The case for uncommon descent?

 Fitness Landscapes Demonstrate Perfection in Vertebrate Limbs Resulted from Intelligent Design

Brian Miller

In two previous articles (here, here), I summarized Stuart Burgess’s new paper (“Universal optimal design in the vertebrate limb pattern and lessons for bioinspired design”) that demonstrates common features of vertebrate limbs are better explained by design than by common ancestry, and I explained how embryological studies further support the design hypothesis. Here, I will detail how the conclusion of design is also bolstered by studies of evolutionary fitness landscapes.

Tutorial on Fitness Landscapes

A common metaphor for visualizing evolution is a fitness landscape (here, here, here), which is a three-dimensional plot of the fitness of an organism as a function of variables associated with different traits such as hair color, the shape and length of bones, and the efficiency of digesting toxins. The number of variables can be very large, so the values of all the variables are projected onto the x and y axes of the graph. These axes could also represent individuals’ genetic sequences. The z-axis corresponds to an individual’s fitness, which is commonly understood as the probability that it will produce offspring (Figure 1). 

Figure 1. Evolutionary Fitness Landscape. The x and y axes represent the values of all trait variables for individuals in a population. The z-axis represents the fitness of an individual as measured by the probability of producing offspring. Populations tend to move uphill as represented by the white arrow-tipped line leading from point (1) to point (2). The path from (1) to (2) could represent an animal’s hair changing from dark grey to white or a fish transforming into an amphibian. © Thomas Shafee, CC BY 4.0, via Wikimedia Commons.

An individual represents a single point on the landscape, a population represents a cluster of points on the landscape, and the genetic variation in the population corresponds to the area or spread of the cluster. The variation can increase through individuals accumulating mutations. The population tends to move uphill since larger z corresponds to individuals producing more offspring (Figure 2). 

Figure 2. Population trajectory on a static fitness landscape. Each dot represents an individual in the population. Within the population, the variation in traits represents the area the dots cover. If the fitness landscape does not change, the population typically moves to the top of the nearest fitness peak and then stops. Refresh this webpage to see the animation. © Randy Olson and Bjørn Østman, CC BY-SA 3.0, via Wikimedia Commons

A dynamic landscape will reshape if environmental conditions change, or individual organisms interact with each other in such a way as to alter their reproductive success (Figure 3). In practice, many peaks will remain relatively fixed since they correspond to the operation of traits in any environment an organism might encounter. If a population reaches the top of a static peak, it could remain trapped there for a period or indefinitely

Figure 3. Population trajectory on a dynamic fitness landscape. The fitness landscape changes with time, so the trajectory of the population also changes. For instance, in rainy seasons finches’ beaks could become thinner and longer, while in dry seasons they could become thicker and shorter. Refresh this webpage to see the animation. © Randy Olson and Bjørn Østman, CC BY-SA 3.0, via Wikimedia Commons

The extent to which a population can traverse a landscape depends on whether the landscape is smooth or rugged. A smooth landscape contains relatively few peaks with gently rising paths connecting the base of one peak to the summit of another (Figures 1 and 4d). An organism could potentially traverse significant distances along such a landscape, resulting in large evolutionary change. In contrast, a rugged landscape contains a multitude of sharp peaks (Figure 4f). Populations will tend to spend most of their time trapped on a local peak, so evolutionary change will be largely confined to minor modifications to existing traits. 

The extent to which a landscape is smooth or rugged depends significantly on whether mutations interact additively (Figure 4a) or epistatically (Figure 4c). If they interact additively, the fitness change of two mutations roughly corresponds to the fitness changes of each individual mutation added together. If they interact epistatically, the fitness change from two mutations might be negative (i.e., detrimental) even if the fitness change from each individual mutation is positive (i.e., beneficial). Additive interactions lead to smooth landscapes supporting evolutionary change while epistatic interactions lead to rugged landscapes greatly limiting evolutionary change. 

Figure 4. Relationship between mutation interactions and fitness landscapes. The top figures represent the fitness for different combinations of two versions of two genes. Genes a and b are the original genes. Gene A is a mutated version of gene a, and gene B is a mutated version of gene b. a) Mutation interactions are additive, so the fitness change from both mutations is approximately the sum of the fitness change from each individual mutation added together. b) Mutation interactions are partially additive and partially epistatic since the fitness of aB is greater ab, and AB is greater than aB, but Ab is not greater than ab. c) Mutation interactions are epistatic since AB’s fitness is less than aB’s and Ba’s fitness. d) Fitness landscape for additive interactions is a smooth peak. e) Fitness landscape for partially additive and partially epistatic interactions is partially rugged. f) Fitness landscape for epistatic interactions is highly rugged. © Thomas Shafee, CC BY 4.0, via Wikimedia Commons

Assessing the Evidence

Empirical studies and theoretical analyses consistently demonstrate that the fitness landscapes associated with complex traits are highly rugged. For instance, paleobiologist Graham J. Slater (2022) in his article “Topographically distinct adaptive landscapes for teeth, skeletons, and size explain the adaptive radiation of Carnivora (Mammalia)” analyzed the landscape for carnivores based on 16 trait variables. He concluded that the fitness landscape is rugged with multiple fitness peaks:

I found evidence of an early partitioning of mandibulo-dental morphological variation in Carnivora (Mammalia) that occurs on an adaptive landscape with multiple peaks, consistent with classic ideas about adaptive radiation.…The dietary adaptive landscape estimated from the first two mandibulodental PC axes by the PhylogeneticEM algorithm contains 21 peaks that are distinct from the ancestral regime.

The ruggedness of landscapes associating with the mechanical design of anatomical structures is further supported by studies on the use of evolutionary algorithms to assist improving robotic designs. Doncieux et al. (2011) observe in their article  “Evolutionary Robotics: Exploring New Horizons”:

The difficulty of a problem often arises with the complexity of the fitness landscape: while a smooth, convex fitness landscape with no noise will be quite easy to deal with, most of the problems from the real world often comes with multimodal, noisy fitness landscapes that feature neutrality regions. The direct consequence is that search may often get stalled, would it be at the very beginning of the algorithm execution (i.e. a boostrap problem) or during the course of evolution (i.e. premature convergence), with no hint on how to escape a local optimum or on how to direct the search within a region where all neighboring candidate solutions are equally rewarded.

The ruggedness appears even more extreme for landscapes based on genetic sequences. Visser and Krug (2014) summarize in their paper “Empirical fitness landscapes and the predictability of evolution” how mutational studies demonstrate that fitness landscapes are rugged even for genetic changes confined to small sections of DNA: 

At the small genomic scales considered so far, it is observed that sign epistasis is common, which reduces the number of accessible mutational pathways and leads to rugged landscapes with multiple fitness peaks. 

Only a limited number of paths are accessible, and those paths require series of mutations that either do not increase the fitness (aka neutral mutations) or reduce it. 

The Implications

The technical literature from paleobiology, robotics, and genetics uniformly concludes that fitness landscapes are generally highly rugged even when only a small portion of relevant variables are studied. The ruggedness and constraints on viable paths is only believed by evolutionary theorists to increase with the number of contributing variables and interactions, and the landscape in sequence space for vertebrate limbs represents a set of variables and interactions of enormous size. 

These observations present two dire challenges to undirected evolutionary models considering Burgess’s study. First, the vast number of suboptimal local peaks in the fitness landscape precludes any possibility of an evolutionary search ever discovering the perfection of design consistently seen in vertebrates and in other taxa. Second, the constraints on viable paths require a portion of any trajectory along the landscape to include multiple specific neutral and harmful mutations. Yet the timescales required for obtaining coordinated neutral and deleterious mutations is prohibitively long (here, here).

