It all started when single-celled organisms started to form colonies of like-minded individuals. The easiest way to do it was for the two daughter cells of a dividing cell to stick together instead of going their own way. They in turn would have had more daughter cells until they formed large clump of cells, but, unless the cells began to perform distinct functions, there was no advantage to forming clumps like that instead of each cell going its own way and fending for itself. Fortunately, there were no large predators around, otherwise a clump of cells would have made a tasty snack and the whole idea would have been abandoned as too risky by half, and we would be stuck now with a world of single-celled organisms and nothing else.
However, with the trial and error which characterises biological development, some of the cells in the clump began to perform specialist functions. For example, as the clump got larger, specialist cells would have been needed to exchange gasses with the environment or the cells at the centre would have been deprived of oxygen and their waste in the form of carbon dioxide would have accumulated because diffusing across a large mass of cells would be too slow to keep up with production and the supply of oxygen would be too slow to keep up with the demand. The same thing applied to getting nutrients into the center of the clump.
So, the clumps which had specialist cells fared better in the competition for resources than those which were just undifferentiated clumps. In fact, the clumps with specialised cells would probably have eaten the undifferentiated clumps and become predators. And with predators there was pressure for increased specialisation for movement, ingestion and excretion, for more efficient respiration and for reproduction. And predation also produced pressure for more motility, for senses like sight and smell and maybe hearing and as the organisms became more complex so they needed nervous systems to coordinate their activities and process and respond to the stimuli their senses were receiving from their environment and some would have evolved defensive armour such as scales and spikes and hard shells and internal structures like cartilage and bone to give their bodies shape and form and to make their swimming apparatus stiffer and more powerful.
But what they never managed to do was find a different way to produce all the different specialist cells by a different method to that used by their single-celled ancestors, so every cell in their body had the full genome whether they needed it or not, and more often than not, they didn't need most of it. A bone cell doesn't need to do what a nerve cell does, and a nerve cell doesn't need to do what a muscle cell does, and neither muscle nor nerve cells need to make bone, and what else needs to make elbow skin other than an elbow skin cell, except perhaps a scrotum skin cell? Yet they all have the genes for doing everything any one cell needs to do.
So, cue creationism's intelligent [sic] designer who has been designing and modifying all these different clumps of specialised cells but who, for some reason, seems incapable of recognising that its designs are heading for disaster unless it can think up a way to make sure each specialised cell has only the genes it needs. For reasons which no creationist apologist has ever managed to explain, their putative designer always behaves as though it can't undo a bad design and start again but is compelled to try to make the best of what it has muddled through with so far. In every way, creationism’s 'intelligent [sic] designer' behaves just like a mindless process operating without a plan, handicapped by acute amnesia, and constantly surprising itself with a new problem it designed just yesterday.
Just like the eccentric British designer and cartoonist, William Heath Robinson, no solution to a problem can be too complex even if it creates a new problem for which another overly complex solution has to be found. Unlikely objects, designed for a completely different purpose, will be pressed into service; a stepladder will be balanced precariously on top of a piano and an umbrella will be used to push a button when prodded by a sink plunger swinging on a length of knotted string. A labour-saving device for peeling potatoes will take half a dozen, intense and serious-looking men to operate it and peeling the potatoes will take considerably longer than had each man been given a potato peeler and left to get on with it. Eggs will be fried in a frying pan held over a candle lit by a match rubbed against a matchbox which swings into action when released by a lever when the scuttle-full of coal, or the boulder suspended on knotted string, lands on it.
And the whole 'irreducibly complex', 'intelligently designed' machine would fail if just one component was taken away or a piece of knotted string broke.
So complex is this system, that a team of researchers has only just worked out how cells pass on their epigenetic settings to their daughter cells.
Their findings are the subject of a paper in Nature and a news release from the University of Hong Kong:
A research team led by Professor Yuanliang ZHAI at the School of Biological Sciences, The University of Hong Kong (HKU) collaborating with Professor Ning GAO and Professor Qing LI from Peking University (PKU), as well as Professor Bik-Kwoon TYE from Cornell University, has recently made a significant breakthrough in understanding how the DNA copying machine helps pass on epigenetic information to maintain gene traits at each cell division. Understanding how this coupled mechanism could lead to new treatments for cancer and other epigenetic diseases by targeting specific changes in gene activity. Their findings have recently been published in Nature.
