https://phys.org/news/2024-10-human-spliceosome-decade-reveals-blueprint.html

"The spliceosome edits genetic messages transcribed from DNA, allowing cells to create different versions of a protein from a single gene. The vast majority of human genes—more than nine in 10—are edited by the spliceosome. Errors in the process are linked to a wide spectrum of diseases including most types of cancer, neurodegenerative conditions and genetic disorders.

"The sheer number of components involved and the intricacy of its function has meant the spliceosome has remained elusive and uncharted territory in human biology—until now.

***

"Every cell in the human body relies on precise instructions from DNA to function correctly. These instructions are transcribed into RNA, which then undergoes a crucial editing process called splicing. During splicing, non-coding segments of RNA are removed, and the remaining coding sequences are stitched together to form a template or recipe for protein production.

"While humans have about 20,000 protein-coding genes, splicing allows the production of at least five times as many proteins, with some estimates suggesting humans can create more than 100,000 unique proteins.(my bold)

***

"Their work revealed that different components of the spliceosome have unique regulatory functions. Crucially, they found that proteins within the spliceosome's core are not just idle support workers but instead have highly specialized jobs in determining how genetic messages are processed, and ultimately, influence the diversity of human proteins.

"For example, one component selects which RNA segment is removed. Another component ensures cuts are made at the right place in the RNA sequence, while another one behaves like a chaperon or security guard, keeping other components from acting too prematurely and ruining the template before it's finished.

"The authors of the study compare their discovery to a busy post-production set in film or television, where genetic messages transcribed from DNA are assembled like raw footage.

"'You have many dozens of editors going through the material and making rapid decisions on whether a scene makes the final cut. It's an astonishing level of molecular specialization at the scale of big Hollywood productions, but there's an unexpected twist. Any one of the contributors can step in, take charge, and dictate the direction. Rather than the production falling apart, this dynamic results in a different version of the movie. It's a surprising level of democratization we didn't foresee," says Dr. Malgorzata Rogalska, co-corresponding author of the study."

***

"Apart from cancer, there are many other diseases caused by faulty RNA molecules produced by mistakes in splicing. With a detailed map of the spliceosome, which the authors of the study have made publicly-available, researchers can now help pinpoint exactly where the splicing errors are occurring in a patient's cells."

Comment: comparison with putting a film together is a good way to conceive of this. The original article is highly sophisticated study:

https://www.science.org/doi/10.1126/science.adn8105

https://www.sciencedaily.com/releases/2024/09/240925172115.htm

"Adults with hemophilia B saw their number of bleeding episodes drop by an average of 71 percent after a single infusion of gene therapy, according to the results of an international Phase III clinical trial published today in the New England Journal of Medicine...

***

"Hemophilia is a genetic disorder that limits the blood's ability to clot and affects around 30,000 people in the United States, mostly males. Left untreated, it can cause spontaneous bleeding, particularly internal bleeding into the joints, which, over time, can cause painful joint damage and mobility issues. Hemophilia B is caused by a lack of clotting factor IX. The gene therapy enables the liver to create factor IX, which allows the blood to clot and protects patients from frequent bleeds.

***

"After at least one year of follow-up, participants in the study had an average 71 percent reduction in bleed rate after receiving the gene therapy, compared to the year prior, when they were treated with prophylactic infusions of factor IX, the standard treatment for the disease. More than half of the 45 patients in the study did not have any bleeds after receiving gene therapy.

"Based on the results of this study, the FDA approved the gene therapy (fidanacogene elaparvovec) in April 2024. Cuker was the site lead for the clinical trial at Penn Medicine, which was one of the top-enrolling sites for the study. It represents the second form of gene therapy approved to treat hemophilia B. The first such therapy (etranacogene dezaparvovec-drlb) was approved in November 2022, and Penn Medicine is one of several medical centers in the United States where this treatment is available to patients.

"Gene therapies have very specific guidelines that determine eligibility and require specialized knowledge to carry out patient screening and selection, education about treatment risks and benefits, and post-therapy monitoring. Penn Medicine offers access to numerous clinical trials for gene therapy and expertise in administering FDA-approved gene therapies.

"In the current study, the most common adverse effect was related to an immune system attack on liver cells that were targeted by the gene therapy, which can render the gene therapy ineffective, if not quickly treated. In the study, affected patients were treated with steroids to limit this immune reaction. Patients in the study will continue to be followed for at least five years to monitor potential long-term side effects.

***

"'We hear from people born with hemophilia that -- even if their disease is well-managed -- there's this burden that's always in the back of their mind. The frequent infusions, the cost of treatment, the need to plan for infusions when traveling, what happens if they do experience a bleed, and so on, is always there," Cuker said. "Now that we have patients who were treated on this study and are essentially cured of their hemophilia, they're telling us about realizing a new, 'hemophilia-free state of mind.' As a physician, it's amazing to see my patients so happy with their new reality.'"

Comment: Here is a clear example of humans clearing up an error in God's systems.

https://aeon.co/essays/we-need-new-metaphors-that-put-life-at-the-centre-of-biology?utm...

"...at least some of that non-coding genome is now known to be involved in regulating genes: altering, activating or suppressing their transcription into RNA and translation into proteins...So, to understand how life really works at the genomic level, we need to understand gene regulation.

***

"At first these non-coding (nc) RNA genes...seemed a mere curiosity. But their numbers have been growing sharply, and now slightly exceed the number of coding genes. Some predict that eventually ncRNA genes will turn out to far outnumber protein-coding genes. The ncRNAs themselves may vary hugely in length, from many hundreds of ‘letters’ to a mere 20 or so. It is not yet known what many of them do, but in general they are thought to play important roles in gene regulation. (my bold)

***

"For us, there is layer after layer of regulatory processes, and we have little notion yet of how it all adds up. The same transcription factor can act on several different genes and can have different effects on the same gene in different types of cell, so that the result depends on some higher-level contextual information. Genes are also regulated by how the physical material of the chromosomes called chromatin – a composite of DNA with attached proteins called histones – is packaged up, which is a poorly understood matter. It’s as though some parts of the genome get filed away where they can’t be read. (my bold)

***

"What’s more, our genes tend to be regulated not by individual molecules but by whole gangs of them. Transcription factors act together with other molecules (especially that regulatory ncRNA) and with regulatory segments of DNA called enhancers, insulators and so on, in vast teams that gather into loose collectives that some call condensates, which emerge like blobs of vinegar in the oil of salad dressing. No one knows how all this works,...

