[00:00:00] Speaker A: Foreign.
[00:00:05] Speaker B: The Future, a podcast about evolution and intelligent Design.
[00:00:12] Speaker C: Welcome to ID the Future. I'm your host, Andrew McDermott. Well, today I'm back with Dr. Jonathan McClatchy to continue a four part series on the intelligent design and irreducible complexity of eukaryotic cell division.
[00:00:25] Speaker D: But before we get to that good stuff, let me tell you about an upcoming event you'll want to be a part of. From the smallest honeybee to the greatest whale, planet Earth is swarming with creatures of all shapes and sizes, each intelligently designed for their habitats. Where did they all come from and what are the implications for a faith in God? Join us at the 7th Annual Dallas Conference on Science and Faith on February 8, 2025 in Denton, Texas or via livestream for a stimulating series of talks on the theme All Creatures Great and Small. Whether you join us in the Dallas area or online, you'll learn about the Miracle of Butterfly Metamorphosis with Paul Nelson, the Amazing Honeybee with Eric Hedin, the Scientific Evidence of the Human Soul with Michael Egnor, the Intelligent Design of Plants with Emily and Daniel Reeves, the Theory of ID as Fuel for Scientific Discovery with Casey Luskin and the Origin of Animal Body Plants with Stephen Meyer. In addition to these in person, attendees can choose from special breakout sessions presented by John West, Richard Sternberg, George Montanez, Ray Bolen, and Stephen Dilley. Other perks to joining in person include a live musical performance on the theme of the conference, a conference bookstore with a large selection of titles by Discovery Institute scientists and scholars, a free book in honor of the late Jonathan Wells, opportunities for book signings with the speakers, and exhibitor tables from our partner organizations. You can learn more and register for the
[email protected] that's scienceandfaith.com for those of.
[00:02:04] Speaker C: You who don't know him. Dr. Jonathan McClatchy is a fellow and resident biologist at the Discovery Institute's center for Science and Culture. He was previously an assistant professor at Sattler College in Boston, where he lectured biology for four years. McClatchy holds a bachelor's degree in forensic biology, a master's degree in evolutionary biology, a second master's in medical and molecular bioscience, and a PhD in evolutionary biology. His research interests include the scientific evidence of design in nature, arguments for the existence of God, and New Testament scholarship. Jonathan is also founder and director of talkaboutdoubts.com welcome back Jonathan.
[00:02:44] Speaker A: Great to be here.
[00:02:46] Speaker C: Well, here we are, our third episode together in a four part series about a subject you've been Studying for years, eukaryotic cell division. Now, just out of curiosity, how long have you been interested in this and what was it that piqued your curiosity?
[00:03:01] Speaker A: I remember taking a class that was dedicated to the eucardic cell division system during my master's degree at the University of Newcastle. So this is going back to 2013, in the fall of 2013. And I remember being fascinated by just the incredible engineering prowess and design of the karyotic cell cycle. And I ended up doing a master's project in this subject and I, I later subsequently went on to do a PhD focusing on the origins of the cardiac cell division system.
[00:03:45] Speaker C: Wow. Did you write a dissertation on it as well?
[00:03:49] Speaker A: That's correct. Yeah, I did my dissertation on that subject.
And then some of the research that went into that dissertation ended up informing my recent paper that I published in the journal Biocomplexity.
[00:04:00] Speaker C: Okay, so you're a decade into this particular subject with your research and your time. Now you've published several articles about eukaryotic cell
[email protected] and listeners, if you're not familiar with that resource, by all means, go check it out. It's our flagship news and commentary site that covers the debate over evolution and the cutting edge evidence that science is revealing for intelligent design. And Jonathan, you also recently published a review paper on it. Where was that published? And is it available to listeners?
[00:04:33] Speaker A: Yeah, you can find it at the Biocomplexity website and I also link to it in some of my Evolution news articles where I give a popular level discussion of the implications of the research supplied in that paper. So you can find it there and you can download a free PDF, it's open access.
[00:04:55] Speaker C: Okay, good to know. And we'll remind listeners at the end about that. Well, let's give a brief summary of how far we've come so far in this series. The previous two episodes in part one, you discussed the irreducible complexity of various components involved in mitosis. What does it mean for a system to exhibit irreducible complexity?