Figure 2.The cryo-EM structure of the yeast replisome in complex with FACT and parental histones (A) and its atomic model (B).Modified from Li et al, Nature (2004)
Figure 2. The cryo-EM structure of the yeast replisome in complex with FACT and parental histones (A) and its atomic model (B).Modified from Li et al, Nature (2004)
Background of the Research
Our bodies are composed of many differentiated cell types. Genetic information is stored within our DNA which serves as a blueprint guiding the functions and development of our cells. However, not all parts of our DNA are active at all times. In fact, every cell type in our body contains the same DNA, but only specific portions are active, leading to distinct cellular functions. For example, identical twins share nearly identical genetic material but exhibit variations in physical characteristics, behaviours and disease susceptibility due to the influence of epigenetics. Epigenetics functions as a set of molecular switches that can turn genes on or off without altering the DNA sequence. These switches are influenced by various environmental factors, such as nutrition, stress, lifestyle, and environmental exposures.
In our cells, DNA is organised into chromatin. The nucleosome forms a fundamental repeating unit of chromatin. Each nucleosome consists of approximately 147 base pairs of DNA wrapped around a histone octamer which is composed of two H2A-H2B dimers and one H3-H4 tetramer. During DNA replication, parental nucleosomes carrying the epigenetic tags, also known as histone modifications, are dismantled and recycled, ensuring the accurate transfer of epigenetic information to new cells during cell division. Errors in this process can alter the epigenetic landscape, gene expression and cell identity, with potential implications for cancer and ageing. Despite extensive research, the molecular mechanism by which epigenetic information is passed down through the DNA copying machine, called the replisome, remains unclear. This knowledge gap is primarily due to the absence of detailed structures that capture the replisome in action when transferring parental histones with epigenetic tags. Studying the process is challenging because of the fast-paced nature of chromatin replication, as it involves rapid disruption and restoration of nucleosomes to keep up with the swift DNA synthesis.
In previous studies, the research team made significant progress in understanding the DNA copying mechanism, including determining the structures of various replication complexes. These findings laid a solid foundation for the current research on the dynamic process of chromatin duplication.
Summary of Research Findings
This time, the team achieved another breakthrough by successfully capturing a key snapshot of parental histone transfer at the replication fork. They purified endogenous replisome complexes from early-S-phase yeast cells on a large scale and utilised cryo-electron microscopy (cryo-EM) for visualisation.
They found that a chaperone complex FACT (consisting of Spt16 and Pob3) interacts with parental histones at the front of the replisome during the replication process. Notably, they observed that Spt16, a component of FACT, captures the histones that have been completely stripped off the duplex DNA from the parental nucleosome. The evicted histones are preserved as a hexamer, with one H2A-H2B dimer missing. Another protein that involved in DNA replication, Mcm2, takes the place of the missing H2A-H2B dimer on the vacant site of the parental histones, placing the FACT-histone complex onto the front bumper of the replisome engine, called Tof1. This strategic positioning of histone hexamer on Tof1 by Mcm2 facilitates the subsequent transfer of parental histones to the newly synthesised DNA strands. These findings provide crucial insights into the mechanism that regulates parental histone recycling by the replisome to ensure the faithful propagation of epigenetic information at each cell division.
This study, led by Professor Zhai, involved a collaborative effort that spanned nearly eight years, starting at HKUST and concluding at HKU. He expressed his excitement about the findings, ‘It only took us less than four months from submission to Nature magazine to the acceptance of our manuscript. The results are incredibly beautiful. Our cryo-EM structures offer the first visual glimpse into how the DNA copying machine and FACT collaborate to transfer parental histone at the replication fork during DNA replication. This knowledge is crucial for elucidating how epigenetic information is faithfully maintained and passed on to subsequent generations. But, there is still much to learn. As we venture into uncharted territory, each new development in this field will represent a big step forward for the study of epigenetic inheritance.’
The implications of this research extend beyond understanding epigenetic inheritance. Scientists can now explore gene expression regulation, development, and disease with greater depth. Moreover, this breakthrough opens up possibilities for targeted therapeutic interventions and innovative strategies to modulate epigenetic modifications for cancer treatment. As the scientific community delves deeper into the world of epigenetics, this study represents a major step towards unravelling the complexities of replication-coupled histone recycling.
About the Research Team
Apart from Professor Yuanliang Zhai’s lab, the research team also includes Professor Xiang David Li from Department of Chemistry of HKU, Professor Yang Liu and Professor Keda Zhou from School of Biomedical Sciences of HKU, Professor Shangyu Dang from Division of Life Science of HKUST, and others. Learn more about Professor Yuanliang Zhai’s work and his research team: https://www.scifac.hku.hk/people/zhai-yuanliang or https://zhai95.wixsite.com/mysite-1
Co-authors include Mr Yuan Gao, Mr Jian Li, Dr Zhichun Xu from School of Biological Sciences (SBS) of HKU; Dr Ningning Li, Ms Yujie Zhang, Dr Jianxun Feng from School of Life Sciences of PKU, Dr Daqi Yu and Dr Jianwei Lin from Department of Chemistry of HKU, and Dr Yingyi ZHANG from Biological Cryo- EM Center of HKUST.
