Saturday, 2 September 2023
Yet more on why the origin of life = the origin of information.
Introducing the Unknome, Biology’s Black Box
"Ome” is not a mantra in science, but it is an increasingly common suffix in biochemistry, genetics, and molecular biology. We all know about the genome. Then there was the epigenome, followed by the proteome. Now there is the interactome, the metabolome, the transcriptome, and others. More “omes” seem to pop up in the literature from time to time. As in the genome representing the set of genes of an individual or species, the suffix -ome denotes a “body” or set of parts that can be described together: the proteome consists of all the proteins in a cell. The transcriptome is the set of DNA transcripts. The interactome is the set of all interacting parts in a process, and the metabolome is the full complement of metabolites in a cell, tissue, or organism at a particular state. A new one is the “unknome” — the set of all components we know nothing about. More on that later. The -ome suffix has also long been used on individual units like ribosome, cytochrome, cryptochrome, and chromosome. Poets should have an easy time writing verses about biochemistry.
The study of all omes can be called Omics, with family members like genomics, proteomics, and transcriptomics. Omics is not just a taxonomical exercise; it is an attempt to get a handle on the bewildering complexity facing cell biologists. And just when they think they’ve got all the members corralled in an ome, complications set in.
Your Genomes (Plural)
For example, the journal Science announced recently that “Your cells don’t have the genome you were born with.” Contrary to what most people were led to believe by 23andMe, none of us have “a” genome, except at conception. From then on, the genome changes cell by cell, tissue by tissue, throughout life. These can add up to tens of thousands of changes per somatic cell. Modifications to the genome by mutations or by developmental processes turn us into universes of genomes!
As a result, every person is actually a mosaic of genomes, varying across the body and often within the same organ or tissue. These DNA changes introduce a diversity to the body’s somatic, or nonreproductive, cells that may be as important to health as the more pervasive alterations inherited from parents. Now, the National Institutes of Health (NIH) has launched a 5-year, $140 million project to map this universe of genomic diversity — and probe why it matters.
Dan Landau calls this “a huge revolution in human genetics.” He is eager to see the results. “We are just at the beginning of this incredible adventure.”
Omics in 3-D
Another review article in Science announces “The Dawn of Spatial Omics.” The editor’s review says,
All of biology happens in space. In living organisms, cells must interact and assemble in three-dimensional tissues. The position of each cell is just as important as its intrinsic nature in determining how a tissue functions or malfunctions in a disease. Recently, many technologies have been invented to profile cells without removing them from their natural context, measuring gene expression and the regulatory landscape of a cell’s genome alongside its spatial location within a tissue. In a review, Bressan et al. describe the features of these methods, collectively named spatial omics, and discuss what is missing for them to unlock their full potential.
The authors, Bressan, Battistoni, and Hannon, begin with a fanfare: “Just as single-cell sequencing has revolutionized many fields of biology, spatial ‘omics,’ in which molecular parameters are measured in situ on intact tissue samples, is set to empower a new generation of scientific discoveries.”
Spatial molecular profiling at the tissue level (and sometimes at the cell level) with “multi-omic” technologies will allow researchers to study the genome, transcriptome, and proteome simultaneously in situ within an organ, tissue, or cell. This adds another layer of information that was hidden from earlier studies
One of the first steps along this journey was the emergence of single-cell “omics” technologies that operate on disaggregated tissues. These methods enabled the discovery of new cell types, cast new light on organismal development, and launched the process of creating comprehensive catalogs of human and mouse tissues. However, biological processes happen in a spatial context, and the three-dimensional (3D) arrangement of cells in a tissue has a profound effect on their functions…. Regardless of their undisputed power, measurements made on disaggregated cells or nuclei lack this layer of information. The need for such knowledge has driven the development of “spatial omics”: methods capable of measuring the molecular characteristics of cells in their native 3D context.
The authors say that “we are at the very beginning of the spatial omics revolution” and that “progress is happening at breakneck speed” that will undoubtedly give scientists “a much deeper understanding of biology in context.”
As an example of the profound effect of spatial and environmental influences on an organism, researchers at Harvard found that specific neurons become active when a mouse makes an error navigating a virtual reality maze.
The researchers found that when a mouse made and corrected a mistake while navigating, the subtype of neurons became active. This held true even when they guided the mouse to err, either by rotating the maze or changing the color cues. However, if the mouse didn’t make a mistake, or made a mistake but didn’t correct it, the neurons didn’t fire.
When the neurons became active, they did so in unison, prompting a follow-up experiment in which the researchers stimulated the cells with light. They found that the neurons are essentially hardwired to each other, meaning that the electrical current telling them to fire can flow directly from one cell to the next.
Studying these neurons in isolation would not have revealed this concerted, dynamic activity
Interactome Sentries
Scientists at Leiden University in the Netherlands found that the “cytosolic interactome protects against protein unfolding” with a continuous process of “biological origami at the molecular level.” According to Phys.org, the
Group leader, Alireza Mashaghi, said, “When a cell experiences stress, a protein can unfold to a completely unfolded chain. Once that has happened, it’s very hard to reverse. But we noticed the cytoplasm puts a break on this process, not allowing the unfolding to go all the way. This protects the proteins and ensures a proper functionality, and also makes it easier for proteins to refold once the stress in resolved.”
Unknome: The Final Frontier
From the Public Library of Science comes word of “The ‘unknome’: the set of gene transcripts we know almost nothing about.” This black box consists of “thousands of understudied proteins encoded by genes in the human genome, whose existence is known but whose functions are mostly not.”
The sequencing of the human genome has made it clear that it encodes thousands of likely protein sequences whose identities and functions are still unknown. There are multiple reasons for this, including the tendency to focus scarce research dollars on already-known targets, and the lack of tools, including antibodies, to interrogate cells about the function of these proteins. But the risks of ignoring these proteins are significant, the authors argue, since it is likely that some, perhaps many, play important roles in critical cell processes, and may both provide insight and targets for therapeutic intervention.
Echoed by Phys.org, this news says that researchers in the UK are putting together a public database of these proteins that they trust will shrink over time. The Unknome [Unknown Genome] Project has started at http://www.unknome.org. The proteins are ranked by how little is known about them, stimulating researchers’ curiosity to find out what they do.
It’s clear that Omics is discovering additional layers of biological information in living systems. Antiquated 1960s-era concepts of genes and proteins, like the Central Dogma, are being overwhelmed by this new vista of multi-dimensional dynamic organization. If the earlier geneticists were looking at a 2-D flat map, the new generation is looking at a thriving city. Old dogmas about Darwinian evolution seem woefully inadequate to understand complexity at this level. Science in the 21st century will require a theoretical framework equipped to handle information flow in time and space. There is one. It’s known as intelligent design
Reviewing a "win" for Darwinism.
An Impressive Instance of Unguided Evolution? Not So Much
On a classic episode of ID the Future, host and biologist Ray Bohlin interviews biophysicist Cornelius Hunter, author of Darwin’s God, about an article in the journal Science concerning a virus invasion of E. coli bacteria. The article subtitle announces “Natural Selection Caught in the Act,” and suggests that an impressive instance of unguided evolution has been directly witnessed. Not so fast, Hunter says. The results were intelligently designed (by the lab scientists), he notes, and the changes are less impressive than they may appear at first glance. Hunter also explains protein-protein binding and counters evolutionist Dennis Venema to argue that the way the vertebrate immune system drives change is not at all analogous to the evolutionary process of random mutations and natural selection. Moreover, Hunter says, the mammalian immune system is itself an enormous challenge for evolutionary theory.
Unfortunately, it’s common for studies such as this one to be hyped up by the scientific community and the establishment media. “Evolutionists are driven by non-scientific factors, non-scientific influences,” says Hunter. “There is a desire for the theory to be true in spite of the science, not because of the science.” Download the podcast or listen to it here.
