Weismannism Research Articles

Bubbling beyond the barrier: exosomal RNA as a vehicle for soma-germline communication.

'Weismann's barrier' has restricted theories of heredity to the transmission of genomic variation for the better part of a century. However, the discovery and elucidation of epigenetic mechanisms of gene regulation such as DNA methylation and histone modifications has renewed interest in studies on the inheritance of acquired traits and given them mechanistic plausibility. Although it is now clear that these mechanisms allow many environmentally acquired traits to be transmitted to the offspring, how phenotypic information is communicated from the body to its gametes has remained a mystery. Here, we discuss recent evidence that such communication is mediated by somatic RNAs that travel inside extracellular vesicles to the gametes where they reprogram the offspring epigenome and phenotype. How gametes learn about bodily changes has implications not only for the clinic, but also for evolutionary theory by bringing together intra- and intergenerational mechanisms of phenotypic plasticity and adaptation.

Small RNA shuffling between murine sperm and their cytoplasmic droplets during epididymal maturation.

Reports that mouse sperm gain small RNAs from the epididymosomes secreted by epididymal epithelial cells and that these "foreign" small RNAs act as an epigenetic information carrier mediating the transmission of acquired paternal traits have drawn great attention because the findings suggest that heritable information can flow from soma to germ line, thus invalidating the long-standing Weismann's barrier theory on heritable information flow. Using small RNA sequencing (sRNA-seq), northern blots, sRNA in situ hybridization, and immunofluorescence, we detected substantial changes in the small RNA profile in murine caput epididymal sperm (sperm in the head of the epididymis), and we further determined that the changes resulted from sperm exchanging small RNAs, mainly tsRNAs and rsRNAs, with cytoplasmic droplets rather than the epididymosomes. Moreover, the murine sperm-borne small RNAs were mainly derived from the nuclear small RNAs in late spermatids. Thus, caution is needed regarding sperm gaining foreign small RNAs as an underlying mechanism of epigenetic inheritance.

Inheritance of Acquired Traits in Insects and Other Animals and the Epigenetic Mechanisms That Break the Weismann Barrier.

The credibility of the Weismann barrier has come into question. Several studies in various animal systems, from mice to worms, have shown that novel environmental stimuli can generate an altered developmental or behavioral trait that can be transmitted to offspring of the following generation. Recently, insects have become ideal models to study the inheritance of acquired traits. This is because insects can be reared in high numbers at low cost, they have short generation times and produce abundant offspring. Numerous studies have shown that an insect can modify its phenotype in response to a novel stimulus to aid its survival, and also that this modified phenotypic trait can be inherited by its offspring. Epigenetic mechanisms are likely at play but, most studies do not address the mechanisms that underlie the inheritance of acquired traits in insects. Here we first review general epigenetic mechanisms such as DNA methylation, histone acetylation and small noncoding RNAs that have been implicated in the transmission of acquired traits in animals, then we focus on the few insect studies in which these mechanisms have been investigated.

Neuronal perception of the social environment generates an inherited memory that controls the development and generation time of C. elegans

An old and controversial question in biology is whether information perceived by the nervous system of an animal can "cross the Weismann barrier" to alter the phenotypes and fitness of their progeny. Here, we show that such intergenerational transmission of sensory information occurs in the model organism, C.elegans, with a major effect on fitness. Specifically, that perception of social pheromones by chemosensory neurons controls the post-embryonic timing of the development of one tissue, the germline, relative to others in the progeny of an animal. Neuronal perception of the social environment thus intergenerationally controls the generation time of this animal.

What prevents mainstream evolutionists teaching the whole truth about how genomes evolve?

The common belief that the neo-Darwinian Modern Synthesis (MS) was buttressed by the discoveries of molecular biology is incorrect. On the contrary those discoveries have undermined the MS. This article discusses the many processes revealed by molecular studies and genome sequencing that contribute to evolution but nonetheless lie beyond the strict confines of the MS formulated in the 1940s. The core assumptions of the MS that molecular studies have discredited include the idea that DNA is intrinsically a faithful self-replicator, the one-way transfer of heritable information from nucleic acids to other cell molecules, the myth of “selfish DNA”, and the existence of an impenetrable Weismann Barrier separating somatic and germ line cells. Processes fundamental to modern evolutionary theory include symbiogenesis, biosphere interactions between distant taxa (including viruses), horizontal DNA transfers, natural genetic engineering, organismal stress responses that activate intrinsic genome change operators, and macroevolution by genome restructuring (distinct from the gradual accumulation of local microevolutionary changes in the MS). These 21st Century concepts treat the evolving genome as a highly formatted and integrated Read–Write (RW) database rather than a Read-Only Memory (ROM) collection of independent gene units that change by random copying errors. Most of the discoverers of these macroevolutionary processes have been ignored in mainstream textbooks and popularizations of evolutionary biology, as we document in some detail. Ironically, we show that the active view of evolution that emerges from genomics and molecular biology is much closer to the 19th century ideas of both Darwin and Lamarck. The capacity of cells to activate evolutionary genome change under stress can account for some of the most negative clinical results in oncology, especially the sudden appearance of treatment-resistant and more aggressive tumors following therapies intended to eradicate all cancer cells. Knowing that extreme stress can be a trigger for punctuated macroevolutionary change suggests that less lethal therapies may result in longer survival times.

