Refuting Creationisn - Understanding Consciousness - No God(s) Required

Study reveals how an anesthesia drug induces unconsciousness | MIT News | Massachusetts Institute of Technology

One of creationism beloved gaps in which they try to shoehorn their ever-shrinking little god, is a scientific explanation for consciousness.

It is true that we don't yet have an explanation for consciousness but no gap in the scientific understanding of anything has ever been filled by a god, or to be more scientific, by an unproven, undetectable supernatural entity, so it's a strangely unrealistic view of science that any (or all) of creationism's gaps, real or imaginary are going to be the exception to the rule and somehow, one day, science is going to reveal the locally popular god in all its glory, having managed to hide itself for millennia.

Being inherently unfalsifiable, of course, there is no possible scientific methodology that could reveal any specified god as the indisputable cause of any phenomenon, so creationist belief that this is about to happen is delusional.

But back to the problem of consciousness.

Refuting Creationism - A Burrowing Dinosaur - 99 Million Years Before 'Creation Week'

Fona herzogae.

Credit: Jorge Gonzalez.

Fona herzogae.

Credit: Jorge Gonzales

Life Underground Suited New Dinosaur Fine | NC State News

If you want to leave a fossil as evidence of your existence, live, or at least die, in a burrow.

If you want to refute creationism, arrange to die 99 million years before they believe the Universe existed.

That's what an otherwise unremarkable dinosaur that was about the size of a large dog, contrived to do in what is now Utah, USA. It, and its relatives, because so many of them died in their borrows, are preserved in exception detail compared to species that lived above ground where their bodies would have been scavenged and destroyed before they could be fossilised.

Creationism Refuted - Stardust Creation 1,300 Years Before 'Creation Week'

Cassiopeia A

JWST

Cassiopeia A

JWST Unveils Stunning Ejecta and CO Structures in Cassiopeia A's Young Supernova

Todays' refutation of creationism comes to us from the field of astronomy and in particular the details of what happened and is still happening in the expanding supernova remnant known as Cassiopeia A which has a super-dense body at its centre, probably a neutron star, the collapsed remains of the parent star.

A neutron star is the remains of an old star that was too large to collapse to a white dwarf but not large enough to become a black hole. In a neutron star, the pressure due to gravity is so intense that even atoms compress, and electrons are forced into protons to become neutrons, so the star becomes nothing but neutrons. Due to conservation of angular momentum a neutron star has a rotation rate in seconds or less.

Cassiopeia A (Cas A) was observed in the night sky 350 years ago. It is 11,000 light years away, so the light the explosion generated reached Earth 11,000 years after the explosion, which simple maths tells us happened 1,350 years before creationists think the Universe was created. It was of course an event in that long, 13.8 billion years pre-'Creation' history of the Universe when 99.99999% of its history, and 99.9975% of the history of Earth occurred.

A supernova like Cas A is the birthplace of star dust out of which Earth and everything on it is made. It is the stuff that connects us to the rest of the universe and to which we, or rather the atoms and molecules that we are made of, will return to be recycled into future planets around future suns, when our own sun swallows up the inner planets then goes supernova itself, and flings our atoms out into the cosmos to be recycled as new suns and planetary systems, maybe to be studied by cosmologists on some other planet wondering about that sudden flash of light in the Milky Way, that was the death of our sun.

As I said in What Makes You So Special? From the Big Bang to You:

Stars died and because they died, you live. You are made by stars out of stardust and in a very real sense; because you are made of the same stuff the Universe is made of and are a part of it, there is something even more wonderful about you. Through you, though not just through you, and maybe not just here on this small planet, the Universe has gained self–awareness and can begin to understand itself.

Through you it can stand on the surface of this beautiful little jewel in the cosmos, can look up in awe at itself and think "Wow!"

What Makes You So Special? From the Big Bang to You, page 152

Secular Humanism - Winning In Britain - Highest Number of MPs Ever Make A Secular Affirmation

300 MPs from the 2024 Parliament.

© House of Commons/Mark Crick.
Crown Copyright and CC BY-NC-ND 2.0

Kier Starmer Labour Prime Minister and the latest in a long line of non-religious UK PMs

Highest number of MPs ever take secular affirmation – Humanists UK

An under-reported fact following the landslide victory for the Labour Party at the last election was the massively increased number of MPs in the Commons who have no religion. Roughly 40% of MPs chose to make a secular affirmation rather than swear a religious oath on taking their seats. This included Sir Kier Starmer and 50% of his cabinet ministers.

The list of openly non-religious Prime Ministers ever since the 1888 when the law requiring all MPs to take a religious oath was abolished, includes Ramsay McDonald, first Labour PM and former president of Humanists UK, David Lloyd George, Neville Chamberlain, Winston Churchill, Clement Atlee and James Callaghan. It is almost exactly 100 years since Ramsay McDonald became the first PM to make a secular affirmation in 1924.

