The Amazing and Miraculous Slicing and Dicing Splicesome

Several months ago a blogging expert told me that I needed to write content that is more relevant to the field of water quality instrumentation. His advice became a New Year’s resolution and, on New Year’s Day, I am breaking it.

I can’t help myself. I’ve always wondered at the miracle we call life but an article I recently read in a chemistry trade journal, C&E News, took that wonder to the stratosphere. Whether you believe in God or not you have to wonder how the subject I am about to explain—the workings of a tiny organelle in a cell called a spliceosome—can possibly exist. If you want to read the article that blew me away you can find it online at: http://cen.acs.org/articles/93/i39/Uncovering-Spliceosomes-Secrets.html.

Take a look at the picture below. It’s an assortment of hundreds of proteins and ribonucleoproteins (complexes of RNA and protein) that makes up the tiny but incredibly complex spliceosome. (Each protein is comprised of thousands of atoms.) To understand what it does first consider this: The lowly fruit fly has 23,000 genes—about the same as the flagship of the animal kingdom—us. Conventional wisdom is that each gene codes for one protein that performs some physiological function. We are what we are because of our genes. So why aren’t fruit flies designing supercomputers? The picture gets still more confusing: Humans and mammals have enough DNA to create millions of genes—far more than we can possibly use. Even more puzzling is that the amount of DNA in a frog is ten times that of a human. So why aren’t we colonizing other galaxies and why aren’t frogs dissecting us?

The answer is the spliceosome. Here’s how it works: A sequence of DNA pairs, i.e. nucleotides, constitutes a gene. These sequences contain the instruction for making proteins but they don’t make them directly. They contain the code for assembling messenger RNA (mRNA). The mRNA attaches to complexes of proteins called ribosomes where it cranks out finished proteins that comprise a living organism.

In 1977 Phillip Sharp of MIT discovered that there is not a one-to-one match between DNA and mRNA. There’s much, much more DNA. Eventually he and others figured out why. The DNA cranks out a “first draft” of mRNA, or pre-mRNA. Then the spliceosome machinery goes to work slicing and dicing. It cuts out sections of the pre-RNA (introns) and stitches them together to create the mRNA that eventually results in the manufacturing of proteins. Sections of mRNA that are not selected (exons) go the cell’s recycling factory. It seems like a waste of DNA but it’s ingenious. By cutting out and reassembling different fragments of mRNA the spliceosome is able to crank out an enormous variety of proteins from one sequence of DNA. So the sequences of nucleotides (DNA base pairs) are not really the blueprint of physiology. The DNA sequences are just the starting material. They can be rearranged in unlimited combinations to code for many more proteins that 23,000 genes could ever create.

But it gets better. Introns can contain hundreds of thousands of nucleotides, Leave out just one nucleotide and the organism can die. The spliceosome is so precise that it rarely makes a mistake. It can change just one single nucleotide to make a completely different product, such as a new muscle type.

Yet spliceosomes do make mistakes and the result can be a debilitating disease such as spinal muscular atrophy, a fatal paralyzing disease in children. In some cancers this miniature machine works in overdrive. Targeting them is a new strategy of cancer drugs that has a promising future. So is the splicesome, as amazing as it is, still just a little flawed? No. The tiny fraction of malfunctions that occur in spliceosome may have deadly consequences but also do something essential for life. It is a constant driver of evolution in which Nature continuously tinkers with “design revisions” of species. Those that don’t work kill the “prototypes” that embody the faulty change. But those that do work advance the fitness of the species and drive evolution forward. The spliceosome strikes the perfect balance between propagating a fit species and making incremental improvements that end up turning worms into human beings.

I am not a biologist. My background is chemistry. Chemistry is the science of chemical reactions—mixing compounds (or ions or atoms) together to make new compounds. Reactions only proceed if they are energetically allowed, i.e. they release energy. Everything that goes on in our body, such as digesting a meal, playing an instrument or developing the theory of general relativity, is the result of chemical reactions that are energetically allowed. Our bodies are factories in which trillions of chemical reactions occur at any given time. And they all do this without any direction from any higher authority, like a massive computer program. To think that something like the spliceosome can carry out an incredibly complex set of chemical reactions without a CPU executing a hard coded set of instructions can only be called a miracle.

We like to think of miracles as events that change history and can’t be explained, like Moses and the Jews crossing the Red Sea or Jesus raising the dead. But miracles are all around us if we only look. In fact they are right inside of us.
Happy New Year. May you see a new miracle every day.