What if a snake had legs? Could a snake have legs? Why would a snake want legs? These might sound like absurd questions, but with advances in the field of developmental biology, we are beginning to understand more about how and why organisms look the way they do. So why does a giraffe have long legs while a tortoise has short ones? Why does an octopus have eight legs while a snake has none? These observable features (phenotypes) typical of each organism are decided during the very early stages of development – during a process known as pattern formation.
Pattern formation is the process by which you go from a clump of cells that look almost identical to fingers and toes. This clump of cells is given a highly intricate mix of signals in the developing embryo that changes over space and time, and dictate what is known as the cell fate (how the cell is specialised in the developed organism).
So, as an embryo, organisms undergo the process of pattern formation. Cell fate is decided, and we start to see a development of recognisable features such as limbs. Taking a step back, the next logical question is to ask, how does this all begin? As is often the case in biology, we can track this process all the way back down to DNA and genetics. Patterning and cell fate are largely determined by signalling molecules, usually proteins, coded for by DNA. Once one signalling molecule is released due to environmental cues, a snowballing process known as a signalling cascade fuels the patterning process.
One type of signal can result in many different responses from cells based on the signal concentration, and so the cascade begins with one molecule leading to more, leading to many more. The result is a beautiful self-regulating soup of finely balanced biochemical interactions. A molecule which governs the patterning of tissues through this non-uniform distribution is known as a morphogen (a term coined by Alan Turing, famously known for cracking the enigma code amongst other work).
So how does this tie in with legs? In most early vertebrate embryos a structure begins to form known as the limb bud. This limb bud is formed by earlier patterning processes governed by a set of genes known as Hox genes. Shortly after, a ridge of tissue forms on the bud. This ridge is the site at which limb growth is induced. This limb bud must now decide what goes where and does so by considering three different axes, creating a 3D plane for cells to navigate.
These axes are very important in patterning. It’s what makes sure you have exactly one thumb, one index finger and so on while also making sure they’re all exactly in the correct order. While there are many molecules involved in this patterning, one in particular is known as sonic hedgehog (abbreviated to Shh). As well as having a funky name, Shh works as a morphogen and dictates cell type using concentration gradients.
Having said that, Shh isn’t only present to act as a morphogen. Shh is a critical protein for maintaining that “self-regulating soup”. Once expression of Shh has been induced by a protein called FGF8, Shh then induces production of another protein called FGF4. FGF4 also contributes to the production of Shh, and so once this molecular wheel of protein expression has been set rolling, a positive feedback loop drives limb production.
Sonic hedgehog is clearly a vital molecule for limb production. Comparing its gene sequence across vertebrates they appear strikingly similar (mouse and human being identical). However, one specific region is found to be missing in some animals. It may come as no surprise to you that it is only found to be missing in snakes. It would be logical to assume that the presence or absence of this DNA sequence will affect limb growth, so how do we know?
Using CRISPR, a modern gene editing technology, it is possible to replace the gene sequence in a mouse with the snake’s version. The result is what was termed a “serpentized mouse”. Or, bluntly, a legless mouse.
A curious mind might ask what would happen if we reversed this process. What would happen if we put a mouse sequence in a snake? I’m afraid the answer is we don’t know. Mice are intensively studied and so we know quite a lot about their genome and how they work. Using CRISPR on snakes has proved difficult, but this has given us some insight on their evolutionary history.
Who knows, perhaps one day we’ll have snakes with legs.