***

"...it’s not hard to see why, the more complex the organism, the fuzzier its molecular mechanisms have to be. A huge machine that works only if all its countless components interlock in precisely coordinated ways is far too fragile – especially if those parts are, like molecules, constantly moving about randomly in a warm, wet environment. By the same token, if life relied on the accurate readout of innumerable genomic instructions in exactly the right order, it would be far too vulnerable to errors. It’s for these reasons that we are not machines – not, that is, like any machine humans have ever built. It’s a far better and more robust solution to find principles that work over many hierarchical levels, with the operation at one level being not too sensitive to the fine details of the levels below. Gene regulation by rather loosely defined condensates rather than by specific molecular switches, say, means that it can still work without every molecule having to be present and correct. (my bold)

"Evolution has, to speak anthropomorphically, evidently ‘designed’ our molecules to work in this fuzzy way. In contrast to the lock-and-key principle by which protein enzymes were long thought to recognise and transform their target molecules, some of the most important proteins in our cells, including many transcription factors, have shapes that are only loosely defined, enabling them to stick to others without being too choosy about it. And those little regulatory RNAs are generally too small to carry enough information for their unions to be very selective; they too work collectively, arriving at a decision, as it were, by committee.

***

"...the true causes of outcomes at the level of traits and of health don’t all come from the bottom up, from the genes, but emerge at all levels in the hierarchy of scales. That’s how life works.

***

"...I discovered to what a considerable extent some important biological molecules don’t necessarily choose their binding partners with exquisite and tight selectivity, but on the contrary are highly promiscuous and form only very transient and weak partnerships. There I learnt how cells of a given type don’t all make identical suites of biomolecules, and how we can quantify their variety.

***

" Our biomolecules appear to make decisions not in the manner of on/off switches but in loosely defined committees that obey a combinatorial logic, comparable to the way different combinations of just a few light-sensitive cells or olfactory receptor molecules can generate countless sensations of colour or smell.

***

"And shouldn’t we have seen that all along? For what, after all, is extraordinary – and challenging to scientific description – about living matter is not its molecules but its aliveness, its agency.

Comment: this article describes the surprised reaction at the degree of complexity, the multi-layer of controls, as if we never escaped the Darwinian approach of cells as blobs. We can now see them as "Barbara McClintock in recognising that the genome is a responsive, reactive system, not some passive data bank: as McClintock called it, a ‘highly sensitive organ of the cell’". So, it is a swarm of regulating ncRNA's in loose control that works! Yes, surprising and highly suggests a designer at work.

https://www.sciencedaily.com/releases/2024/07/240711111459.htm

"International joint research led by Akihisa Osakabe and Yoshimasa Takizawa of the University of Tokyo has clarified the molecular mechanisms in thale cresses (Arabidopsis thaliana) by which the DDM1 (Decreased in DNA Methylation 1) protein prevents the transcription of "jumping genes." DDM1 makes "jumping genes" more accessible for transcription-suppressing chemical marks to be deposited. Because a variant of this protein exists in humans, the discovery provides insight into genetic conditions caused by such "jumping gene" mutations.

"Disentangled DNA is often referred to as a "string." In a cell, however, it looks more like a "string ball," only the looping patterns are much more complex. The smallest unit is called a nucleosome. It consists of a section of DNA wrapped around a protein (histone) scaffolding. Transposons, genes that can "jump" to different locations in the genome, are "tucked away" in nucleosomes, which makes it difficult for the cell to deposit chemical marks that suppress transposon transcription. DDM1 is a protein known for maintaining such suppressing chemical marks, but it has not been clear how it can access transposons when they are neatly "tucked away."

"'Jumping genes are fascinating," says Osakabe, the first author of the paper, "because they can cause significant changes in the genome, both good and bad. Studying how proteins like DDM1 manage these genes helps us understand the basic mechanisms of life and can have important practical applications."

***

"The high-resolution images showed the exact positions where DDM1 bound to the DNA in the nucleosome. As a result, the specific binding site, which normally closes the nucleosome, got more "flexible" and opened up to allow suppressing chemical marks to be deposited, preventing transposons from being transcribed.

"This seemingly minor detail could be the start of major improvements.

"'The human version of DDM1, called HELLS, works similarly," says Osakabe. "In the long term, such discoveries could lead to new treatments for genetic diseases in humans caused by similar genes. This new knowledge also provides insights into how plants and other organisms control their DNA, which could improve our ability to grow better crops or develop new biotechnologies.'"

Comment: jumping genes seemed uncontrolled, appearing anywhere. Now we know they are controlled, not rogue elements. Everything in the genome is there for a reason. Purposelessness in evolution does not exist, except in Darwin's theory.

https://www.quantamagazine.org/most-life-on-earth-is-dormant-after-pulling-an-emergency...

"Researchers recently reported the discovery of a natural protein, named Balon, that can bring a cell’s production of new proteins to a screeching halt. Balon was found in bacteria that hibernate in Arctic permafrost, but it also seems to be made by many other organisms and may be an overlooked mechanism for dormancy throughout the tree of life.

"For most life forms, the ability to shut oneself off is a vital part of staying alive. Harsh conditions like lack of food or cold weather can appear out of nowhere. In these dire straits, rather than keel over and die, many organisms have mastered the art of dormancy. They slow down their activity and metabolism. Then, when better times roll back around, they reanimate.