[00:05:13] Speaker A: So this is when we have a system that's comprised of multiple well matched interactive components that contribute to some higher level objective, and the removal of any one of the parts causes the system to effectively cease functioning. And so by an unguided process, without knowing where the target lies. How would you assemble such a system by numerous small successive modifications without passing through any maladaptive intermediates. And so the argument from irrespective of complexity is not merely a negative critique of evolutionary processes, although it is that, but it's also more than that, a positive inference to design, because design or conscious agency, rational liberation is the only sort of process that we know that has the ability to visualize complex higher level objective and then bring everything together needed to realize or actualize that complex higher level objective. And so that on the hypothesis of design, these sorts of systems are not particularly surprising, but they're wildly surprising on the falsity of design. And so in view of that top heavy likelihood ratio, it favors a design perspective.
[00:06:26] Speaker C: Yeah, and I like the way you put that. And in part two, episode two of this series, we focused in on some of the molecular machinery responsible for the process, namely the mitotic spindle and the motor proteins that play a role in chromosome movement and spindle organization. Now tell us what we're going to be zooming into in today's discussion.
[00:06:47] Speaker A: So today we're going to be talking about the various checkpoints that ensure that the cell cycle can progress into the next stage. And there are basically three major checkpoints. There's the restriction checkpoint, also known as the G1 checkpoint, which is basically when the cell makes a decision to commit to another round of the cell cycle.
There's another checkpoint known as the DNA damage checkpoint, and then there's another checkpoint known as the spindle assembly checkpoint.
[00:07:24] Speaker C: Right. And we can think of them as sort of quality control points along the cell division process. Why are they so essential to the success of the cell cycle?
[00:07:35] Speaker A: So, so the checkpoints are absolutely essential for the success of the cell cycle because it makes sure that there's no DNA damage, such as double strand breaks, for example, in the case of the DNA damage checkpoint, or that the kinetochores are correctly associated with microtubules before anaphase can progress. Otherwise it could result in aneuploidy where your cells have an inappropriate number of chromosomes.
So, as you said, the checkpoint pathways can basically be thought of the cell's surveillance systems that function to arrest the cell cycle in response to detected problems in the cell division or in chromosome replication. And so the checkpoint pathways ensure that DNA replication doesn't commands before all the components necessary for its completion have been produced.
They also ensure that the replication process is not derailed by damaged DNA, that cells don't attempt to divide before genome duplication is complete, and that each daughter cell receives a complete set of chromosomes.
And checkpoint pathways are essential for an organism's viability.
And although a cell can complete its cycle successfully without them, their absence results in infidelity of chromosome transmission. And they've greatly raised susceptibility to DNA damaging agents. And so the consequences of inactivation of the checkpoint pathways is genome instability, which inevitably leads to cancer.
[00:09:12] Speaker C: All right, so the checkpoints have three different types of proteins operating in order to solve these problems and do this quality control. What are these three different types of proteins?
[00:09:25] Speaker A: Yeah, so the activation of checkpoint pathways involves proteins known as sensors, transducers, and effectors. So sensors detect the cellular defect and they trigger an appropriate response. Sensors are specific to the type of damage, and this ensures that the correct response is initiated. DNA damage, for example, is typically characterized by the formation of single stranded DNA, in which case the activation of the corresponding checkpoint pathway is dependent upon the binding of sensors to single stranded DNA. Sensor proteins activate transducer proteins, and the transducers function to initiate the appropriate response to damage. So transducers include protein kinases and proteases, and they serve to activate the effect of proteins which carry out the response itself. So transducers that are activated in response to damaged DNA, for example, will in turn activate effective proteins that play a role in the repair of DNA damage.
So production of nucleotides and cell cycle inhibition as well.
[00:10:30] Speaker C: Okay, so sensors, transducers, and effectors. Okay, the three types of proteins involved. Well, let's look at each of these checkpoints briefly. What does the restriction checkpoint do?