Compounding the challenge, the fitness landscape is only rugged in regions near existing limb designs. The landscape between these regions represent vast seas of nonviable intermediates (here, here, here, here). The only plausible explanation for the perfection of design observed in vertebrate limbs is that a mind engineered them, for only a mind can choose highly optimized solutions out of a sea of possibilities. 

Darwin skeptic Lee Spetner holds court.

 

Homology by design?

 Developmental Biology of Vertebrate Skeletons Shows Similarities are Better Explained by Design

Brian Miller

In an article yesterday, I reported on Stuart Burgess’s new paper in the journal Bioinspiration & Biomimetics, “Universal optimal design in the vertebrate limb pattern and lessons for bioinspired design.” He demonstrates that the common features of vertebrate limbs are better explained by design than by common ancestry. He explains how the limbs are engineered around the triple-hinged layout because that layout is the best for allowing diverse complex motions. He also details how the instantiation of that layout in each vertebrate group (e.g., birds) is optimally designed for the group’s environment and behaviors. Here, I will describe how embryological studies further undermine evolutionary explanations for the limbs’ similarities and, by extension, support Burgess’s conclusion. 

Evolutionary Predictions

Evolutionists assume that the traits they classify as homologous share similarities due to their having evolved from a common ancestor. For instance, the forelimb of a mammal is similar in many ways to the wing of a bird. The forelimb of each is believed to have evolved from the forelimb of a common ancestor that possessed the same similarities. Evolutionists predicted that homologous traits should share similar developmental pathways — the specific steps of cell migration and differentiation that form the trait as an egg develops into an offspring. 

Manfred D. Laubichler is a distinguished theoretical biologist and historian of science. In his article “Homology in Development and the Development of the Homology Concept,” he summarizes this expectation:

The core assumption of the biological homology concept is that homologues are the units of phenotypic evolution. As such they are individuated quasi-autonomous parts of an organism that share certain elements and variational properties. Therefore, if two characters are to be homologous, they can only differ in those aspects of their structure that are not subject to shared developmental constraints. The role of developmental mechanisms is to guarantee the identity of two structures since they limit the variational properties of quasi-autonomous units

In other words, the differences between homologous traits in different species result from the ways their common ancestor’s developmental pathway was free to change, and the similarities between their traits correspond to the ways the pathway could not change. In the context of vertebrates, homologous limbs should result from highly similar developmental pathways since the three-hinged layout was maintained in most of the ancestors due to developmental and operational constraints. 

Failure of the Prediction

Yet the embryological evidence demonstrates that this central prediction is false. Evolutionary biologists Tatsuya Hirasawa and Shigeru Kuratani detail in their article “Evolution of the vertebrate skeleton: morphology, embryology, and development” how homologous bones often develop from different developmental pathways supported by different genes:

Historical continuities of skeletal elements as step-wise morphological changes along a phylogenic lineage are inferable from detailed comparative analyses. However, within these continuities, discontinuities of genetic and developmental bases arise in which morphologically homologous bones are produced through different developmental processes. 

The differences can include homologous bones originating in different regions of the embryos in different types of cells, and they can employ very different cell migration, cell differentiation, and genetic mechanisms and pathways. The authors explain how this discovery conflicts with evolutionary expectations: 

A similar reductionist argument was once widespread with a vague expectation in the dawn of evolutionary developmental biology; namely, that morphologically homologous structures should be patterned through certain unchanged infrastructures, like function of evolutionarily conserved sets of regulatory genes or gene regulatory networks.

Implications

Other research has identified many additional differences in vertebrate limb development (here, here). The same holds true for the entire body plans of different vertebrate groups. These often-dramatic differences in both developmental pathways and their genetic bases severely challenge the claim that homologous limbs can be explained by common ancestry. 

As an analogy, two versions of Microsoft Windows look very similar, and their programming and the computers that run them are also very similar. The similarities in both the operating systems’ appearance and the underlying software and hardware suggest that one operating system served as the basis for the other or they share a common ancestral source. In contrast, Microsoft Windows and Mac OS also look very similar, but their programming and the computers that run them are very different. Their similarity in appearance is not the result of common ancestry but of a software engineer choosing to design one similarly to the other. 

In the same way, two vertebrate limbs might look similar, but the similarity can result from fundamentally different developmental pathways supported by different sets of genes. Consequently, the similarity is best explained by a mind choosing to craft them based on the same general design pattern. Other common design patterns in biology have been discussed in recent articles by biologist Emily Reeves and science journalist David Coppedge (here, here), further illustrating how the design framework is essential to advancing what we understand of the higher-level organization of living systems. 

A world finetuned for science?

 Plate Tectonics and Scientific Discovery

Guillermo Gonzales

 you haven’t seen it, you should read Casey Luskin’s detailed Summary of a recent study arguing for the importance of plate tectonics for advanced life. The basic conclusions of the study are that plate tectonics is important for advanced life in multiple ways and that planets with plate tectonics are very rare. This comports with what Jay Richards and I wrote in The Privileged Planet: How Our Place in the Cosmos Is Designed for Discovery, out now in an expanded 20th-anniversary edition, and what my former colleagues Donald Brownlee and Peter Ward wrote in Rare Earth almost a quarter century ago. But here, I would like to focus on those aspects of plate tectonics that are important for technology. 

Plate tectonics is an important part of continent building. Continents provide vast areas of dry land. Dry land is needed to make and control fire, which as Michael Denton argued in Fire-Maker, is the key starting point for advanced technology. Dry land also provides ready access to diverse minerals at or very near the surface, concentrated there by biological and geologic processes, including plate tectonics. Think of gold, copper, iron, uranium, salt, and coal, among many others.

The Continents Hold Other Treasures

There too we find time-stamped archives of Earth’s deep history, where we can dig up fossils and sample ice cores in the polar regions. Some fossils are of ancient sea creatures that died and ended up on the seafloor, covered by sediment, and were later transported to the continents or uplifted by plate motions. Yes, Earth’s dynamic geology destroys much information about its past, but at the same time it preserves often delicate features of ancient life. (See the photo at the top, a fossil leaf from the Eocene, 34 million years old, which I found at the Florissant Fossil Quarry in Colorado. The site is world famous for the quality and variety of its fossils.)

Plate motions also build mountain ranges. Mountains are important for a diverse biosphere. They are also important for mining minerals and for astronomical observations. Mountain ranges greatly increase the exposed surface area, making mineral deposits more accessible. The biggest, most expensive observatories are placed on high mountains to get above most of the mass of the atmosphere. A planet having only tectonics (without plates moving) might have a few high volcanic mountains, but they would remain active for long periods, preventing safe operation of observatories at their summit. This contrasts with, say, the Hawaiian Islands, which are over a hot spot in the crust with the oceanic plate slowly moving over it. The biggest volcano on Hawaii has already moved off the hot spot, causing it to be inactive and serving as a platform for observatories. 

The Magnetic Field

Plate tectonics also contributes to the generation of Earth’s magnetic field. The magnetic field serves as a kind of global positioning system. Yes, people have used magnetic navigation for centuries, but I have in mind something more subtle. Geologists use the remnant magnetic field in ancient lava flows to reconstruct the motions of the continents over a large portion of Earth’s history. One aspect of the magnetic field that makes it especially useful to scientists is its semi-regular polarity reversals. This creates a kind of unique bar-code pattern over geologically long periods. It was this pattern, measured on the seafloor, that convinced geologists of the superiority of plate tectonics theory over competing theories in the early 1960s.

