Cellular Scripts

Once Cassius developed cell membranes and DNA, it was sufficiently close to a modern bacterial cell that we can definitely say that life had begun. During the next billion years or so, the Earth presumably filled with many diverse forms of life, and cells gradually developed more and more sophisticated structures and chemistry. During this period, cells developed the citric acid cycle, photosynthesis, and the many other tricks of a healthy cell metabolism. The advent of life had a profound effect on the world-- including the creation of an atmosphere full of oxygen, making the Earth unique among planets and Solar System bodies. However, that portion of cellular evolution doesn't contain any particular surprises in the use of DNA, so we won't spend any time on it here. During this period, Fred and Roscoe were long gone from the scene, replaced by the modern systems of protein transcription and gene replication. However, Fred still had some unused tricks up its little chemical sleeves. Sometime in the next billion years or so, it reappeared in a slightly different form, and dramatically changed the biological world, once again. Early Cells Let's fast-forward to a period after the emergence of the first life forms, but before more complex cells appeared-- some time between 1.8 and 3.8 billion years ago. After a great deal of 'classic' evolution, these early cells probably contained a loop of DNA, a close approximation of modern DNA transcription and replication, and a reasonable set of protein enzymes that performed many of the modern metabolic functions. The cells also had a cell membrane and/or a cell wall that protected them from the outside environment, but which still allowed them to productively interact with it. Most likely they used proteins that were built from most or all of the modern amino acids. These early bacteria-like life forms may have linked up with others of their own kind to form chains and mats, similar to modern bacteria. However, they were definitely single-cell organisms, and they lacked many of the interior details of today's eukaryotic cells. For example, the early cells probably had no distinct nucleus, no endoplasmic reticulum, no mitochondria, no chloroplasts, and none of the other organelles that are found in the simplest protozoa and other eukaryotic cells. Like modern bacteria, they may have had protein filaments to help give the cell shape within the cell walls, but they probably did not yet have motile elements such as the cilia or flagella found in modern cells. These cells might be called the Last Universal Common Ancestor or LUCA, since they were about to embark on some fundamental changes that would split them into the three major branches of modern life-- Prokaryotes (bacteria and cyanobacteria), Archaea (thermobacteria and kin), and Eukaryotes (protozoa, plants, animals and fungi). However, before we get to that, let's consider some physical logistics of cell development. Structural Blueprints We have already talked about the use of short 'helper' RNA chains that could guide the tertiary folding of large proteins, or merge proteins into larger supercatalyst structures. For these tasks, the distances required would only be in the range of a few dozen base pairs, so an RNA strand itself could simply link between match sites in each individual enzyme and 'tether' them into place. There would have been a huge selective advantage for any cell that could develop a similar 'blueprint' system to lay out the physical details of larger cell structures. That would make it much easier for the cells to lay out the precise chemical arrangements of larger and more sophisticated organelles such as cilia or a flagellum. To create that kind of structure, a cell needed two types of genetic information. First of all, it needed to build the proteins or other polymers that would make up the structure itself-- and regular protein-coding genes would work fine for that. Secondly, to make a cell structure work, the cell needed to specify quantitative information such as the size, shape and position of each component. This function was not unlike a modern blueprint or engineering drawing, but it needed to be stored in the DNA. Not only did the cell need a way to store the 'numbers', but it had to transfer that information to the structure itself, while it was being assembled. We've already talked about RNA 'helper' chains that could position a few enzymes close together. Unfortunately, it would be very hard for a simple RNA strand to directly position components in a large structure like a flagella. To do that with an RNA molecule would require a sequence many thousands of base pairs long, and it seems too likely that it would break, or tangle., or be dissolved back to its nucleotides before it finished its mission What could our early cells do to build cellular organelles more efficiently, so they would be able to evolve quickly enough to survive the next cataclysmic comet collision? Or just get a competitive jump on the neighboring cells that have been eyeing them hungrily? It's time to take another look at Fred. Cellular Scripts Many chapters ago, we talked about Fred's ability to position amino acids in a protein chain. Could a cell use a similar approach to position larger molecules? Let's consider a Fred-like protein (though probably way larger than the original Fred). We'll name it Foxy. As usual, Foxy's elbow is designed to ratchet along a backbone chain (definitely RNA or DNA, now that we have firmly established the modern system genetic transmission). When Foxy's elbow matches to different base pairs, it changes the conformation of another functional group, its knee. Foxy's knee is quite a bit larger, so it's capable of binding to entire large molecules, and not just single amino acids (as Fred did) or backbone molecules (as Roscoe did). Foxy Step by Step Let's put a Foxy into the neighborhood of some freshly synthesized interesting proteins, and see what might happen. 