[00:10:42] Speaker A: Yeah, so commitment to another round of cell division depends on a number of conditions, such as the presence of sufficient nutrients to support an increase in mass synthesis of the protein, proteins, and nucleotide precursors that are necessary for genome duplication.
So the point at which a mammalian cell irreversibly commits itself to another round of division is known as the restriction point.
And without the necessary conditions for passing this point, eukaryotic cells enter into the so called G0 state where cell proliferation does not occur. And whether a cell commits to another end of proliferation or not is determined by the restriction checkpoint pathway. And so, basically, there are molecules known as mitogens that bind to a mitogen receptor and activate the mitogen receptor. And this triggers an intercellular signaling pathway that results in the activation of G1CDK and G1S CDK. So, CDK, if you remember, means stands for cyclin dependent kinases. And kinases are a class of proteins that phosphorylate substrates and often trigger a conformational change in their substrates, which can activate or deactivate its substrate. So in the case of the activated G1CDK and the G1S CDK, these, these go on to phosphorylate a substrate in order to.
So there's a protein called RB which gets phosphorylated. And when RB is phosphorylated, it releases another protein, a transcriptional regulator. And so that transcriptional regulator, when it's liberated by the RB protein after it's been phosphorylated and changes conformation, freeing the transcriptional regulator. That transcriptional regulator then goes and drives the expression of genes that facilitate entry into S phase of the cell cycle, which is the phase of the cell cycle in which the DNA is replicated. So the restriction checkpoint is also known, Therefore, as the G1S checkpoint because it facilitates, or it facilitates entry from G1 phase into S phase of the cell cycle.
[00:13:11] Speaker C: Okay, got it. What about the DNA damage checkpoint?
[00:13:15] Speaker A: Yeah. So during replication, the DNA duplex is separated into two strands, each of which serves as a template for the synthesis of a novel strand. And this is known as semi conservative replication. But sometimes replication could be impeded by an inadequate supply of nucleotides or a double strand break, resulting in a stalled replication fork. So in such cases, the DNA replication comes to a halt, and this leads to the accumulation of single stranded DNA. Single stranded DNA is bound by sensor proteins, which trigger the activation of the checkpoint pathway. So the sensor proteins activate transducers or protein kinases, which activate various effectors, and that leads to the cell cycle arrest and DNA repair. So in response to, let's say you've got a double strand break, and this leads to activation of protein kinases that phosphorylate a protein known as P53. Now, P53 is ordinarily degraded by proteasomes in the absence of DNA damage. The proteasomes are basically the cell shredders. And P53 normally gets degraded by those shredders. But in response to this DNA damage, this double strand break, then P53 gets phosphorylated, and that activates and stabilizes P53 so it's no longer degraded by the cell's proteosomes. And p53 then drives the expression of another protein known as p21.
And p21 then binds to the G1S CDK and the SCDK to inactivate it and therefore arrest the cell cycle so that it does not progress until the DNA damage has been taken care of.
[00:15:11] Speaker C: Okay, I'm just struck by how all these subsystems and proteins are able to be activated and deactivated exactly when they're needed.
It's just such amazing sophisticated machinery and engineering that goes into all this? Well, is there a checkpoint that also monitors the all important chromosome segregation during mitosis?
[00:15:37] Speaker A: Yeah, so this is known as a spindle assembly checkpoint. And there's an important protein complex known as the anaphase promoting complex or cyclosome, which is responsible, as the name suggests, for driving entry from metaphase into anaphase during mitosis. Hence it's called the anaphase promoting complex or cyclosome or APCC for short. And the anaphase promoting complex is able to drive entry into anaphase by polyubiquity late substrates, in particular a protein called securin and also cyclin B. Cyclin B is the cyclin molecule that was responsible for driving entry into mitosis by interacting with CDK1. And cyclin B has to be degraded before entry into anaphase happens. And securin is also, as I said, polyubiquitylated by the anaphase promoting complex. And polyubactylation is like a tag for the cell shredders or proteasomes. So when the proteasome recognizes the polyubicitylation tag, then it goes and degrades these substrates. So in the case of securin, securin has been inhibiting a protein known as saparase. Saparase is responsible for cutting or cleaving the cohesin rings tether the sister chromatids together. And so when securin is degraded, separase is no longer inhibited. So separates can go and cleave the cohesin rings that tether the sister chromatids together. And this facilitates the separation of the sister chromatids towards the poles of the cell as they're driven by these spindle microtubules. Now, you don't want that happening prematurely, otherwise it can result in aneuploidy where the cell has the wrong number of chromosomes. This is aneuploidy is the consequence of what we call nondisjunction, which is the failure to properly separate.
