Unintelligent Design - How A Virus Saved The Unintelligent Designer's Blushes Early In Multicellular History

A virus that infected animals hundreds of millions of years ago has become essential for the development of the embryo

I've remarked before how similar biological systems are to the machines the late William Heath Robinson designed for solving simple, everyday problems. Simple solutions were eschewed for more complicated ones and unlikely items were used in ways they weren't intended for, such as a grandfather clock standing on a piano to support a platform balanced on top. Everything was held together by pieces of knotted string and labour-saving devices took far more people than would have been needed to do the job more simply.

And yet, the whole contraption worked, or at least looked as though it would if were ever made, but take any part away and the whole thing would fail, in an example of what creationists call 'irreducible complexity'.

So, let's pretend that creationism's, 'intelligent'[sic] designer really is behind the design of living organisms and see how closely Heath Robinson unwittingly parodied it:
Just such an example of a Heath Robinson machine in biology was revealed a few days ago in an open access paper published in Science Advances, explaining how a virus which became incorporated in the genome of an early multicellular organism provided a solution to a problem of the designer's own making. The problem it solves was how to overcome the problem created by choosing the same method of cell replication in multicellular organisms that single-celled organisms use, where the entire genome needs to be replicated at each division.

The entire 'point' of multicellularity, and what gave it its success over single-celled organisms is division of labour, in other words, specialisation, so the organisms can be divided into tissues and organs that perform a specialised task. This means that every cell has to have the potential to carry out every function, in the genes it inherits from its parent cell, yet only a few genes are need for its particular specialty.

The process by which this is achieved is the complicated epigenetic system which turns off unneeded genes as the cells differentiate into different cell lines in the developing embryo, and these settings can't normally be reversed.

However, the sperm and egg which then fused to form the zygote from which a new embryo develops, are themselves specialised cells with all the epigenetic settings of their parent cells with an additional few of their own, and these are inherited by the zygote, so to make cell differentiation possible again, the zygote is quickly (within minutes of fertilisation) reset to a state of totipotency.

So, to overcome the epigenetic settings problem that is a problem of the designer's own making, the zygote needs to be epigenetically reprogrammed and this happens in two stages: first to produce a 'totipotent' cell with the potential to produce all the different cells in the embryo as well as the placenta, umbilical cord, and amniotic sack in which the embryo will develop, and then, soon after cell division begins, 'pluripotent' cells from which the different stem cells for the required specialised cell lines will develop.

How this was helped by a virus is the subject of the paper by researchers from the Spanish National Cancer Research Centre (CNIO), Madrid, Spain. First, a little AI background:

What do the terms 'totipotency' and 'pleuripotency' mean in the context of embryo development? Totipotency and pluripotency are terms used in the context of embryonic development to describe the developmental potential of cells.

1. Totipotency:
   • Definition: Totipotent cells have the ability to differentiate into any cell type in the body, as well as into extraembryonic tissues (such as the placenta).
   • Occurrence: In the early stages of embryonic development, the zygote is totipotent. The cells formed after the first few divisions of the zygote are also totipotent until they differentiate into specific cell lineages.
   • Example: A totipotent cell can give rise to both embryonic and extraembryonic tissues, including the cells of the placenta.
2. Pluripotency:
   • Definition: Pluripotent cells have the ability to differentiate into cells of all three germ layers (ectoderm, mesoderm, and endoderm), which give rise to various tissues and organs in the body.
   • Occurrence: Pluripotency is typically observed in cells of the inner cell mass of the blastocyst, which is a stage in early embryonic development.
   • Example: Embryonic stem cells (ESCs) are an example of pluripotent cells. They can differentiate into a wide range of cell types but cannot give rise to extraembryonic tissues like the placenta.

In summary, totipotent cells have the highest developmental potential, being able to give rise to both embryonic and extraembryonic tissues. Pluripotent cells, on the other hand, can differentiate into cells of all three germ layers but do not have the potential to form extraembryonic tissues. Both totipotency and pluripotency are critical concepts in understanding the early stages of embryonic development.

Is that related to epigenetics? If so, how?

Yes, the concepts of totipotency and pluripotency are closely related to epigenetics, which refers to the study of heritable changes in gene expression or cellular phenotype that do not involve alterations to the underlying DNA sequence. Epigenetic mechanisms play a crucial role in the regulation of gene expression during embryonic development, and they are intimately connected to the transitions between different developmental states, such as the transition from totipotency to pluripotency.

