Protein function, promiscuity, moonlighting and philosophy
I recently received an email from a graduate student in Philosophy regarding protein function. Not sure if that person wants his name advertised, so I will keep it to myself.
“I am a fan of your blog, and interested in the philosophy of biology. One particularly interesting question is what makes something have a function; when it comes to artifacts, we just check with whoever designed the thing. It gets more complicated when functions change, and things are used for purposes other than what they were originally designed for, but it’s still pretty straightforward. However, biological functions can’t go that route (unless maybe one is a fan of intelligent design). I’m curious what you think about this, after seeing you mention your interest in predicting the function of genes and proteins. Is the function of something just the causal role that it plays in some larger mechanism? Do you have to include evolutionary considerations? If you ever have the time, I’d love to hear your thoughts about this.”
Thanks very much
My rather rambling answer follows:
“Ouff, you’ve opened a pretty big can of worms, which many of us are having a problem with.
Function in biology is context dependent. An enzyme catalyzes a biochemical reaction, say, removing a phosphate molecule from a protein, However, by removing that phosphate from the protein, the enzyme changes something in the function of the cell, as phosphate molecules are the ‘signaling currency’ of the cell. So the enzyme fulfills a cellular function as well. Finally, suppose this cell is in a developing embryo, and the phosphate removal in this type of protein in many catalyzes the creation of a limb, or a particular organ or tissue: now we have a whole organismal functional context. Which one of those: the biochemical, cellular or organismal is the ‘real’ function of the cell? Well, obviously all three are ‘real’.
To add a twist, suppose that a this enzyme is also active in removing phosphates from proteins in the adult animal. Now the animal has reached maturity, and because of a mutation in one of the cells that enzyme does not work anymore. The intra-cellular signaling becomes defective and the protein accumulates in its ‘phosphorylated’ form. This signals a division of the cell, and suddenly you have a pre-cancerous situation. So from a health point of view, this mutant plays a role in the survival and proliferation of cancer cells. Interestingly, a protein that causes our spittle to froth (don’t try doing this around other people, gross), was first discovered as a nasopharenygeal cancer associated protein, and it is named as such. Many genes and proteins are named after they are found to do one thing, even though we generally associate them with something else, simply because of the context in which they were discovered.
Also, there are moonlighting proteins, which may simply perform different functions. A protein called APIS is part of the proteasome: a cellular protein shredder which is itself a rather large protein complex. APIS also plays a role in transcribing DNA to RNA: thus, it is part of a protein creation complex, and of a destruction complex. See this short paper on Moonlighting proteins.
Yes, evolutionary considerations always come in to play, it is the lens through which we examine all biological phenomena. Evolution does cause certain proteins to be ‘multi-purposed’, also, some types of protein structures are more amenable to a certain set of functions than others. Furthermore, certain proteins are ‘promiscuous‘: certain enzymes may work on more than a single substrate (“Promiscuous” is different from “moonlighting”, where enzymes do completely different jobs; being “promiscuous” means a single enzyme does the same thing, but with different partners: i.e. catalyze the destruction of a sugar, but with different types of sugar molecules). Promiscuous enzymes can clearly show a ‘trajectory of evolution’ i.e. going from being very specific for one substrate, to non-specific for several substrates (or vice-versa). Promiscuity is a good example of molecular adaptation and tradeoff: a promiscuous enzyme means you have a jack-of-all-trades in your genomic complement, and you have to spend less energy on controlling the production of several different enzymes for several different tasks. However, the flipside of having a jack of all trades is that he is the master of none: the catalysis reactions are generally less efficient, which may cause problems for the cell/organism.
Phew, I hope I managed to convey some of the complexities of this issue, and how we try to deal with them in a systematic fashion.
[… edited out]
Cheers,
me”
The difference between moonlighting...
...and promiscuous
Khersonsky O, Roodveldt C, & Tawfik DS (2006). Enzyme promiscuity: evolutionary and mechanistic aspects. Current opinion in chemical biology, 10 (5), 498-508 PMID: 16939713
Jeffery, C. (2003). Moonlighting proteins: old proteins learning new tricks Trends in Genetics, 19 (8), 415-417 DOI: 10.1016/S0168-9525(03)00167-7
…is your font intended to be unreadable?