And so we only want that to happen once you have proper association between the kinetochore and the microtubule. And so there's a checkpoint known as the mitotic checkpoint pathway, which is this middle assembly checkpoint. And this is mediated by a protein complex known as the mitotic checkpoint complex, which is comprised of CDC 20, which is also a co activator of the anaphase protein complex, as well as Mad2, Bub3 and Bub R1. And these proteins bind to the anaphase promoting complex and inhibit it from carrying out its polybactylation.
And so when the kinetochores and microtubules are properly associated, then these mitotic checkpoint complex proteins release the APCC CDC 20 complex. So the CDC 20 is a coactivator of the anderphase Moyni complex and it's able to go and then polyubiquitylate securin and cyclin B, thereby deriving entry from metaphase to anaphase. So that's in a condensed form, the process of the mitotic checkpoint or the spindle assembly checkpoint.
[00:19:02] Speaker C: Yeah, it's a bit like the components of a chemical switchboard where you turn on and off different things that you might need during the process.
Again, amazing stuff. Well, you mentioned various checkpoint silencing pathways that are utilized during eukaryotic cell division, briefly. What are those mechanisms and what do they do?
[00:19:25] Speaker A: Yeah, so there are various checkpoint silencing pathways. So in metazoans, checkpoint components are transported away from kinetochores along microtubules towards the spindle poles in an ATP dependent manner by cytoplasmic dynein dinactin motor complexes. And this process is known as stripping. So when dynein is inhibited, the removal of MAD1 and MAD2 from the Kinetochore is prevented.
When MAD1 in fact, is artificially tethered to correctly attached kinetochores, the onset of anaphase is delayed.
And so required for recruitment of dynein to kinetochores are the proteins spindly and rzz.
And in cases of spindly motif mutants are unable to bind dynein. Dynein is not recruited to the kineticore. In such cases, the checkpoint is silenced by a second pathway. There's another protein known as P31 Comet, which has also been associated with checkpoint silencing. And in fact, by structural mimicry of MAD2, P31 Comet is able to bind to MAD2 at the dimerization interface and this inhibits its activity. And there's another protein that has been shown to be involved in checkpoint silencing by dephosphorylating checkpoint proteins, and that's protein phosphatase 1.
So that's a short introduction to the process of checkpoint silencing.
[00:20:58] Speaker C: Yeah. Now you dedicated a whole article just to the spindle assembly checkpoint. Why is this one so elegant? And what are the consequences to the cell if it's not there?
[00:21:09] Speaker A: Yeah, I find that to be a particularly fascinating system. It was also a focus of my dissertation research when I was doing my doctoral work, and I find it to be particularly fascinating because you have and elegant, as I summarized earlier, you have the phase promoting complex which is able to cut or sorry, is able to polyubiquity late the securin, which then liberates separase to cut the cohesin ring that has resisted chromatids together. But you don't want that happening prematurely. And so you have this whole spindle assembly checkpoint to ensure that that doesn't happen in an untimely fashion, which could be detrimental to the cell and result in aneuploidy where you have the wrong number of chromosomes.
And so it's a very elegantly engineered and designed system. And as to the consequences to the cell if it's not there, as I said, it can result in the cell having the wrong number of chromosomes. So this is what we call aneuploidy. And that can result in cancer. And during meiosis, which is the formation the equivalent or the equivalent process, except in the formation of gametes or sex cells, it can actually result in trisomy conditions, the most famous of which is trisomy 21, which is where you have an extra copy of chromosome 21, which is known as down syndrome. So it's very, very important for the spindle assembly checkpoint to be functioning properly.