Here's how epigenetics is related to totipotency and pluripotency:

1. Epigenetic Changes in Totipotency:
   • The zygote, formed by the fusion of sperm and egg, is totipotent. As the zygote undergoes cell divisions, epigenetic changes occur to establish different cell lineages.
   • Epigenetic modifications, such as DNA methylation and histone modifications, play a role in regulating gene expression during the differentiation of totipotent cells into more specialized cell types.
2. Epigenetic Changes in Pluripotency:
   • Pluripotent cells, such as embryonic stem cells (ESCs), have a unique epigenetic signature that allows them to maintain their pluripotent state while retaining the potential to differentiate into various cell types.
   • Epigenetic modifications contribute to the activation or repression of specific genes, influencing the fate of pluripotent cells as they commit to different cell lineages.
3. Epigenetic Reprogramming:
   • During the transition from totipotency to pluripotency, and later during the differentiation of pluripotent cells into specific cell types, there is a process called epigenetic reprogramming.
   • Epigenetic reprogramming involves erasing existing epigenetic marks and establishing new ones to allow for the activation or repression of genes required for the specific cell fate.
4. Maintenance of Pluripotency:
   • The maintenance of pluripotency in stem cells relies on a delicate balance of epigenetic modifications. Key genes associated with pluripotency need to be kept active, while differentiation-associated genes must be appropriately silenced.

Understanding the interplay between totipotency, pluripotency, and epigenetics is crucial for unraveling the complexities of embryonic development and stem cell biology. Epigenetic regulation ensures the precise control of gene expression patterns that guide the differentiation of cells into distinct cell types during development.

Some viruses known as retroviruses can hide from a cell's defences by inserting the DNA template for their RNA into the genome of the cell. If this mutates it can no longer produce new virus particles but is stuck in the genome of the cell and all its descendants just as though it were part of the normal genome. If this happens in a cell in the germ line, the remnants of the retrovirus will be passed to future generations, as an endogenous retrovirus 'fossil' of the ancient virus. It was one of these that the Spanish team discovered was later coopted to overcome the problem epigenetics had caused.

How the CNIO team discovered the roll of one these retroviruses in this process is the subject of a news release:

All animals have evolved thanks to the fact that certain viruses infected primitive organisms hundreds of millions of years ago. Viral genetic material was integrated into the genome of the first multi-cellular beings and is still in our DNA today. Researchers from the CNIO (Spanish National Cancer Research Centre) describe now in the journal Science Advances for the first time the role played by these viruses in a process that is absolutely vital for our development, and which occurs a few hours after fertilisation: the transition to pluripotency, when the oocyte goes from having two to four cells.

Before this step, each of the two cells of the embryo is totipotent, i.e., it may develop inside an independent organism; the four cells of the next stage are not totipotent but are pluripotent, because they can differentiate into cells of any specialised tissue of the body.

For Sergio de la Rosa and Nabil Djouder, first author and senior author respectively, the finding is relevant for the field of regenerative medicine and for the creation of artificial embryos, as it opens up a new way to generate stable cell lines in the totipotency phases. Djouder leads the Growth Factors, Nutrients and Cancer Group at the CNIO.

We are 8% retrovirus

Genetic material from the now so-called ‘endogenous retroviruses’ was integrated into the genomes of organisms that may have been drivers of the Cambrian explosion, a period more than 500 million years ago when the world’s seas underwent a biodiversity boom. Over the past decade, genetic sequences from these viruses have been found to make up at least 8-10% of the human genome.

Until recently, these viral remnants were considered to be ‘junk DNA’, genetic material that was unusable or even harmful. Intuitively, it was thought that having viruses in the genome could not be good. However, in recent years we are starting to realise that these retroviruses, which have co-evolved with us over millions of years, have important functions, such as regulating other genes. It’s an extremely active field of research.

Segio De la Rosa, first author.
Growth Factors, Nutrients and Cancer Group
Molecular Oncology Programme
Spanish National Cancer Research Centre (CNIO), Madrid, Spain.

The transition from totipotency to pluripotency, a question of pace The research published in Science Advances shows that the MERVL endogenous retrovirus sets the pace in embryo development, especially during the specific step of the transition from totipotency to pluripotency and explains the mechanism that makes this happen.

It is a totally new role for endogenous retroviruses. We discovered a new mechanism that explains how an endogenous retrovirus directly controls pluripotency factors.

Nabil Djouder, lead author
Growth Factors, Nutrients and Cancer Group
Molecular Oncology Programme
Spanish National Cancer Research Centre (CNIO), Madrid, Spain.

This new action mechanism involves URI, a gene that Djouder’s group is researching in depth. Years ago, it was discovered that if URI is deleted in laboratory animals, embryos do not even get to develop. De la Rosa wanted to find out why, and which is how its link to the MERVL retrovirus was discovered.