Challenging dogmas: How transgenerational epigenetics reshapes our views on life.

The emergence of the field of transgenerational epigenetics inheritance (TEI) has profoundly reshaped our understanding of the relationships between environment, soma, and germ cells as well as of heredity. TEI refers to the changes in chromatin state, gene expression, and/or phenotypes that are transmitted across several generations without involving changes to the DNA sequences. TEI has direct connections with, and feeds from, the fields of molecular biology, genetics, developmental biology, and reproductive biology, among others. However, the expansion of TEI-related research, has profoundly reshaped boundaries within each field and often led to the erosion of theories and concepts considered as tenets of biology. We first explore how the molecularization of biology has shifted the definition of epigenetics to include the notion of heredity and how epigenetics has refined our understanding of the central dogma of biology. The demonstrated transfer of environmental information from soma to germ cell through extracellular vesicles and subsequent alteration of health outcomes in offspring has put a definite end to the long-held principle of the Weismann barrier. TEI has also simultaneously led to the revival of the inheritance of acquired characteristics while further eroding the concept of an epigenetic "blank slate" in mammals. Using an historical framework, and via the exploration of central studies in the field, in this perspective article, we will draw a compelling argument for the revolutionary aspect of TEI in biology.

The Illusions of the Modern Synthesis

The Modern Synthesis has dominated biology for 80 years. It was formulated in 1942, a decade before the major achievements of molecular biology, including the Double Helix and the Central Dogma. When first formulated in the 1950s these discoveries and concepts seemed initially to completely justify the central genetic assumptions of the Modern Synthesis. The Double Helix provided the basis for highly accurate DNA replication, while the Central Dogma was viewed as supporting the Weismann Barrier, so excluding the inheritance of acquired characteristics. This article examines the language of the Modern Synthesis and reveals that it is based on four important misinterpretations of what molecular biology had shown, so forming the basis of the four Illusions: 1. Natural Selection; 2. The Weismann Barrier; 3. The Rejection of Darwin’s Gemmules; 4. The Central Dogma. A multi-level organisation view of biology avoids these illusions through the principle of biological relativity. Molecular biology does not therefore confirm the assumptions of the Modern Synthesis.

Neuronal Perception of the Social Environment Generates an Inherited Memory that Controls the Development and Generation Time of <i>C. Elegans</i>

An old and controversial question in biology is whether information perceived by the nervous system of an animal can ‘cross the Weismann barrier’ to alter the phenotypes and fitness of their progeny. Here we show that such intergenerational transmission of sensory information occurs in the model organism, C. elegans, with a major effect on fitness. Specifically, that perception of social pheromones by chemosensory neurons controls the post-embryonic timing of development of one tissue – the germline – relative to others in an animal’s progeny. Neuronal perception of the social environment thus intergenerationally controls the generation time of this animal.

What Is Lost in the Weismann Barrier?

The Weismann barrier has long been regarded as a basic tenet of biology. However, upon close examination of its historical origins and August Weismann’s own writings, questions arise as to whether such a status is warranted. As scientific research has advanced, the persistence of the concept of the barrier has left us with the same dichotomies Weismann contended with over 100 years ago: germ or soma, gene or environment, hard or soft inheritance. These dichotomies distract from the more important questions we need to address going forward. In this review, we will examine the theories that have shaped Weismann’s thinking, how the concept of the Weismann barrier emerged, and the limitations that it carries. We will contrast the principles underlying the barrier with recent and less recent findings in developmental biology and transgenerational epigenetic inheritance that have profoundly eroded the oppositional view of germline vs. soma. Discarding the barrier allows us to examine the interactive processes and their response to environmental context that generate germ cells in the first place, determine the entirety of what is inherited through them, and set the trajectory for the health status of the progeny they bear.

Environmentally Induced Epigenetic Transgenerational Inheritance and the Weismann Barrier: The Dawn of Neo-Lamarckian Theory.