Ecosystems vs. Darwinism
Ecosystems — A Tribute to Intelligent Design, or to Chance and Adaptation?
Although intelligent design is evident in the biochemistry of the cell and the physiological systems of the body, living organisms are not independent but exist in a web of life, interdependent upon other living things in an ecosystem.
As we think about all the species of animals, birds, and fishes on Earth, it becomes apparent that each one requires a certain type of food, suitable for its anatomy. Domestic livestock, including cattle, horses, sheep, and goats, can be nourished through grazing on grasses and broadleaf weeds, although each has different preferences.1 Among the wild animals, carnivores have varying needs for prey that match their size and abilities. With the thousands of species of birds, the preferred menu selections stretch from sips of nectar to berries, insects, smaller animals, carrion, or fish.
Variety and Quantity
Considering that water covers 71 percent of the Earth’s surface, it’s not surprising that the variety and quantity of fish inhabiting oceanic and freshwater ecosystems is legion.
The total number of living fish species — about 32,000 — is greater than the total of all other vertebrate species (amphibians, reptiles, birds, and mammals) combined.2
Fish species include herbivores and carnivores (smaller fish get eaten by bigger fish). The largest marine species include baleen whales that are uniquely outfitted to obtain their nourishment from the smallest organisms:
[Baleen whales] are the largest animals on Earth, yet they live off some of the smallest. They can grow to lengths of 30 meters (90 feet), but it is the microscopic zooplankton, krill and small fish that sustains them.3
The main point here is not a lesson on what different creatures eat, but that the multiplied billions of creatures on Earth all need to be fed according to their specific dietary needs and their physiological and anatomical specifications. Anyone who has taken care of animals knows that concern over providing sufficient food of the right type never takes a vacation. Not many of us have pet hummingbirds, but if we did, we might lose weight just making sure they didn’t:
Hummingbirds have a very high metabolism and must eat all day long just to survive. They consume about half their body weight in bugs and nectar, feeding every 10-15 minutes and visiting 1,000-2,000 flowers throughout the day.4
Caring for more prosaic animals is also demanding
Cows are natural grazers, preferring to eat 5 to 9 meals a day, plus drinking. For this reason, cows have free access to fresh food and water throughout the day….So just how much does a cow eat? While each cow is different, a typical milk-producing dairy cow, weighing around 600kg, eats around 29kg [64 pounds] of feed each day and may drink about 100L of water (about a bathtub’s worth).
Apart from domesticated animals, wildlife depends upon an ecosystem in which the lives of multiple species are interconnected. We can observe how many species of living things thrive in a given ecosystem, but to take for granted the finely tuned balance within these life-nourishing habitats is to overlook layered evidence for design.
Let’s Look at a Few Specific Examples
In the wild, an apex predator such as a lion is equipped to hunt prey, but of course an abundance of suitable prey must exist within its territory. The prey, typically herbivores, need sufficient grassland to graze upon and water to drink. Seasonal weather changes must be moderate, so that vegetation and surface water are available year-round. The perspective of naturalism takes it for granted that these requirements are simply adaptations that occurred in time and location without any thought or foresight.
Consider another example. A raptor such as a red-tailed hawk is equipped with the ability of flight, sight and talons to hunt and capture small creatures. Rather than ascribing the sophisticated, finely tuned characteristics of such a bird of prey and its ecosystem to unguided evolutionary adaptations, purposeful design provides an explanation more consistent with the specific, interdependent functionality in this and other examples.
Design or Adaptation?
Surviving a cold winter that can last four to six months or longer, when no plant growth occurs and insects vanish, would seem impossible for many types of birds. However, several species of songbirds manage just fine, even when the average temperature falls well below freezing, eating seeds, nuts, and berries. Is this evidence for design, or is it just natural adaptation?
If the ability of birds to thrive across the Earth is just a matter of adaptation, the process works unbelievably well with the thousands of species of birds. “New research estimates there are between 50 billion and 430 billion birds on Earth.”5 The sheer number and variety of birds thriving in multiple environments on every continent argues that something far more than luck and unguided nature is behind it all.
Our increased understanding of the biochemical complexity within any living organism, coupled with a growing awareness of the delicately balanced ecosystems sustaining life on Earth, suggest ingenious foresight, planning, and design with every type of life we observe.6
Fish far outnumber birds on our planet, with estimates of 3.5 trillion fish inhabiting the oceans,7 and each one of these trillions of creatures needs a regular supply of food accessible to it in a suitable form and quantity. Let’s imagine an experiment: given a planet with oceans empty of life, how much intelligence would it take to design an interdependent ecosystem capable of supporting thousands of species of fish over a time frame stretching across hundreds of millions of years?
From Molecules to Gills
Oh, and if you, as a designer substitute, think of a type of fish to introduce into the pond, you’ll have to design everything about it, from molecules to gills. “Trial and error will save the day!” you say? “Once life gets going as a single-cell organism, chance and natural selection will succeed where human intelligence falls short.” Ah, yes. That makes sense.
Notes
“Understanding Working Rangelands — Cattle, Sheep, Goats, and Horses: What’s the Difference for Working Rangelands?” Univ. of California, Agriculture and Natural Resources, publ. 8524 (July, 2015).
https://www.nationalgeographic.com/animals/fish .
Jon Lapidese, “Baleen Whales — The Gentle Giants of the Ocean,” https://oceanwide-expeditions.com/blog/baleen-whales-the-gentle-giants-of-the-ocean
https://www.adirondackcouncil.org/page/blog-139/news/10-facts-about-hummingbirds–and-other-interesting-tidbits-1101.html .
How many birds are there in the world? | National Geographic .
Marcos Eberlin, Foresight: How the Chemistry of Life Reveals Planning and Purpose, https://www.discovery.org/store/product/foresight/ .
“How Many Fish Live in the Ocean?” WorldAtlas.
Friday, 1 September 2023
Thursday, 31 August 2023
Wednesday, 30 August 2023
Tuesday, 29 August 2023
The chain of Command.
But I want you to realize that the head of every man is Christ, and the head of the woman is man, a and the head of Christ is (The)God.
Our brother Paul is taking us back to the garden with this exposition
Note please:
1Corinthians ch.11:7-9NIV"A man ought not to cover his head, b since he is the image and glory of God; but woman is the glory of man. 8For man did not come from woman, but woman from man; 9neither was man created for woman, but woman for man."
So there are two bases for seniority in this chain ,temporal priority, the man was created before the woman and Christ was created before all others and of course His God is eternal.
Also of note there is a widening of the gap has one ascends the chain the one atop this particular chain of command is infinite in both capability and in due authority so he transcends the rest of the chain. Any comparative gaps between the other members of the chain are relatively insignificant.
Two the transmission of life JEHOVAH the God and Father of Jesus is the ultimate source of life which he transmitted to humanity through his living logos beginning with the first man and through him the first woman. Only one member of this chain of command is called Ho Theos and he is the same one who is ALWAYS called Ho Theos,the God and Father of our Lord Jesus Christ JEHOVAH God.
The riot act: for those who missed it the first time
There will be no anonymous commenting on this site period.
Against unknown?III
Unknown: Scripture also teaches that, in a certain sense, the Father also "receives" something from the Son (e.g., Jn 16:15.23). Jesus submitted himself (hypotasszó) to the Father (1 Cor 15:28), "that God may be all in all", but this in no way implies inferiority, as he also subjected himself (hypotasszó) to Mary and Joseph (Lk 2:51), and Col 3:11 claims that "Christ is all, and in all".