Earthquakes and Earthquake Zones

Plate motions generate earthquakes, which generate seismic waves that travel throughout Earth’s interior. Geologists have installed seismometers around the world to measure them and locate the earthquake epicenters and make a 3D map of Earth’s interior. This wouldn’t be possible on water worlds. Remarkably, geologists have discovered that earthquakes overwhelmingly occur in certain restricted regions, namely the crustal plate boundaries. We don’t know when earthquakes are going to happen, but we do know where they happen. Though people haven’t taken full advantage of this information, they could greatly reduce deaths from earthquakes by moving away from earthquake-prone areas.

Plate tectonics is yet another example of the correlation between the requirements for life and the requirements for doing science that we describe in The privileged planet.

Continuing to make it clear that there is no place like home.

 

More on "Junk" DNA Proving to be junk science.

 Hey, Please Ask Dawkins About His “Junk DNA” Goof

David Klinhhoffer

Our friend Brian Keating, a cosmologist at UC San Diego, does wonderful interviews for his Into the Impossible podcast. A particularly fun recent one was with Richard Dawkins. Near the end, Dr. Keating asked Dr. Dawkins for an example of a memorable scientific error he’s made. I leaned forward with curiosity. Dawkins volunteered that he had made a mistake about the so-called “handicap principle” relating to sexual selection. What I was hoping was that he would admit to the really major goof he made on “junk DNA,” a topic with so much consequence for the debate about intelligent design. But no.

Keating mentions that this is only Part 1 of a two-part conversation with Dawkins. Be sure to subscribe to Into the Impossible so that you’ll know right away when that one comes out. Perhaps Dr. Keating will consider asking Dawkins about “junk DNA” and what evolution would expect. On that, Dawkins seemed to changed his mind in a remarkable fashion. As of 2009 in his book The Greatest Show on Earth, he wrote, “the greater part (95 per cent in the case of humans) of the genome might as well not be there, for all the difference it makes.” Got that? 95 percent of the human genome is useless detritus, evolutionary garbage. And that would make sense if Darwinism is correct. It’s also the opposite of what ID proponents predicted.

With the Greatest of Ease

But the ID folks were dramatically vindicated. As of 2012, just three years later, after the results of the ENCODE project were published, Dawkins had completely flipped. Now, because ENCODE had indicated widespread function in the genome, putting the “junk” thesis out of business, Dawkins turned his earlier contention on its head. With the greatest of ease, he now argued that widespread function was just what Darwinian evolution would expect.

In a Conversation with Rabbi Jonathan Sacks, he said:

I have noticed that there are some creationists who are jumping on [the 2012 ENCODE results] because they think that’s awkward for Darwinism. Quite the contrary it’s exactly what a Darwinist would hope for, is to find usefulness in the living world […] we thought only a minority of the genome was doing something, mainly that minority which only codes for protein, and now we find that actually the majority of it is doing something. What it’s doing is calling into action the protein coding genes. […] The program that’s calling them into action is the rest that had previously been written off as junk.

Before, junk DNA fit beautifully with evolution. In the 2012 presentation, the opposite is the case: function rather than junk is “exactly what a Darwinist would hope for.” What a difference three years can make.

Watch the full podcast with Professor Keating below. And for more, see Casey Luskin’s post here, “‘Junk DNA’ from Three Perspectives: Some Key quotes.”

We continue our pursuit of straight answers from trintarians.

 AservantofJEHOVAH:

"Is it compatible with trinitarian orthodoxy to claim that Jesus of Nazareth is the MOST High God?"

The real war on drugs,

 

On those parts of the cosmos where nothing truly matters.

 

Darwin is becoming ever more Deniable?

 

Designed intelligence?

 There Is No Known Evolutionary Rule for Animal Intelligence

Denyse O Leary

Cambridge neuropsychologist Nicholas Humphrey argues that warm-bloodedness (endothermy) enables mammals and birds to be more sentient than, say, cold-blooded reptiles and fish. In an excerpt from his book, Sentience: The Invention of Consciousness (MIT Press 2023), he argues that that development put these endotherms on the road to consciousness.

For one thing, as temperature goes up various bodily processes actually become more energetically efficient, so the costs can be partially offset. In particular, the cost of sending an impulse along a nerve decreases until it reaches a minimum at about 37 degrees Celsius. The result is that, although the overall running costs for the body go up with being warm-blooded, the costs for the brain are reduced. This means that mammals and birds can support larger and more complex brains with relatively little extra outlay of energy.

NICHOLAS HUMPHREY, “DID WARM-BLOODEDNESS PAVE THE PATH TO SENTIENCE?,” MIT PRESS, APRIL 15, 2024

He asks us to consider how warm-bloodedness might specifically affect the qualities we associate with intelligence:

It’s a well-established fact of physiology that the functional characteristics of neurons change with temperature. It’s been found for a range of animals — warm and cold-blooded — that the conduction speed for all classes of neurons increases by about 5 percent per degree Centigrade, while the refractory period decreases by roughly the same amount. This implies that when the ancestors of mammals and birds transitioned from a cold-blooded body temperature of, say, 15 degrees Celsius (59 degrees Fahrenheit) to a warm-blooded temperature of 37 degrees Celsius, the speed of their brain circuits would have more than doubled.

We’ve remarked already on the “lucky accidents” that have, at several points, played a part in the evolution of sensations. If warm-bloodedness played these key roles, first in changing the way animals thought about the autonomy of the self, second in preparing the brain for phenomenal consciousness, here was an accident as lucky as they come.

HUMPHREY, “PATH TO SENTIENCE?”

But the Situation Is Not Clear-Cut

When researchers have tested reptiles, using the same tests used on birds, the results have been surprising:

The lizards’ success on a worm-based test normally used on birds was “completely unexpected,” said Duke biologist Manuel Leal, who led the study.

He tested the lizards using a wooden block with two wells, one that was empty and one that held a worm but was covered by a cap. Four lizards, two male and two female, passed the test by either biting the cap or bumping it out of the way.

The lizards solved the problem in three fewer attempts than birds need to flip the correct cap and pass the test, Leal said. Birds usually get up to six chances a day, but lizards only get one chance per day because they eat less. In other words, if a lizard makes a mistake, it has to remember how to correct it until the next day, Leal said. He and Duke graduate student Brian Powell describe the experiment and results online in Biology Letters.

ASHLEY YEAGER, “BRAINY LIZARDS PASS TESTS FOR BIRDS,” DUKE TODAY, JULY 12, 2011

Significantly, the lizards had to learn a new task. They don’t feed themselves in the wild by flipping caps. And when the researchers raised the bar by switching which well held the worm, two of the lizards figured it out. As a result, the researchers named them Plato and Socrates.

That’s hardly the only instance of reptile intelligence observed by researchers. For example, the New York Times interviewed comparative psychologist Gordon M. Burghardt on monitor lizards:

Other studies have documented similar levels of flexibility and problem solving. Dr. Burghardt, for instance, presented monitor lizards with an utterly unfamiliar apparatus, a clear plastic tube with two hinged doors and several live mice inside. The lizards rapidly figured out how to rotate the tube and open the doors to capture the prey. “It really amazed us that they all solved the problem very quickly and then did much better the second time,” Dr. Burghardt said. “That’s a sign of real learning.” 

