Small GTPases

They say as biologists age, they start to think more about evolution. Re-reading Richard Dawkins' famous book The Selfish Gene,¹ I started to realize maybe it's true and I'm getting older. My son would definitely agree with this—the “getting older” part, I mean. But, in my defense, it is impossible to read Professor Dawkins' book without dwelling on the expanse that is evolutionary theory. In reality, how do biologists not think about evolution, at least while they are in the lab?

I trained with a very good evolutionary biologist. Although, he would consider himself an immunologist, he went into this field because he wanted to find rapidly evolving genes and figured the immune response, with its constant battle against the forces of evil, would be a good place to look. This brings me to the point: People truly focused on evolutionary theory are measuring drift, or rate of change. To do this, of course, they need rapidly-evolving genes. This raises the question: Are these the most interesting or important genes from an evolutionary point of view? Consider, for instance, the immune genes my mentor studies. They evolve to counteract a specific threat that may only occur in a few, or possibly even one, species on the planet. You can especially see this in the immune response of plants, one plant gene co-evolving to counteract one pathogenic gene. I like to think of these genes in terms of a suburban neighborhood, probably because that is the environment where I grew up. What tells us more about the dynamics of a neighborhood: The houses where the inhabitants have lived for a long time and have a sustainable group dynamic, or the houses where the inhabitants have lived for a short amount of time, moving constantly? If we visit the house where the inhabitants move frequently and ask about the neighborhood, most likely, they won't be able to tell us much information. They haven't lived there that long, and since they will move soon, they aren't that interested in getting to know their neighbors. Now, if we visit the house where the inhabitants have lived since the suburb was created, they will likely know everything about their neighbors and the area. They will have a vested interest in their neighborhood. The rapidly evolving immune genes can be compared to the people who inhabit a home for a short time and then move on when their job is finished.

Small GTPases would be in the second category of inhabitants, the ones who lived there since the beginning. From the stand point of evolutionary drift, they are probably not the best genes to study. But from a selfish gene point-of-view, they are extremely successful, making them possibly even some of the earliest genes, or replicators, as Professor Dawkins might say. In a recent review in our journal, van Dam et al. say that small GTPases are, and I quote interwoven with the origin of unique eukaryotic cell features.² I find this statement to be eloquent, but I would like to take it further by saying that small GTPases are interwoven into the very fabric of life. They have most likely been around from the beginning, if not very close to it. They are found in both prokaryotes and eukaryotes, and they meet the criteria for one of Professor Dawkins successful replicators. They are small genes with few, if any, introns. Thus, the chance of a chiasm interrupting their sequence is minimal, also they perform the most basic yet important functions.

Let me offer another illustration of my point with a game. Think about your office. What is the most important thing in your office? What is the one thing without which you can do nothing else? Your immediate answer might be your computer. But think in more basic terms. What is your answer now? Of course, it is the on-off switch. You need switches to turn on the lights in your office, to turn on your computer, printer and so on. They so basic that we rarely ever think about them, but they are everywhere and almost nothing works without them. Another example of an office “must have” might be your mobile phone. Even your phone is equipped with an on-off switch.

Just like the electronic on-off switch, small GTPases have made themselves valuable to the greater system by being nature's on-off switch. I know this is an oversimplified example, but it helps make my point. From an evolutionary standpoint, and possibly why they are so prevalent in diseases, small GTPases are central to the proper working of the system. Turn them off and signaling stops. Turn them on and signaling starts. Turn them on in an unregulated fashion and you have a runaway system. Switches run our lives. If a switch doesn't flip, or flips at the wrong time, disaster ensues.

In conclusion, the ‘simple’ genes we work on should be considered evolution's success story. Maybe Professor Dawkins would be so bold as to call them extraordinary replicators. Maybe you, or Professor Dawkins himself, won't go so far as to call small GTPases extraordinary replicators, but I will.