Aservantof JEHOVAH:John ch.16:23NIV"In that day you will no longer ask me anything. Very truly I tell you, my Father will give you whatever you ask in my name. "
John ch.16:15NIV"All that belongs to the Father is mine. That is why I said the Spirit will receive from me what he will make known to you.”"
Colossians ch.3:11NIV"being strengthened with all power according to his glorious might so that you may have great endurance and patience, "
So nothing about the most high God receiving any authority from his Son
He did submit to to his human parents why?
Galatians ch.4:4N8V"But when the set time had fully come, God sent his Son, born of a woman, born under the law,"
The law of course was made for man not angels or God-men. So the human not God-man Christ in obedience to the law honored his Father and mother
Exodus ch.20:12 ,Mark ch.2:27
The God and Father of Jesus is the MOST HIGH God and thus has no co-equals
Luke ch.1:32NIV"He will be great and will be called the Son of the MOST HIGH. The LORD God will give him the throne of his father David, "
John ch.10:29NIV"My Father, who has given them to me, is GREATER than ALL c ; no one can snatch them out of my Father’s hand"
So the union of Father and Son is not a union of co-equals
Only the God and Father of Jesus is ever called Ho Theos in an unqualified way so the God and Father of Jesus is not merely a unique person but a unique God which falsifies the trinity no member of the trinity is supposed to be the unique God in and of himself.
1Corinthians ch.15:28NIV"When he has done this, then the Son himself will be made subject to him who put everything under him, so that(The) God may be all in all."
Also consider:
Matthew ch.24:36KJV"But of that day and hour knoweth no man, no, not the angels of heaven, but my FATHER ONLY. "
So even if we buy your utterly unscriptural God-man fudge how come the holy spirit does not know.
ID is perfectly natural?
The Return of Natural Theology
Influenced by a long line of materialist thinkers, Charles Darwin proposed the mechanism of natural selection as a substitute for God. But how does his evolutionary theory’s explanatory power measure up to recent scientific discoveries? On a new episode of ID the Future, physicist Dr. Brian Miller discusses the resurgence of natural theology in modern science with Pat Flynn, co-host of the Philosophy for the People podcast. Natural theology advances arguments for God based on reason and the discoveries of science. It’s an ancient pursuit that fell out of favor in the 19th century as a materialist account of life’s origins took center stage. But modern scientific findings point to mind, not a mindless process, as the likeliest explanation for a life-friendly universe. As a result, the pendulum is swinging back to teleology, ushering in a new heyday for natural theology.
In addition to giving a historical overview of natural theology, Miller and Flynn also discuss fundamental problems in origin-of-life studies that demand a better explanation than materialists can offer. “Here’s the fundamental challenge,” Miller says. “All natural processes tend to create greater disorder (entropy)…The origin of life requires chemicals to go into a state of both high order and high energy. That never happens without help!”
What about the multiverse as an escape hatch from the evidence of a universe intelligently designed to allow for life? That proposed design-defeater, Miller argues, also faces a huge problem.
Tune in for all this and more in a lively, wide-ranging conversation between Miller and his philosopher host Pat Flynn. Download the podcast or listen to it here.
Monday, 28 August 2023
The receipts of the Darwinian pathway to the blood clotting cascade?
Has Russell Doolittle Provided an Evolutionary Explanation of the Blood Clotting Cascade?
In two previous articles (here and here ), I reviewed the process of vertebrate blood clotting and summarized why it cannot readily be explained by naturalistic unguided processes, such as those proposed by neo-Darwinian evolutionary theory. In this final installment, with the foregoing challenges in mind, let us inspect Russell Doolittle’s paper on the evolution of vertebrate blood clotting1 to determine to what extent his analysis assuages these concerns. Since Doolittle has also published a book dealing with this subject2, in which he elaborates on the arguments expressed in the paper in more detail, I occasionally will refer to things said in the book as well.
Do Gene Duplications Explain Vertebrate Blood Clotting?
Doolittle contends that “Many of the proteins involved [in coagulation] are clearly related to one another by gene duplications, and in the past, sequence-based phylogenies have offered insights into the relative order in which certain factors appeared.”3 But sequence similarity does not necessarily imply common ancestry (due to the possibility of common design) and common ancestry does not necessarily imply a stepwise evolutionary pathway. Michael Behe explains this point:
Although useful for determining lines of descent… comparing sequences cannot show how a complex biochemical system achieved its function—the question that most concerns us in this book. By way of analogy, the instruction manuals for two different models of computer put out by the same company might have many identical words, sentences, and even paragraphs, suggesting a common ancestry (perhaps the same author wrote both manuals), but comparing the sequences of letters in the instruction manuals will never tell us if a computer can be produced step-by-step starting from a typewriter… Like the sequence analysts, I believe the evidence strongly supports common descent. But the root question remains unanswered: What has caused complex systems to form?4
This aside, however, Doolittle’s proposed mechanism runs into the problem enumerated above — namely, that duplicating a gene coding for one of the blood clotting factors would lead to that factor becoming over-expressed, disrupting the cascade’s delicate balance and leading to excessive clotting. This difficulty is nowhere even acknowledged in Doolittle’s paper, let alone addressed.
Doolittle raises a valid concern: “The question may be asked, how can new factors be introduced into an existing pathway?” Good question. How does Doolittle respond? He writes, “It was long ago suggested that in the case of clotting pathways, new factors that are the products of gene duplications could easily be sandwiched into the middle of pathways where they initially were only performing the same operation as the original gene product. Only a few amino acid replacements were likely needed to broaden the proteolytic specificity to the point where the duplicon could itself activate the other surviving gene product.”5 In support of this thesis, Doolittle notes that “all of the vitamin-K dependent proteases (prothrombin, factors VII, IX, and X, and protein C) cleave after arginine residues in the same general regions of their homologous substrates.”6 This, again, however, runs into the problem described above — namely, that gene duplication events would be likely to upset the delicate balance of the system, increasing the risk of thrombosis. Such duplicate genes are thus unlikely to be preserved by selection. Moreover, a few specific amino acid replacements in animals such as vertebrates (assuming none of them are beneficial until all have arisen) are unlikely to happen on a realistic timescale. As has been much discussed at Evolution News in the past, and in the academic literature, evolution depends on prohibitively long times to attain and fix multiple co-dependent mutations, where none of them confer a fitness benefit until all have arisen.7,8,9,10,11,12 Doolittle gives a time window for the emergence of the coagulation cascade of approximately fifty to a hundred million years, since fibrin clots have never been detected in any protochordate (i.e., organisms lacking a backbone but possessing a notochord at some stage during development) though it has been identified in the earliest vertebrates — that is, jawless fish. Thus, he argues, blood clotting must have arisen between the emergence of protochordates and jawless fish. As he writes in his book,
Because fibrin clots have never been observed in our nearest non-vertebrate relatives, the protochordates, we must accept that the clotting system was assembled in the relatively brief interval since protochordates diverged from the lineage leading to vertebrates and the appearance of creatures like the hagfish and lamprey. In years, the available time is estimated to have been 50 to 100 million.13
Given that it is highly probable that each step in the evolution of coagulation would require multiple co-dependent mutations (since each proenzyme would have to evolve in a coordinated way with its activating enzyme), this time window appears to be quite brief. Compounding this is the fact that the mutations in the evolving gene duplicate would need to occur in a coordinated way with its own activating enzyme to ensure that the new factor is active only when needed.