According to Humanists UK:

Antivaxxer Disinformation News - Flu-Like Symptoms After Vaccination Show The Vaccine is Working

COVID-19 Vaccine Side Effects and Long-Term Neutralizing Antibody Response: A Prospective Cohort Study: Annals of Internal Medicine: Vol 0, No 0

According to data published in Annals of Internal Medicine, people who experience flu-like symptoms - chills, tiredness, headaches, and feeling unwell, after a COVID mRNA vaccination tend to have a higher antibody count. This was based on a prospective cohort study of 363 participants from the San Fransico Bay area of California, US, who were vaccinated in 2021 and self-reported their symptoms.

Those who reported these symptoms had antibody levels about 1.5 time those of people who had no such symptoms after 1 month and at least 6 months after vaccination. In addition to those with self-reported symptoms, comparable results were found in 147 people who were objectively assessed for elevated skin temperature and increased heart rate.

The conclusion is that rather than acting as a deterrent, these symptoms should not be a deterrent but should be welcomed as evidence that the vaccine has worked.

More details are given in the report in Annals of Internal Medicine:

Malevolent Designer News - How Creationism's Divine Malevolence Victimises Hibernating Bats

Hyphae and spores of the fungus that causes white-nose syndrome (in green) invading the lab grown skin cells of little brown bats.

Credit: Klein Lab / UW–Madison

A hibernating little brown bat,Myotis lucifugus, infected with white-nose syndrome.

Photo credit: Jonathan Mays

A stealth fungus has decimated North American bats but scientists may be a step closer to treating white-nose syndrome

Creationism's malevolent designer seems to be in two minds about bats.

On the one hand it gives them a super-duper immune system that means they can harbour viruses like the corona viruses, one of which became SARS-CoV-2 that caused COVID-19; on the other hand, it designs a nasty fungus that is currently decimating populations of bat in North America, against which even their super-duper, intelligently [sic] designed immune system is ineffective.

The fungus, known to science as Pseudogymnoascus destructans, which causes the disease known as white-nose syndrome, is an invasive organism that uses various strategies to invade the skin of hibernating bats with deadly consequences. It was first detected in a New York cave in 2006.

Creationism Refuted - Evidence of Hominin Activity in Southern Spain - 1.4 Million Years Before 'Creation Week'

Partial skeleton of an elephant (Mammuthus meridionalis) unearthed from layer 5 of the upper archaeological level of the late Early Pleistocene site of Fuente Nueva-3.

Credit: Palmqvist et al., Journal of Iberian Geology (2024)

Entrapment of an elephant in the quicksand of layer 5 of the upper archaeological level of the late Early Pleistocene site of Fuente Nueva-3.

Credit: Palmqvist et al., Journal of Iberian Geology (2024)

Prehistoric quicksand trap in Spain reveals doomed elephants and early scavenging behavior | Archaeology News Online Magazine

A team of archaeologists from Malaga University have uncovered the earliest evidence of ancient hominin activity in Europe - at 1.4 million years ago.

The evidence from the Fuente Nueva-3 archaeological site in Orce, southeastern Spain shows that hominins scavenged alongside giant hyenas for animals which became stuck in a quicksand trap in what is now the Guadix-Baza Depression.

The team included Professor of Paleontology Paul Palmqvist and Professor of Stratigraphy and Paleontology María Patrocinio Espigares. They showed that the site consisted of two distinct archaeological levels, an upper (UAL) and a lower (LAL) level, the latter of which contains a high density of manuports, while the UAL contains remains of megafauna such as mammoths, Mammuthus meridionalis, and many hyena coprolites, showing significant scavenging activity

Refuting Creationism - No Ancestral Couple, Not Even An Ancestral Species - All Modern Humans Are Hybrids

Reconstruction of a Neanderthal woman.

‘A history of contact’: Princeton geneticists are rewriting the narrative of Neanderthals and other ancient humans

Our understanding of our relationship with contemporaneous archaic hominins such as Neanderthals has changed over the past 25 years or so. It was once believed that, as separate species, there would have been no successful interbreeding, despite a few fossils suggesting a mixture of both Neanderthal and Homo sapiens feature, then Nobel Prize-winning Svante Pääbo's group at the Max Plank Institute analysed a Neanderthal genome and showed that modern Eurasia Homo sapiens have 2-3% Neanderthal DNA, so interbreeding must have taken place.

Since then, the same team has discovered a second extinct hominin, the Denisovans, and shown that they too interbred with Neanderthals in Eurasia and Homo sapiens in East and Southeast Asia, especially.

And now we know that Africans' too carry evidence of Neanderthal genetic ingression.

In other words, ever since Homo sapiens left Africa and moved into the territory of at least two archaic hominins, the descendants of an earlier migration out of Africa, probably Homo erectus, have behaved much like a ring species of incompletely speciated geographical subspecies where barriers to hybridization had not fully evolved.

Malevolent Designer - How A Respiratory Pathogen Manipulates Our Immune System.

Haemophilus influenzae (H. flu)

A microscopic view of Haemophilus influenzae bacteria.