A smooth transition

The findings show that one of the functions of URI is to enable the action of molecules essential for acquiring pluripotency; if URI does not act, neither do the pluripotency factors, and the cell remains in a state of totipotency. It turns out to be an endogenous retrovirus protein, MERVL-gag, which modulates the action of URI.

The researchers found that during the totipotency phase, when there are only two cells in the oocyte, expression of the MERVL-gag viral protein is high; this protein binds to URI and prevents it from acting. However, the levels gradually change, so that the levels of MERVL-gag viral protein go down and URI can enter into action: pluripotency appears.

It’s a smooth transition. When there is a high expression of viral protein, there are fewer pluripotency factors; as ERV expression decreases, URI stabilises such factors.

Segio De la Rosa.

Symbiotic co-evolution

“Our findings reveal symbiotic co-evolution of endogenous retroviruses with their host cells in order to guarantee the smooth and timely progression of early embryonic development,” explain the authors in Science Advances.

In other words, the three-way relationship between the viral protein, URI and pluripotency factors is finely modulated, “to allow sufficient time for the embryo to adjust and coordinate the smooth transition from totipotency to pluripotency and cell lineage specification during embryonic development,” concludes Djouder.

In their open access papers, the team say:

Abstract

The smooth and precise transition from totipotency to pluripotency is a key process in embryonic development, generating pluripotent stem cells capable of forming all cell types. While endogenous retroviruses (ERVs) are essential for early development, their precise roles in this transition remains mysterious. Using cutting-edge genetic and biochemical techniques in mice, we identify MERVL-gag, a retroviral protein, as a crucial modulator of pluripotent factors OCT4 and SOX2 during lineage specification. MERVL-gag tightly operates with URI, a prefoldin protein that concurs with pluripotency bias in mouse blastomeres, and which is indeed required for totipotency-to-pluripotency transition. Accordingly, URI loss promotes a stable totipotent-like state and embryo arrest at 2C stage. Mechanistically, URI binds and shields OCT4 and SOX2 from proteasome degradation, while MERVL-gag displaces URI from pluripotent factor interaction, causing their degradation. Our findings reveal the symbiotic coevolution of ERVs with their host cells to ensure the smooth and timely progression of early embryo development.

INTRODUCTION

The transition of a fertilized oocyte into a totipotent zygote marks the beginning of embryonic development. This transition relies on extensive replacement of the maternal transcriptome by the zygotic genome activation, together with well-orchestrated epigenetic reprogramming of both parental nuclei (1–3). The totipotent zygote generates the entire living organism by later segregating the two first cell lineages to establish the pluripotent inner cell mass (ICM), as well as the surrounding outer trophectoderm (TE) layer that nourishes and sustains development. Within the ICM, a second lineage specification takes place at the late preimplantation stage to form both the pluripotent epiblast (EPI) from which the embryo proper derives as well as the primitive endoderm (PrE) that will give rise to the extraembryonic endoderm layers of the yolk sac. TE, EPI, and PrE cells constitute the blastocyst, a structure formed at the last preimplantation stage.

The octamer-binding 4 (OCT4) and the sex-determining region Y box 2 (SOX2) transcriptional factors are indispensable to the foundation of pluripotency in the early embryo, and for the complete segregation of the EPI and TE lineages between eight-cell (8C) stage to the early blastocyst before implantation (4). However, in the early 2C embryo, which is considered to have two equally totipotent blastomeres, differences in the developmental potential and pluripotency lineage contribution between the two blastomeres have been reported (5–7). OCT4 and SOX2 activity in the early embryo blastomeres is known to predict cell lineage contribution. Specifically, long stable binding of OCT4 and SOX2 to DNA, as well as their heterogeneous target gene expression patterns reportedly bias cell fate in the 4C mouse embryo (7–9). Furthermore, their DNA binding depends on histone H3 arginine 26 (H3R26) methylation levels (8, 9), which are controlled by the coactivator-associated arginine methyltransferase 1 (CARM1), which is heterogeneously expressed at the first steps of murine development (7, 10, 11). However, the mechanisms that control the stability of the pluripotency factors that are indispensable for cell fate decisions remain to be elucidated. Approximatively, 10% of the mammalian genome is composed of nontransposable endogenous retroviruses (ERVs), remnants of ancient viral infections that have become integrated into the genome of their hosts, and erroneously considered to be nonfunctional “junk” DNA. ERVs become active in a specific pattern during embryo development, potentially regulating chromatin organization and transcription (12–14). The murine class III ERV with leucine transfer RNA primer binding site (MERVL) is specifically expressed during the zygotic genome activation at the 2C stage (12, 15), is one of the first transcripts expressed in the totipotent embryo, and reportedly acts as a proximal promoter to drive genes related to totipotency (12). Accordingly, activation of MERVL in pluripotent stem cells can induce a 2C-like cell state (14, 16, 17). Moreover, while derepression of ERVs can be lethal at various embryonic stages (18–21), depletion of MERVL specifically causes lineage segregation failure in early mouse embryo (22, 23). MERVL also encodes the group-specific antigen (gag) protein, known as MERVL-gag which forms virus-like particles (15); however, the mechanism by which ERVs control cell fate in the early embryo at the transition from totipotency to pluripotency requires further investigation. Understanding this mechanism is crucial, as the stability of pluripotency factors is indispensable for cell fate decisions during the timely progression of embryonic development.