"Sitting around in a dormant state is actually the norm for the majority of life on Earth: By some estimates, 60% of all microbial cells are hibernating at any given time. Even in organisms whose entire bodies do not go dormant, like most mammals, some cellular populations within them rest and wait for the best time to activate.

“'We live on a dormant planet,” said Sergey Melnikov, an evolutionary molecular biologist at Newcastle University. “Life is mainly about being asleep.”

***

"Some hibernation factors dismantle cellular machinery; others prevent genes from being expressed. The most important ones, however, shut down the ribosome — the cell’s machine for building new proteins. Making proteins accounts for more than 50% of energy use in a growing bacterial cell. These hibernation factors throw sand in the gears of the ribosome, preventing it from synthesizing new proteins and thereby saving energy for the needs of basic survival.

***

"Previously, all known ribosome-disrupting hibernation factors worked passively: They waited for a ribosome to finish building a protein and then prevented it from starting a new one. Balon, however, pulls the emergency brake. It stuffs itself into every ribosome in the cell, even interrupting active ribosomes in the middle of their work. Before Balon, hibernation factors had only been seen in empty ribosomes.

***

"Balon’s ability to halt the ribosome’s activity in its tracks is a critical adaptation for a microbe under stress, said Mee-Ngan Frances Yap, a microbiologist at Northwestern University who wasn’t involved in the work. “When bacteria are actively growing, they produce lots of ribosomes and RNA,” she said. “When they encounter stress, a species might need to shut down translation” of RNA into new proteins to begin conserving energy for a potentially long hibernation period.

***

"Balon can do this because it latches on to ribosomes in a unique way. Every ribosomal hibernation factor previously discovered physically blocks the ribosome’s A site, so any protein-making process that’s in progress must be completed before the factor can attach to turn off the ribosome. Balon, on the other hand, binds near but not across the channel, which allows it to come and go regardless of what the ribosome is doing.

***

"Despite Balon’s mechanistic novelty, it’s an exceedingly common protein. Once it was identified, Helena-Bueno and Melnikov found genetic relatives of Balon in upward of 20% of all the bacterial genomes cataloged in public databases. With help from Mariia Rybak, a molecular biologist at the University of Texas Medical Branch, they characterized two of these alternate bacterial proteins: one from the human pathogen Mycobacterium tuberculosis, which causes tuberculosis, and another in Thermus thermophilus, which lives in the last place you’d catch P. urativorans — in ultra-hot underwater thermal vents. Both proteins also bind to the ribosome’s A site, suggesting that at least some of these genetic relatives act similarly to Balon in other bacterial species.

"Balon is notably absent from Escherichia coli and Staphylococcus aureus, the two most commonly studied bacteria and the most widely used models for cellular dormancy. By focusing on just a few lab organisms, scientists had missed a widespread hibernation tactic, Helena-Bueno said. “I tried to look into an under-studied corner of nature and happened to find something.'”

Comment: we sleep one-third of our lives, so this approach is not an unusual view. The use of one protein over and over points to design.

https://www.sciencealert.com/embryo-development-linked-to-a-500-million-year-old-viral-...

"A critical early stage of embryonic development has been linked to a virus that mixed with the ancestral DNA of complex organisms like ourselves more than 500 million years ago.

"Genetic material from endogenous retroviruses – which infected the earliest organisms on Earth, leaving markers in our DNA – is estimated to make up around 8 to 10 percent of the modern human genome.

"'Until recently, these viral remnants were considered to be junk DNA, genetic material that was unusable or even harmful," says biologist Sergio de la Rosa, from CNIO. (my bold)

***

"Through a detailed study of mouse models, the team was able to identify a retroviral protein called MERVL-gag, which helps manage the pace of embryo development just a few hours after fertilization.

"The key development in question is when the first few totipotent cells (capable of becoming any of the cells that form the entire organism) give rise to pluripotent cells (capable of becoming cells that form any tissues of the body, but not placental tissue).

"This gradual process of specialization in the embryo is what turns a blob of cells into either a cat, a sea cucumber, an earthworm, or a human being, and the researchers showed how MERVL-gag influences a gene called URI – thought to be essential in enabling molecules to become pluripotent.

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

"The team found high levels of expression of the MERVL-gag protein in the early totipotency phase of embryo growth, with these levels then steadily decreasing as URI becomes more influential on the behavior of cells.

"What we're seeing here is a careful balance between proteins, genes, and pluripotency, the result of hundreds of millions of years of evolution, and none of it would be possible without an ancient virus.

***

"'We are starting to realize that these retroviruses, which have co-evolved with us over millions of years, have important functions, such as regulating other genes," says de la Rosa. "It's an extremely active field of research.'"

Comment: Well, more 'junk DNA' is not. It fits my thesis everything happens for a reason. It also fits my thesis we have viruses because they help code DNA, with good and bad results.

https://phys.org/news/2023-03-youre-stuck-genome-corals.html

"Some corals live to be hundreds, and even thousands, of years old. They were born with genes that were successful back in their parent's generation, so how can these old corals still be successful now? Especially in a changing climate? It's possible that the generation and the filtering of mutations that occur in different parts of a big coral act as a proving ground for adaptive genetics for the future.

***

"Nearly every animal must make a living with a set of genes that remains virtually unchanged during their lifetime, but a recent study of tropical reef building corals shows something different. These very long-lived animals are constantly changing and testing their genes—and some of these changes make it into the next generation. In this way a centuries-old coral might be a cauldron of genetic innovation, and it might help prepare them for climate change.

***

"The López-Nandam study found that the mutations that made it into the next coral generation had far fewer protein changes. This means that the corals were somehow filtering out the most likely deleterious mutations, and passing on changes that did not hurt the coral cells or that potentially benefited them.

"Overall, this study agrees with previous studies that found mutations in the tissues of large, long-lived corals are evolutionarily important. These mutations can add to the genetic diversity of coral populations and increase their ability to adapt to new conditions. In most animals this process also happens when offspring inherit new mutations that happen in the eggs and sperm of their parents, but takes many generations.