Image: Adobe

Respiratory bacteria ‘turns off’ immune system to survive - UQ News - The University of Queensland, Australia

Regular readers may recall my recent article explaining how bowel cancer has been cleverly 'designed' to switch off our immune system to prevent the cancer cells from being detected and attacked.

Well, it seems this same technique has been employed by the malevolent designer to make a bacterial pathogen better at making us sick when it infects the lining of the respiratory system of vulnerable people.

Or at least that is what an intellectually honest intelligent [sic] design creationist has to believe (if there is such a thing) because, in rejecting the science that shows how organism's evolve by a mindless, unintelligent natural process without the involvement of supernatural magic, and attributing it all to their putative designer, they are tacitly accepting that it also designs parasites such as these bacterial pathogens.

And we can exclude Michael J. Behe's scientifically nonsensical notions of 'genetic entropy' and 'devolution' [sic] from some assumed created initial perfection - made possible by the religious dogma of 'The Fall', because an ability that conveys an advantage to a pathogen and makes it able to produce more offspring than what went before, can't logically be described as less perfect than something worse, and of course, there is no known mechanism which would cause a detrimental mutation to increase in the species gene pool, other than riding piggyback on a mutation that conveys a greater advantage.

Refuting Creationism - Evidence Of Species Selection In The Pyrenees - Untouched By The Legendary Global Flood

The location of Coro Trasito is indicated by the orange dot.

Map created using USGS ArcGIS Online Map Viewer.

The location of Coro Trasito is indicated by the orange dot.

Map created using USGS ArcGIS Online Map Viewer.
https://doi.org/10.1371/journal.pone.0306448.g001

Early Pyrenean Neolithic groups applied species selection strategies to produce bone artefacts - Universitat Autònoma de Barcelona - UAB Barcelona

Because the Bronze Age mythmakers made up a tale about it, creationists believe their all-loving god committed a global genocide against all living species by flooding the world to a depth sufficient to cover the highest mountain (i.e. at least 29,000 feet, the height of Everest) about 4,000 years ago or less. Such a flood would have obliterated all signs of human civilisation on the planet and covered it with a thick layer of sediment containing the fossils of all the animals and plants jumbled together, from disconnected land-masses.

The problem with that belief is that there is evidence of human activity from long before that time, even in places like the Pyrenees between Spain and France, where archaeologists are uncovering evidence of human habitation and domestication of animals 7,000 years ago, in caves such as the Coro Trasito, located 1,548 metres above sea level, in Huesca, Spain.

Refuting Creationism - LUCA Had Evolved 4.2 Billion Years Ago And Already Suffered From Viral Parasites

A digital representation illustrating how LUCA was already under attack from viruses even at 4.2 billion years ago.

Science Graphic Design

A digital representation illustrating how LUCA was already under attack from viruses even at 4.2 billion years ago.

Science Graphic Design

July: LUCA | News and features | University of Bristol

Contrary to the Bible's laughable model of a 10,000-year-old universe consisting of a small flat planet with a dome over it, containing nothing that was unknown to the Bronze Age hill farmers whose best guess became part of the Hebrew creation myth, scientists at the University of Bristol have shown that the last universal common ancestor of all living organisms (LUCA) had evolved within 400 million years of Earth forming some 4.6 billion years ago.

They have calculated that LUCA was about as complex as a prokaryote, had already evolved an immune system and was engaged in an arms race with viruses.

Refuting Creationism - Scientists Now have the Genome of a Mammoth from 42,000 Years Before 'Creation Week'.

Model of a Woolly mammoth

By Thomas Quine, via Wikimedia (CC BY 2.0)

52,000-year-old wooly mammoth skin recovered from permafrost and found that it contained fossils of ancient chromosomes.

Love Dalén/Stockholm University

First ever 3D reconstruction of 52,000-year-old woolly mammoth chromosomes thanks to serendipitously freeze-dried skin | ScienceDaily

52,000 years ago, a full 42,000 years before creationism’s putative creator god created a universe comprised of a small flat planet with a dome over it, under which there was nothing that wasn't known to Bronze Age Canaanite hill farmers, a wooly mammoth somehow contrived to die and be quickly preserved in permafrost near what is now Belaya Gora, Sakha Republic, Siberia, where it was recovered in 2018, preserved in such a condition that skin cells could be identified under a microscope.

Mammoths, of course, along with their close relatives, elephants, were unknown to the authors of the tales in the Bible which creationists think are real history and science.

A microscope image of subdermal muscle from the ancient skin shows remnants of mammoth nuclei. The new study revealed that fossils of ancient chromosomes survive in this skin sample.

Elena Kizilova/Institute of Cytology and Genetics SB RAS

Carbon dating has shown the preserved mammoth to be more than 42,000 years old and an analysis of its mitochondrial DNA (mtDNA) gives a date close to 52,000 years old.

The research team co-led by Marcela Sandoval-Velasco and Juan Antonio Rodríguez of the Center for Evolutionary Hologenomics, University of Copenhagen, Copenhagen, Denmark, and Olga Dudchenko and Cynthia Pérez Estrada of The Center for Genome Architecture and Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, USA, used STAR Methods combined with Hi-C to analyse and reconstruct the genome from the ancient DNA (aDNA) recovered from the mammoth skin.