EMILY ANTHES, “COLDBLOODED DOES NOT MEAN STUPID,” NEW YORK TIMES, NOVEMBER 19, 2013

Training a reptile.

Anoles and monitor lizards are considered to be among the most intelligent lizards. But it hasn’t been customary until recently to credit any lizards with much intelligence. That may be due to mishandling in some cases. Anthes notes at the Times that tests for reptile intelligence should take into account normal differences between, say, mammal behavior and reptile behavior: “By using experiments originally designed for mammals, researchers may have been setting reptiles up for failure. For instance, scientists commonly use “aversive stimuli,” such as loud sounds and bright lights, to shape rodent behavior. But reptiles respond to many of these stimuli by freezing, thereby not performing.”

Warm-bloodedness enables the mammal and the bird to be active for much longer than the reptile and to be active in colder temperatures. Thus, mammals and birds likely encounter more situations where they can (and must) demonstrate sentience and intelligence. But warm-bloodedness does not seem to be an essential component of those qualities.

Animal Intelligence Remains Something of a Mystery 

One thinks of the invertebrate octopus and the brainless crab, which pass animal intelligence tests while breaking all the rules about which life forms are supposed to be smart. If there is a fixed evolutionary rule about which types of animals are intelligent, it has not been discovered yet.

Molecular biology is only the complex beginning of Darwinism's explanatory deficits?

 The Extracellular Space: Where the Rest of Life Takes Place

Howard Glicksman

When it comes to the discussion of how life came into being, whether by intelligent design or by the unguided processes proposed by evolutionary biology, I have a pet peeve.

It’s that almost all of the discussion from both camps revolves around just molecular and cellular biology — DNA, RNA, genes and their regulatory networks (GRNs), proteins and their various shapes, sizes, and functions, the cell membrane and cytoskeleton, and all the other fascinating intricacies of the cell. 

Don’t Get Me Wrong

When it comes to the dialogue about the causal hurdles that life must overcome, every component mentioned above is important. And to my mind, they all favor ID.  

After all, as chemist James Tour wrote in his chapter in The Mystery of Life’s Origin: The Continuing Controversy, when considering what is known about the laws of chemistry, “we’re still clueless about the origin of life.” Biologist Douglas Axe, in his book Undeniable: How Biology Confirms Our Intuition That Life Is Designed, tells us that “of the possible genes encoding protein chains 153 amino acids in length, only about one in a hundred trillion trillion trillion trillion trillion trillion is expected to encode a chain that folds well enough to perform a biological function.”

Zooming Out

But what about multicellular organisms, like us? Isn’t there more to think about and explain than just molecular and cellular biology? Here’s how Steve Laufmann and I posed the problem in our book Your Designed Body.

Zooming out from a single cell, the human body as a whole is made up of around thirty trillion cells. It needs to solve all the same kinds of problems that a cell does, plus quite a few more. And it needs new ways to solve old problems, ways completely different from how the same problems were solved at the cellular level. 

For example, a single-celled organism is like a microscopic island of life. The cell gets what it needs and gets rid of what it doesn’t need from its surrounding environment. In contrast, a large multi-cellular organism (like you) is more like a continent with a deep and dark interior. Most of the cells reside deep in the interior with no direct access to the body’s surrounding environment. For a multi-cellular organism, then, harvesting the raw materials its cells need and getting rid of toxic byproducts becomes a major logistical problem. 

Several hundred such problems must be solved for a complex body to be alive. And many of the solutions to these basic problems generate new problems that must also be solved, or that constrain other solutions in critical ways. The result is that for a complex body to be alive, thousands of deeply interconnected problems must be solved, and many of them solved at all times, or life will fail. 

The bottom line is that, as hard as it is for a cell to maintain life, it’s much harder for an organism with a complex body plan like yours.

Besides knowing what’s going on inside our cells (within the intracellular space), don’t we also need to consider what’s going on outside our cells (but within our body) — in the extracellular space? Where one-third of our body’s total water resides? Where the various biomolecules that provide the framework for structure and support to all the different tissues in our body are located? Where the precise chemistry allowing for tissue survival and proper nerve and muscle function must be present? And much, much more.

My Experience as a Physician

As a hospice physician, I can tell you that all this is a matter of “life and death.” It’s something that evolutionary biologists rarely mention. This may be, at best, because they’ve never considered or understood it, or at worst, because they can’t explain it and it undermines their theory. 

Let me give you a practical example from what I see and do every day. That way, you can understand why adding what goes on inside the extracellular space as a causal hurdle for multicelluar life is important. Meet my patient Joe.

Joe had had several heart attacks and now his heart wasn’t pumping as well as it should. In fact, it was doing so at one-quarter its normal strength — meaning he had heart failure. Since his heart wasn’t pumping efficiently, it caused a reduction in the force of arterial blood flow which turned on certain hormone systems in his body. These systems were designed (yes — designed) to try to correct such a situation. Unfortunately, this caused Joe’s body to start holding on to excessive amounts of water. 

Joe’s body’s inability to control how much water was in his extracellular space put him at risk of death. Fluid was taking up more and more space in his lungs, making it harder and harder to breathe. Since he kept going in and out of the hospital and his physicians could not solve his recurrent fluid overload problem, he was put on hospice. By the time I first saw him, Joe could barely move or even talk without becoming short of breath. Fortunately for Joe, I knew exactly what medication adjustments were needed to safely remove his excessive fluid. Within a few months, we were able to discharge him alive from our service.    

The above case (and I’ve had dozens of them) clearly shows that what’s going on in the extracellular space matters. It matters so much that to not even talk about it, in the context of biological origins, is frankly unscientific.   

It also shows that my pet peeve about the absence of this discussion in the origins debate is my own fault. So, please watch this space for articles in the future on the extracellular space and ID. 

This Titan is guilty of war crimes?

 

Our self-styled betters in their own words.

 Whatever you think about think about JEHOVAH'S Witnesses We (unlike our self-styled betters) can guarantee you that it will never be our politicians, magistrates,police trampling your rights,

Ps. We know that the religious left also have their version of the police state .

Lizard brain for the win?

 

Pope francis the universalist?

 

Franciscan media

...Fazio asked Pope Francis how he imagines God. “Like a generous father,” the pope responded, citing the prodigal son parable (Lk 15:11–32). Pope Francis said that he believes “in a God who is not scandalized by our sins because he is a father and accompanies us.” The pope asked: “Does God accompany sinners or immediately condemn them to hell? No, he chooses to accompany us. . . . So it’s hard to even imagine hell, a father who condemns someone for all eternity.” The pope said he hopes that hell is empty. 

In fact, we cannot believe in hell in the same way that we believe in the God described in the Bible. The former is a possibility while the latter is a fact... 

Alfred Russel Wallace for the win?

 Alfred Wallace’s Views Hold Up Well Today — Unlike Those of His Friendly Rival Charles Darwin

Evolution News

On a classic episode of ID the Future, science historian Michael Flannery concludes his conversation with host Michael Keas about his book Intelligent Evolution: How Alfred Russel Wallace’s World of Life Challenged Darwin. Wallace was co-founder with Charles Darwin of the theory of evolution by random variation and natural selection. Unlike Darwin, however, he saw teleology or purpose as essential to life’s history, and a teleological view as essential to the life sciences. According to Flannery, Wallace’s views on the nature of the cell, the special attributes of humans, the irreducible nature of life, and the fine-tuning of the universe hold up well today. They are also remarkable in foreshadowing modern intelligent design theory. Wallace and Darwin disagreed on much of this, yet they maintained a mutual respect. In this, Flannery says, the two are a great model for scientists who disagree today.