"The López-Nandam study goes a step further and shows that this adaptive process can happen within a single coral colony in a single generation—mutations are filtered to remove the harmful ones, potentially giving rise to patches of coral with new adaptive alleles…maybe even new mutations that can help counteract some of the stresses of climate-induced heat waves."

Comment: a different form of editing than in bacteria. Actively screening new mutations that serendipitously pop up.

https://www.sciencealert.com/soil-bacteria-discovery-could-allow-us-to-produce-electric...

"It may sound surprising, but when times are tough and there is no other food available, some soil bacteria can consume traces of hydrogen in the air as an energy source.

"In fact, bacteria remove a staggering 70 million tonnes of hydrogen yearly from the atmosphere, a process that literally shapes the composition of the air we breathe.

"'We have isolated an enzyme that enables some bacteria to consume hydrogen and extract energy from it, and found it can produce an electric current directly when exposed to even minute amounts of hydrogen.

***

"Prompted by this discovery, we analyzed the genetic code of a soil bacterium called Mycobacterium smegmatis, which consumes hydrogen from air.

"Written into these genes is the blueprint for producing the molecular machine responsible for consuming hydrogen and converting it into energy for the bacterium. This machine is an enzyme called a "hydrogenase", and we named it Huc for short.

"Hydrogen is the simplest molecule, made of two positively charged protons held together by a bond formed by two negatively charged electrons. Huc breaks this bond, the protons part ways, and the electrons are released.

"In the bacteria, these free electrons then flow into a complex circuit called the "electron transport chain", and are harnessed to provide the cell with energy.

***

"Hydrogen represents only 0.00005 percent of the atmosphere. Consuming this gas at these low concentrations is a formidable challenge, which no known catalyst can achieve. Furthermore, oxygen, which is abundant in the atmosphere, poisons the activity of most hydrogen-consuming catalysts.

***

"With Huc isolated, we set about studying it in earnest, to discover what exactly the enzyme is capable of. How can it turn the hydrogen in the air into a sustainable source of electricity?

"Remarkably, we found that even when isolated from the bacteria, Huc can consume hydrogen at concentrations far lower even than the tiny traces in the air. In fact, Huc still consumed whiffs of hydrogen too faint to be detected by our gas chromatograph, a highly sensitive instrument we use to measure gas concentrations.

"We also found Huc is entirely uninhibited by oxygen, a property not seen in other hydrogen-consuming catalysts.

***

"""In short, this research shows how a fundamental discovery about how bacteria in soils feed themselves can lead to a reimagining of the chemistry of life."

Comment: this is how extremophiles can survive using enzymes of this sort.

https://phys.org/news/2023-03-insights-bacterial-immune.html

"Bacteria, for example, take up foreign DNA through a process called horizontal gene transfer, which is much faster than the vertical inheritance from generation to generation.

"However, every living organism also faces risks by taking up foreign genetic information, as it could potentially be dangerous if, for example, important genes are damaged by integration into its own chromosome, resulting in major disadvantages for the organism as a whole. Therefore, bacteria have developed numerous mechanisms protecting them from absorbing harmful DNA. Many of the molecular processes involved were discovered in recent years, leading to the recent coinage of the term "bacterial immune system."

***

"Using the bacterium Corynebacterium glutamicum as an example, the researchers showed that the so-called Mks protein system has an additional element that can bind to plasmid DNA and cut it apart.

***

"Plasmids are small, usually ring-shaped, double-stranded DNA molecules that can replicate independently of the chromosome in their host cell. They play an important role in the ecology and evolution of bacteria, as they are an important vehicle of lateral gene transfer, enabling the rapid transfer of genetic information and thus the expression of selection advantages. In principle, all bacteria can exchange plasmids with each other even across species.

"This happens directly from bacterium to bacterium via a transfer mechanism known as conjugation. Both advantageous and disadvantageous plasmids utilize such bridges between bacterial cells to switch from one bacterium to another.

***

"'In previous research, we have investigated systems that are generally involved in the organization of DNA in bacterial cells and, among other things, ensure the packaging of genetic information into the compressed form of chromosomes," Weiß continues.

"In this context, the research team obtained initial indications that C. glutamicum possesses two such systems, one of which is not involved in the organization of the chromosome, but can prevent the multiplication of certain plasmids, although the mechanism responsible for this was previously unknown.

"Now, the Kiel researchers, together with experts led by Dr. Anne Marie Wehenkel from the Institut Pasteur in Paris, have discovered the DNA scissors of the Mks system in a structural study. "We were able to prove experimentally that this new subunit of the Mks system forms a specific protein, a so-called nuclease, which can cut DNA. This element has the task of degrading plasmids in order to keep harmful DNA away from the bacterial cell, while the other components of the Mks system are important for the recognition of plasmid DNA," Weiß says.

***

"'Bacteria use certain plasmids as a source of new, not immediately vital, genetic information. It is therefore obvious that a defense mechanism must be selective and not destroy all plasmids," says Bramkamp.

"'We were able to prove that in C. glutamicum there is indeed a directed selection according to beneficial and detrimental genetic information. When we artificially switched off the Mks system and thus all plasmids remained in the bacterial cells, detrimental effects on the cell, possibly triggered by DNA stress, were evident. However, these did not occur when the defense mechanism was active," Bramkamp continues.

'With the current work, the Kiel researchers are presenting important new findings about the bacterial immune system overall, which expand the understanding of plasmids as mediators of not only beneficial but also harmful genetic information. In future, they want to investigate which molecular mechanisms allow bacterial cells to differentiate between "good" and "bad" mobile DNA."

Comment: an advance in Shapiro's work on how bacteria handle additions to their DNA.

https://phys.org/news/2022-04-enzyme-strigolactone-hormone-growth.html

"As sessile organisms, plants have to continually adapt their growth and architecture to the ever-changing environment. To do so, plants have evolved distinct molecular mechanisms to sense and respond to the environment and integrate the signals from outside with endogenous developmental programs.