Creationism in Crisis - UK's Most Intact Dinosaur Fossil Was Living 125 Million Years Before 'Creation Week'

Jeremy Lockwood at the excavation site,
Compton Bay, Isle of Wight]

An artist’s impression of Comptonatus chasei.

Image credit: John Sibbick

Research reveals the most complete dinosaur discovered in the UK in a Century | University of Portsmouth

The fossil remains of a dinosaur, discovered in the cliffs of Compton Bay, Isle of Wight, England, have been shown to be a species new to science. The fossils were discovered in 2013 by the late fossil collector Nick Chase, who sadly died of cancer before his finds could be fully analysed. Nick Chase had a record of fossil discovery, including the most complete Iguanodon skull ever found, yet never had a new species named after him

That has now been rectified by retired GP and PhD student at the School of the Environment, Geography and Geosciences, University of Portsmouth, UK, Jeremy Lockwood, who helped with the dinosaur's excavation and has spent years analysing it to determine that it is a new species which he has named Comptonatus chasei. It has proven to be the most intact dinosaur ever discovered in Britain.

Together with David Martell, also of the School of the Environment, Geography and Geosciences, University of Portsmouth and Susannah Maidment of the Fossil Reptiles, Amphibians and Birds Section, Natural History Museum, London, UK, Dr Lockwood has published his findings, open access, in the Journal of Systematic Palaeontology. Their work is also explained in a University of Portsmouth press release:

Refuting Creationism - Extinct Giant Kangaroo Walked on All Fours - 2.5 Million Years Before 'Creation Week'

Imaginative AI reconstruction of a Protemnodon.

Illustration by Superinnovators x AI

July: Ancient large kangaroo moved mainly on four legs | News and features | University of Bristol

Science works because scientists, unlike religious fundamentalists, don't have fixed dogmas and doctrines they must adhere to and so are free to re-examine the evidence, reassess their conclusions and change their minds.

Unlike creationists, scientists are free to question, reassess and rethink without fear of a terrible fate awaiting them for having the temerity to question the cult dogma, or the social stigma, ostracism and in some cases threats of physical violence, that would be heaped upon a fundamentalist who questioned the basic tenets of the cult.

So, scientists are free from the sophophobia that charcterises creationism and which the cult leaders go to great lengths to inflict on their followers, and, unlike with creationism, the standing of a scientists who changes his or her mind with good reason goes up, while the social standing in creationist circles of a creationists who shows intellectual integrity and changes his or her mind will actually go down, in the prevailing anti-intellectual culture of the creationist cult!

Refuting Creationism - Evolution of Dingoes in 4,000 years

Dingo, Canis dingo,
Phillip Island, Gippsland, Victoria, Australia

Juergen & Christine Sohns/Nature Pl

Dingo, Canis dingo

ABC Eyre Peninsula: Gary-Jon Lysaght

What were dingoes like before the European invasion? Centuries-old DNA reveals a surprising history

Just about the time creationists believe their omnibenevolent god committed global genocide in a fit of pique, humans were introducing a domestic dog to Australia, where it was to become feral and begin the slow process of allopatric speciation.

Dingoes are an interesting study of evolution in progress, demonstrating how an isolated population diverges away from the parent population over time due to different environmental selectors and genetic drift as the isolated population adapts to local environmental change.

There is also the 'founder effect' where the founder population is not a representative sample of the parent population but contains a different range of allele frequencies. Some of these may be the reason it was able to invade the new territory in the first place, so it already starts off with some advantages, which may be selected for in the new environment. This has been described as surfing on a wave of selection as the new population advances into its new territory, so changing its allele frequency further away from its parent population.

All these processes that give rise to allopatric speciation can be seen in the Australian dingoes.

Malevolent Designer News - How Bowel Cancer Is Designed To Outwit Our Imune System

Example hematoxylin and eosin (H&E) staining for polypoid cancer

Kayhanian, H., Cross, W., van der Horst, S.E.M. et al. (2024)

Bowel cancer turns genetic switches on and off to outwit the immune system | UCL News - UCL – University College London

You're creationism's favourite invisible designer and you want to make people suffer and die from bowel cancer. So, you design a tumour that grows, spreads, and destroys essential tissues and systems. All good so far.

But there is a problem: when you designed humans you gave them an immune system to protect them from the parasites you had designed to make them sick, and this immune system can detect the bowel cancer cells and kill them!

What do you do?

Well, obviously, you design the cancer cells so they outwit the immune system you designed, and since you designed it, you know exactly what its weaknesses and vulnerabilities are.

Easy peesy! You just design the cancer cells so they switch the immune system off!

