatogenesis and produce ∼150 × 106 spermatozoa each day in a healthy man, germ cells must migrate progressively across the seminiferous epithelium yet remain attach to the nourishing Sertoli cells. This active cell migration process involves precisely controlled restructuring events at the tight (TJ) and anchoring junctions at the cell–cell interface. (...) While the hormonal events that regulate spermatogenesis by follicle‐stimulating hormone and testosterone from the pituitary gland and Leydig cells, respectively, are known, less is known about the mechanism(s) that regulates junction restructuring during germ cell movement in the seminiferous epithelium. The relative position of tight (TJs) and anchoring junctions in the testis is of interest. Sertoli cell TJs that constitute the blood–testis barrier (BTB) are present side by side with anchoring junctions and are adjacent to the basement membrane. This intimate physical association with the TJs, the anchoring junctions and the basement membrane (a modified form of extracellular matrix, ECM) suggests a role for the ECM in the junction dynamics of the testis. Indeed, evidence is accumulating that ECM proteins are crucial to Sertoli cell TJ dynamics. In this review, we discuss the pivotal role of tumor necrosis factor α (TNFα) on BTB dynamics via its effects on the homeostasis of ECM proteins. In addition, discussion will also be focused on the novel findings regarding the role of non‐basement‐membrane‐associated ECM proteins and components of focal adhesion (a cell–matrix anchoring junction type) in the regulation of junction dynamics in the testis. BioEssays 26:978–992, 2004. © 2004 Wiley Periodicals, Inc. (shrink)

Today, human pluripotent stem cell technologies find widespread application across biomedical research, as models for early human development, as platforms for functional human genomics, as tools for the study of disease, drug screening and toxicology, and as a renewable source of cellular therapeutics for a range of intractable diseases. The foundations of this human pluripotent stem cell revolution rest on advances in a wide range of disciplines, including cancer biology, assisted reproduction, cell culture and organoid technology, somatic (...) cell nuclear transfer, primate embryology, single‐cell biology, and gene editing. This review surveys the slow emergence of the study of human pluripotency and the exponential growth of the field during the past several decades. (shrink)

Although the ability to perform gene therapy in human germ-line cells is still hypothetical, the rate of progress in molecular and cell biology suggests that it will only be a matter of time before reliable clinical techniques will be within reach. Three sets of arguments are commonly advanced against developing those techniques, respectively pointing to the clinical risks, social dangers and better alternatives. In this paper we analyze those arguments from the perspective of the client-centered ethos that traditionally (...) governs practice in medical genetics. This perspective clarifies the merits of these arguments for geneticists, and suggests useful new directions for the professional discussion of germ-line gene therapy. It suggests, for example, that the much discussed prospect of germ-line therapy in human pre-embryos may always be more problematic for medical genetics than adult germ-line interventions, even though the latter faces greater technical difficulties. (shrink)

Cancers often express hundreds of genes otherwise specific to germ cells, the germline/cancer (GC) genes. Here, we present and discuss the hypothesis that activation of a “germline program” promotes cancer cell malignancy. We do so by proposing four hallmark processes of the germline: meiosis, epigenetic plasticity, migration, and metabolic plasticity. Together, these hallmarks enable replicative immortality of germ cells as well as cancer cells. Especially meiotic genes are frequently expressed in cancer, implying that genes unique to meiosis (...) may play a role in oncogenesis. Because GC genes are not expressed in healthy somatic tissues, they form an appealing source of specific treatment targets with limited side effects besides infertility. Although it is still unclear why germ cell specific genes are so abundantly expressed in cancer, from our hypothesis it follows that the germline's reproductive program is intrinsic to cancer development. (shrink)

