Monday, 8 July 2024
On the irreducible complexity of asexual reproduction.
Herding Chromosomes in the Mitosis Corral
My head is swimming after reading several recent papers on cell division. The multiplicity of molecules involved, and how they get where they need to be and do what they need to do — it is all so astonishing, it beggars description. I wish there were better ways to communicate to laypersons the emotional impact of learning about cell biology without drowning them in jargon like this excerpt from one paper about centrosomes:
During interphase, Cep57 forms a complex with Cep63 and Cep152, serving as regulators for centrosome maturation. However, the molecular interplay of Cep57 with these essential scaffolding proteins remains unclear. Here, we demonstrate that Cep57 undergoes liquid–liquid phase separation (LLPS) driven by three critical domains (NTD, CTD, and polybasic LMN). In vitro Cep57 condensates catalyze microtubule nucleation via the LMN motif-mediated tubulin concentration. In cells, the LMN motif is required for centrosomal microtubule aster formation. Moreover, Cep63 restricts Cep57 assembly, expansion, and microtubule polymerization activity….
Specialists are comfortable with this kind of talk, but we have a world of students being told that cells “emerged” by chance, and “evolved” into humans by blind, purposeless processes over millions of years. The facts above scream “No way!” but how do we tell non-scientists that without burying them in unfamiliar terms? Analogies and pictures can only go so far. I try my best, but simple explanations cannot do justice to the reality.
For students whose knowledge of mitosis may be limited to light-microscope images of dividing cells, or high-school biology diagrams of the five stages of cell division (interphase, prophase, metaphase, anaphase, telophase —“Ho-hum, will that be on the test?”), let me try to unpack some of the awesome wonders hidden in the above paragraph. It comes from a paper in PNAS by 15 specialists at the Institute of Bioinformatics and Structural Biology in Taiwan’s National Tsing Hua University. Respond with applause at each line:
Some molecules join forces to control other molecules!
Molecules assemble in compartments without a membrane to work in harmony!
Important things won’t happen unless all the parts are together! — and bad things happen if they fail!
Biochemistry is not your normal chemistry, where molecules collide like bumper cars and sometimes join up or break up. This is robotic factory work at a high level. With apologies to Jonathan Maclatchie, who knows the jargon and wrote at a more scholarly level recently (here), and to all the other practicing scientists who talk like this as their daily routine, we have to get the hay down where the cows can eat it. Students become so indoctrinated into materialistic scientism by the time they reach grad school (if they seek a career at that level), it becomes difficult for them to buck the evolutionary consensus once they start learning the real guts of cell biology. One almost must achieve tenure before being able to see without evolutionary blinders on. It happened one day to Michael Behe when he stared at an electron micrograph of a bacterial flagellum, and pondered: “That’s an outboard motor. That’s not a chance assemblage of parts.” His thought started a Revolution.
With hopes of generating some of the awe I felt in my reading, here goes my translation of what this paper revealed. The PhDs can skip the lay talk by clicking the link to the research.
The Mitosis Ranch
Trying to visualize this, I thought of the following analogy. Say a rancher must duplicate the cows in a corral and create two corrals with identical numbers and types of cows. He first has his cowboys yoke identical cows together (yokes representing the centromeres). They line the cows up between the two corrals, head to tail. Then other cowboys rope the cows from opposite directions, lassoing specialized “horns” on the yokes — the kinetochores. It takes a few tries for a cowboy to lasso the horn on his side of the yoke, but each one keeps trying till succeeding. An inspector checks that each yoked pair has one and only one rope on each side, and that the ropes are taut. When he gives a signal (the checkpoint), another cowboy goes down the line and breaks the yokes. The cowboys then pull their cows into the opposite corrals, and a gate closes between them.
The reality in cell division is much, much more intricate, but something like that really happens every time a eukaryotic cell divides. Hundreds of “cowboys” know their roles and know when to go into action. In the cell, though, the “cowboys” are blind and work in the dark. Are we beginning to be astonished yet? There’s much more!
Temporary Meeting Spaces
The PNAS paper reveals new knowledge about how the right molecules come together in the centrosome, a structure critical for pulling chromosomes apart during cell division. In mitosis, there are two centrosomes, one on each side of the cell. Centrosomes are where the mitotic spindle sends out the “ropes” to pull the chromosomes apart into the daughter corrals. Within each centrosome, two marvelously-symmetric centrioles grow perpendicular to each other (see here). They will be the organizing centers for the spindle microtubules. Microtubules will grow out from the centrosome and attach to the chromosomes — one microtubule per sister chromatid — at specialized link points called kinetochores. Like a rope, each microtubule is composed of multiple strands of tubulin, conferring stability to each spindle fiber.