Simpler Blood Clotting Systems in Jawless Fish
There are two extant genera of jawless fish — hagfish (pictured above) and lamprey. Doolittle predicts, from an evolutionary framework, that jawless vertebrates would have a simpler blood clotting cascade than the human system described above. Doolittle limits the scope of his analysis to the lamprey, for which there was better genomic data than for hagfish. Doolittle’s research has revealed that lampreys lack both factor IX and factor VIII.14,15 It may thus be concluded that factors IX and VIII are not essential, at least in the jawless vertebrates. Why are jawless vertebrates not hemophilic, unlike humans who lack these factors? Without knowing more about how coagulation works in jawless vertebrates, it is impossible to say for sure. Clearly, there are other differences as well — since apparently there are two factor X genes in lamprey. Is it possible that one of those is functioning as a factor IX gene? There are also three factors VII. Unfortunately, the precise mechanisms of coagulation in lampreys have yet to be elucidated. Given that humans who are deficient in factors IX or VIII suffer from hemophilia, this provides an indirect justification for believing that there are, quite probably, compensating mechanisms in lampreys that have yet to be uncovered.
Failing to Address Behe’s Argument
A crucial point is that, even if Doolittle’s entirely evolutionary scheme were correct, it would not even address — much less refute — Behe’s original thesis about the blood clotting cascade. In Darwin’s Black Box, Behe only argued that the common pathway is irreducibly complex — he does not give an assessment of whether the intrinsic pathway (to which these factors IX and VIII, missing in jawless fish, belong) or the extrinsic pathway are irreducibly complex as well.16 To summarize, in Darwin’s Black Box, Michael Behe only argued for irreducible complexity of the common pathway — i.e., the pathway after the convergence of the extrinsic and intrinsic initiation pathways, or what Behe calls the components “after the fork.” Behe made this very explicit in his book, where he wrote:
Leaving aside the system before the fork in the pathway, where some details are less well known, the blood-clotting system fits the definition of irreducible complexity.17
The system “before the fork in the pathway” is the intrinsic and extrinsic initiation pathways highlighted by Doolittle. But Behe explicitly leaves this part of the system “aside” and does not argue it is irreducibly complex. Thus, even if Doolittle’s arguments held merit, they would still not refute, even address, the portion of the pathway that Behe argues is irreducibly complex.
Regarding the systems “after the fork,” to my knowledge, there are no vertebrates with a functional coagulation system that lack thrombin, fibrinogen, factor X, or factor V. Clearly, there also has to be some way of activating factor V in response to tissue damage. Thus, to be conservative, blood coagulation must require a minimum of five parts (and probably more) – the very components which Behe argues comprise the irreducibly compelx portion of the blood clotting cascade. Behe’s argument has not been refuted. This same mistake was made in response to Behe by Kenneth Miller, as has been previously noted at Evolution News by Casey Luskin.
Co-Option of Thrombin / Fibrinogen
Doolittle concedes that “it seems unlikely that thrombin and fibrinogen would appear simultaneously,” and posits that “one already existed with an alternative function.”18 He suggests that “fibrinogen may have had a role in cell-cell interactions, a property of many proteins with fibrinogen-related domains.”19 Doolittle postulates that “a more likely scenario, however, is that thrombin had an early role in agglutinating thrombocytes by proteolyzing cell surface proteins, something it is known to do today, attacking a set of G-protein-coupled receptors called PAR proteins.”20 On this hypothesis, “a tissue factor would become exposed during the course of injury, activating prothrombin that would then clump cells which were the ancient ancestors of mammalian platelets. A GLA domain could have helped to keep thrombin localized on the surface of the thrombocytes.”21 The emergence of fibrinogen “would allow thrombin to broaden its attack, generating a more durable clot composed of fibrin. Duplications of the prothrombin gene would lead to the appearance of factors VII, X, and eventually IX.”22
Such a scenario, however, presents a number of problems. One is acknowledged by Doolittle himself: “Besides the GLA domain, thrombin has two kringle domains, usually thought to have an affinity for fibrin. The kinds of domains that interact with tissue factor, however, are the EGF domains found in factors VII, X, and IX.”23 He, therefore, has to postulate that “there was much domain shuffling in the early stages and that thrombin originally had EGF domains, or no peripheral domains at all.”24 Second, he makes no attempt to estimate how durable a clot composed of nothing more than clumped cells would be — though, if the initial flow rate was relatively low, this issue could be less of a concern. Finally, a duplication of a prothrombin gene would result in a second prothrombin gene. Doolittle makes no attempt to determine how difficult it would be for factors VII, X and IX to arise from a duplicated prothrombin gene (and evolve in a coordinated way with their corresponding activating enzymes), nor how the overexpression problem described above may be overcome.
Doolittle’s Four Stage Scenario
In his book, Doolittle proposes four stages in the evolution of vertebrate blood clotting, based on the presence or absence of coagulation factors in various animals.
The first stage, according to Doolittle, “existed in the last common ancestor of jawless and jawed vertebrates and was characterized by the presence of only six different proteins, three of which are vitamin K-dependent proteases.”26 These six proteins included tissue factor, factor VII, factor X, factor V, prothrombin and fibrinogen. The second stage, Doolittle suggests, involved the emergence of factors VIII and IX prior to the evolution of jawed fish. The third stage was characterized by the acquisition of prekallikrein and factor XII. A duplication of the gene coding for prekallikrein, resulting in the origins of factor XI, led, according to Doolittle’s scenario, to the fourth stage.
Notice that even the primitive system that constitutes stage one contains all of the four components that Behe claimed to comprise the irreducibly complex system — that is, thrombin, fibrinogen, factor X and factor V — in addition to tissue factor and factor VII (key components of the extrinsic pathway, required for initiating coagulation in response to tissue damage). Behe’s hypothesis predicts that every coagulation system will contain these four proteins (or equivalents), in addition to there being some way of activating factor V in response to tissue damage. This is preciselywhat the data show. The only aspect of the coagulation cascade that emerged subsequent to the origins of coagulation itself, then, so far as can be told by the data, are the components that make up the intrinsic pathway. That the intrinsic pathway is redundant is not particularly surprising, since there only needs to be one mechanism by which factor V is activated. Adding the intrinsic pathway is certainly helpful, though not necessarily essential. The intrinsic pathway serves to amplify the coagulation response initiated by the extrinsic pathway, and provides additional layers of activation and enzyme generation. Again, Behe’s fundamental thesis about irreducible complexity of the blood clotting cascade has not been refuted or even touched by Doolittle’s arguments.
But perhaps the most damning problem confronting Doolittle’s proposed scenario is that his analysis entirely ignores all of the clotting inhibitors (such as antithrombin, protein C, and protein S) that prevent excessive clot formation, as well as those factors that dismantle clots (as he himself acknowledges27). And this even though he correctly notes elsewhere that “this suppression of activity is very important; there is enough prothrombin in one milliliter of plasma to clot all the fibrinogen in the whole body if the prothrombin were all converted to thrombin.”28 Thus, the emergence of the pathway for coagulation along the lines suggested by Doolittle would likely result in runaway thrombosis without the simultaneous advent of inhibitors.
A Formidable Challenge
In summary, the coagulation cascade presents a formidable challenge to evolutionary theory. While Doolittle is to be commended for his work in attempting to provide an evolutionary account for coagulation, the failure of those attempts underscores the difficulty of the problem. They simply do not address the issues at the heart of Behe’s argument in Darwin’s Black Box, which remains untouched by Doolittle’s thesis.
Notes
Doolittle RF. Step-by-step evolution of vertebrate blood coagulation. Cold Spring Harb Symp Quant Biol. 2009;74:35-40.
Doolittle RF. The Evolution of Vertebrate Blood Clotting. University Science Books 2013.
Doolittle RF. Step-by-step evolution of vertebrate blood coagulation. Cold Spring Harb Symp Quant Biol. 2009;74:35-40.
Behe, Michael J. (1996). Darwin’s Black Box: The Biochemical Challenge to Evolution. Free Press, kindle.
Ibid.