(Recipient of the 2020 Everett Mendelsohn Prize.) This article revisits the development of the protoplasm concept as it originally arose from critiques of the cell theory, and examines how the term “protoplasm” transformed from a botanical term of art in the 1840s to the so-called “living substance” and “the physical basis of life” two decades later. I show that there were two major shifts in biological materialism that needed to occur before protoplasm theory could be elevated to have equal (...) status with cell theory in the nineteenth century. First, I argue that biologists had to accept that life could inhere in matter alone, regardless of form. Second, I argue that in the 1840s, ideas of what formless, biological matter was capable of dramatically changed: going from a “coagulation paradigm” that had existed since Theophrastus, to a more robust conception of matter that was itself capable of movement and self-maintenance. In addition to revisiting Schleiden and Schwann’s original writings on cell theory, this article looks especially closely at Hugo von Mohl’s definition of the protoplasm concept in 1846, how it differed from his primordial utricle theory of cell structure two years earlier. This article draws on Lakoff and Johnson’s theory of “ontological metaphors” to show that the cell, primordial utricle, and protoplasm can be understood as material container, object, and substance, and that these overlapping distinctions help explain the chaotic and confusing early history of cell theory. (shrink)

The cell is not only the structural, physiological, and developmental unit of life, but also the reproductive one. So far, however, this aspect of the cell has received little attention from historians and philosophers of biology. I will argue that cell theory had far-reaching consequences for how biologists conceptualized the reproductive relationships between germs and adult organisms. Cell theory, as formulated by Theodor Schwann in 1839, implied that this relationship was a specific and lawful one, that (...) is, that germs of a certain kind, all else being equal, would produce adult organisms of the same kind, and vice versa. Questions of preformation and epigenesis took on a new meaning under this presupposition. The question then became one of whether cells could be considered as autonomous agents producing adult organisms of a given species, or whether they were the product of external, organizing forces and thus only a stage in the development of the whole organism. This question became an important issue for nineteenth-century biology. As I will demonstrate, it was the view of cells as autonomous agents which helped both Charles Darwin and Gregor Mendel to think of inheritance as a lawful process. (shrink)

August Weismann proposed that genetic changes in somatic cells cannot pass to germ cells and hence to next generations. Nevertheless, evidence is accumulating that some environmental effects can promote heritable changes in the DNA of germ cells, which implies that some somatic influence on germ line is possible. This influence is mostly detrimental and related to the presence of oxidative stress, which induces mutations and epigenetic changes. This effect should be stronger in males due to the particular (...) characteristics of sperm. Here, we propose the hypothesis that females are able to avoid males with oxidatively damaged DNA in the germ line by using oxidative‐dependent (pre‐ and post‐mating) signals. This new hypothesis may shed light on unsolved questions in evolutionary biology, such as the benefits of polyandry, the lek paradox, or the role of sexual selection on the evolution of aging. BioEssays 30:1212–1219, 2008. © 2008 Wiley Periodicals, Inc. (shrink)

The relationship of embryonal carcinoma (EC) cells, the stem cells of germ cell‐ or embryo‐derived teratocarcinoma tumors, to early embryonic cells came under intense scrutiny in the early 1970s when mouse chimeras were produced between EC cells and embryos. These chimeras raised tantalizing possibilities and high hopes for different areas of research. The normalization of EC cells by the embryo lent validity to their use as in vitro models for embryogenesis and indicated that they might reveal information about (...) the relationship between malignancy and differentiation. Chimeras also showed the way for the potential introduction of genes, selected in EC cells in vitro, into the germ line of mice. Although EC cells provided material for the elucidation of early embryonic events and stimulated many studies of early molecular differentiation, after years of intense scrutiny, they fell short as the means of genetic manipulation of the germ line, although arguably they pointed the way to the development of embryonic stem (ES) cells that eventually fulfilled this goal. (shrink)

The purpose of this essay is to stimulate academic discussion about the ethical justification of using human primordial stem cells for tissue transplantation, cell replacement, and gene therapy. There are intriguing alternatives to using embryos obtained from elective abortions and in vitro fertilisation to reconstitute damaged or dysfunctional human organs. These include the expansion and transplantation of latent adult progenitor cells.