1. Foxy binds to an mRNA chain. At the first base pair it moves into its first conformation, and binds a large structural protein at the knee. 2. Foxy moves on to the second RNA base pair. It shifts to the second conformation, and binds a different structural protein at the knee, linking it to the first protein. 3. Foxy continues down the chain, shifting between the two conformations, and binding different proteins. It gradually forms a large structure, built from two different proteins, whose sequence is determined by the base pair sequence in the RNA chain. 4. When Foxy reaches the end of the RNA chain, the new structure is complete. Foxy Scripting What we've just seen is the first use of RNA data to specify and assemble a larger structure in a cell. We'll call this Foxy data a script, since it codes a set of physical actions rather than anything chemical. It is similar to Fred, but on a much grander scale. You might think of Foxy as the very first Turing machine, reading some 'programming code' and turning it into something tangible. What is the evolutionary impact of that? Well, in this particular case, probably nothing. It's just a random large structure made from two random proteins, and the odds are very low that it would have a positive impact on cell survival. About the best we can say for it is that it probably didn't do anything lethal, since it's just a structure, and unlikely to be metabolically poisonous. The first Foxy proteins might have linked up with random RNA scripts, and formed random structures, for quite a while before accidentally creating an assembly that turned out to be at all useful to the cell. Of course, once that happened, things would have changed dramatically for cells, and for the Foxy gene itself. The first structure made by a Foxy might have been a combination of a contractile fiber and another protein-- to make a proto-cilia. It may have assembled a long sequence of enzymes that produced a beneficial chemical that couldn't be produced by simpler means. It may have created a useful pore in a membrane, or a more effective stacking of photosynthetic units. Whatever it was, the cells containing Foxy (and the useful structure it produced) would have then survived and reproduced more effectively. Their success would have established that particular Foxy gene into the cell lineage. And in turn, Foxy would have been available to work on different scripts that might produce some other useful structure, somewhere else in the cell. Controller and Script If you stop and take a look at what Foxy just did, you may notice that there are actually three entirely different genetic components to the Foxy system. First of all, to make Foxy work, there must be genes to create the actual structural components that Foxy assembles. The very first Foxy probably used some existing proteins, but for new structures to arise, a cell might need to develop new 'building block' molecules. Secondly, there's the gene that forms Foxy itself. Foxy's structure is very important, since it needs to have the right knee formation that will bind to some specific molecules, and move them into place. But, genetically speaking, it's just a plain old protein-coding gene, just like almost all of the DNA before it. And finally, independently, there is the script that Foxy reads. Changes in the script will change the arrangement of the two proteins in the new Foxy-based structure, and nothing more. This isn't a 'classic' gene at all, but it's still a useful hunk of genetic code, in the form of structural data. Once a Foxy script developed, plain old Darwinian evolution would come into play in the script, and organisms with whichever sequence of proteins had the most survival value would pass along that useful script sequence to their progeny. Second Foxy Script Once Foxy was established as the way to specify one structure, the same Foxy protein could eventually read a different script, and create an entirely different structure from the same two structural proteins (or perhaps different ones). Eventually, a single Foxy protein could potentially build hundreds or thousands of entirely different structures. All a cell needed to do was to deliver a Foxy to the correct location, feed it a script, and let it assemble something interesting from whichever raw materials were in the neighborhood. Foxy Structure In our example, we drew Foxy with a size and structure that is similar to Fred, back from the earliest days of protein transcription. However, by the time Foxy came on the scene, cells were much more sophisticated-- they probably were about as complex as a modern bacteria. That means that Foxy was probably much more 'professional' a protein, and it most likely was built from hundreds or thousands of amino acids. It may have acted as a mechanical switch, similar to the original Fred. But there are plenty of other ways that Foxy may have worked. For example, it may have sent some sort of messenger molecule to moderate the action of a large synthetic complex, or it may have activating or deactivating some other genes. We'll talk more about some of the possible variations, later. Foxy Evolution Of course, as Foxy became more and more established, it probably would have evolved into more effective forms. Cells may have needed to develop more than one Foxy variation, with different 'attachments' at the knee to position different types of structural molecules. Foxy variations might also have changed the elbow, to be able to read scripts in different ways, or to interact with the gene header, or to coordinate with promoters and other cell regulators. Script Evolution Improved versions of Foxy were just improved proteins, not unlike the evolutionary improvement of an enzyme. However, once Foxy appeared, there was an additional way the cells could evolve-- by developing a better script, to position the structural components in a more effective way. This 'script evolution' is very different from regular protein evolution. First of all, small changes in the script would have a much larger impact on the cell than a similar change in a protein-coding gene. You might say that Foxy