Find the podcast and listen to it here. 

The crocodilian explosion?

 Fossil Friday: The Sudden Appearance of Crocs in the Triassic Fossil Record

Gunter Bechly

This Fossil Friday we will look at a clade of reptiles that is called Pseudosuchia, which includes living crocodiles and their fossil relatives such as the featured Postosuchus from the Late Triassic of Texas. Like so many other groups, pseudosuchians appeared very abruptly in the Early Triassic period after the ‘Great Dying’ of the end-Permian mass extinction event about 250 million years ago.

Just a few weeks ago a new fossil poposauroid pseudosuchian was described from the Middle Triassic Favret Formation in Nevada (Smith et al. 2024). The new genus received the almost unpronounceable name Benggwigwishingasuchus. The find was very surprising, because only marine organisms (e.g., ichthyosaurs and ammonites) were previously known from these sediments, which have been produced in an open sea environment. A co-author of the study remarked that their first reaction was “What the hell is this?” (Baisas 2024). They certainly did not expect to find a terrestrial animal in these layers, but the well-preserved leg bones left no doubt that this reptile lacked any secondary aquatic adaptations and had a primarily terrestrial mode of life (Klein 2024). Because the preservation of the skeleton suggests a minimal post-mortem transport, the researchers suppose that it lived along the shores of the ancient Panthalassan Ocean. The authors concluded that the new discovery “implies a greater undiscovered diversity of poposauroids during the Early Triassic, and supports that the group, and pseudosuchians more broadly, diversified rapidly following the End-Permian mass extinction” (Smith et al. 2024). They also emphasize that more generally “recent studies have inferred a rapid diversification of archosaurs and their stem lineages, which established major clades by the end of the Early Triassic” (Smith et al. 2024).

A Kind of “Explosion”

In other words, all the subgroups of archosaurs appeared abruptly in a kind of “explosion,” similar to the sudden appearance of 15 different families of marine reptiles in the Early Triassic (Bechly 2023a), or the sudden appearance of different groups of gliding and flying reptiles during the Middle Triassic (Bechly 2023b). Also, dinosaurs appeared so suddenly in the Late Triassic that one expert commented that “it’s amazing how clear cut the change from ‘no dinosaurs’ to ‘all dinosaurs’ was” (University of Bristol 2018). And famous paleontologist Peter Ward (2006: 160) explained that “the diversity of Triassic animal plans is analogous to the diversity of marine body plans that resulted from the Cambrian Explosion.” The Triassic period proves to be a real carpet bombing of bursts of biological creativity (Bechly 2024), which does not resonate well with a Darwinian paradigm at all.

References

Baisas L 2024. Say hello to the surprising crocodile relative Benggwigwishingasuchus eremicarminis. Popular Science July 11, 2024. https://www.popsci.com/science/triassic-crocodile/

Bechly G 2023a. Fossil Friday: The Triassic Explosion of Marine Reptiles. Evolution News March 31, 2023. https://evolutionnews.org/2023/03/fossil-friday-the-triassic-explosion-of-marine-reptiles/

Bechly G 2023b. Fossil Friday: The Explosive Origin of Flying Reptiles in the Mid Triassic. Evolution News May 19, 2023. https://evolutionnews.org/2023/05/fossil-friday-the-explosive-origin-of-flying-reptiles-in-the-mid-triassic/

Bechly G 2024. Fossil Friday: Discontinuities in the Fossil Record — A Problem for Neo-Darwinism. Evolution News May 10, 2024. https://evolutionnews.org/2024/05/fossil-friday-discontinuities-in-the-fossil-record-a-problem-for-neo-darwinism/

Klein N 2024. Diverse growth rates in Triassic archosaurs—insights from a small terrestrial Middle Triassic pseudosuchian. The Science of Nature 111:38, 1–5. DOI: https://doi.org/10.1007/s00114-024-01918-4

Smith ND, Klein N, Sander PM & Schmitz L 2024. A new pseudosuchian from the Favret Formation of Nevada reveals that archosauriforms occupied coastal regions globally during the Middle Triassic. Biology Letters 20(7):20240136, 1–8. DOI: https://doi.org/10.1098/rsbl.2024.0136

University of Bristol 2018. Dinosaurs ended – and originated – with a bang! University of Bristol press release April 16, 2018. http://www.bristol.ac.uk/news/2018/april/dinosaurs-ended-and-originated-with-a-bang-.html

Ward PD 2006. Out of Thin Air. Joseph Henry Press, Washington DC, 296 pp. https://books.google.at/books?id=baJVAgAAQBAJ

Origin of Life science is not a thing?

 

More on why there is no place like home.

 Beauty and Our Privileged Planet

Guillermo Gonzalez

This past July 13 several Discovery Institute fellows (Jay Richards, Melissa Cain Travis, and I) participated in the “Encountering Beauty in the Sciences” conference at the Museum of the Bible. I spoke on the topic “Beauty and Scientific Knowledge,” which was a first for me.

My basic thesis is that there is a connection between beauty in nature and the acquisition of important knowledge about nature. I made a cumulative case argument based on multiple relatable examples. As a corollary, I also argued that Earth’s residents enjoy more beautiful phenomena that lead to scientific advancement than would hypothetical extraterrestrial beings in other places in the cosmos, if there are any.

I was inspired to make this argument from the evidence for design I collected in the pages of The Privileged Planet, whose new and expanded 20th anniversary edition is out today. As Jay Richards and I argue in our book, nature seems designed in such a way that the most habitable places are the best places to do science. In addition, Earth is particularly gifted with life and the tools to do science. I am now convinced that beauty is in the mix as well. 

The Starry Heavens

The beauty of the starry heavens attracts us. We can say the same about rainbows, total solar eclipses, certain minerals, comets, aurorae, meteors, and electrical storms. These phenomena are not only beautiful; they have also revealed important scientific truths about nature. I would rank their importance to science roughly in the order I just listed them.

That these aspects of nature are beautiful is hardly controversial. People spend big bucks to go see a total solar eclipse, or spend vacation time camping away from cities, at least in part, to enjoy the views of the dark night skies. They will vacation in Fairbanks, Alaska, to see the aurorae. People will even pause their busy lives, if only briefly, to gaze at a rainbow.

It’s obvious how dark nights have given us important knowledge about the nature of reality. And, we cover the scientific value of total solar eclipses in Chapter 1 of The Privileged Planet. But, rainbows?

A Clue Across the Sky

I like to think of rainbows as a clue writ large across the sky. They are not only beautiful, but they seem completely out of place and out of the ordinary. When I see one, I feel like exclaiming, “Who ordered that?!” or “How does that form?” Rainbows invite us to ask questions.

Over the centuries scholars proposed theories to explain rainbows. The first breakthrough came in the early 14th century when the Dominican theologian and physicist Theodoric of Freiberg proposed an essentially correct explanation. He arrived at his theory through the application of geometry and experimentation with glass spheres filled with water, simulating what happens within raindrops when sunlight passes through them. Theodoric and others after him not only advanced our understanding of the rainbow phenomenon, but they also advanced the entire field of optics.