Doolittle RF. Step-by-step evolution of vertebrate blood coagulation. Cold Spring Harb Symp Quant Biol. 2009;74:35-40.
Hössjer O, Bechly G, Gauger A. On the waiting time until coordinated mutations get fixed in regulatory sequences. J Theor Biol. 2021 Sep 7;524:110657.
Sanford J, Brewer W, Smith F, Baumgardner J. The waiting time problem in a model hominin population. Theor Biol Med Model. 2015 Sep 17;12:18.
Durrett R, Schmidt D. Waiting for two mutations: with applications to regulatory sequence evolution and the limits of Darwinian evolution. Genetics. 2008 Nov;180(3):1501-9. Erratum in: Genetics. 2009 Feb;181(2):819-20; author reply 821-2.
Behe MJ, The Edge of Evolution: The Search for the Limits of Darwinism. Free Press 2007.
Behe MJ, Snoke DW. Simulating evolution by gene duplication of protein features that require multiple amino acid residues. Protein Sci.2004 Oct;13(10):2651-64. doi: 10.1110/ps.04802904. Epub 2004 Aug 31. PMID: 15340163; PMCID: PMC2286568.
Axe DD. The Limits of Complex Adaptation: An Analysis Based on a Simple Model of Structured Bacterial Populations. Bio-Complexity2010.
Doolittle RF. The Evolution of Vertebrate Blood Clotting. University Science Books 2013, 184.
Doolittle RF, Jiang Y, Nand J. Genomic evidence for a simpler clotting scheme in jawless vertebrates. J Mol Evol. 2008 Feb;66(2):185-96. doi: 10.1007/s00239-008-9074-8.
Doolittle RF. Bioinformatic Characterization of Genes and Proteins Involved in Blood Clotting in Lampreys. J Mol Evol. 2015 Oct;81(3-4):121-30.
Behe, Michael J. Darwin’s Black Box: The Biochemical Challenge to Evolution. Free Press 1996, kindle.
Ibid.
Doolittle RF. Step-by-step evolution of vertebrate blood coagulation. Cold Spring Harb Symp Quant Biol. 2009;74:35-40.
Ibid.
Ibid.
Ibid.
Ibid.
Ibid.
Ibid.
Ibid., 185.
Ibid.
Doolittle RF. The Evolution of Vertebrate Blood Clotting. University Science Books 2013, 196.
Ibid., 17.
Sunday, 27 August 2023
Christendom's genius for explaining away obvious logic
1Corinthians ch.15:27NIV"For he “has put everything under his feet.” c Now when it says that “everything” has been put under him, it is CLEAR that this does not include God himself, who put everything under Christ. "
The word of JEHOVAH is addressed to the wise, those who know that humility and logic are necessary prerequisites to clear thinking. It ought to be clear that the God who put everything under Christ feet is not his equal or that one who always had everything under his feet would not need anyone else's authorisation to wield that authority ,and yet some apparently loose a grasp of basic logic when it comes examining the bible. The most plain manifestation of this malaise for me is failure to grasp the concept of supremacy.
Supremacy according to Merriam Webster:: the quality or state of being supreme
especially : a position of unquestioned authority, dominance, or influence
2:ultimate authority or power.
So Supremacy excludes equality. The two concepts are mutually exclusive one who is equal to even one other than himself is not supreme/ does not possess supremacy, our Brother Paul might say that this should be clear.
But the trinity doctrine causes brain damage especially that part of the brain responsible for our grasp of basic logic.
Luke ch.1:32NIV"He will be great and will be called the Son of the MOST HIGH. The LORD God will give him the throne of his father David," (we'll bypass the Trinitarian style proof of David's Godhood) Note that the God and Father of Jesus Christ is Supreme.
He is both the greatest person and the greatest God. This totally excludes there being any other person or God being his equal by definition. Yet Trinitarians ignore what ought to be clear and claim that the God of Jesus is not the most high God and that in fact there are three distinct entities that are a least equal to him . Indeed as I have pointed out the trinity doctrine blinds its adherents to a clear identification of the MOST HIGH God JEHOVAH If the trinity is true there is no most high God.
Saturday, 26 August 2023
On secular occultism.
J. P. Moreland on the Contradictions of Scientism
Are the hard sciences the only source of truth about reality? On a classic episode of ID the Future, host Michael Keas begins a conversation with philosopher J. P. Moreland about Moreland’s book Scientism and Secularism: Learning to Respond to a Dangerous Ideology. As Moreland explains, scientism is the belief that only the hard sciences can provide any reliably true knowledge. It’s a claim that also gets applied to other disciplines outside science as well, suggesting that claims of reality in any field of human knowledge cannot be known one way or another. “It’s in the drinking water,” Moreland says, but it’s also self-refuting, and therefore irrational — and very damaging besides. Moreland gives examples. This is Part 1 of a conversation. Download the podcast or listen to it here.
Speaking of ID some more
An Intriguing Conversation with Casey Luskin About Intelligent Design
Ha, well this is a new frontier for intelligent design. Live Life in Motion is a podcast with Sam Kleckley about personal fitness, sponsored by, among other fine products, Rebel Rabbit, which I had not heard of. Sam shares enthusiastically that Rebel Rabbit is a cannabis-infused soda drink that comes in two strengths, billed as a healthier alternative to alcohol. Which it may well be! It’s news to me that there was such a thing. Anyway, Sam is also a thoughtful and curious individual who put aside his accustomed subjects and had on our geologist colleague Casey Luskin for an hour to talk about ID — everything, and I mean everything, about ID — biology, cosmology, education, and more. They had a great conversation, really quite charming, made more intriguing by the fact that Sam is evidently a searcher, uncertain, as he says, about what he believes about god or gods. Find the podcast on Apple (here) or Spotify (here). God bless the curious and the open-minded.
Seafaring simians?
Fossil Friday: Did Monkeys Raft Four Times Across the Atlantic?
A few years ago, I published an article at Evolution News titled “Rafting Stormy Waters” (Bechly 2018), which discussed the various highly implausible events of oceanic dispersal with vegetation rafts to explain the biogeographic patterns of living animals. This includes the dispersal of monkeys from Africa to South America that implied a 60-day voyage of 1,400 km across the Eocene early Atlantic Ocean (Gabbatiss 2016).
Now, a new fossil find has made this problem much worse. Marivaux et al. (2023) describe in the journal PNAS a new primate genus from the Paleogene of Western Amazon and provide a new phylogenetic analysis of the earliest fossil Neotropical monkeys. This phylogenetic study shows that three genera of fossil monkeys, all known by fossil teeth from the Early Oligocene of South America, are not related to living New World monkeys (Platyrrhini), but are nested in three distinct African clades respectively: Ashaninkacebus is nested within the Eosimiidae clade (Marivaux et al. 2023), Perupithecus is nested within the Oligopithecidae clade (Bond et al. 2015), and Ucayalipithecus is nested within the Parapithecidae clade (Seiffert et al. 2020). This implies three independent Eocene colonization events of South America by rafting from Africa, additional to the dispersal of platyrrhine monkeys, and additional to the dispersal of caviomorph rodents.
Beyond Ridiculous
Did viable populations of monkeys really raft successfully four times across the Atlantic Ocean from Africa to South America? Seriously? One such event is already a stretch, but four times is beyond ridiculous. If such events happened so often with unlikely passengers like monkeys, why don’t we find many more cases of similar Neotropic-Afrotropic relationships in much more likely candidates such as reptiles or insects, which could far more easily survive long transoceanic rafts? Not to mention the simple fact that in the whole history of human seafaring we have never observed rafting vertebrates in the middle of the ocean and only observed rafting dispersal events in cases of relatively close islands and even there only with reptiles. Longrich (2021) called this an “incredible ocean crossing” which “beat odds that make Powerball lotteries seem like a safe bet.” Something is clearly wrong here, and I mean way off. But evolutionary biology has a cheap cop out that was made explicit by Nobel laureate George Wald (1954):
Given so much time, the [nearly] “impossible” becomes possible, the “possible” becomes probable, and the “probable” becomes virtually “certain.”