Silencing of tumor suppressor genes (TSGs), by DNA methylation, is well known in adult cancers. However, based on the “stem cell” theory of tumorigenesis, the early epigenetic events arising in malignant precursors remain unknown. A recent report1 demonstrates that, while pluripotent embryonic stem cells lack DNA methylation and possess a “bivalent” pattern of activating and repressive histone marks in numerous TSGs, analogous multipotent malignant cells derived from germ cell tumors (embryonic carcinoma cells) gain additional silencing modifications to (...) those same genes. These results suggest a possible mechanism by which aberrant differentiation, mediated by histone and DNA methylation, instigates tumor progression. BioEssays 29:842–845, 2007. © 2007 Wiley Periodicals, Inc. (shrink)

Recent results from studies on animals suggest that functional germ cells may be generated from human pluripotent stem cells, giving rise to three possibilities: research with these so‐called artificial gametes, including fertilization experiments in vitro; their use in vivo for therapy for the treatment of human infertility; and their use in assisted reproductive technologies in vitro. While the legal, philosophical, and ethical questions associated with these possibilities have been already discussed intensively in other countries, the debate in Germany is (...) still at its beginning. A systematic and detailed analysis of the legal framework in Germany is provided with regard to the three possibilities, including the applicable statutory laws as well as the constitutional law. The question emerges as to whether the statutory laws as well as the constitution justify a distinction to be made between embryos of artificial and natural origin. This question is subject to philosophical analysis, discussing the distinction between person and thing, dignity and price, personality and property, and nature and technique. As a result, the criterion of naturalness alone may not be sufficient to differentiate between embryos of natural and artificial origin, and other criteria need to be identified. (shrink)

An understanding of the factors behind the evolution of multicellularity is one of today’s frontiers in evolutionary biology. This is because multicellular organisms are made of one subset of cells with the capacity to transmit genes to the next generation and another subset responsible for maintaining the functionality of the organism, but incapable of transmitting genes to the next generation. The question arises: why do somatic cells sacrifice their lives for the sake of germline cells? How is germ/soma separation (...) maintained? One conventional answer refers to inclusive fitness theory, according to which somatic cells sacrifice themselves altruistically, because in so doing they enhance the transmission of their genes by virtue of their genetic relatedness to germline cells. In the present article we will argue that this explanation ignores the key role of policing mechanisms in maintaining the germ/soma divide. Based on the pervasiveness of the latter, we argue that the role of altruistic mechanisms in the evolution of multicellularity is limited and that our understanding of this evolution must be enriched through the consideration of coercion mechanisms. (shrink)

Determinations of the ethical acceptability of genetic therapy have relied on several distinctions in attempts to separate ethically acceptable genetic therapy from those possible therapies that could lead to genetic modifications of future human beings. One distinction that has been proposed is that genetic modifications of human somatic cells is ethically acceptable but that Germ-Line genetics modifications would be ethically objectionable. This paper examines several serious difficulties which call into question the ethical relevance of a somatic/Germ-Line distinction. Keywords: (...) double effect, future generations, Germ-Line modification CiteULike Connotea Del.icio.us What's this? (shrink)

Stem-cell nomenclature is in a muddle! So-called stem cells may be self-renewing or emergent, oligopotent (uni- and multipotent) or pluri- and totipotent, cells with perpetual embryonic features or cells that have changed irreversibly. Ambiguity probably seeped into stem cells from common usage, flukes in biology's history beginning with Weismann's divide between germ and soma and Haeckel's biogenic law and ending with contemporary issues over the therapeutic efficacy of adult versus embryonic cells. Confusion centers on tissue dynamics, whether stem (...) cells are properly members of emerging or steady-state populations. Clarity might yet be achieved by codifying differences between cells in emergent populations, including embryonic stem and embryonic germ (ES and EG) cells in tissue culture as opposed to self-renewing (SR) cells in steady-state populations. BioEssays 28: 301–308, 2006. © 2006 Wiley Periodicals, Inc. (shrink)