For the past 120 years, the Weismann barrier and associated germ plasm theory of heredity have been a doctrine that has impacted evolutionary biology and our concepts of inheritance through the germline. Although August Weismann in his 1872 book was correct that the sperm and egg were the only cells to transmit molecular information to the subsequent generation, the concept that somatic cells do not impact the germline (i.e., the Weismann barrier) is incorrect. However, the doctrine or dogma of the Weismann barrier still influences many scientific fields and topics. The discovery of epigenetics, and more recently environmentally induced epigenetic transgenerational inheritance of phenotypic variation and pathology, have had significant impacts on evolution theory and medicine today. Environmental epigenetics and the concept of epigenetic transgenerational inheritance refute aspects of the Weismann barrier and require a re-evaluation of both inheritance theory and evolution theory.

AMPK Regulates Developmental Plasticity through an Endogenous Small RNA Pathway in Caenorhabditis elegans.

Caenorhabditis elegans larvae can undergo developmental arrest upon entry into the dauer stage in response to suboptimal growth conditions. Dauer larvae can exit this stage in replete conditions with no reproductive consequence. During this diapause stage, the metabolic regulator AMP-activated protein kinase (AMPK) ensures that the germ line becomes quiescent to maintain germ cell integrity. Animals that lack all AMPK signalling undergo germline hyperplasia upon entering dauer, while those that recover from this stage become sterile. Neuronal AMPK expression in otherwise AMPK-deficient animals is sufficient for germline quiescence and germ cell integrity and its effects are likely mediated through an endogenous small RNA pathway. Upon impairing small RNA biosynthesis, the post-dauer fertility is restored in AMPK mutants. These data suggest that AMPK may function in neurons to relay a message through small RNAs to the germ cells to alter their quiescence in the dauer stage, thus challenging the permeability of the Weismann barrier.

Transgenerational epigenetic reprogramming of early embryos: a mechanistic model.

The notion that epigenetic information can be transmitted across generations is supported by mounting waves of data, but the underlying mechanisms remain elusive. Here, a model is proposed which combines different lines of experimental evidence. First, it has been shown that somatic tissues exposed to stressing stimuli release circulating RNA-containing extracellular vesicles; second, epididymal spermatozoa can take up, internalize and deliver the RNA-containing extracellular vesicles to oocytes at fertilization; third, early embryos can process RNA-based information. These elements constitute the building blocks upon which the model is built. The model proposes that a continuous stream of epigenetic information flows from parental somatic tissues to the developing embryos. The flow can cross the Weismann barrier, is mediated by circulating vesicles and epididymal spermatozoa, and has the potential to generate epigenetic traits that are then stably acquired in the offspring. In a broader perspective, it emerges that a natural ‘assembly line’ operates continuously, aiming at passing the parental epigenetic blueprint in growing embryos.

The deteriorating soma and the indispensable germline: gamete senescence and offspring fitness.

The idea that there is an impenetrable barrier that separates the germline and soma has shaped much thinking in evolutionary biology and in many other disciplines. However, recent research has revealed that the so-called 'Weismann Barrier' is leaky, and that information is transferred from soma to germline. Moreover, the germline itself is now known to age, and to be influenced by an age-related deterioration of the soma that houses and protects it. This could reduce the likelihood of successful reproduction by old individuals, but also lead to long-term deleterious consequences for any offspring that they do produce (including a shortened lifespan). Here, we review the evidence from a diverse and multidisciplinary literature for senescence in the germline and its consequences; we also examine the underlying mechanisms responsible, emphasizing changes in mutation rate, telomere loss, and impaired mitochondrial function in gametes. We consider the effect on life-history evolution, particularly reproductive scheduling and mate choice. Throughout, we draw attention to unresolved issues, new questions to consider, and areas where more research is needed. We also highlight the need for a more comparative approach that would reveal the diversity of processes that organisms have evolved to slow or halt age-related germline deterioration.

The active role of spermatozoa in transgenerational inheritance.

The active uptake of exogenous nucleic acids by spermatozoa of virtually all animal species is a well-established phenomenon whose significance has long been underappreciated. A growing body of published data demonstrates that extracellular vesicles released from mammalian somatic tissues pass an RNA-based flow of information to epididymal spermatozoa, thereby crossing the Weismann barrier. That information is delivered to oocytes at fertilization and affects the fate of the developing progeny. We propose that this essential process of epigenetic transmission depends upon the documented ability of epididymal spermatozoa to bind and internalize foreign nucleic acids in their nuclei. In other words, spermatozoa are not passive vectors of exogenous molecules but rather active participants in essential somatic communication across generations.