The next breakthrough came when Isaac Newton began experimenting with glass prisms in the 17th century to make artificial rainbows. These were the first rudimentary “rainbow makers” or spectroscopes. Later, chemists heated elements in a flame and discovered that each has a unique spectrum. The spectroscope revealed the “fingerprints” of the elements. At the same time, astronomers captured the spectra of distant stars with spectroscopes attached to telescopes. They talked with the chemists and soon astronomers learned how to determine the chemical composition of stars and nebulae. 

Spectra of the Galaxies

Cosmology was born just over a century ago when astronomers began getting spectra of galaxies. They discovered that nearly all the galaxies they observed had red-shifted spectra. That discovery led to the realization that the universe had a beginning. The spectroscope, even today, is the most important tool of the astronomer. It is no exaggeration to say that rainbows provided clues that unlocked the most profound truths about the nature of nature.

What’s more, rainbows are connected to our existence. You need an atmosphere. You need a water cycle. A dune world won’t do. A completely cloud covered sky won’t do. Of all the places in the Solar System, Earth’s surface is the best one for seeing rainbows.

I’ll leave the other examples I listed as an exercise for the reader.

The most pregnant pause of all?

Wrap Your Mind Around the Synapse — Just Try

David Coppedge 

After poring through scientific papers and articles, the complexity of synaptic transmission baffles me. For a neural signal to make it through the steps of packaging neurotransmitters, sending them across a gap, and then triggering a response inside the next neuron, seems needlessly complicated. Dozens of proteins and factors are involved at every synaptic crossing.

Why would evolution, or intelligent design, end up with such a method? It looks like a kludge. The power lines that engineers build do not operate that way. They keep continuous contact for the nonstop flow of electrons. It wouldn’t make sense at each power pole to convert the electricity to chemical energy and back again. Why does the body do it? 

But one has to admit that it works very well, and extremely rapidly. Within milliseconds, a signal from your foot makes it to the brain and back again. On its way, that signal repeatedly undergoes the energy conversion at each synapse. Signals from the feet continuously traverse nearly two meters of nerve fibers packed with molecular machines and ion pumps, crossing synapses at each junction. It’s uncanny, but that’s what biophysicists and biochemists have found. Professors at UC Santa Barbara estimate that some neural signals can travel over 100 miles per hour!

As an avid hiker and backpacker, I have often crossed streams, walking across narrow logs over rushing water. I have leaped from rock to rock to get over a boulder pile, at each moment needing to decide where to place my feet, adjusting quickly if I feel the rock moving. The flow of information from eyes to brain to feet and back again, giving rapid and continuous feedback on my path, is something I am tremendously grateful for. Those synapses have given me invigorating experiences and have saved me from nasty falls uncountable times. The rapid, risky movements of gymnasts and parkour players and squirrels far exceed my exploits, but any of us who have walked irregular paths, up and down stairs, or quickly dodged a moving object have reason to be interested in how the body accomplishes rapid signaling through neurons. Now, cryo-electron microscopy has allowed scientists to peer deeper into the mysteries of the synapse.

Advancing Knowledge

The basic function of the synapse has been understood for many years. Neurotransmitter molecules, usually glutamate (the anion of the amino acid glutamic acid), are packaged into synaptic vesicles (SVs) with COPI proteins like birds in a cage. This process is elaborate in itself, as my article on coatomers described last year. Triggered by calcium ion bursts, the SVs bind to the membrane facing the cleft and release their neurotransmitters into the gap. The molecules bind to receptors on the receiving side, triggering another chain of ion channels that continue the signal down the neuron. The signal propagates all the way to the next synapse.

This much was known, but there were many questions. Biochemists have been limited in their ability to envision the details in the 20-nanometer synaptic cleft and adjacent neural receptors. In PNAS, Richard G. Held and colleagues from Stanford described how they observed synaptic vesicles at the nanoscopic scale by applying cryo-electron tomography after “slicing” synapses from the hippocampus with focused ion-beam milling. This gave them an unprecedented view of the positions of numerous proteins during movement of neurotransmitters across the synapse. Sure enough, the SVs look like little balls with protein tethers attached to guide them.       

Zooming In

Jeremy S. Dittman of Cornell commented on the paper in PNAS. He summarized what happens in preparation for traversing the synapse:

Many of the big questions currently being explored by synaptic biologists are centered on the mechanistic details of the exocytic process and how the two sides of the synapse coordinate signal transmission with reception,briefly summarized as follows: On the presynaptic side, small neurotransmitter-filled synaptic vesicles (SVs) traffic to the cleft-facing electron-dense region of the plasma membrane termed an “active zone” (AZ) where they become tightly attached to the membrane by a core set of proteins (a process termed vesicle docking and priming). Upon arrival of an action potential and subsequent opening of presynaptic voltage-gated Ca2+channels (VGCCs), elevated Ca2+ triggers some of these prepared SVs to fuse with the plasma membrane within a fraction of a millisecond, rapidly transmitting a chemical signal across the cleft

This all happens in a fraction of a millisecond. Let that sink in. 

A local reserve of SVs replenishes the “release-ready” vesicles on a subsecond time scale to sustain ongoing synaptic activity. Just after fusion, the bolus of neurotransmitter rapidly dissipates within the cleft via diffusion, binding to transporters, and in some synapses, by enzymatic degradation.

The neurotransmitters only have a brief window of time to bind to one of the receptors on the receiving neuron, usually AMPA receptors. The signals are received by a protein-dense region called the post-synaptic density (PSD). 

Held et al. wanted to know if the neurotransmitters follow a direct path from AZ to receptor, in what has been dubbed a “nanocolumn” (NC). The surprising answer was: some do, but others do not. A membrane-proximal synaptic vesicle (MPSV) usually travels straight to an AMPA receptor but might travel obliquely to a different one, or to a different receptor like NMDA. This mechanism possibly allows additional information to be conveyed to the receiving neuron. 

Whether AMPA receptors were corralled within PSD nanoclusters or randomly distributed across the postsynaptic membrane, the average response to the fusion of a MPSV (mean number of open AMPA receptors) was similar. By contrast, variability between each distinct MPSV simulation was increased when AMPA receptors were clustered instead of uniformly distributed. One implication of this simulation is that, assuming AMPA receptors adopt a clustered arrangement within the PSD, then some SVs have a larger postsynaptic impact than others. Given previous observations that NCs at these synapses may be altered by synaptic plasticity, perhaps the lack of correlation between MPSVs and PSD nanoclusters observed in this study provides a substrate for boosting synaptic strength via tightening the alignment between MPSVs and PSD receptor clusters. Combined with previous proposals for enhanced AMPA receptor clustering in response to plasticity induction, these effects could harness the variability observed on the simulations of Held et al to produce a large enhancement in synaptic strength.

For those interested in getting into the weeds, the paper and commentary give the names of numerous proteins involved in this rapid transfer of information across the synapse. The authors conclude with a statement of fine tuning:

Together, our data support a model in which synaptic strength is tuned at the level of single vesicles by the spatial relationship between scaffolding nanoclusters and single synaptic vesicle fusion sites.

As impressed as Dittman was by the work, he realizes it leaves many questions:

How are the AZ protein complexes arranged to couple Ca2+ elevation to exocytosis on such a rapid time scale? And related to this, are there special sites in the AZ where SVs dock, prime, and fuse or can SVs fuse anywhere on the AZ membrane? Are SV fusion sites precisely aligned with postsynaptic receptor clusters to ensure maximal receptor activation? Are there different types of synaptic transmission events that convey distinct information between the synaptic partners?