What can you tell me about the aetiology of bowel cancer in humans? The aetiology of bowel cancer, also known as colorectal cancer, involves a combination of genetic, environmental, and lifestyle factors. Here's a detailed overview:

Genetic Factors

1. Hereditary Syndromes:
   • Familial Adenomatous Polyposis (FAP): Caused by mutations in the APC gene, leading to the development of numerous polyps in the colon and rectum, which can turn into cancer if not managed.
   • Lynch Syndrome (Hereditary Nonpolyposis Colorectal Cancer, HNPCC): Caused by mutations in mismatch repair (MMR) genes (e.g., MLH1, MSH2), leading to a higher risk of colorectal cancer and other cancers.
2. Family History:
   • Individuals with a first-degree relative with colorectal cancer have a higher risk, suggesting a genetic predisposition even outside of known hereditary syndromes.
3. Genetic Mutations:
   • Sporadic mutations in genes such as KRAS, BRAF, and PIK3CA are common in colorectal cancer.
   • Microsatellite instability (MSI) and chromosomal instability (CIN) play roles in tumorigenesis.

Environmental and Lifestyle Factors

1. Diet:
   • High intake of red and processed meats has been associated with an increased risk.
   • Low fiber intake is also linked to higher incidence rates.
2. Physical Inactivity:
   • Sedentary lifestyle increases the risk, while regular physical activity is protective.
3. Obesity:
   • Increased body weight, particularly abdominal obesity, is a risk factor.
4. Alcohol Consumption:
   • High alcohol intake is associated with an increased risk of colorectal cancer.
5. Smoking:
   • Long-term tobacco use is a known risk factor.

Other Risk Factors

1. Age:
   • The risk increases with age, with most cases diagnosed in individuals over 50.
2. Inflammatory Bowel Disease (IBD):
   • Conditions like Crohn's disease and ulcerative colitis increase the risk of colorectal cancer due to chronic inflammation.
3. Diabetes:
   • Type 2 diabetes is associated with a higher risk of colorectal cancer.
4. Previous Cancer History:
   • Individuals with a history of colorectal cancer or adenomatous polyps are at increased risk for recurrence.

Molecular Pathways

1. Adenoma-Carcinoma Sequence:
   • Most colorectal cancers develop from adenomatous polyps through a series of genetic mutations and epigenetic changes.
2. Serrated Pathway:
   • Involves serrated polyps, which follow a different molecular pathway characterized by mutations in the BRAF gene and widespread DNA methylation (CIMP - CpG island methylator phenotype).
3. Microsatellite Instability (MSI):
   • A hallmark of Lynch syndrome and some sporadic cancers, involving defects in DNA mismatch repair.

Prevention and Early Detection

1. Screening:
   • Regular screening (e.g., colonoscopy, fecal occult blood test) can detect precancerous polyps and early-stage cancer, significantly reducing mortality.
2. Diet and Lifestyle:
   • A diet high in fruits, vegetables, and fiber, along with regular exercise, can reduce the risk.
   • Limiting alcohol consumption and avoiding smoking are also beneficial.

Understanding these factors is crucial for both prevention and early detection strategies, improving patient outcomes and reducing the burden of colorectal cancer.

Or that's what you would have to believe if you were an intelligent [sic] design creationist, because you believe there is only one designer capable of that degree of control over living organisms.

Yes, I know your guru, Michael J Behe tried to give you a work-around for the parasite/cancer problem by inventing the biologically nonsensical, but Bible-literalist consistent, notions of 'devolution' and 'genetic entropy', but anything which benefits the cells, in this case the cancer cells, can't be called 'devolutionary' nor the result of 'genetic entropy' from some initial perfection, because something better can't be less perfect than something worse.

So, what has this intelligent [sic] designer come up with to make its bowel cancer better at killing us in an especially nasty way?

Well, nothing actually, because what the researchers from University College London, UK (UCL) and the University Medical Centre, Utrecht, Holland, who investigated it found was that it had evolved naturally, with no evidence of magic or malevolent intent anywhere in the mindless, unplanned process.

What they found is the subject of an open access paper in Nature Genetics and a press release from UCL:

Bowel cancer turns genetic switches on and off to outwit the immune system

Bowel cancer cells have the ability to regulate their growth using a genetic on-off switch to maximise their chances of survival, a phenomenon that’s been observed for the first time by researchers at UCL and University Medical Center Utrecht.

The number of genetic mutations in a cancer cell was previously thought to be purely down to chance. But a new study, published in Nature Genetics, has provided insights into how cancers navigate an “evolutionary balancing act”.

The researchers found that mutations in DNA repair genes can be repeatedly created and repaired, acting as ‘genetic switches’ that take the brakes off a tumour’s growth or put the brakes back on, depending on what would be most beneficial for the cancer to develop.

Researchers say the findings could potentially be used in personalised cancer medicine to gauge how aggressive an individual’s cancer is so that they can be given the most effective treatment.

Cancer is a genetic disease caused by mutations in our DNA. DNA damage occurs throughout life, both naturally and due to environmental factors. To cope with this, cells have evolved strategies to protect the integrity of the genetic code, but if mutations accumulate in key genes linked to cancer, tumours can develop.

