Let’s now take a brief journey around other complex aspects of cells. It begins from a nuclear pore complex, just in time to see its thousand or so parts disassemble with ease in front of our eyes. Think about the kind of exquisite control involved not only in assembling a machine made up of a thousand parts, but also in designing it to be disassembled easily, its parts moved, with some of them going on to serve a function in the process of cell division.
As we continue our journey, we arrive in the nucleus, just in time to see cell division take place. The genome of the eukaryotic cell is stored in many highly compact packages called “chromosomes.” They line up in the middle of the cell as the nucleus disassembles. Before the cell divides, an exact copy of each chromosome is made, with each piece, called a “chromatid,” joined at the middle. A complex structure called a “kinetochore” forms around each side of the middle. Spindles then emerge from two opposite sides of the cell. As the cell divides, the chromatids separate. The spindles attach to the kinetochores and pull the chromatids to opposite sides of the cell. New nuclei form around the two sets of chromatids, and finally the cell body is split, forming two daughter cells.
Let’s take a closer look at one of the chromosomes. It consists of a thread of DNA, wrapped around little spools called “histones.” Some of the histones have little tails which can be modified to activate or repress genes. When the cell is ready to divide, chromosomes form into a neat X shape, but most of the time they are more like a ball of noodles. Yet there is something remarkable about this noodle clump. There are no knots. It is not tangled. You can pull out a piece of the noodle and put it back in, without disturbing the structure. It is folded into a fractal shape similar to a “Hilbert curve,” a shape that can fill a two dimensional space without ever overlapping. For chromosomes, this is also true in three dimensions.1
Chromosomes have two regions, one for inactive and another for active genes. The non-tangled structure of the noodle allows pieces to be moved easily between the two regions. If evolutionary theorists are to be believed, apparently all by itself, nature found the perfect structure in which to store and manage huge amounts of genetic information in a microscopically small space.
What about the information stored in these chromosomes? When biologists looked at bacteria, which are single-celled organisms with prokaryotic cell structures, they found that gene sequences were continuous. However, when they looked at eukaryotic cells, they were surprised to find that gene sequences were usually broken up into regions which they called “exons” (the regions where proteins were expressed), separated by regions that didn’t code for the gene, which they called “introns” (because they interrupted the expressed regions). Introns are typically about ten times longer than exons.
This system of introns and exons turns out to be incredibly useful. Exons can be pieced together in many different ways to create different proteins with differing structures, called “isoforms.” The whole process is called “alternative splicing” and it allows for much more genetic diversity. In fruit flies, for example, about 50 genes can each make over 1,000 isoforms.
The process of creating an isoform is highly elaborate. A miniature machine called the “spliceosome” cuts out the introns from a genetic sequence, and then a cascade of proteins act as repressors or activators to determine which exons will be used in the required isoform.
Introns pose yet another formidable challenge to the evolution of a protein. If multiple isoforms depend on the structure of a particular gene sequence, that sequence can’t easily evolve without changing the isoforms produced from it. Evolutionary theorists suggest that introns were the result of an invasion by a parasite or genetic element that left its mark all over the genome, breaking up genes. But by incredible luck, cells didn’t die from their genes being broken up. The forces of serendipity combined with a large quantity of time just happened to turn this parasitic invasion into an elaborate system of splicing, where one gene sequence can actually produce multiple isoforms.
Within the genetic material of an organism are transposable elements, or “transposons” for short. These are sequences that can move around in the genome, earning them the nickname of “jumping genes.”
There are two main types. The first uses what could be described as a “copy and paste” mechanism. The gene sequence is copied from DNA into RNA, and then pasted back into DNA somewhere else in the genome, by a machine called “reverse transcriptase.”
The second type uses a “cut and paste” mechanism. The sequence to be cut has markers on either side of it. “Transposase” enzymes bind to these markers and cut the relevant sequence out of the genome. They then paste it into another place that is also marked out in the genome. In other words, the cell already had the cut, copy and paste functions of a word processor well before humans invented them.