That last question opens the possibility of reasons for the kludge of synaptic transmission: “distinct information” can be transmitted depending on the neurotransmitter, its path, its timing, and its receptor. Indeed, a team of researchers in China and Singapore has been inspired to mimic the synapse in smart wearable materials to allow for more efficient and variable information flow via multiplexing — i.e., conveying multiple types of information over the same communication channel. Why? Because “Information in biological entities is conveyed by solvated ion carriers in water environments, allowing integration, parallelism, and optimal power consumption to control motion,” they said in their paper that was published in PNAS.

Pruning and Self-Tuning

Functioning neural circuits rely on the precise wiring of neurons to their appropriate synaptic partners. Initially, these connections are imprecise, with neurons making contacts with multiple different potential partners. These connections become more precise through a process called synaptic pruning, which eliminates unnecessary synapses.

To me, it’s not enough to quote Hebb’s Law that “New branches tend to be added at the loci where spontaneous activity of individual branches is more correlated with retinal waves, whereas asynchronous activity is associated with branch elimination.” Something else is controlling the synchronization of activity, else the pruning would leave only the strongest branch. A rose gardener knows when the pruning has been optimized for flowering. Something is telling a nerve network when optimality has been reached.

Another paper in PNAS offered additional reasons for synapses instead of direct junctions. Xiong et al. wrote about self-tuning of presynaptic neurons, even in lowly roundworms:

Faced with a myriad of internal and external challenges, neurons display remarkable adaptability, adjusting dynamically to maintain synaptic stability and ensure the fidelity of neural circuit function. This homeostatic adaptability is essential not only for neural circuit integrity but also has implications for various psychiatric and neurological pathologies. At the presynaptic terminal, the influx of calcium through specific ion channels is necessary for the exocytosis of neurotransmitter-filled synaptic vesicles. Our studies in the nematode Caenorhabditis elegans reveal a sophisticated mechanism where the abundance of presynaptic calcium channels is negatively regulated by the efficiency of synaptic vesicle exocytosis. This self-regulating mechanism ensures that presynaptic neurotransmitter release is autonomously adjusted, thereby maintaining synaptic function and safeguarding the robustness of neural communication.

Now I’m starting to get it. The reason for the kludgy synapse design is greater flexibility, information flow, and adaptability. And if the transmission still occurs within milliseconds, who is going to complain about the result? I can still jump onto that rock without falling. Life is good.

Only a designed universe can be known?

 

Settled science vs. Scientific advancement?

 

A complex beginning?

 The Elegant Spindle Assembly Checkpoint

Jonathan McLatchie

In a recent article, I discussed the astounding role of motor proteins in eukaryotic cell division. But this is just one of many incredible engineered features associated with mitosis. In this and a subsequent article, I will provide an overview of the elegant molecular mechanisms that underlie the spindle assembly checkpoint and discuss the implications of its dysfunction.

Without this exquisitely engineered system, the cell risks distributing an uneven number of chromosomes to the daughter cells, potentially resulting in cancer or (in the case of meiosis), trisomy conditions such as Down Syndrome (which is characterized by an extra copy of chromosome 21).

Mitotic division (“M phase”) is the culmination of the eukaryotic cell cycle for somatic cells. Mitotic cell division is divided into six phases, illustrated in the figure above. The first is prophase, which is characterized by chromosome condensation (the reorganization of the sister chromatids into compact rod-like structures). Following condensation, assembly of the mitotic spindle apparatus occurs outside the nucleus between the two centrosomes which have duplicated and moved apart to the poles of the cell. 

The second stage of mitosis is prometaphase, which is marked by the disintegration of the nuclear envelope. This is followed by metaphase, where sister chromatids are attached to opposite spindle poles by microtubules bound to protein complexes called kinetochores. In animal cells, 10-40 microtubule-binding sites are associated with any one kinetochore. In yeast, each kinetochore contains only one attachment site. At this point, the chromosomes are seen to be aligned at the cell’s equator (the metaphase plate). The sister chromatids are themselves held together by the protein cohesin.

At anaphase, the sister chromatids separate to form two daughter chromosomes that are pulled towards opposite poles of the spindle. Microtubules bound to kinetochores, as well as the centrosome, are reeled in towards the cell’s periphery by specialized dynein motor proteins that “walk” towards the minus end of the microtubule but are held stationary by cargo-binding domains that are anchored to the cell cortex.

The next phase in the cycle is telophase, the stage at which the daughter chromosomes de-condense at the spindle poles and a new nuclear envelope is assembled. A contractile ring is then formed, marking the final stage of the process — cytokinesis. The contractile ring is comprised of actin and myosin filaments. The cell thus differentiates to form two new daughter cells, each with a nucleus containing a complete and identical set of chromosomes.

The consequences of improper attachment can be catastrophic, with segregation of two chromosome copies to a single daughter cell. The spindle assembly checkpoint pathway is responsible for inhibiting progression of mitosis from metaphase to anaphase until each of the sister chromatids has become correctly bi-oriented and securely associated with the mitotic spindle.

Controlling Metaphase-to-Anaphase Progression

Progression from metaphase to anaphase is mediated by the anaphase promoting complex or cyclosome (APC/C), an E3 ubiquitin ligase. When bound to a protein, Cdc20, the APC functions to ubiquitinate securin (a protein that prevents the cleavage of cohesin by the enzyme separase), as well as the S and M cyclins, thereby targeting them for destruction.1,2,3 The APC/C is phosphorylated by cyclin dependent kinases (Cdks), thus rendering it able to bind to Cdc20 and form the APC/CCdc20 complex. The APC/CCdc20 complex is autoinhibitory, since destruction of Cdks results in a decreased rate of APC/C phosphorylation and, as a consequence, binding of Cdc20.

Microtubule attachment to kinetochores during prometaphase is governed by a “search and capture” mechanism.4,5,6 The property of dynamic instability facilitates the process by which microtubules “search” for kinetochore attachment sites. When a microtubule encounters a kinetochore, the kinetochore is “captured” by means of side-on attachment. The sister chromatids are subsequently positioned at one of the poles of the cell, where more microtubules become attached. After the kinetochore becomes associated with a microtubule from the other pole, the chromosomes move to the equator. Though this process has been viewed for decades as being stochastic, recent work has suggested that it may in fact be more deterministic than previously recognized (see this article for a good discussion).7

This checkpoint pathway relies on a specialized mechanism for monitoring the security of kinetochore-microtubule attachment.8,9 In the case of improper attachment, the kinetochore sends out a signal — the wait anaphase signal — that inhibits activation of APC/CCdc20, thereby arresting metaphase-to-anaphase progression.

Monitoring Spindle-Kinetochore Attachment

The precise mechanism by which the spindle checkpoint system detects improper chromatid biorientation has not been fully elucidated. Two main hypotheses have been proposed, each with its own supporting data.10 One proposal suggests that the system monitors the level of tension at the kinetochore.11,12,13 Another hypothesis is that the system detects attachment of the ends of the microtubules to the kinetochore.14 The spindle assembly checkpoint pathway most likely uses a combination of those two mechanisms.