Bowel cancer is the fourth most common cancer in the UK, with around 42,900 cases a year. Though still predominantly a cancer that affects older people, cases among the under 50s have been increasing in recent decades.

Disruption of DNA repair mechanisms is a major cause of increased cancer risk. About 20% of bowel cancers, known as mismatch repair deficient (MMRd) cancers, are caused by mutations in DNA repair genes. But disrupting these repair mechanisms is not entirely beneficial to tumours. Though they do allow tumours to develop, each mutation increases the risk that the body’s immune system will be triggered to attack the tumour.

Cancer cells need to acquire certain mutations to circumvent mechanisms that preserve our genetic code. But if a cancer cell acquires too many mutations, it is more likely to attract the attention of the immune system, because it’s so different from a normal cell. We predicted that understanding how tumours exploit faulty DNA repair to drive tumour growth – whilst simultaneously avoiding immune detection – might help explain why the immune system sometimes fails to control cancer development.

Dr Marnix Jansen, senior author
UCL Cancer Institute
University College London, London, UK

In this study, researchers from UCL analysed whole genome sequences from 217 MMRd bowel cancer samples in the 100,000 Genomes Project database. They looked for links between the total number of mutations and genetic changes in key DNA repair genes.

The team identified a strong correlation between DNA repair mutations in the MSH3 and MSH6 genes, and an overall high volume of mutations.

The theory that these ‘flip-flop’ mutations in DNA repair genes might control cancer mutation rates was then validated in complex cell models, called organoids, grown in the lab from patient tumour samples.

Our study reveals that DNA repair mutations in the MSH3 and MSH6 genes act as a genetic switch that cancers exploit to navigate an evolutionary balancing act. On one hand, these tumours roll the dice by turning off DNA repair to escape the body’s defence mechanisms. While this unrestrained mutation rate kills many cancer cells, it also produces a few ‘winners’ that fuel tumour development.

The really interesting finding from our research is what happens afterwards. It seems the cancer turns the DNA repair switch back on to protect the parts of the genome that they too need to survive and to avoid attracting the attention of the immune system. This is the first time that we’ve seen a mutation that can be created and repaired over and over again, adding it or deleting it from the cancer’s genetic code as required.

Dr Suzanne E. M. van der Horst, co-author
University Medical Center Utrecht, Holland.

The DNA repair mutations in question occur in repetitive stretches of DNA found throughout the human genome, where one individual DNA letter (an A, T, C or G) is repeated many times. Cells often make small copying mistakes in these repetitive stretches during cell division, such as changing eight Cs into seven Cs, which disrupts gene function.

The degree of genetic disarray in a cancer was previously thought to be purely down to chance accumulation of mutations over many years. Our work shows that cancer cells covertly repurpose these repetitive tracts in our DNA as evolutionary switches to fine-tune how rapidly mutations accumulate in tumour cells.

Interestingly, this evolutionary mechanism had previously been found as a key driver of bacterial treatment resistance in patients treated with antibiotics. Like cancer cells, bacteria have evolved genetic switches which increase mutational fuel when rapid evolution is key, for example when confronted with antibiotics. Our work thus further emphasises similarities between evolution of ancient bacteria and human tumour cells, a major area of active cancer research.

Dr Hamzeh Kayhanian, first author
UCL Cancer Institute
University College London, London, UK

The researchers say that this knowledge could potentially be used to gauge the characteristics of a patient’s tumour, which may require more intense treatment if DNA repair has been switched off and there is potential for the tumour to adapt more quickly to evade treatment – particularly to immunotherapies, which are designed to target heavily mutated tumours.

A follow-up study is already underway to find out what happens to these DNA repair switches in patients who receive cancer treatment.

Overall our research shows that mutation rate is adaptable in tumours and facilitates their quest to obtain optimal evolutionary fitness. New drugs might look to disable this switch to drive effective immune recognition and, hopefully, produce better treatment outcomes for affected patients.

Dr Hugo J. G. Snippert, co-senior author
University Medical Center Utrecht, Holland.

This research was funded with grants from Cancer Research UK, the Rosetrees Trust, and Bowel Research UK.

Cancer’s evasion of immune system destruction is a key element of its ability to grow and spread. Understanding exactly how bowel cancers do this is crucial to optimising treatment for patients. Bowel Research UK are delighted that our funding has contributed to producing this exciting new data, and we look forward to seeing how these discoveries could change treatments for future patients.

Georgia Sturt
Research and Grants Manager at Bowel Research UK

Abstract
Mismatch repair (MMR)-deficient cancer evolves through the stepwise erosion of coding homopolymers in target genes. Curiously, the MMR genes MutS homolog 6 (MSH6) and MutS homolog 3 (MSH3) also contain coding homopolymers, and these are frequent mutational targets in MMR-deficient cancers. The impact of incremental MMR mutations on MMR-deficient cancer evolution is unknown. Here we show that microsatellite instability modulates DNA repair by toggling hypermutable mononucleotide homopolymer runs in MSH6 and MSH3 through stochastic frameshift switching. Spontaneous mutation and reversion modulate subclonal mutation rate, mutation bias and HLA and neoantigen diversity. Patient-derived organoids corroborate these observations and show that MMR homopolymer sequences drift back into reading frame in the absence of immune selection, suggesting a fitness cost of elevated mutation rates. Combined experimental and simulation studies demonstrate that subclonal immune selection favors incremental MMR mutations. Overall, our data demonstrate that MMR-deficient colorectal cancers fuel intratumor heterogeneity by adapting subclonal mutation rate and diversity to immune selection.

