In my previous column on “Monsters” I discussed the genetic basis for the Cyclops and the Werewolf. Then, in “More Monsters,” I discussed the homeotic genes that act as master regulators of organ identity. But really those genes are so last century. They all code for proteins, and it is the proteins that do the real work. But there’s a whole new type of master regulator out there, one that doesn’t even make a protein.
These regulators are called microRNAs.
That’s what all the cool kids now have in their genetic toolboxes.
You know, those kids that are a little bit older than you, that aced their molecular biology courses but dropped out of high school because they didn’t like all those ‘RULES’. They didn’t like ‘THE MAN’. So now they hang out in a boarded-up mansion at the dark end of a dead-end street, smoking God-knows-what, and hassling you whenever you wander down their way.
The truth is that you’ve got no good reason to enter their neighborhood.
No good reason at all.
Except for that guy whose beard looks like it’s made from twisted fingernails. Or that girl whose head is swollen as if her brain expands beyond the limits of her skull. Or that thing that humps around the yard, ignoring nettles and broken glass: someone told you it’s a baby but it looks more like a giant maggot.
Those kids don’t like you. And you don’t really like them. But you want to know how they did it. Did it to themselves. How they changed, evolved into something so new, so different, so horrible.
What Is a microRNA?
The “Central Dogma” of molecular biology, first stated by Francis Crick back in 1958, is that there is a sequential transfer of information from DNA to RNA to protein. DNA is transcribed to make messenger RNA and this is then translated to make protein. MicroRNAs, or miRNAs for short, play key roles in regulating the ability of messenger RNA to be translated into protein.
The microRNA is aptly named. miRNAs are short RNA molecules of about 22 nucleotides in length. Significantly, they don’t code for proteins. Instead miRNAs have sequences that are partially complementary to those already present on messenger RNAs. This level of complementarity means that a miRNA can bind to a messenger RNA target, in much the same way two strands of DNA bind to each other to make the famous double helix.
What happens when a miRNA binds to its target messenger RNA? The targeted messenger RNA may be degraded. Or the targeted messenger RNA may be prevented from being translated to make a protein. Either way, no protein is made.
Now this might seem just an interesting bit of scientific trivia if there were only a few miRNAs and a few targets. But a single miRNA can target many different messenger RNAs, thereby controlling the whole suite of their encoded proteins. And, complex organisms like you and I have over 250 families of miRNAs. One estimate has it that over 60% of the human genes are regulated by action of miRNAs. So, within the past decade, miRNAs have gone from being a scientific oddity to being recognized as central regulators that control most biological processes.
What’s more, miRNAs can be readily used by scientists to knock out the expression of the genes they study. A molecular biologist can design an artificial miRNA to target a specific messenger RNA, introduce it into the organism—sometimes by using cloning techniques, sometimes by simply feeding the artificial miRNA to the organism—and then see how loss of the gene activity affects the organism. In other words, miRNAs have become a useful tool for molecular studies.
microRNAs and Evolution
One area where miRNAs are having an impact is on our understanding of evolution, with some fascinating research in this area being performed by Kevin Peterson, a colleague of mine at Dartmouth College. These studies get to the heart of how complexity has arisen during the process of evolution. Or, to put it another way, what is the difference between you and a worm?
My choice for comparison is not whimsical. I think you will agree with me that the human body is more complex than that of a worm (I am resisting the opportunity to make a joke here, but you’re welcome to suggest some exceptions to this rule). Indeed, back in the late 1800s, the German scientist and artist Ernst Haeckel drew an Evolutionary Tree of Life based on the form and structure of organisms—their morphology. You’ll notice in the figure below that he placed ‘MAN’ at the top of the tree, separated by a great distance from invertebrates like the ‘Worms’. Scientists who study the cell types within an organism also agree that there are many more cell types in a human than in a worm. You ARE more morphologically complex than a worm.
But…when the human genome sequence was completed in 2003 it was deduced to encode only about 20,000 genes. I write ‘only’ because, for all intents and purposes, this is the same number of genes as had been found previously in the genome of the worm C. elegans. Many found this shocking. If we’re more complex, shouldn’t we have more genes than a lowly worm? Some people, no doubt, stomped on a few worms just to demonstrate their evolutionary superiority.
But let me clarify a point. The genes I am referring to are those that encode proteins. And yes, in point of fact, there is little correlation between the number of protein-coding genes and the complexity of organisms.
However, when it comes to miRNAs, it’s a different story altogether. There is a good correlation between morphological complexity and the number of miRNA families present in an organism. For example, worms have 56, fruit flies have 81, zebrafish have 101, rodents have 192, and primates have 257 families of miRNAs based on recent count from Peterson’s lab.
What then are the miRNAs doing that results in this morphological complexity? One clue comes from seeing where the miRNAs are expressed in organisms. For example, during evolution, vertebrates acquired 41 new types of miRNAs not found in invertebrates. These new miRNAs are expressed in cell types or tissues found specifically in the vertebrates such as the liver and pancreas. Another clue comes from seeing what happens if cells lack miRNAs. For example, cancer cells—uncontrolled, chaotically growing cancer cells—turn out to have a low level of miRNAs. Even more exciting, you can inhibit cancer cell growth in liver cells by re-introducing miRNAs back into them, indicating that the liver cells need the miRNAs to help maintain their identity as liver cells.
In short, miRNAs appear to grant organisms an ability to do wonders with an apparently limited repertoire of genes, acting as key players in the development and maintenance of new tissues and organs. All this arising from the exquisite level of control that miRNAs exert on gene expression. A miRNA can be likened to a conductor corralling a troupe of itinerant musicians and eliciting a beautiful symphony from them.
Are We Not Men? We are Devo!
Once gained during evolution, miRNAs are seldom lost, making it fairly easy to trace evolutionary relationships among organisms.
Seldom lost…so what happens if they are lost?
A recent study on a simple flatworm (Acoelomorpha) suggests the answer. And, let me make it perfectly clear, this flatworm is indeed very simple: it has one orifice that serves as both mouth and anus, and it lacks a central nervous system. It is so simple that it has typically been placed on the Tree of Life somewhere above jellyfish but clearly below more complex animals like sea urchins, insects, vertebrates, and, of course, humans.
But even though quite simple in appearance, it now seems this flatworm is more closely related to humans than it is to insects or jellyfish. It has a simple morphology not because it is evolutionarily ancient, but rather because it has LOST its complexity during recent evolution. Significantly, going along with this loss of morphological complexity has been the loss of many of its miRNAs. To put it another way, this flatworm has evolutionary ancestors that are more complex and which have a greater wealth of miRNAs.
Truly, devolution in action.
And, the suggestion that a bunch of miRNAs is all that stands between you and a worm!
1. “MicroRNAs and the advent of vertebrate morphological complexity,” by A. M. Heimberg, L. F. Sempere, V. N. Moy, P. C. J. Donoghue, and K. J. Peterson. My column this month is largely inspired by the research of Kevin Peterson, which continues to illuminate the changing miRNA repertoire of organisms during evolution and in the case of Acoelomorpha indicates how loss of miRNAs may contribute to devolution. This key scientific publication from his lab was published in the Proceedings of the National Academy of Sciences in 2008.
2. THE TIME MACHINE, by H. G. Wells. With future diverging streams of humanity giving rise to the incurious Eloi and the brutish Morlocks, Wells suggests two directions for human devolution. The complexity of human brains is currently speculated to arise in part due to brain-specific miRNAs. So, one explanation for Wells’s devolving humans could be a loss of brain miRNAs or a decreased role for them in the regulation of gene expression.