It does not require that one be a Darwin doubter to recognize that this hardly qualifies as good science, as shown, for example, in this highly recommended article by Lu (2021) from an AI perspective. Time is not the hero of the plot when actual improbabilities and probabilistic resources are ignored or glossed over with fancy storytelling according to the unspoken dogma of evolutionary biology: It must have been possible because it happened. After all, God forbid if we were to consider explanations beyond blind naturalistic mechanisms.
References
Bechly G 2018. Rafting Stormy Waters: When Biogeography Contradicts Common Ancestry. Evolution News June 27, 2018. https://evolutionnews.org/2018/06/rafting-stormy-waters-when-biogeography-contradicts-common-ancestry/
Bond M, Tejedor MF, Campbell KE Jr, Chornogubsky L, Novo N & Goin F 2015. Eocene primates of South America and the African origins of New World monkeys. Nature 520(7548), 538–541. DOI: https://doi.org/10.1038/nature14120
Gabbatiss J 2016. The monkeys that sailed across the Atlantic to South America. BBC January 26, 2016. https://web.archive.org/web/20160127084123/http://www.bbc.com/earth/story/20160126-the-monkeys-that-sailed-across-the-atlantic-to-south-america
Longrich NR 2021. One incredible ocean crossing may have made human evolution possible. The Conversation April 29, 2021. https://theconversation.com/one-incredible-ocean-crossing-may-have-made-human-evolution-possible-157479
Lu CP 2021. Infinite Dilemma 1: Not Enough Time. Towards Data Science February 3, 2021. https://towardsdatascience.com/neo-darwinistic-concepts-of-chance-and-time-through-the-lens-of-ai-2eee4d5c2bd6
Marivaux L, Negri FR, Antoine P-O et al. 2023. An eosimiid primate of South Asian affinities in the Paleogene of Western Amazonia and the origin of New World monkeys. PNAS 120(28):e2301338120. DOI: https://doi.org/10.1073/pnas.2301338120 (PDF: https://hal.science/hal-04153825/document)
Seiffert ER, Tejedor MF, Fleagle JG, Novo NM, Cornejo FM, Bond M, de Vries M & Campbell KE Jr 2020. A parapithecid stem anthropoid of African origin in the Paleogene of South America. Science 368(6487), 194–197. DOI: https://doi.org/10.1126/science.aba1135
Wald G 1954. The Origin of Life. Scientific American 191, 45–53. https://www.scientificamerican.com/article/the-origin-of-life/
Friday, 25 August 2023
Why the lab is not a window on the prebiotic earth.
Hands-On Chemistry Can’t Simulate Prebiotic Earth
When scientists claim they have simulated early Earth chemistry to create life from non-life, are they being honest? A new episode of ID the Future is the fourth and final installment in a series of conversations between philosopher of science Dr. Stephen Meyer, author of Signature in the Cell: DNA and the Evidence for Intelligent Design, and Dr. James Tour, a world-renowned synthetic organic chemist at Rice University. Dr. Tour has recently been engaged in a series of back-and-forth responses to attacks on his work from YouTuber “Professor” Dave Farina. This has given Tour a new opportunity to critique experts in the field of abiogenesis and allows an interested public to better evaluate both sides of the argument.
In Part 4, Meyer and Tour evaluate the work of chemist Bruce Lipshutz; specifically his work designing surfactant molecules that enable amide/peptide bonds. By itself, Lipshutz’s work developing synthetic techniques for doing chemistry in water is interesting and has value. But for those tempted to think that his work validates chemical evolutionary theories of the origin of life, Tour has bad news. Peptides don’t form in aqueous environments like water. A realistic prebiotic environment would not be capable of producing the reactions necessary to form proteins. And Lipshutz acknowledges this. In their conversation, Tour and Meyer discuss how Lipshutz applies hands-on chemistry that bears no resemblance to the likely conditions of a prebiotic Earth. If anything, the work of Lipshutz and others in origin of life research is actually simulating the need for intelligent agency to move simple chemicals in a life-friendly direction. Says Meyer, “Even the modest movement they get towards life seems to be intelligently designed at each step of the way, and even the vocabulary will sometimes reveal that: ribozyme engineer, designer surfactants. Very curious!”
Download the podcast or listen to it here.
Thursday, 24 August 2023
Common design on the march?
From Winston Ewert, New Peer-Reviewed Paper on Dependency Graph Model
Winston Ewert has published a new paper in the journal BIO-Complexity expanding on his previous research related to the pattern of similarities between species. He further demonstrated how the distribution of similarities fits his dependency graph model better than the standard common ancestry model. The paper can be downloaded here. I described the superior explanatory power of Ewert’s model here. His original BIO-Complexity paper is here.
The Dawkins Test
One of the central predictions of evolutionary theory is that similarities between species should consistently point to the same evolutionary tree based on the premise of common ancestry. The branching points in the tree should correspond to the common ancestor of a group of organisms (e.g., mammals) that first acquired all the traits common to that group (e.g., glands to produce milk and three bones in the inner ear).
Richard Dawkins stated that a reliable test of the design hypothesis for life is whether similarities are highly inconsistent with a single tree. Data collected over the past several decades has demonstrated that the distribution of similarities is far more inconsistent with common ancestry than any evolutionist imagined, so the intelligent design framework has passed the Dawkins test. Casey Luskin cited numerous studies detailing the inconsistencies here.
This data undermines evolutionary theory at its core. Nearly all the arguments for the grand evolutionary narratives (e.g., transformation of fish into humans) rest on the assumption that similarities reliably point to common ancestry. In many groups, the high level of inconsistency of similarities with any evolutionary tree demonstrates that this foundational assumption is false.
Particularly problematic, the places where evolutionists most require reliable data is where the data is most inconsistent. For instance, a central icon of evolution is the “whale series” consisting of fossils that purportedly illustrate a land mammal incrementally transforming into a fully aquatic mammal. The animals in the series are not believed to have directly descend from or evolved into each other, but their similarities are interpreted as their having descended from animals that are part of an ancestor-descendent series encompassing the land-sea transition.
The challenge is that the rescaled consistency index (RCI) for aquatic mammals and their purported ancestors is 0.24. An RCI value of 1.0 corresponds to perfect consistency of all traits with one evolutionary tree, and a value of 0.0 corresponds to traits that are randomly distributed. An RCI value significantly lower than 0.5 indicates that similarities are so inconsistent with the assumption of common ancestry that arguments for evolution based on similarities, such as with the whale series, become highly suspect. As another key example, the RCI for primates and their purported relatives is 0.29, so claims related to the evolution of humans resting on similarities in fossils also carry little weight.
Dependency Graph Model
In contrast, the pattern of similarities fits design-based models, as I previously described here. To summarize, human engineers use design modules, such as engines, in different creations to meet common goals. Likewise, similarities between species are often not consistent with an evolutionary tree, but they appear implemented in different creatures for a common purpose. Ewert’s framework is the first to identify modules based on proteins.
In Ewert’s first paper, he identified modules as sets of proteins from distinct families. Some modules are dependent on smaller modules, and the smaller modules are at times used by multiple larger modules (Figure 1). Ewert demonstrated quantitatively that the protein data far better fits the dependency graph model than common ancestry.
Figure 1. Part of a dependency graph for proteins in the Ensemble database from Ewert (2018), Figure 12. Circles represent modules, which are sets of proteins. An arrow represents a dependency relationship between two modules. The head of the arrow points to a set of proteins contained in the module connected to the arrow’s tail. The tail module also contains other proteins and possibly other modules. The protein data could be forced into a tree, but the interrelationships inconsistent with that tree would be lost.