was a 'magnifier' that could translate a relatively short script into a relatively large structure. Once a structure was scripted, it became much more easily controlled, genetically speaking. If conditions changed and a different arrangement was more useful, the script could simply change again to some different sequence. In fact, there may have been more than one optimum sequence in a structure, with different arrangements that would entirely different functions. In that case, a cell might evolve into two distinct species based strictly on a difference in the script sequence, even while both still used the exact same Foxy protein. Digital Control The first successful Foxy gene probably didn't do anything real significant-- it would be extremely unlikely for it to put together a complete flagella, for example. But once it accomplished anything useful for the cell, it would become established in the cellular genome. Besides just creating a new structure, Foxy also introduced a new type of gene coding which would be extremely significant for later evolution. In a nutshell, Foxy allows cells to contain script genes that are 'digital', while all previous genes were 'analog'. A mutation in the script that Foxy reads will have a precise impact on the placement of a molecule in the cell. That means that evolutionary forces can act on that stretch of genetic code, and have measurable and predictable consequences on the size, shape or position of cell elements. Foxy allows evolution to proceed in small, precisely-controlled steps, which is frequently not the case for protein evolution. Its benefit is similar to the controls that various generations of helper chains offered for enzyme positioning, but on a much larger scale. Improvements vs Lethals One way to look at the genetic consequences of Foxy's scripts, is to consider the chances that a mutation will result in lethality, as compared to the chance of improvement. A small mutation in a protein-coding gene will change one amino acid in a protein, which has pretty much a random affect on the function of the gene. Depending on the substitution, it may result in a small conformational change, or it may mean a huge change. However if the gene is already well-optimized, nearly all changes will be deleterious, and many may remove its functionality completely. Overall, there might be a 10% chance of causing a lethal change, and a .1% chance of being beneficial. On the other hand, a small script change in a script used by a Foxy gene is pretty much guaranteed to result in a small structural change-- all it can do is change one element in a structure, or perhaps change its size a little. So it may only have a 1% chance of lethality, along with a 10% chance of making a small decrease in quality and a 5% chance of making a small increase in quality. In other words, changes in a Foxy script have a much better chance of being successful. When it comes to evolution, the smaller but more controlled changes will be much more effective. Reading Frames Note that this particular Foxy reads RNA one base pair at a time. Sort of a throw-back to the original Fred. As in the original Fred, the linkage between elbow and knee probably could never get very fancy, so it's unlikely that the knee would get into very many conformations. That means it's possible that Foxy might only code for 2 different positions, despite the four available base pairs. As with Fred's later evolution, Foxy might later evolve into wider reading frames and more sophisticated actions. That wouldn't be as much of a struggle as it was for Fred, since we're now in the full protein world where cells can make any sort of protein enzyme that they want. However, many script actions were probably quite simple, and most versions of Foxy probably still read just one nucleotide at a time. Foxy Data A large percentage of positioning information would probably be very repetitive-- put 2 stands here, then 1 strand there, and repeat that pattern for the entire diameter of a cell. That means that the genetic data read by Foxy would probably have a different overall 'texture' than the protein coding portions of the gene. Protein genes look almost random when you examine their raw nucleotide sequence, but the example we just mentioned might read AATAATAAT for several hundred repetitions. In fact, many scripts might simply alternate two structures via a simple ATATATAT, AATTAATT or AAATTT pattern. Even more simply, some Foxy data might code for the length of a structure, with no other details at all-- do this 100 times and then stop, or move this by 100 nudges and then stop. Those cases might use an AAAAAAAAA sequence, or they might use some other pattern and completely ignore the base pair choices (since they only read the length). In the latter case, the actual sequence of pairs would mean nothing at all, and it might evolve into some specific pattern for entirely non-genetic reasons (for example, to increase DNA stability, or to help form tertiary structures in the DNA chain). Foxy Reliability One very important property of evolution based on Foxy scripts is that it is more focused and reliable. Changing a Foxy script will have a fairly predictable result. Something will be shifted in position, or made bigger or smaller, or a different enzyme component will substitute for the original. Script changes are 'directed', since the action taken by the Foxy protein in response to the script keeps its actions within specific bounds. The result is that Foxy structures could be 'fine-tuned' very easily, which would make them particularly useful for determining sizes and shapes for organelles. Replication Slippage When cells replicate repetitive data via complementary base pairing, an interesting phenomenon results-- called replication slippage . One strand of DNA will sometimes shift by one or more base pairs, relative to the other strand, and result in either an increase or a decrease in the length of the repeating pattern. When the change happens in Foxy data, this slippage is an excellent way to 'fine tune' a