The unconventional prefoldin RPB5 interactor (URI) is an atypically large member of the unconventional prefoldin complex (24, 25). Although the function of the URI prefoldin-like complex remains largely unknown, prefoldins have proven to be essential for the health and integrity of cells, protecting against unfolded protein aggregation (25). URI has been initially identified as a downstream component of the nutrient and growth factor signalling cascade and has been shown to coordinate nutrient availability with gene expression (24, 26). Moreover, findings indicate that overexpressing URI in mice facilitates oncogenic activity (27–29), while its genetic ablation in adult mice leads to organ failure (28, 30). Maintaining homeostatic URI levels is therefore essential to preserve organ homeostasis during adulthood, and hence, URI might have a critical role during mouse embryo development. This is supported by studies conducted in Caenorhabditis elegans and Drosophila showing that deletion of prefoldin results in embryonic lethality (31, 32). However, it remains unknown whether URI is required for early embryonic development and how it interacts with key players in the first lineage specifications during preimplantation mouse embryos.

Fig. 1. URI concurs with blastomere pluripotency bias in the early mouse embryo.
(A) Immunofluorescence (IF) of URI in murine preimplanted embryos at different time points of embryonic development. Bottom represents magnifications for single embryo; dotted lines indicate ICM compartment. Scale bar, 100 μm. BF, bright-field. (B) URI intensity across early murine development from (A). One-way analysis of variance (ANOVA; Tukey post hoc test); ****P < 0.0001; ns, nonsignificant. (C) Uri expression along murine preimplantation development from normalized RNA-seq dataset analysis. Data are represented as mean of pooled embryos ±95% confidence intervals. (D) IF of URI and CARM1 speckles in mouse 2C embryos. Scale bars, 10 and 5 μm. (E) URI intensity in high versus low CARM1 speckles in 2C blastomeres from (D). Paired t test; ****P < 0.0001. (F) IF of URI and CARM1 nuclear speckles in 4C embryos. Scale bars, 10 and 5 μm. (G) URI intensity in high versus low CARM1 speckles number from (F). Matched one-way ANOVA (Tukey correction); *P < 0.05, **P < 0.01, and ****P < 0.0001. (H) Linear regression and correlation analysis of URI and CARM1 speckles number in 4C embryos from (F). a.u., arbitrary units. (I) IF of URI and BAF155 in mouse 4C blastomeres. Scale bars, 25 and 10 μm. (J) URI intensity in high versus low BAF155 blastomeres from (I). Matched one-way ANOVA (Geisser-Greenhouse correction and Holm-Sidak post hoc test); **P < 0.01. (K) Scheme summarizing URI expression among blastomeres at early developmental stages. Total number of embryos is referred in each panel. Repository accession number for sequencing dataset analysis are indicated in respective panel and compiled in table S1. Mo, Morula embryo; eBl, early blastocyst embryo; lBl, late blastocyst embryo.

All this elaborate Heath Robinson contraption to overcome the fact that our putative designer (that we're still pretending is real, remember!) used the same method to reproduce cells in multicellular organisms with the need for cell-specialisation, that it used for their single-celled ancestors, when it could and should have designed a method that just reproduced the genes a daughter cell was going to need! A wonderfully inept contraption of which William Heath Robinson would have been proud.

Epigenetics, probably better than almost anything else in nature, falsifies the idea that any intelligence was involved in the evolution of multicellularity and ultimately of almost every living thing we can see. None of it makes an iota of sense as the work of even an incompetent designer, let alone a supremely intelligent one with the gift of perfect foresight.

But evolution, which has no foresight, and no reverse gear so can't dump a bad design and start again, but is obliged to make do with whatever works and move on, explains epigenetics perfectly, without the need for magic or inept supernatural designers.

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