Application to Protein Sequences
In Ewert’s recently published article, he did not identify modules as sets of distinct proteins. Instead, he focused on variations in the protein prestin between a variety of mammal species including those capable of echolocation. The protein plays a critical role in mammal hearing by serving as a motor protein in the outer hair cells. The versions of the protein supporting echolocating bats, whales, and dolphins show the same amino acid alterations compared to the versions in mammals lacking echolocation. The pattern of alterations is not simple. Different pairs of mammals share similar amino acid alterations. Constructed evolutionary trees for mammals based on common ancestry lose this information while Ewert’s model highlights it.
To visualize the interrelationships, Ewert created a program called AminoGraph that identifies modules as specific amino acid alterations from an archetypal sequence that is a representative version of the protein. One module depends on another if it includes the latter’s alterations plus additional alterations. The program takes as input amino acid sequences for the same protein in different species, and it creates from this data the most consistent graph of module dependences.
The program displays sets of sequences that are not related as each input sequence directly linking to the archetypal sequence (Figure 2a). It displays data that best fits a common ancestry model as a standard evolutionary tree (Figure 2b), and it displays data that corresponds to modules with complex interrelationships as a dependency graph (Figure 2c). Ewert tested the program on simulated data corresponding to unrelated sequences, sequences connected by common ancestry, and sequences connected through a specific dependency graph. In each case, the program properly identified the correct structure and accurately identified most of the modules and their interrelationships, thus confirming the reliability of the program.
Figure 2. Comparison of different graphs generated by AminoGraph. The grey circles represent the archetypal sequences. The black circles represent the input sequences. The blue circles represent modules. If the data best fits the common ancestry model, the modules represent the common ancestors of sequences pointing to them, and the archetypal sequence represents the common ancestor of all the sequences.
Results for Prestin Protein
Ewert ran AminoGraph on the sequences of prestin proteins from species of echolocating bats, bats without echolocation, echolocating whales, whales without echolocation, and other mammals without echolocation. The generated dependency graph revealed a key insight into how the prestin proteins were modified to respond to the high sound frequencies generated in echolocation. The reengineering in each echolocating mammal employed some combination of two modules labeled Echolocation A and Echolocation B (Figure 3).
Figure 3. Dependency graph of prestin proteins from different mammals generated by AminoGraph. The prestin molecules in echolocating aquatic mammals and bats used module Echolocation A, module Echolocation B, or both.
Future Research
This result naturally leads to research into the effects of amino acid modifications. The design framework predicts that alterations coordinate in each module to support echolocation in a way that best serves the needs of the species that employ it. Another expectation is that the prestin modules must coordinate with other modules for echolocation to function at a level that would benefit its possessor. This prediction appears consistent with the numerous similarities between echolocating mammals in both their genetics (here, here) and their overarching design logic (here, here).
In contrast, the standard evolutionary framework provides no insight into how echolocation is implemented in different mammals. The commonly accepted evolutionary tree requires echolocation to have evolved independently three times as illustrated in Ewert (2023), Figure 1. Yet the maximum possible time for the evolution of a fully aquatic mammal or a bat is insufficient for more than two coordinated mutations to appear. Any evolutionary scenario for echolocation would require far more than two coordinated mutations (here,here), so evolution fails to explain this trait’s origin even once, let alone multiple times.
Ewert’s model could be applied to several other proteins in echolocation and in other biological systems to gain similar insights. It represents a valuable tool in the developing theory of biological design, which should eventually supplant phylogenetic analyses.
Wednesday, 23 August 2023
The blood clotting cascade is irreducibly complex in any language.
The Incredible Design of Vertebrate Blood Clotting
Recently, a commenter on the Center for Science and Culture’s Facebook page asked about a paper by the late biochemist Russell F. Doolittle (1931-2019)1 in relation to Michael Behe’s claim, defended in Darwin’s Black Box2 (and in the video below), that the blood clotting cascade is irreducibly complex. Doolittle claims to show “Step-by-step evolution of vertebrate blood coagulation.” However, in a series of three articles I will respond to this claim. First, I will provide a brief description of the blood clotting cascade, for the purpose of bringing readers unfamiliar with the pathway up to speed. Second, I will discuss why vertebrate coagulation is considered to be an irreducibly complex system that poses a significant challenge to evolutionary explanations. Third and finally, I will summarize the key points of the Doolittle paper and offer an evaluation of whether it calls Behe’s argument into question. Since Doolittle has also published a book dealing with this subject3, in which he elaborates on the arguments expressed in the paper in more detail, I will occasionally refer to things said in the book as well.
The Formation of the Platelet Plug
Blood clotting, also known as coagulation, is a complex physiological process that plays a crucial role in maintaining the integrity of the circulatory system. It involves a series of intricate molecular and cellular interactions that result in the formation of a clot at the site of injury within a blood vessel. This process prevents excessive bleeding while promoting wound healing.
Upon injury, platelets adhere to the exposed collagen fibers in the damaged area.4 The platelets then undergo a conformational change and release various substances stored within their granules, which promote further platelet activation and attract more platelets to the site of injury, forming a plug over the hole. Activated platelets bind together, forming aggregates or clumps, reinforcing the platelet plug and creating a temporary seal over the injured area. This seal is a short-term solution, however, and is not strong enough to hold for long. As blood continues to flow through the injured vessel, it can dislodge the loosely adhering platelets. Thus, the formation of this platelet plug (and the injury itself) initiates the coagulation cascade.
The Fibrin Gel
The coagulation pathway involves many different components, which can be difficult to keep track of. For ease of following the description that follows, I recommend referring to the figure below, which depicts aspects of the human coagulation system. An arrow from one component to another indicates that the former activates the latter. A barred line signifies inhibition of one protein by another
Vertebrate blood coagulation is best understood by focusing first on the ultimate objective of the cascade, which is the formation of a fibrin gel that reinforces the initial platelet plug, thereby strengthening the clot. The clot itself is made of fibers composed of the protein fibrin, which circulates in an inactive form (fibrinogen) in the blood plasma5,6 , shown in the figure below.
Fibrinogen is comprised of three pairs of polypeptide chains, known as Aα, Bβ, and γ chains, which are held together by disulfide bonds. Fibrinogen becomes activated when another protein, called thrombin, cleaves specific peptide bonds in the fibrinogen molecule, specifically near the N-terminus of the Aα and Bβ chains.7 This cleavage removes small peptide fragments called fibrinopeptides A and B, respectively, from the fibrinogen molecule, resulting in a similar protein with remarkably different functions referred to as fibrin. The cleavage of fibrinopeptides exposes new binding sites on the fibrin molecule, allowing the individual fibrin molecules to polymerize into a clot.8 The fibrin molecules further aggregate and form a mesh-like network, which is stabilized by the enzyme factor XIIIa.9 Factor XIIIa catalyzes the crosslinking of fibrin molecules through the formation of covalent bonds between specific amino acid residues, creating a stable fibrin clot. The resulting fibrin clot, together with the platelets, provides a physical barrier at the site of injury, preventing further blood loss. It also serves as a scaffold for other components of the clotting process, which aggregate on the fibrin network to form a stable blood clot.
If the pathway consisted only of fibrinogen and thrombin, thrombin would constantly cleave fibrinogen, and the consequence would be uncontrolled and excessive clotting throughout the bloodstream. To avoid this, it is essential that the process be carefully regulated. Blood clotting involves the use of proenzymes, which are enzymes that are retained in an inactive state and need to be converted into active enzymes through specific cleavage by proteases such as thrombin.