***

"The work stems from a study by Shabek, published in Nature in 2018, unraveling molecular and structural changes in an enzyme, MAX2 (or D3) ubiquitin ligase. MAX2 was found in locked or unlocked forms that can recruit a strigolactone sensor, D14, and target for destruction a DNA transcriptional repressor complex, D53. Ubiquitins are small proteins, found in all eukaryotes, that "tag" other proteins for destruction within a cell.

***

"They found that in the unlocked conformation, MAX2 can target the repressor proteins and biochemically decorate them with small ubiquitin proteins, tagging them for destruction. Removing these repressors allows other genes to be expressed—activating a massive gene network that governs shoot branching, root architecture, leaf senescence, and symbiosis with fungi, Shabek said.

"Sending these repressors to the proteasome disposal complexes requires the enzyme to relock again. The team also showed that MAX2 not only targets the repressor proteins, but once it is locked, the strigolactone sensor itself is destroyed, returning the system to its original state.

"Finally, the study uncovered the key to the lock, an organic acid metabolite that can directly trigger the conformational switch."

Comment: Once again, a complex mechanism which involves a giant enzyme molecule o drive the process. Without these specialized molecules, there would be no life. Design is required.

https://phys.org/news/2021-09-insights-klf4-gene.html

"The study, published in the journal Nature Communications, reveals that the binding of KLF4 can cause DNA to condense into a separate liquid phase in a process called biomolecular condensation, which recruits other factors that influence gene expression.

"'Cells regulate the expression of their genes with proteins called transcription factors," said co-corresponding author Dr. Josephine C. Ferreon, assistant professor of pharmacology and chemical biology and member of the Dan L Duncan Comprehensive Cancer Center at Baylor. "In the current study, we focused on master transcription factor KLF4, which is known to selectively mediate gene expression and reprogramming that determines cell fate."

***

"'Imagine mixing oil and water, how they form separate layers, or two liquid phases," Ferreon said. "When KLF4 interacts with specific chromatin regions, it forms a condensate—a separate liquid phase—that preferentially recruits other molecules that help open the chromatin and mediate gene transcription."

"Other transcription factors participate in biomolecular condensation through unstructured protein regions, but the researchers showed that KLF4 droplets form in cells even if its unstructured regions are not present. Instead, KLF4 droplet formation depends on regions called zinc fingers, which are known to bind DNA. Single molecule fluorescence experiments show that the three KLF4 zinc fingers, which usually bind in a row to one DNA, can 'bridge' between two DNA molecules.

"'This type of biomolecular condensation involving zinc fingers and DNA has not been seen before," Ferreon said.

"'Formation of this biomolecular condensate is strongly enhanced by a DNA modification called CpG methylation, a change that influences gene expression," said co-corresponding author Dr. Kevin MacKenzie, associate professor of pathology and immunology and of pharmacology and chemical biology at Baylor. "Our results suggest that the local sequence of DNA and its CpG methylation state enable KLF4 to drive DNA into a separate phase, which helps to organize chromatin in three dimensions."

"'Hundreds of human transcription factors contain tandem zinc fingers like those in KLF4, so this class of rapidly evolving proteins may be implicated in chromatin organization through similar 'bridging' interactions," said MacKenzie.

Comment: Expression of instructions from DNA must rely upon DNA 3-D relationships, which means DNA is more than a simple code but designed to have 3-D influences.

https://phys.org/news/2021-09-proteins-symphonies-genes-statistical-theory.html

"'Many scholars at the crossroad between physics and biology are now approaching what is probably the most crucial puzzle of biology," said co-author Alessandro Giuliani. "How is it possible that, starting from the same genetic background in the fertilized egg, around 400 highly differentiated cell types can arise, each endowed with a specific physiological role?"

"Biology-based theories often center on regulator proteins, called transcription factors, that biochemically conduct a symphony of genes to be expressed together. By contrast, many physicists have focused on expression waves, the rhythmic changes in expression levels across the genome, driven by relaxation and condensing of the DNA molecule itself.

"'It is something like the so-called hola, common in soccer and in other sport events, in which the spectators stand up simultaneously giving rise to a 'wave' spreading all over the stadium," Giuliani said.

"To get at the heart of the issue, the group focuses on a specific type of cell found in breast cancer with a proven track record of consistently behaving the same way to stimuli.

"They used statistical mechanics to make sense of how DNA molecules fold by assessing the collective behavior of a huge number of microscopic players in terms of ensemble properties, unlike classical top-down perspectives, like Newton's laws.

"Ultimately, the researchers landed in favor of expression waves, acknowledging that while transcription factors play a vital role, they are second fiddle to the changing shape of DNA."

Comment: Not yet fully understood, but it shows the point that DNA is not just a protein-producing code but by having its shape adjusted many possible results are produced. Only exquisite design by a designer can create this.

https://www.quantamagazine.org/mathematical-analysis-of-fruit-fly-wings-hints-at-evolut...

"Persevering until they had perfectly mounted about 2,000 pairs, the scientists then photographed the wings in high resolution and systematically compared the photos in 30,000 places.

"This was no mere exercise in taxonomy. Rather, the study, which was recently published in the journal eLife, has offered an exceptionally detailed look at the variation that can exist within a species. The results begin to resolve a long-standing tension in biology.

"On one hand, despite dramatic mutations in individuals’ genes and diverse environments in which they grow, members of a species develop into strikingly similar creatures. This robustness ensures that almost all individuals are functional. On the other hand, for evolution to occur, members of a species need diverse traits that natural selection can act upon. Those two forces — robustness and evolvability — tug in opposite directions. One wants less variation, and one wants more.

***

"Unexpected simplicity emerged from this rich data. The scientists saw a narrow range of possible appearances for the wings, which mostly diverged in a small set of characteristics. The variation was concentrated near the hinge of the wing and showed up in a few particular spots, such as the shape of the frontmost vein. Moreover, these variable traits were linked: When one of the traits on a wing was far from the average, the other traits usually were, too. This was true no matter which genetic or environmental modifications that fly experienced, implying that these factors individually have very limited influence.