Incidentally, how do these distant centrosomes know how many chromosomes there will be and come up with the right number of microtubules? I asked an AI engine that question. It said,
The centrosome doesn’t inherently “know” the number of chromosomes. Instead, the process of microtubule formation is guided by checkpoints in the cell cycle and regulatory proteins. During mitosis, each pair of chromosomes attaches to a kinetochore, which then attaches to the spindle fibers formed from the centrosome. The number of chromosomes determines the number of kinetochores, which in turn helps regulate the number of microtubules needed for proper chromosome separation. It’s a complex and coordinated process involving many proteins and regulatory mechanisms
OK, Well; Point Taken
Back to the “temporary meeting spaces” at centrosomes. The centrosome has no membrane. But when Cep57 (centrosome protein #57 out of dozens known so far) is present, a temporary barrier forms around the required ingredients. This happens by “liquid-lipid phase separation” (LLPS), something like how oil droplets form in water (see my previous article on condensates here). But first, the temporary meeting space (peri-centriolar matrix, or PCM) has to grow by an order of magnitude, from 300 nanometers to micrometers, as all the required ingredients assemble. “Human Cep57,” they say, “is a coiled-coil scaffold at the pericentriolar matrix (PCM), controlling centriole duplication and centrosome maturation for faithful cell division.”
Before the onset of mitosis, the centriole undergoes centriole-to-centrosome conversion by recruiting more centrosomal components and expanding the PCM into a micron-sized structure. This expansion leads to an increase in the microtubule nucleation factors, facilitating the rapid assembly of the mitotic spindle during mitosis. It is a central question of how the PCM assembles into a dense compartment enriched with hundreds of different proteins in the human centrosome during PCM expansion. Liquid–liquid phase separation (LLPS) is a compelling concept for elucidating the organizational principles underlying membrane-less organelles. In LLPS systems, multivalent interactions through folded domains or intrinsically disordered regions drive phase separation, resulting in the formation of dynamic biomolecular condensates accessible to cognate clients
“Hundreds of different proteins.” Did you catch that? How do the right ones all end up within the membraneless condensate? How could blind evolution ever accomplish such a meet-up? Interestingly, the “intrinsically disordered regions” of some of these proteins, which might have been considered poorly designed by some, play a key role in the phase separation. Notice, too, that the condensate is “dynamic” and “accessible” to the “cognate clients” that belong there, while keeping non-members out.
The authors point out that a deficiency of just this one component, Cep57, results in disorganization of the PCM, and a terrible disease:
Cep57 mutations are genetically linked to mosaic-variegated aneuploidy (MVA), a rare disease characterized by an abnormal number of chromosomes. The MVA syndrome manifests in various disorders, including skeletal anomalies, microcephaly, and childhood cancers
Cep57 is not the only vital part. “Cep57, Cep63, Cep152, Cep192, CDK5RAP2 (Cep215), and pericentrin are essential scaffolding proteins for PCM integrity.”
How’s Your Awe Meter So Far?
It’s difficult to convey the wonder of these realities without getting bogged down in jargon and detail. For more awe, add these considerations:
All this takes place in spaces too tiny to see with the naked eye.
Scientists have only discovered most of these intricate details within the lifetimes of many alive today.
The sequence of amino acids in each protein involved is far too improbable to have originated by chance.
Several million cells divide every second in our bodies.
Cells have been dividing since the beginning of life on earth.
The accuracy of cell division is so extraordinarily high, many animals alive today are recognizable from their counterparts in the fossil record.
We are truly privileged to behold details of wonders that were concealed from the eyes of people for thousands of years. If Romans and Babylonians and ancient Chinese were impressed by the sight of a baby at birth, how much more should we be awestruck, dumbfounded, indeed reverent at what biochemists are learning today about realities too small for human eyes? Sure, some observations like evil and suffering are hard to understand, yet even these are better situated for explanation in a design context. As my college biology prof used to say, “The amazing thing is not that we get sick. The amazing thing is that we are ever well,” considering how many things must work correctly each moment of every day. Never become complacent about these realities taking place inside us. We are witnessing intelligent design at a level never comprehended throughout all human history.
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