TFAP2C Safeguards Weismann's Barrier to Preserve Human Germline Identity During Primordial Germ Cell Specification from Lineage Primed Progenitors

The germline is fundamental to reproduction. How germline cell precursors, called primordial germ cells (PGCs), establish and maintain germline identity during peri-implantation development in humans remains elusive. Here, we show using human embryo attachment culture that human primordial germ cell (hPGC) specification begins at day 12 post fertilization. Next, using single cell RNA-sequencing of more than 100,000 cells during differentiation into hPGC-like cells (hPGCLCs), we show that hPGCLC specification in vitro involves first resetting pluripotency towards a new transitional state of pluripotency with shared characteristics between naive and primed, followed by differentiation into lineage primed TFAP2A+ progenitors that serve as a common precursor to amnion gastrulating cells and hPGCLCs. At the point of hPGCLC specification, TFAP2C functions upstream of SOX17 to protect the germline cells from crossing the Weismann’s barrier to adopt somatic cell fates. Keeping cells within Weismann’s barrier ensures the transmission of hereditary material to future generations.

AMPK regulates germline stem cell quiescence and integrity through an endogenous small RNA pathway.

During suboptimal growth conditions, Caenorhabditis elegans larvae undergo a global developmental arrest called “dauer.” During this stage, the germline stem cells (GSCs) become quiescent in an AMP-activated Protein Kinase (AMPK)-dependent manner, and in the absence of AMPK, the GSCs overproliferate and lose their reproductive capacity, leading to sterility when mutant animals resume normal growth. These defects correlate with the altered abundance and distribution of a number of chromatin modifications, all of which can be corrected by disabling components of the endogenous small RNA pathway, suggesting that AMPK regulates germ cell integrity by targeting an RNA interference (RNAi)-like pathway during dauer. The expression of AMPK in somatic cells restores all the germline defects, potentially through the transmission of small RNAs. Our findings place AMPK at a pivotal position linking energy stress detected in the soma to a consequent endogenous small RNA–mediated adaptation in germline gene expression, thereby challenging the “permeability" of the Weismann barrier.

Insulin-like signalling to the maternal germline controls progeny response to osmotic stress.

In 1893 August Weismann proposed that information about the environment could not pass from somatic cells to germ cells1, a hypothesis now known as the Weismann barrier. However, recent studies have indicated that parental exposure to environmental stress can modify progeny physiology2–7 and that parental stress can contribute to progeny disorders8. The mechanisms regulating these phenomena are poorly understood. We report that the nematode C. elegans can protect itself from osmotic stress by entering a state of arrested development and can protect its progeny from osmotic stress by increasing the expression of the glycerol biosynthetic enzyme GPDH-2 in progeny. Both of these protective mechanisms are regulated by insulin-like signalling: insulin-like signalling to the intestine regulates developmental arrest, while insulin-like signalling to the maternal germline regulates glycerol metabolism in progeny. Thus, there is a heritable link between insulin-like signalling to the maternal germline and progeny metabolism and gene expression. We speculate that analogous modulation of insulin-like signalling to the germline is responsible for effects of the maternal environment on human diseases that involve insulin signalling, such as obesity and type-2 diabetes8.

Vertically- and horizontally-transmitted memories - the fading boundaries between regeneration and inheritance in planaria.

ABSTRACTThe Weismann barrier postulates that genetic information passes only from the germline to the soma and not in reverse, thus providing an obstacle to the inheritance of acquired traits. Certain organisms such as planaria – flatworms that can reproduce through asymmetric fission – avoid the limitations of this barrier, thus blurring the distinction between the processes of inheritance and development. In this paper, we re-evaluate canonical ideas about the interaction between developmental, genetic and evolutionary processes through the lens of planaria. Biased distribution of epigenetic effects in asymmetrically produced parts of a regenerating organism could increase variation and therefore affect the species' evolution. The maintenance and fixing of somatic experiences, encoded via stable biochemical or physiological states, may contribute to evolutionary processes in the absence of classically defined generations. We discuss different mechanisms that could induce asymmetry between the two organisms that eventually develop from the regenerating parts, including one particularly fascinating source – the potential capacity of the brain to produce long-lasting epigenetic changes.

Soma to germline inheritance of extrachromosomal genetic information via a LINE-1 reverse transcriptase-based mechanism.

Mature spermatozoa are permeable to foreign DNA and RNA molecules. Here I propose a model, whereby extrachromosomal genetic information, mostly encoded in the form of RNA in somatic cells, can cross the Weismann barrier and reach epididymal spermatozoa. LINE-1 retrotransposon-derived reverse transcriptase (RT) can play key roles in the process by expanding the RNA-encoded information. Retrotransposon-encoded RT is stored in mature gametes, is highly expressed in early embryos and undifferentiated cells, and becomes downregulated in differentiated cells. In turn, RT plays a role in developmental control, as its inhibition arrests developmental progression of early embryos with globally altered transcriptomic profiles. Thus, sperm cells act as recipients, and transgenerational vectors of somatically derived genetic information which they pass to the next generation with the potential to modify the fate of the developing embryos.

Breaking the germ line-soma barrier.

Azim Surani discusses how induced pluripotent stem cells have enabled researchers to demonstrate that it is possible to cross the germ line–soma barrier, known as the Weismann barrier.