***

"The photos of fly wings offered no clues as to the mechanisms that restrict the possible morphologies that can develop. Rather, the results substantiated the extensive power of these guardrails. Natural selection must mostly act on the significant diversity exhibited in the small number of linked, variable traits, while robustness tightly constrains the rest."

comment: variation in fruit fly's wings is tiny. Darwin theory demands enough variation to allow evolution to advance to more complex forms. If the variations are this tiny, Darwin's theory is constrained. Small species adaptations are changes in degree. A completely new species is a change in kind. That possibility requires new design, not offered by the small variations seen in this study .

https://phys.org/news/2021-08-brca2-protein-complex-important-dna.html

***

"The initials BRCA2 may be best known for a gene associated with many cases of breast cancer, and the protein encoded by the BRCA2 gene is critical to repairing breaks in DNA.

"The breakdown of this interaction is a hallmark of many cancers. Now, U-M scientists have determined the structure of a complex of two proteins—BRCA2 together with MEILB2—that allows repairs to happen efficiently in cells undergoing cell-splitting, called meiosis. Their results, reported in Nature Structural and Molecular Biology, have major implications for cancer and infertility.

***

"In germ cells—the cells that give rise to sperm or eggs—DNA breaks occur in every chromosome before the cells undergo meiosis. The breaks ensure mixing of genes to create genetic diversity rather than exact copies of the parents. In meiosis, each germ cell splits twice so that each egg or sperm ends up with only one copy of each chromosome. Then when egg meets sperm, the embryo has the right number of chromosome pairs.

"Before the first split occurs, the chromosomes in the germ cell pair up tightly and then each chromosome within a pair breaks and rejoins with pieces from its partner to exchange genes in a process called crossover. Then all these DNA breaks need to be rejoined quickly.

Think of a sandwich, Nandakumar explains. The "bun" is composed of four identical copies of a protein called MEILB2 on the top and bottom, with the two BRCA2 proteins between. The MEILB2 protein sandwich carries the BRCA2 protein precisely to the DNA break points.

***

"'While we have known BRCA2 was necessary for DNA recombination in meiosis, we didn't know how it was able to do this critical job efficiently," Nandakumar said. "The MEILB2 that is part of this repair complex is only supposed to be present in cells that undergo meiosis but MEILB2 has also been found in several cancers. It may be that MEILB2 is very efficiently 'hijacking' the BRCA2 in cancer cells, preventing proper repair of the DNA."

"Without other factors usually found in meiotic cells, the BRCA2 in these MEILB2-positive cancers might not get to the DNA breakpoints."

Comment: another highly complex process in making egg and sperm that runs at extremely fast micro-second rates. Must be designed all at once not by any stepwise process. Shows how there must be a designer.

https://inference-review.com/article/the-origin-of-novel-genes

"The four studies find that organisms with different morphologies possess different sets of genes. Given that genes provide much of the information encoding the morphology of living organisms, this finding may not seem a surprise. That novel genes do not accumulate with Darwinian gradualism in the phylogeny is perhaps more surprising. The authors describe bursts of innovation: upon the origin of placental mammals, 357 novel genes; upon the origin of the metazoan, 1,189 novel genes; upon the origin of the land plants, 1,167 novel genes; and upon the origin of the flowering plants, 2,525 novel genes.

"Equally surprising is evidence that the patterns of presence and absence of many genes in these studies do not form a nested hierarchy congruent with the accepted phylogeny. Particular genes often appear in more than one clade (Figure 1). This leads the authors to infer massive gene losses and frequent horizontal gene transfer in the history of life.

"The unexpected nature of these findings was not lost on the authors of the studies, nor the editors of the journals that published their manuscripts. Three of the paper titles emphasize unexpected novelty and one emphasizes unexpected loss. But all four show similar patterns. More is revealed in each than a single title can convey.

***

"In the 1850s, Charles Darwin considered it obvious that the morphological variation of life was continuous: “all the parts and organs of many independent beings” are “linked together by graduated steps.”

***

"It is far from clear how these homology groups might be linked in graduated steps. The evolution of novel genes is a subject with a substantial literature all its own, which has recently shifted from the view that all new genes begin as duplicates of pre-existing genes to a view that many genes evolve de novo from noncoding sequences. The mechanisms underlying this process are not well understood.

***

"Rather than emerging gradually, a few at a time, the evidence presented in these four papers suggests the occurrence of punctuated bursts. At every major phylogenetic node that was examined, the appearance of hundreds, and in some cases thousands, of novel homology groups was detected.

"Evolution by bursts is, of course, not expected if natural selection is the main driver. “[N]atural selection acts only by taking advantage of slight successive variations,” Darwin remarked; “she can never take a great and sudden leap, but must advance by the short and sure, though slow steps.”5 The findings presented in these papers suggest otherwise. It seems that the evolution of life is characterized by leaps involving large numbers of novel homology groups.

***

"The fossil record depicts the appearance of the first angiosperms as a sudden event, with no clear progenitors. This was known, in part, to Darwin, who famously complained to the director of Kew Gardens in 1879 that the origin of the dicotyledonous angiosperms was an “abominable mystery.”7 The mystery has since deepened to include all other angiosperms.

***

"These studies by the teams of Holland and Paps are not alone in finding bursts of novel genes in the history of life. In a paper published earlier this year, Zhang et al. conducted an analysis of plants similar to Bowles et al., with better sampling of charophytes and bryophytes.10 Despite using different gene clustering methods and a smaller set of species, they found gene gains at key nodes on similar orders of magnitude.

***

"ALL FOUR STUDIES under review found massive gene losses for phylogenetic nodes at the base of the major groups of living organisms. This suggests that major evolutionary transitions do not occur solely by means of tinkering with existing genes. Instead, it seems that vast numbers of existing genes are jettisoned and replaced by entirely different ones. Such processes would represent a radical overhaul in the genetic composition of organisms. How this might be accomplished is another mystery.