I liked this discussion of biological function in a philosophical context (you probably need a subscription to read it):
http://www.springerlink.com/content/e82r028576316x7q/?p=71f9b393d5f3461a918a1cfa1bbff8a3&pi=4
Marc
I am a biologist at the core but I took a couple of philosophy courses in college where we asked basic questions such as “what does it mean for something to exist?” I’m not sure what drove my wife more crazy, my never-ending banter about the transcriptional mechanism behind endothelin-1 or my attempt to prove that my stinky gym bag didn’t really exist and therefore it was OK to leave it in the back of my car. When I look at Ouff’s question (is that really his name?) I wonder if he’s just trying to stir up controversy or if he’s really on to something. In fact, the more that we get into the “function” of proteins, the more we become mired in controversy. There’s an ever growing cache of technology that allows us to look deeper into the “function” of proteins and ample evidence highlighting the complicated interactions between genes, proteins and biological functions. Take for example the human brain. Just looking at the complicated interplay of proteins in the brain atlas will make you dizzy.
Hello,
I’m the grad student mentioned (and my name isn’t Ouff!). I’m not just trying to stir up controversy; rather, I think this is a question that is deeply puzzling upon a bit of reflection. Consider it from two sides:
First, if we’re talking about artifacts, a thing’s function is (roughly, and with some exceptions) just a matter of what it was intended to do. The function of something is not just what it does; something that does not perform its function is malfunctioning, and something that might not ever have been able to perform its function (a toaster with a flawed design) would still have the function of toasting. This is just spelling out the idea that function attribution crucially involves what something is supposed to do, and not just what something happens to do.
If we’re talking about non-biological, non-artifactual entities (the kinds of things in physical sciences, such as thunderstorms, noble gases, rivers, and planets), it does not seem that they have functions. It would be odd to take seriously the idea that the function of an asteroid is such-and-such. Clearly asteroids do all sorts of things, but they don’t have a function (although they could be used *as* something, and thus given a function, as when a tree stump functions *as* a chair when I sit on it–but that’s not the function of a tree stump).
What I take from Professor Friedberg’s comments above is that biological functions are context-dependent, and thus one thing can have multiple functions, depending on the context. That seems right to me, but then it poses a bit of a problem for the notion of malfunction. In one context, the function of the heart is to pump blood; in another, it’s to produce noises useful for diagnosis (and he gives some other fascinating examples above of multiple functions). It’s hard for me to see how to make sense of a heart malfunctioning in any serious way, beyond saying that, for a heart to malfunction is just for it to be failing to do something that we want it to do. Maybe that’s fine, but that’s not very rigorous. What happens to be in our interest is not a very solid basis for grounding scientific taxonomies (imagine a Nazi-like, medical experimentation scenario: if a community of evil scientists decides its in their interests for certain people to die, then on their view the hearts of those people are malfunctioning when they successfully pump blood). It’d be nice if we could have something a bit more objective than that.
The other way to go is to say (roughly) that something’s function is whatever it was that got the thing to have been selected for. So hearts have the function of pumping blood because that’s what they were selected for; not so for making thumping noises. Then we can make sense of malfunction, because we have an objective criterion for function-determination. But there are a host of problem on this view as well.
Maybe these are all just philosophers’ worries, with no real import (but of course I don’t really think that!). But it remains interesting (at least to me) that biology is rife with ascriptions of functions to all sorts of things, and this is a practice that’s simply not found in the physical sciences. It seems unlikely that we could do justice to biological theorizing by replacing all instances of “the function of X is Y” and its ilk with “X does Y”, but why is that? Is it a remnant of teleological thinking, just an artifact of the language that we’re stuck with, or is the notion of biological function an important theoretical notion that has yet to be fully articulated?
Hi Corey,
Too much to answer, but you may want to familiarize yourself with the concept of ontology (in information science, not in philosophy with which I am sure you are familiar). http://en.wikipedia.org/wiki/Ontology_%28information_science%29 Then look to the various biological ontologies http://www.obofoundry.org/ and specifically the gene ontology which is widely use to describe biological functions. http://geneontology.org/