[00:22:39] Speaker C: Yeah. While it's useful to note that scientists are still trying to elucidate or understand or unpack some of these checkpoint pathways and how they work, you write in one of your articles that the more deeply you explore the cell cycle, the more you come to the realization that it represents one of the most remarkable evidences of design in the biological universe. In what ways can an engineering approach be useful to biology and helpful?
[00:23:07] Speaker A: Yeah, I think that when we observe these systems, we're observing and looking at engineered systems. I mean, these resembles a robotic factory, that is assembly lines and so forth, and very tight regulatory control systems, etc. Which is typically associated with engineered systems. And so I think that we do ourselves a disservice when we fail to appreciate the engineering nature, engineered nature of these systems. And I think that we can. That it's helpful to our understanding of these systems to think about them through an engineering lens.
[00:23:47] Speaker C: Yeah. And would you say that sort of approach is starting to gain in popularity now? An engineering perspective on biology?
[00:23:56] Speaker A: Certainly. And here at the Discovery Institute we have a, the intelligent design community, we have an engineering research group as well, which is interested in exploring these sorts of questions and the application of engineering to biology.
[00:24:12] Speaker C: Yeah, yeah. It's exciting stuff. Quality control, repair, protection, These checkpoints sound awfully important when it comes to the success of the cell division process that powers life. So I'm really glad we unpacked all that. Our discussion of the molecular mechanisms underpinning cell cycle progression has barely scratched the surface. And as Jonathan mentions in his writing, entire books have been written on the subject. It's always nice to know there's still lots to learn about it and lots more resources to explore. So Jonathan, where can listeners go to learn more about the intelligent design of the eukaryotic cell cycle?
[00:24:49] Speaker A: Sure. So I mentioned previously in the previous episode, the textbook, which I'd recommend by David Morgan, the Cell Cycle Principles of Control. It's getting a little dated at this point, but it's still a very great introduction introductory resource to the sales cycle. As far as I know, that's the only textbook that is solely dedicated to that particular subject. So yeah, I'd recommend that as a starting point. I'd also suggest looking for my paper at the Bio Complexity website. There's a free PDF, it's open access and I've also written several articles Evolution News Unpacking the Engineering Prowess Design of Eukaryotic Cell Cycle. So these are some resources I would suggest.
[00:25:36] Speaker C: Yeah. And we have one more episode in our four episode series here covering this. What are we going to cover in part four?
[00:25:43] Speaker A: So in part four we're going to look at the disparity between the eukaryotic cell division system and the bacterial cell division apparatus. Because these are a universe apart, there's essentially nothing in common either in terms of the protein components or the underlying logic. And as we'll see, the vast majority of the components of eukaryotic cell division machinery do not have homologues among prokaryotes, either among bacteria or in the archaea, even among the Asgard archaea, which are believed to be the closest living relatives among archaea of eukaryotic cells.
And so most of the components of the eukaryotic cell division system appear to be eukaryotic de novo innovations that arose after the split between eukaryotes and archaea. And in fact phylo stratigraphic analysis has revealed that or people have inferred through phylostratographic analysis that the last cardic common ancestor had essentially modern like cell cycle complexity. And so this creates further headaches for a naturalistic perspective on the origins of the eukaryotic cell. And in fact I think is better explained by design. And we'll dig into this in far more detail in our next episode.
[00:26:58] Speaker C: Yeah, well, I'm looking forward to it. Lots of big words. But Jonathan, you do a good job of helping us understand this at the lay level because we're not all in your shoes. And hey, listeners, I get to have lunch with this guy. I get to sit down and, and really hear from him with these systems as we prep for these. And, and it's just truly amazing, you know, for him to share all this, this research and, and what he's learned about these intricate systems inside the cell. Well, Jonathan, thank you very much for joining us today.
[00:27:30] Speaker A: Thank you. Great to be here.
[00:27:32] Speaker C: Now, if you haven't listened to parts one and two of this series, go back and do so. And in the show notes for this episode, we'll include links to Jonathan's published paper and his articles on the topic. For ID the Future, I'm Andrew McDermott. Thanks for listening.
[00:27:48] Speaker B: Visit us at idthefuture.com and intelligent design.org this program is copyright Discovery Institute and recorded by its center for Science and Culture.