structure over the course of many generations. A slight change in the size or position of a structure will rarely be lethal, and it might confer a selective advantage to that individual . That new bit of improved script data could then expand into the population as a whole. Rather than shoddy design in the replication machinery, replication slippage may actually be an elegant way to achieve controlled and gradual evolutionary change, at least on the species level . Controlled Slippage The amount of slippage is controlled by the DNA polymerase enzyme that handles the replication, and different versions of that enzyme produce different amounts of slippage . It would be highly advantageous for an organism to be able to control the amount of slippage in each script (and the resulting amount of evolutionary change caused by it). Some scripts will produce a relatively high percentage of advantageous changes when they slip, while others will not. That means that any organism that could conserve the sequence of some scripts and allow others to mutate freely, would have had a large selective advantage. One way cells could control the amount of slip is via their choice of nucleotides in the script sequence. As long as there is a different amount of slippage between A-T pairs versus C-G pairs, then stable, unchanging scripts can use a preponderance of one set of nucleotides, and more labile scripts can use the other. It's also possible the the 'script ID' header sequence contains information that guides DNA polymerase into the optimum level of slippage. Or the slippage frequency could be different on different chromosomes, with more 'conservative' chromosomes containing the older, more vital scripts that would not benefit from slippage changes. Foxy Variations The version of Foxy that we just described used a conformation shift to position two different structural molecules. That made its action very similar to the original Fred-- and in fact, it probably would have been a reasonable way for the first Foxy to work. However, by this stage of life, gene regulation and cell metabolism had become much more advanced, and there are many other ways that Foxy could have managed the formation of larger, more complex structures. For example, a Foxy could link to some ribosomes, and switch their production on and off to produce an alternating chain of proteins. It might sit on a promoter region, and turn entire complexes of genes on or off as it read a script. Or it might choose between different scripts that it would deliver to some other Foxy, depending what its own script was saying. In larger cells, a Foxy script might control the production of a small signal molecule that would diffuse to distant parts of the cell, and then manage the synthesis or assembly of components. That way, a single Foxy protein could coordinate activities throughout the cell. A Foxy protein and a script might also act as a timing device during cell development, or during any other process that might need a tight control of actions over a relatively long time period. The key step that would make that work would be some way to 'ratchet' Foxy along the script chain at some regular interval. That could be accomplished with the assistance of any of the chemical 'clocks' that are already known to be present in cells. Timed Foxys Foxy could have worked as a timing device by taking a complete chain of script RNA, and reading it slowly, one nucleoside every minute or every day. That would be an effective way to 'guide' the an organism that needed to do different things over its lifetime, or over some sort of time cycle that couldn't be regulated by some other means. A timed Foxy would have needed a link to one of the internal chemical clocks found in many cells, or it could have responded to some regular event such as tidal flows or daylight cycles. Foxys and Foxys As Foxy took on a larger role in cell structuring, it's likely that some Foxy proteins took control of the expression of other Foxy genes. For example, a Foxy timing sequence might activate other Foxy proteins at specific times, to guide the formation of a very complex structure that required several Foxys to build. The 'master' Foxy protein might guide other Foxys via conformational changes that would 'nudge' the secondary Foxys into different positions. As an alternative, it might use gene ID to choose between different secondary Foxys, or control them with other regulatory structures. Stacking Foxy controls on top of each other would allow the formation of increasingly complex structures, and it would also help isolate different aspects of a structure into different scripts so they could evolve more effectively. A basic script might control the small-scale features of a structure (and changes to its script would affect layout of individual proteins). At the same time, a master script would control larger-scale features (and changes to its script would affect the layout of large groups of proteins). Foxy Programming Over time, Foxy proteins, in combination with other regulatory proteins, could have developed a 'programming language' for cell development and control. Since one Foxy protein could be used to read many different scripts, such a system might only need a relatively small number of Foxy proteins-- depending on how wide a range of physical actions would be required. Meanwhile, there could be thousands or even millions of scripts controlling the small details of cell expression. Ideally, the dimensions and position of every cell organelle would be specified via a script-- that way it would be extremely easy for evolution to shift any cell structure into the perfect size and location, using precise digital control. After a few billion years of evolution, Foxy scripts in modern cells may now be stacked up in subroutines hundreds of layers deep. That would mean that a small, digital change in a high-level script could create a new species with an extremely different overall structure, but with all the smaller details still intact and functional. Previous Home Next