Main
In human cells, DNA mismatch repair (MMR) is performed by protein complexes consisting of MutL homolog 1 (MLH1) and PMS1 homolog 2 (PMS2), known as MutL_α, and MutS homolog 2 (MSH2) and MutS homolog 6 (MSH6), known as MutS_α¹. Alternatively, MSH2 can pair with MutS homolog 3 (MSH3) in a complex called MutS_β. MutS_α and MutS_β each function as DNA mismatch detection modules with partially overlapping specificities, whereas MutL_α (MLH1/PMS2) executes MMR. Although the mutagenic impact of isolated MSH6 or MSH3 loss is relatively mild, combined MSH6/MSH3 inactivation in model systems drives a robust hypermutator phenotype². Importantly, while MMR had previously been treated as a single linear pathway focused on postreplicative mismatch correction, recent studies indicate that MutSα and MutSβ also participate in the repair of endogenous mutational processes during interphase (for example, due to 5-methylcytosine deamination or oxidative damage) independent of MLH1 (refs. ^3,4,5; Fig. 1a,b). Overall, these studies suggest that MutS cooperates with MutL during canonical postreplicative repair of misincorporated bases, while MutS can liaise with other partners such as MBD4 in the interphase noncanonical repair of endogenous DNA damage.

Fig. 1: Subclonal MSH6^F1088fs and MSH3^K383fs homopolymer frameshift mutations drive increased mutation burden in the MMRd CRC GEL WGS cohort.

a, MS-instable CRC. b, The MMR system safeguards genomic integrity by detecting and repairing replication-associated mismatches (left, blue). Recent studies indicate that MutS also participates in the repair of endogenous mutational damage independent of MLH1 (right, pink). c, Volcano plot showing the relationship between MS frameshifts in individual genes and total mutation burden in multiple linear regression analysis. For each independent variable, the P value of a two-sided t-test is plotted as −log₁₀(P). Two-sided F statistic (accounting for multiple independent variables in the regression model) P = 4.2 × 10⁻⁷. d, Pie charts showing mutation categories for MSH3 (top) and MSH6 (bottom). e, Cases with MSH6^F1088fs and/or MSH3^K383fs homopolymer frameshifts (in red), and cases without such mutations (in blue) ranked by mutation burden (n = 217). Clonal alterations in MMR genes MLH1, PMS2, MSH2 and MSH6, as well as subclonal MSH6^F1088fs and MSH3^K383fs frameshift status, are indicated below. Insets show MSH6^F1088fs and MSH3^K383fs mutation variant allele fraction. Extended Data Fig. 1a–c shows analysis restricted to BRAFV600E tumors. f–h, Number of SNV (f), number of InDel (g) and total mutation burden (h) according to MSH6^F1088fs and MSH3^K383fs mutation status. Median values are represented by horizontal black lines.

Loss of MMR proficiency occurs in about 15% of colorectal cancers (CRCs) resulting in the accumulation of single-nucleotide mismatches and frameshift variants due to short insertion and deletion (InDel) mutations in repetitive homopolymer sequences⁶. In most cases, this is due to sporadic MLH1 hypermethylation. The relentless accumulation of somatic variants renders MMR-deficient (MMRd) tumors immunogenic and provokes extensive immunoediting⁷. While many of the genetic targets associated with immune escape (for example, HLA (human leukocyte antigen) complex and B2M (beta-2 microglobulin) mutations) have been characterized, the evolutionary trajectories MMRd tumors take to navigate their immune selection landscape remain unknown⁸.

Here we visualize the clonal architecture of evolving MMRd tumors to allow joint analysis of individual tumor subclones and the immune microenvironment at clonal resolution. We find that subclonal MMRd lineages harness hypermutable homopolymer sequences in MSH6 and MSH3 to adapt cellular mutation rate and mutation bias to subclonal immune selection. This strategy allows MMRd tumor subclones to engage in an evolutionary arms race with the evolving immune system and efficiently explore immune adaptation solutions while minimizing the deleterious impact of prolonged genomic hypermutation on cellular fitness.

Kayhanian, H., Cross, W., van der Horst, S.E.M. et al.
Homopolymer switches mediate adaptive mutability in mismatch repair-deficient colorectal cancer. Nat Genet (2024). https://doi.org/10.1038/s41588-024-01777-9

Copyright: © 2024 The authors.
Published by Springer Nature. Open access.
Reprinted under a Creative Commons Attribution 4.0 International license (CC BY 4.0)

---

Advertisement

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.