The journal paper can be accessed here: https://www.nature.com/articles/s41586-024-07152-2
AbstractThis Heath-Robinson solution to a problem which no intelligent designer would design in the first place, is repeated in every one of your 17 trillion cells and in every cell of every multicellular organism on the planet. A hugely wasteful and error-prone, needlessly complex system of which any intelligent designer would be ashamed, but which creationist frauds fool their ignorant dupes into believing is evidence of intelligence. In reality of course, it's evidence of exactly the opposite.
In eukaryotes, DNA compacts into chromatin through nucleosomes1,2. Replication of the eukaryotic genome must be coupled to the transmission of the epigenome encoded in the chromatin3,4. Here we report cryo-electron microscopy structures of yeast (Saccharomyces cerevisiae) replisomes associated with the FACT (facilitates chromatin transactions) complex (comprising Spt16 and Pob3) and an evicted histone hexamer. In these structures, FACT is positioned at the front end of the replisome by engaging with the parental DNA duplex to capture the histones through the middle domain and the acidic carboxyl-terminal domain of Spt16. The H2A–H2B dimer chaperoned by the carboxyl-terminal domain of Spt16 is stably tethered to the H3–H4 tetramer, while the vacant H2A–H2B site is occupied by the histone-binding domain of Mcm2. The Mcm2 histone-binding domain wraps around the DNA-binding surface of one H3–H4 dimer and extends across the tetramerization interface of the H3–H4 tetramer to the binding site of Spt16 middle domain before becoming disordered. This arrangement leaves the remaining DNA-binding surface of the other H3–H4 dimer exposed to additional interactions for further processing. The Mcm2 histone-binding domain and its downstream linker region are nested on top of Tof1, relocating the parental histones to the replisome front for transfer to the newly synthesized lagging-strand DNA. Our findings offer crucial structural insights into the mechanism of replication-coupled histone recycling for maintaining epigenetic inheritance.
Li, N., Gao, Y., Zhang, Y. et al.
Parental histone transfer caught at the replication fork.
Nature (2024). https://doi.org/10.1038/s41586-024-07152-2
© 2024 Springer Nature Ltd.
Reprinted under the terms of s60 of the Copyright, Designs and Patents Act 1988.
It's not even humorous and entertaining like William Heath-Robinson's ridiculously complicated, irreducibly complex, machines.
The Unintelligent Designer: Refuting The Intelligent Design Hoax
ID is not a problem for science; rather science is a problem for ID. This book shows why. It exposes the fallacy of Intelligent Design by showing that, when examined in detail, biological systems are anything but intelligently designed. They show no signs of a plan and are quite ludicrously complex for whatever can be described as a purpose. The Intelligent Design movement relies on almost total ignorance of biological science and seemingly limitless credulity in its target marks. Its only real appeal appears to be to those who find science too difficult or too much trouble to learn yet want their opinions to be regarded as at least as important as those of scientists and experts in their fields.
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The Malevolent Designer: Why Nature's God is Not Good
This book presents the reader with multiple examples of why, even if we accept Creationism's putative intelligent designer, any such entity can only be regarded as malevolent, designing ever-more ingenious ways to make life difficult for living things, including humans, for no other reason than the sheer pleasure of doing so. This putative creator has also given other creatures much better things like immune systems, eyesight and ability to regenerate limbs that it could have given to all its creation, including humans, but chose not to. This book will leave creationists with the dilemma of explaining why evolution by natural selection is the only plausible explanation for so many nasty little parasites that doesn't leave their creator looking like an ingenious, sadistic, misanthropic, malevolence finding ever more ways to increase pain and suffering in the world, and not the omnibenevolent, maximally good god that Creationists of all Abrahamic religions believe created everything. As with a previous book by this author, "The Unintelligent Designer: Refuting the Intelligent Design Hoax", this book comprehensively refutes any notion of intelligent design by anything resembling a loving, intelligent and maximally good god. Such evil could not exist in a universe created by such a god. Evil exists, therefore a maximally good, all-knowing, all-loving god does not.
Illustrated by Catherine Webber-Hounslow.
Available in Hardcover, Paperback or ebook for Kindle
Illustrated by Catherine Webber-Hounslow.
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