The Dumpling Conundrum

UNC Medicine Biologists Find Protoype of the Genetic Code
June 5, 2015 
This story is about the origin of life on Earth, but before we get to that, let’s start in the kitchen.
When you stop and think about it, a pot of soup should have gotten the nod over King Kong as the Eighth Wonder of the World.
You take the simplest things you have lying around — water, a bone or two, veggies, a few spices and maybe a few pieces of meat or noodles if you’re feeling adventurous — put them in a pot, come back a few hours later and you have something far tastier and more nourishing than anything you had before.
It’s as if something hops into the pot, pulls all the flavor out of each ingredient and shuffles them all around into the broth. The first human to see this happen must have seriously freaked out, pondering what could have transformed all of his food and water into soup.
Now we know that science performed this 'ingredient to soup alchemy': diffusion, dissolution, chemical reactions. And soup science has been around for a very long time: about 3.4 billion years.
Scientists believe that all life started as a bowl of soup. Puddles of water mixed with the methane, nitrogen, ammonia and carbon dioxide stewed in the heat of the young Earth. Just like in the soup pot, those ingredients change and the basic building blocks of life — amino acids, carbohydrates and basic nucleotides — begin to form.

Eventually those small molecules assemble into proteins and RNA: the machinery necessary for an organism to function and replicate.
But between the building blocks and the protein-RNA life machines is a giant simmering pot of mystery, and two biologists from the UNC School of Medicine recently developed models that may open the lid and give us a preliminary whiff of what’s going on in there.
The main problem with our current picture is that both proteins and RNA are gigantic molecules and in today’s organisms, proteins are responsible for building RNA while RNA contains the genetic instructions to build proteins. So immediately you have a classic “chicken or egg” question.
Many scientists subscribe to the “RNA world” theory which holds that RNA randomly and spontaneously built itself and then provided the code to build the first proteins. But Charles Carter and Richard Wolfenden, the UNC Medical School biologists, have an issue with this picture as well, which we will call the “Dumpling Conundrum.”
RNA is a long strand of connected nucleic acids. Today those long strands, called messengers, have instructions: groups of three nucleic acids that code for a specific amino acid. Another type of RNA, called transfers, carries an amino acid and has a set sequence of nucleic acids that match the messenger. As one transfer after another matches the messenger, the amino acids they carry are bound together to form basic proteins. The nucleic acid sequence on the messenger is what scientists call the genetic code.
It sounds pretty complex and that is the basic argument of the Dumpling Conundrum. All of the pieces for RNA and the genetic code were there in that primordial soup, but all of those pieces coming together and creating a cohesive code without any other molecules to help is about as likely as flour stirred into a soup spontaneously coalescing into a dumpling.
What Carter and Wolfenden propose is a “RNA/Peptide World" where both small RNA fragments and small groups of amino acids spontaneously formed and then helped build each other up to the behemoth molecules that power life today. Tiny little clumps of flour that, over time, merged and built into a dumpling. They recently published two papers in the journal Proceedings of the National Academy of Sciences on how part of that RNA/peptide world might have come about. 
The nice thing about life on Earth is that it is pretty unoriginal, meaning that for 3.4 billion years life has built its genetic material from the same 4 or 5 nucleic acids and its proteins from the same 20 amino acids, so scientists can study the fundamental chemistry of how life began by studying those same molecules.
That is exactly what Carter and Wolfenden did, and they picked up the story about midway through the dumpling construction. Small RNA messengers and transfers had already sprung up as well as the first Ford Model-T versions of enzymes and other proteins.

The first study examined how the amino acids behave across a range of temperatures. Amino acids all have the same backbone, but what separates one type from another is a chemical side chain that can be anything from a single hydrogen atom to a series of carbon rings. The size and polarity (how well something interacts with water) of these side chains determine how a protein folds into the correct shape to carry oxygen or flex a muscle fiber or generally do what you need it to do.

The issue is that polarities can change at different temperatures, and Earth was much hotter 3.4 million years ago than it is now, so Wolfenden wanted to test whether these side chain polarities would be completely out of whack at a much higher temperature. He found that as temperatures change, the polarity of all 20 amino acids changed dramatically, but they kept their relationship with each other. For example at 20 degrees, glutamate is more polar than alanine. At 80 degrees, the polarity of both of them has changed, but glutamate is still more polar than alanine.

Transfer-RNAThis is important because those polarity and size relationships allow proteins to fold correctly. If alanine were more polar than glutamate at a higher temperature, the protein would fold differently. The fact that those relationships hold at high temperatures means that the rules for protein folding have been the same since the first protein was made, and to take that a step further, the relationship between genetic code and protein folding has been the same since the dawn of proteins.

The second paper deals with the behind-the-scenes of early protein building. Above, we saw that RNA transfers carry amino acids, and when they match up with the messenger, they add their amino acid to a growing protein. But that begs the question, “Where did the transfer get the amino acid in the first place, and how does it know it’s the specific one the messenger has asked for?”

That, as it turns out, was a job for some of the earliest enzymes, called urzymes. Urzymes are the four-wheels-and-an-engine version of modern enzymes. They will do the job, but without any of the precision, performance, and luxury features you would see on a modern enzyme.

The particular urzymes Carter investigated had the job of matching transfers with the correct amino acids so that the transfer that is supposed to carry tyrosine always carries tyrosine. Today’s version of that urzyme would read the three amino acids that interact with the messenger, know that they found the transfer for tyrosine and attach a tyrosine molecule to it. 
You would think the urzyme would probably operate the same way, but Carter began to notice similarities in some of the transfers. Transfers look a lot like tire irons, and the three nucleic acids that match the messenger are only one head. Carter saw that transfers meant to carry amino acids of similar sizes would be built the same on the other side of the tire iron. For example, the transfers for phenylalanine and tyrosine look similar because they carry the largest, fattest amino acids.
Those three amino acids have different polarities, however. Tyrosine has an oxygen atom that allows it to interact with water much more readily than the other two, so if you were to try to build a protein with phenylalanine where a tyrosine should be, it could be close, but not quite right. 
Carter thinks this correlation of size might be a prototype of the genetic code. Imagine a bunch of very small RNA molecules floating around, trying to build proteins that will help them reproduce. The vast majority will get it wrong but by dumb luck a few will get it right and reproduce. Now imagine that one RNA  comes along with a code to sort amino acids by size. This makes its job much easier, allows it to make bigger, better proteins and even though it will get its protein formula wrong 99% of the time, it is infinitely better at building proteins than the random builders so it reproduces it while the randoms die out. Then the process repeats when it begins to develop a code for size and polarity, which is what they do today. That one gets its proteins correct nearly 100% of the time, allowing the proteins to get bigger and bigger, which allows the RNA to get bigger and bigger.

Wolfenden and Carter say this intermediate genetic code may have been the key not only to the genetic code, but also to the rapid growth of life on this planet.

This research does not fully answer the question of how the first RNA and protein molecules formed or how long this process might have taken, but the idea of an intermediate genetic code represents a significant point between gravy and dumplings in the primordial soup.

— Daniel Lane

Daniel Lane covers science, engineering, medicine and the environment in North Carolina.