Available in Hardcover, Paperback or ebook for Kindle

Advertisement

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

Advertisement

Thank you for sharing!

Tweet Link

Refuting Creationism - What The Bible's Authors Forgot About

Aerial photograph of “funerary avenues” (foreground) and the Khaybar Oasis (background), facing south‐west.

© AAKSAK and the Royal Commission for AlUla

Location of the AlUla and Khaybar Counties, with details of the Khaybar Oasis and Volcano cores zones under the remit of RCU.

© AAKSAK and the Royal Commission for AlUla.

A struggling people languishing across barren lands? No, evidence shows life in ancient Saudi Arabia was complex and thriving

Living not a stone's throw from the Canaanite Hills where the authors of genesis made up their origin myths and filled the gaps in their knowledge and understanding with magical tales of invisible sky gods made of nothing creating things out of nothing with a few magic words, there was a thriving community of semi-nomadic farmers. These neolithic people traded extensively in the area and may even have been ancestral to the Middle Eastern pastoralists, or at least had a strong cultural influence on them.

Contrary to the Bible's authors' tales of a Universe consisting of a small, flat planet with a dome over it, being magicked up out of nothing between 6,000 and 10,000 years ago, and a global genocidal flood 4000 years ago, there were people building circular buildings in what is now North West Saudi Arabia between 6,500 and 8,000 years ago, and the remains of their dwellings show no signs of ever having been inundated.

That the Bible's authors, who had only oral traditions to go on, failed to acknowledge these near neighbours, speaks to their culturally chauvinistic parochialism and their intention to create the belief that they, and they alone, were the descendants of a magically-created first couple, created without ancestors, although they show some signs of awareness of other people in their tale of the sons of that first couple managing to find wives.

So, how do we know about these neolithic people from North West Arabia? From the artifacts and remains of buildings which would have been destroyed and swept away, or at least covered in a deep layer of fossil-bearing silt, by a global flood deep enough to cover the highest mountains in which almost every living thing perished, had it been a real event.

How these were discovered is the subject of an article in The Conversation by Jane McMahon, Research Associate, Discipline of Archaeology, University of Sydney, New South Wales, Australia. Her article is reprinted here under a Creative Commons license, reformatted for stylistic consistency:

Refuting Creationism - More On The Oldest Cave Art From 41,200 Years Before Creation Week

The oldest known cave art

Leang Karampuang in the Maros-Pangkep karst,
South Sulawesi, Indonesia

Found in a cave in Indonesia, we can now show the world’s oldest figurative art is 51,200 years old

Just a couple of days ago I wrote about the oldest known cave art, in Indonesia from 41,200 years before Creationists believe the Universe existed. As expected, this news has been completely ignored by creationists, presumably through fear of having to consider the terrifying prospect of being wrong and so not as important as they like to think they are.

Here then is an article about the discovery from The Conversation by four of the authors of the paper in Nature from Australian Universities - Adhi Oktaviana, PhD Candidate in Archaeology, Griffith University; Adam Brumm, Professor of Archaeology, Griffith University; Maxime Aubert, Professor of Archaeological Science, Griffith University and Renaud Joannes-Boyau, Professor in Geochronology and Geochemistry, Southern Cross University.

Their article is reprinted under a Creative Commons license, reformatted for stylistic consistency:

Refuting Creationism - The Swamp Monster from 300 Million BCE

Fossil Gaiasia jennyae skull and spine

Credit: C. Marsicano.

Gaiasia jennyae (artist's impression)

Credit: Gabriel Lio

Giant salamander-like creature was a top predator in the ice age before the dinosaurs - Field Museum

Way back in the 99.9975% of Earth's history that occurred before creationism's legendary 'Creation Week' with its small, flat planet with a dome over it that Creationists think was the entire universe, there was something nasty lurking in the southern swamps.

It was some 300 million years before 'Creation Week' to be approximately precise and had already made it to the apex predator of its time, strongly suggesting there were other edible things roaming the same ancient swamps.

The creature, known to science as Gaiasia jennyae was a giant amphibian, a descendant of amphibians that had been extinct for 40 million years from a phylum that was to give rise to the reptiles and eventually the dinosaurs some 40 million years later.

As an amphibian, it would have been tied to water for reproduction as its eggs were fertilised externally in water and its larval form would have lived in water, probably breathing with gills, like the tadpoles of frogs, newts, toads and salamanders of today.

It's modus operandum appears to have been a slow ambush predator, laying in a swamp with its huge mouth open ready to snap up anything that came within range with interlocking jaws and the front of its mouth bristling with large, sharp teeth that gave its prey little chance of surviving. It's skull alone was over 2 feet long and the whole creature was larger than an adult human being.

Gaiasia was a stem tetrapod, in other words it was close to creatures that had evolved from Tiktaalik, the lobe-finned fish that first crawled onto land and would later evolve into the terrestrial tetrapod vertebrates, amphibians, reptiles, birds and mammals that comprise the world's larger land animals and several aquatic species that have returned to the water.