The importance of tension sensing in the spindle assembly checkpoint was first examined in insect spermatocytes, using a micromanipulation needle to apply tension to an improperly associated chromosome. Tension resulted in the commencement of anaphase in 56 minutes, whereas it was delayed by 5 to 6 hours in the absence of tension.15

Aurora kinase B plays a crucial role in tension sensing, and its inhibition results in an accumulation of improperly attached kinetochores.16,17,18,19,20 Aurora kinase B is believed to induce the inhibitory signal that destabilizes kinetochore-microtubule attachments by phosphorylating components of the kinetochore’s microtubule attachment site, including the mammalian histone-H3 variant centromere protein A (CENP-A) at serine 7.21,22 Aurora kinase B is itself recruited to the centromere by phosphorylation of CENP-A at the same residue by Aurora kinase A.23 When the function of Aurora kinase B is inhibited, one also observes a decrease in concentration of checkpoint components BubR1, Mad2 and CENP-E, and also an inability of BubR1 to rebind to the kinetochore following a decrease in tension at the centromere.24 Aurora kinase B is inactivated only after correct biorientation has occurred.

The role of microtubule attachment is demonstrated by the activity of checkpoint proteins at the kinetochore. For instance, Mad2 is present on unattached kinetochores during prometaphase, but is removed from the kinetochores as they become associated with the spindle.25 Moreover, when mammalian cells are treated with low concentrations of taxol and other microtubule-targeting drugs (thereby removing tension but retaining microtubule-kinetochore attachment), the onset of anaphase is significantly delayed.26,27

A Factory Assembly Line

Eukaryotic cell division is, in many respects, like a factory assembly line, complete with quality-control check points and robotic machines. The sheer number of things that need to go just right for successful division to take place without major complication renders it implausible that such an elegant process could have been produced by a gradual, unguided process. 

By what mechanism is the wait anaphase signal generated? Moreover, how is the spindle assembly checkpoint turned off when proper kinetochore-microtubule attachment has been established? My next article will be taken up with these questions.

Notes

Zachariae, W., Nasmyth, K. (1999) Whose end is destruction: cell division and the anaphase-promoting complex. Genes and Development 13, 2039-2058.

Barford, D. (2011) Structural insights into anaphase-promoting complex function and mechanism. Philosophical Transactions of the Royal Society B. 366, 3605–3624.

Schrock MS, Stromberg BR, Scarberry L, Summers MK. APC/C ubiquitin ligase: Functions and mechanisms in tumorigenesis. Semin Cancer Biol. 2020 Dec;67(Pt 2):80-91.

Kirschner, M., Mitchison, T. (1986) Beyond self-assembly: From microtubules to morphogenesis. Cell 3(9), 329-342.

Biggins S., Murray A.W. (2001) The budding yeast protein kinase Ipl1/ Aurora allows the absence of tension to activate the spindle checkpoint. Genes and Development 15: 3118–3129.

Hauf, S., Watanabe, Y. (2004) Kinetochore orientation in mitosis and meiosis. Cell 119, 317-327.

Soares-de-Oliveira J, Maiato H. Mitosis: Kinetochores determined against random search-and-capture. Curr Biol. 2022 Mar 14;32(5):R231-R234.

Lara-Gonzalez, P., Westhorpe, F.G., Taylor, S.S. (2012) The Spindle Assembly Checkpoint. Current Biology 22, 966-980.

McAinsh AD, Kops GJPL. Principles and dynamics of spindle assembly checkpoint signalling. Nat Rev Mol Cell Biol. 2023 Aug;24(8):543-559.

Pinsky, B.A., Biggins, S. (2005) The spindle checkpoint: tension versus attachment. Trends in Cell Biology 15(9), 486-493.Li, X., Nicklas, B. (1995) Mitotic forces control a cell-cycle checkpoint. Nature 373, 630-632.

Nicklas, R.B., Ward, S.C., Gorbsky, G.J. (1995) Kinetochore Chemistry Is Sensitive to Tension and May Link Mitotic Forces to a Cell Cycle Checkpoint. The Journal of Cell Biology. 130(4), 929-939.

Larson JD, Asbury CL. Relax, Kinetochores Are Exquisitely Sensitive to Tension. Dev Cell. 2019 Apr 8;49(1):5-7.

Waters, J.C., Chen, R., Murray, A.W., Salmon, E.D. (1998) Localization of Mad2 to Kinetochores Depends on Microtubule Attachment, Not Tension. The Journal of Cell Biology 141, 1181-1191.

Li, X., Nicklas, B. (1995) Mitotic forces control a cell-cycle checkpoint. Nature 373, 630-632.

Adams, R.R., Maiato, H., Earnshaw, W.C., Carmena, M. (2001) Essential roles of Drosophila inner centromere protein (INCENP) and Aurora-B in histone H3 phosphorylation, metaphase chromosome alignment, kinetochore disjunction, and chromosome segregation. Journal of Cell Biology 153, 865-880.

Biggins S., Murray A.W. (2001) The budding yeast protein kinase Ipl1/ Aurora allows the absence of tension to activate the spindle checkpoint. Genes and Development 15: 3118–3129.

Kallio, M.J., McCleland, M.L., Stukenberg, P.T., Gorbsky, G.J. (2002) Inhibition of aurora B kinase blocks chromosome segregation, overrides the spindle checkpoint, and perturbs microtubule dynamics in mitosis. Current Biology 12, 900-905.

Tanaka T.U, Rachidi N., Janke C., Pereira G., Galova M., Schiebel E., Stark M.J., Nasmyth K. (2002) Evidence that the Ipl1-Sli15 (Aurora kinase-INCENP) complex promotes chromosome bi-orientation by altering kinetochore-spindle pole connections. Cell 108: 317–329.

Hauf, S., Cole, R.W., LaTerra, S., Zimmer, C., Schnapp, G., Walter, R., Heckel, A., van Meel, J., Rieder, C.L., Peters, J.M. (2003) The small molecule Hesperadin reveals a role for Aurora B in correcting kinetochore-microtubule attachment and in maintaining the spindle assembly checkpoint. Journal of Cell Biology 161, 281-294.Zeitlin, S.G., Shelby, R.D., Sullivan, K.F. (2001) CENP-A is phosphorylated by Aurora B kinase and plays an unexpected role in completion of cytokinesis. Journal of Cell Biology 155, 1147-1157.

Liu, D., Lampson, M. (2009) Regulation of kinetochore–microtubule attachments by Aurora B kinase. Biochemical Society Transactions 37(5), 976-980.

Kunitoku, N., Sasayama, T., Marumoto, T., Zhang, D., Honda, S., Kobayashi, O., Hatakeyama, K., Ushio, Y., Saya, H., Hirota, T. (2003) CENP-A phosphorylation by Aurora-A in prophase is required for enrichment of Aurora-B at inner centromeres and for kinetochore function. Developmental Cell 5, 853-864.

Ditchfield, C., Johnson, V.L., Tighe, A., Ellston, R., Haworth, C., Johnson, T., Mortlock, A., Keen, N., Taylor, S.S. (2003) Aurora B couples chromosome alignment with anaphase by targeting BubR1, Mad2, and Cenp-E to kinetochores. Journal of Cell Biology161(2):267-80.

Waters, J.C., Chen, R., Murray, A.W., Salmon, E.D. (1998) Localization of Mad2 to Kinetochores Depends on Microtubule Attachment, Not Tension. The Journal of Cell Biology 141, 1181-1191.

Waters, J.C., Chen, R., Murray, A.W., Salmon, E.D. (1998) Localization of Mad2 to Kinetochores Depends on Microtubule Attachment, Not Tension. The Journal of Cell Biology 141, 1181-1191.

Hoffman, D.B., Pearson, C.G., Yen, T.J., Howell, B.J., Salmon, E.D. (2001) Microtubule-dependent changes in assembly of microtubule motor proteins and mitotic spindle checkpoint proteins at PtK1 kinetochores. Molecular Biology of the Cell 12(7), 1995-2009.