Almost half of the human genome is made up of transposable elements. As a result of evolutionary thinking, they were long thought to be mere junk DNA or genetic parasites. But then researchers found that the most common transposon, called “LINE1,” which makes up nearly a quarter of the human genome, is actually a critical regulator of the first stages of embryonic development. Its purpose is to work with other gene regulatory proteins to turn off and on programs and genes that are needed for the embryo to develop. Not quite so junk after all! 2
Incidentally, why are LINE1 elements so common in the human genome? The researchers suggested that these elements make the early stages of development far more robust. Since LINE1 is repeated thousands of times in the genome, it becomes virtually impossible for a mutation to disrupt the function of development. This makes sense, because if anything goes wrong in the incredibly complicated development of an organism, it could be fatal or highly damaging. It’s almost as if these were design features, built in to prevent mutations and therefore stop evolution from taking place. Research has also shown that transposable elements stabilize the three dimensional folding patterns of the DNA molecule inside the nucleus.3
While transposable elements are critical for development, the organism doesn’t want bits of its genome jumping around whenever it likes. This is why transposons can be suppressed by yet another layer of complexity, called “methylation.” This is where a group of atoms in what is called a “methyl group” are added to a DNA segment, without changing the nucleotide sequence. They are like little flags attached to certain letters in the sequence. Methylation can switch genes off, and prevent them from being transcribed.
Markers such as these, along with histone tails and other modifications, come under the category of “epigenetics.” These tweaks can change the meaning and interpretation of the coding sequence, without changing the genetic content. They are like comments or notes connected to a line in a book, but that don’t change the line itself. They are yet another intriguing layer of complexity found within the cell.
If we wished to see an example of cellular complexity outside of a human cell, we would find it in the pond-dwelling single-celled organism Oxytricha trifallax. As single-celled creatures, populations of Oxytricha come about through replication of themselves. They also engage in a form of sex when they aren’t busy munching on algae, but the purpose isn’t to reproduce. It’s literally to exchange DNA. This enables them to replace old genes and DNA parts.
The Oxytricha cell is ten times larger than a human cell. It contains two nuclei, one to house its active DNA, and one that serves as an archive of the genetic material it will pass on to the next generation. Unlike most other single-celled organisms, it stores its archive genome in thousands of scrambled, encrypted pieces. When it’s time to mate, this genome is broken up into roughly 225,000 pieces, which are then massively rearranged to produce about 16,000 chromosomes, containing about one gene each. This is very different from the 46 chromosomes humans inherit from father and mother.
The scientists who researched Oxytricha described this process as a form of encryption and decryption.4 Curiously, almost half of the 225,000 pieces overlap, and they can be cut in different ways. Some of the genes are also scrambled in intriguing ways. Some contain sequences that are inverted, or regions that are partitioned into even and odd-numbered segments. The most scrambled gene is fragmented into 245 segments that assemble into a protein 1,300 nucleotides in length. There are also many nested genes that are weaved with each other in an elaborately tangled order. All of this implies massive scale and coordination in the rearrangement of its archive genome, in order to assemble its 16,000 chromosomes.
Why does Oxytricha go through this complex process for replicating itself, when most other single-celled organisms don’t? I think the encryption of its genome probably makes it much harder for mutations to cause lasting damage over generations. To put it bluntly, its encrypted genome seems specifically designed to limit evolution. Perhaps also the remarkable nature of this humble pond-dwelling creature is meant to serve as a lesson for us – that behind the seemingly simple hides incredible ingenuity, the mark of a designer.
My purpose for taking you on this brief journey into some of the deeper complexity found in cells is to show you that, as scientists explore further inside, life increasingly looks like the equivalent of advanced nanotechnology. As well as clever molecular machinery, it also uses the biological equivalent of highly advanced programs, ingenious information processing and storage, and smart encryption and decryption techniques.
I doubt this is what Charles Darwin expected to be in the cell when he came up with the theory of evolution. The finches he observed on the Galapagos Islands could access different food sources depending on the sizes and shapes of their beaks. But if they were to break themselves up into thousands of pieces and then assemble the pieces into a different functional arrangement, as does the pond-dwelling Oxytricha with its archive genome, or arrange into a three-dimensional Hilbert curve where nothing overlaps, as do our own chromosomes, then perhaps Darwin would have drawn very different conclusions about the development of life on Earth.
1 See the article “The Human Genome In 3 Dimensions” by Brandon Keim, posted at wired.com on October 8, 2009. 2 Percharde et al, “A LINE1-Nucleolin Partnership Regulates Early Development and ESC Identity”, Cell, 2018. 3 See the article “’Jumping genes’ help stabilize DNA folding patterns” by Julia Evangelou Strait, posted at medicine.wustl.edu on January 23, 2020. 4 Chen et al, “The Architecture of a Scrambled Genome Reveals Massive Levels of Genomic Rearrangement during Development”, Cell, 2014.