Thrombin itself exists in an inactive form, prothrombin. To convert prothrombin into active thrombin, another enzyme (factor Xa), along with its cofactor (factor Va), assembles on the surface of platelets or other phospholipid membranes to form the prothrombinase complex.10 This complex provides the platform for the subsequent activation of prothrombin. The conversion of prothrombin to thrombin, mediated by the prothrombinase complex, occurs (as with fibrinogen) through a proteolytic cleavage of prothrombin at specific sites. Curiously, factor V also exists in an inactive state, but is cleaved and activated (to form factor Va) by thrombin itself (a small trace of which circulates in the bloodstream due to a low rate of cleavage of prothrombin by factor Xa).11 Once activated, factor Va plays a critical role in the amplification of the coagulation process by enhancing the activity of factor X and promoting the production of more thrombin. This makes the coagulation cascade autocatalytic, since the activation of clotting factors leads to the activation of more of the same proteins.
Factor Xa also exists in an inactive form, factor X. Factor X may be activated by two different pathways: the extrinsic and intrinsic pathway. In the extrinsic pathway, so-named because it is triggered by the external factors, tissue factor (also known as factor III) is released.12 Tissue factor forms a complex with factor VII, leading to the activation of factor X. The first step of the intrinsic pathway, so-named because all of the components required for its initiation and progression are present within the blood itself, involves the activation of factor XII (also called Hageman factor) by contact with negatively charged surfaces, such as exposed collagen at the site of injury.13 Activated factor XII then activates factor XI, which, in turn, activates factor IX. Activated factor IX (IXa) forms a complex with its cofactor, factor VIIIa, on a phospholipid surface. This complex, along with calcium ions, is called the tenase complex or intrinsic tenase.14,15 The tenase complex plays a crucial role in amplifying the clotting process by cleaving, and thereby activating, factor X.
Preventing Excess Clotting
To prevent excess clotting and ensure that the clotting cascade remains localized to the site of injury, there are several regulatory mechanisms.16 Antithrombin III (ATIII) is a natural anticoagulant that inhibits the activity of thrombin and several other coagulation factors, including factor Xa and factor IXa. It achieves its anticoagulant effects through a mechanism called “serpin” inhibition.17 Serpins (serine protease inhibitors) are a class of proteins that regulate the activity of proteases, including those involved in blood clotting. ATIII binds to Thrombin’s active site, effectively blocking its ability to cleave fibrinogen into fibrin. By inhibiting thrombin, antithrombin III indirectly helps regulate the activation of factor V and thereby prevents excessive clotting.18
Thrombin not only activates factor V but also activates protein C, which, in the presence of its cofactor protein S, inactivates factor Va (activated form of factor V).19 Protein C cleaves factor Va at specific sites, rendering it less active and inhibiting its procoagulant properties. This negative feedback loop helps to limit and regulate the clotting process. Tissue factor pathway inhibitor (TFPI) is a protein that directly inhibits the activity of factor Xa and the factor VIIa-tissue factor complex.20 By inhibiting these factors, TFPI also indirectly prevents excessive activation of factor V and, thereby, of thrombin.
Clot Retraction and Dissolution
After the clot is formed, it undergoes retraction, which involves the contraction of fibrin by platelets within the clot, resulting in the clot becoming denser.21 This process helps to reduce the size of the clot and brings the edges of the wound closer together. Eventually, as the wound heals, the clot needs to be dissolved to restore normal blood flow. Plasmin, a proteolytic enzyme, breaks down the fibrin meshwork into soluble fragments, leading to the dissolution of the clot.22 Plasmin is generated from plasminogen by tissue plasminogen activator (t-PA) or urokinase-type plasminogen activator (u-Pa), among other molecules.
The Role of Vitamin K
Several of the proteins discussed here depend upon vitamin K for their synthesis — these are prothrombin, factors VII, IX, and X, as well as proteins C and S (i.e., the anticoagulant proteins that serve to inhibit excessive clot formation). Vitamin K is essential for the post-translational modification of these clotting factors. Without adequate vitamin K, these proteins cannot undergo the necessary chemical changes, which would impair their ability to function properly in the coagulation process. For this reason, deficiency in vitamin K can lead to a bleeding disorder known as vitamin K deficiency bleeding, or coagulopathy.
Summary
In summary, vertebrate blood clotting is an incredible, tightly regulated, multi-component cascade that intuitively points to intelligent design. This is in view of its goal-directedness towards its final end, which is producing a successful clot. In a second article in this series, I will discuss why unguided evolutionary explanations are implausible in accounting for the origins of the coagulation pathway
Notes
Doolittle RF. Step-by-step evolution of vertebrate blood coagulation. Cold Spring Harb Symp Quant Biol. 2009;74:35-40.
Behe, MJ. Darwin’s Black Box: The Biochemical Challenge to Evolution. Free Press 1996.
Doolittle RF. The Evolution of Vertebrate Blood Clotting. University Science Books 2013.
Periayah MH, Halim AS, Mat Saad AZ. Mechanism Action of Platelets and Crucial Blood Coagulation Pathways in Hemostasis. Int J Hematol Oncol Stem Cell Res. 2017 Oct 1;11(4):319-327.
Kattula S, Byrnes JR, Wolberg AS. Fibrinogen and Fibrin in Hemostasis and Thrombosis. Arterioscler Thromb Vasc Biol. 2017 Mar;37(3):e13-e21.
Pieters M, Wolberg AS. Fibrinogen and fibrin: An illustrated review. Res Pract Thromb Haemost. 2019 Mar 4;3(2):161-172.
Greenberg CS, Miraglia CC, Rickles FR, Shuman MA. Cleavage of blood coagulation factor XIII and fibrinogen by thrombin during in vitro clotting. J Clin Invest. 1985 May;75(5):1463-70.
Weisel JW, Litvinov RI. Fibrin Formation, Structure and Properties. Subcell Biochem. 2017;82:405-456. doi: 10.1007/978-3-319-49674-0_13.
Lorand L. Factor XIII and the clotting of fibrinogen: from basic research to medicine. J Thromb Haemost. 2005 Jul;3(7):1337-48.
Krishnaswamy S. The transition of prothrombin to thrombin. J Thromb Haemost. 2013 Jun;11 Suppl 1(0 1):265-76.
Keller FG, Ortel TL, Quinn-Allen MA, Kane WH. Thrombin-catalyzed activation of recombinant human factor V. Biochemistry. 1995 Mar 28;34(12):4118-24.
Mackman N, Tilley RE, Key NS. Role of the extrinsic pathway of blood coagulation in hemostasis and thrombosis. Arterioscler Thromb Vasc Biol. 2007 Aug;27(8):1687-93.
Grover SP, Mackman N. Intrinsic Pathway of Coagulation and Thrombosis. Arterioscler Thromb Vasc Biol. 2019 Mar;39(3):331-338.
Autin L, Miteva MA, Lee WH, Mertens K, Radtke KP, Villoutreix BO. Molecular models of the procoagulant factor VIIIa-factor IXa complex. J Thromb Haemost. 2005 Sep;3(9):2044-56.
Childers KC, Peters SC, Lollar P, Spencer HT, Doering CB, Spiegel PC. SAXS analysis of the intrinsic tenase complex bound to a lipid nanodisc highlights intermolecular contacts between factors VIIIa/IXa. Blood Adv. 2022 Jun 14;6(11):3240-3254.
Dahlbäck B. Blood coagulation and its regulation by anticoagulant pathways: genetic pathogenesis of bleeding and thrombotic diseases. J Intern Med. 2005 Mar;257(3):209-23.
Sanrattana W, Maas C, de Maat S. SERPINs-From Trap to Treatment. Front Med (Lausanne). 2019 Feb 12;6:25.
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