***

"Bowles et al. found that 323 homology groups were present in fungal and land plant genomes, but absent from all other taxa.12 Instead of being lost in the lineages between fungi and land plants, the genes could simply have jumped. This may turn out to be a more elegant solution to the problem.

"The incongruence between patterns in the absence or presence of homology groups and widely accepted phylogenies raises a broader issue. A single phylogeny is clearly an inadequate model for the history of life, but there is no obvious replacement. This question is wide open."

Comment: Gould's gaps and punctuation stares at you in your face. Behe laughs about the losses. This question is not 'wide open' as this discontinuity is perfect evidence of God the designer at work stepping in.

DAVID: It is an issue of direct control or second-hand control, and how one views a purposeful God.

dhw: Agreed. How does that make direct control more “logical” than allowing organisms to do their own designing, especially if you claim that your controlling God’s goal was to directly design humans, and he did this by directly designing millions of branches of life that had no connection with humans.

Remember my concept is to design humans over the time evolution took. This is an area of your constant confusion about what I think in regard to God's motives.

dhw: I remain baffled by your reference to “dhw confusion” in the heading of this thread.

DAVID: Go back in recent history and fix your memory. You put the wrong answer under this heading:
Genome complexity: how humans correct errors - dhw, 2020-11-08, 08:41.

Here is the post:
QUOTE: "It is probably most accurate to say that primary and secondary emotions have phenomenal consciousness (experiential feeling), but lack access consciousness (the ability to rationally access, manipulate and reflect upon emotions).

dhw: This is what I mean when I talk of different levels of intelligence/consciousness. But in the context of evolution, the basic drive is not confined to the brain and the exploitation of resources (i.e. finding food) – it also encompasses finding different modes of survival (e.g. avoiding predators, using or building shelters, countering every threat to existence). And I would suggest that this all begins at cellular level, with “phenomenally conscious” cells cooperating over billions of years to form increasingly complex structures, INCLUDING the brain and every other organ we know of and every other life form we know of. This is the “continuum” of evolution that David talks of, as organisms branch out into an ever more variegated bush, with just one of millions of “lines” leading to humans. The cell communities that form the brain itself would have followed precisely the same process of complexification as they responded to new requirements, including control of their new organs. The brains of most life forms would have settled once they had achieved “satisfaction and homeostasis” but, as we know, the human brain continued to expand as “access consciousness” enabled early humans to rationalize and manipulate – not just in terms of reflecting on emotions etc, but also reflecting on and implementing new methods of surviving and/or exploiting their environment.

dhw: Please pinpoint what you consider to be “confused”.

I repeat. What I received from you was comment under the wrong post title answering a different post title comment. I commented on the confusion and straightened out the mix up. Forget the issue, as we proceeded properly after that.

Under: "Sensory neurons do more than accept":
QUOTE: "The findings suggest that the sensory cortex is not just sensory, as previously thought. Instead of responding only to stimuli around us, Dr. Maravall's study suggests that the sensory neurons are also involved in processing the meaning of the stimuli, and planning the subsequent behavioural responses."

dhw: Wow, we have cells processing information and planning what to do with it. Sounds like intelligence to me.

DAVID: Why not? God designed them that way.

dhw: You could hardly have clearer signs of intelligence than processing information and planning what to do with it. This is the focal point of our discussion and, as an agnostic, I have no problem with your proposal that your God designed the intelligence of cells.

I know you do

DAVID: It is an issue of direct control or second-hand control, and how views a purposeful God.

Agreed. How does that make direct control more “logical” than allowing organisms to do their own designing, especially if you claim that your controlling God’s goal was to directly design humans, and he did this by directly designing millions of branches of life that had no connection with humans.

dhw: I remain baffled by your reference to “dhw confusion” in the heading of this thread.

DAVID: Go back in recent history and fix your memory. You put the wrong answer under this heading:
Genome complexity: how humans correct errors - dhw, 2020-11-08, 08:41.

Here is the post:
QUOTE: "It is probably most accurate to say that primary and secondary emotions have phenomenal consciousness (experiential feeling), but lack access consciousness (the ability to rationally access, manipulate and reflect upon emotions).

dhw: This is what I mean when I talk of different levels of intelligence/consciousness. But in the context of evolution, the basic drive is not confined to the brain and the exploitation of resources (i.e. finding food) – it also encompasses finding different modes of survival (e.g. avoiding predators, using or building shelters, countering every threat to existence). And I would suggest that this all begins at cellular level, with “phenomenally conscious” cells cooperating over billions of years to form increasingly complex structures, INCLUDING the brain and every other organ we know of and every other life form we know of. This is the “continuum” of evolution that David talks of, as organisms branch out into an ever more variegated bush, with just one of millions of “lines” leading to humans. The cell communities that form the brain itself would have followed precisely the same process of complexification as they responded to new requirements, including control of their new organs. The brains of most life forms would have settled once they had achieved “satisfaction and homeostasis” but, as we know, the human brain continued to expand as “access consciousness” enabled early humans to rationalize and manipulate – not just in terms of reflecting on emotions etc, but also reflecting on and implementing new methods of surviving and/or exploiting their environment.

Please pinpoint what you consider to be “confused”.

Under: "Sensory neurons do more than accept":
QUOTE: "The findings suggest that the sensory cortex is not just sensory, as previously thought. Instead of responding only to stimuli around us, Dr. Maravall's study suggests that the sensory neurons are also involved in processing the meaning of the stimuli, and planning the subsequent behavioural responses."

dhw: Wow, we have cells processing information and planning what to do with it. Sounds like intelligence to me.

DAVID: Why not? God designed them that way.

You could hardly have clearer signs of intelligence than processing information and planning what to do with it. This is the focal point of our discussion and, as an agnostic, I have no problem with your proposal that your God designed the intelligence of cells.

dhw: ...we KNOW organisms change their structures IN RESPONSE to new conditions.

DAVID: What major structures change in species adaptation? Nothing major we know of. Yes we also differ about design. Logically God must directly design, rather than putting it off to a secondary independent mechanism by cells.

dhw: It’s difficult to distinguish between adaptation and innovation when we consider all the different changes from land-based pre-whale life to marine life. And I have absolutely no idea why a divine 3.8-billion-year-old programme for every single life form, econiche, strategy and natural wonder in the history of life on Earth, or a vast number of individual operations on legs and brains and pelvises, and lectures delivered on nest-building etc., should be regarded as more “logical” than the invention of an intelligent mechanism capable of doing its own designing.

It is an issue of direct control or second-hand control, and how views a purposeful God.

dhw: I remain baffled by your reference to “dhw confusion” in the heading of this thread.

Go back in recent history and fix your memory. You put the wrong answer under the this heading:

Genome complexity: how humans correct errors - dhw, 2020-11-08, 08:41

DAVID: (under “DNA fights off viruses”) Bacteria edit their DNA to self-destruct and save the colony. I would ask how did this developed? Did bacteria learn this on their own or did it happen by design?

dhw: They seem to behave just like ants. And yes, I would suggest that just like ants, they design and pass on different ways of surviving different threats.

Under: "Sensory neurons do more than accept":
QUOTE: "The findings suggest that the sensory cortex is not just sensory, as previously thought. Instead of responding only to stimuli around us, Dr. Maravall's study suggests that the sensory neurons are also involved in processing the meaning of the stimuli, and planning the subsequent behavioural responses."

dhw: Wow, we have cells processing information and planning what to do with it. Sounds like intelligence to me.

Why not? God designed them that way.

DAVID: What major structures change in species adaptation? Nothing major we know of. Yes we also differ about design. Logically God must directly design, rather than putting it off to a secondary independent mechanism by cells.

It’s difficult to distinguish between adaptation and innovation when we consider all the different changes from land-based pre-whale life to marine life. And I have absolutely no idea why a divine 3.8-billion-year-old programme for every single life form, econiche, strategy and natural wonder in the history of life on Earth, or a vast number of individual operations on legs and brains and pelvises, and lectures delivered on nest-building etc., should be regarded as more “logical” than the invention of an intelligent mechanism capable of doing its own designing.

I remain baffled by your reference to “dhw confusion” in the heading of this thread. What do you find confusing about the concept of cellular intelligence as the driver of evolution, compared to the labyrinthine theory of divine programmes and dabbles and every life form with no connection to humans being part of the direct design of humans? Meanwhile, thank you for two more articles which fit in neatly with the concept of bacterial and cellular intelligence:

DAVID: (under “DNA fights off viruses”) Bacteria edit their DNA to self-destruct and save the colony. I would ask how did this developed? Did bacteria learn this on their own or did it happen by design?

They seem to behave just like ants. And yes, I would suggest that just like ants, they design and pass on different ways of surviving different threats.

Under: "Sensory neurons do more than accept":
QUOTE: "The findings suggest that the sensory cortex is not just sensory, as previously thought. Instead of responding only to stimuli around us, Dr. Maravall's study suggests that the sensory neurons are also involved in processing the meaning of the stimuli, and planning the subsequent behavioural responses."

Wow, we have cells processing information and planning what to do with it. Sounds like intelligence to me.

dhw: … even today we see some life forms changing themselves IN RESPONSE to new conditions, and nobody has ever seen such changes take place BEFORE conditions have changed.

DAVID: Again your mishmash trying to compare simple adaptations within species to speciation. I don't know how God created species, pre-programming or dabbling or whatever. All I do know is design by a designing mind is required.

I am not comparing them. I am pointing out that we KNOW organisms change their structures IN RESPONSE to new conditions. I don’t know what your “whatever” can refer to, since you have only ever offered us the two methods, and you have only ever argued that evolutionary innovations take place BEFORE the new conditions for which they are used. I am not objecting to the case for design, which is covered by my cellular intelligence theory, which in turn leaves open the possibility of your God as designer of cellular intelligence.

What major structures change in species adaptation? Nothing major we know of. Yes we also differ about design. Logically God must directly design, rather than putting it off to a secondary independent mechanism by cells.

dhw: I'm afraid the idea of pre-whales waking up one morning to find their legs have turned into fins elicits more of a giggle than a nod from me.

DAVID: I agree, but the giggle has to explain the fossil record gaps.

dhw: Firstly, every major fossil find is a sensation, because preservation over millions and millions of years is so unlikely, and secondly, if your God can restructure cell communities, why do you think he is incapable of designing cell communities to do the same thing – especially since we know there is such a mechanism for restructuring without his intervention (i.e. adaptation).

All quite minor. Again extrapolating to major change in design.

dhw: I am always surprised that you refuse to consider your God capable of designing a mechanism to produce all the billions of changes you make him preprogramme 3.8 billion years ago, or keep personally dabbling one by one.

DAVID: My reasoning is designing a mechanism to design for the future makes control one step away from the first designer, introducing possible errors.

dhw: According to you, your God’s design introduced errors anyway. We have a whole thread devoted to that subject, and the problem with your “control” theory is dealt with on that thread (which has broadened out again into a discussion of your whole theory of evolution). [Your "design for the future" theory was dealt with on this thread.] But you are right – my theory (theistic version) has God deliberately sacrificing control, and I offer a logical reason for his doing so under “Theodicy”.

DAVID: I don't view your theory in theodicy as logical based on my view of God in control.

dhw: You are simply saying that my theory is illogical because it differs from your theory! My idea that your God did not WANT control is no more and no less feasible than your idea that he did. Nothing to do with logic. Your theory leads you to admitting that you have no idea why he would have created bad bugs. You call that logic. My theory explains logically how the bad bugs could have come into existence, and why your God allowed them to do so, and it also explains the vast variety of life forms and natural wonders which have/had nothing to do with humans.

Each theory has a background of facts to be considered. Our considerations differ. My view of Godadn his intentions are not yours.