A History Of DNA, Part II: Proteins Vs. DNA

In the early part of the 20th century, when Griffith published his work, there was generally an assumption that the genetic material must be a protein. Why did they think that? They thought it because pretty much everything that happens in the cell is done by a protein. It makes sense that if you got something complex and important that is being done in the cell, like providing information, it is probably going to be a protein.

By weight, if you analyze the content of a typical chromosome, there is five to ten times more protein than there is DNA. Another thing that was going against DNA is that if you look at what nucleic acids (DNA and RNA) are made of, they are a string of subunits (called nucleotides). Proteins are made of 20 different kinds of amino-acids. Nucleic acids, on the other hand, are made up of only four different kinds of nucleotides.

Another thing they knew about nucleic acids was that they are actually structurally quite boring. Proteins have a complex structure that determines their function. Nucleic acids seemed to be strings that laid there. They didn’t have these complex structures. So, the sequence of the building blocks of nucleic acids seemed rather simple (with only four elements), the structure of nucleic acids seemed kind of simple and not very useful. Everybody assumed that it must be proteins that were somehow holding the code.

There was, however, one nagging piece of evidence that argued against proteins. If you heat proteins up, they break down. They break down because those chemical interactions that hold proteins together start to break apart. The protein loses its configuration and changes its shape. The problem here is that when Griffith had heated up those S strain bacteria to kill them, he probably denatured a lot of the proteins. So, there was some evidence that it might not be proteins, but nonetheless most biochemist thought that they should be looking at proteins in the early part of the 20th century.

How did scientists try to solve this problem? Back then, they did biochemical procedures that would selectively break down particular kinds of molecules. This kind of work was done in the early 1940’s, by three researchers at the Rockefeller Institute; Oswald Avery, Colin MacLeod, and Maclyn McCarty. These guys were biochemists who had being developing relatively sophisticated techniques at that time for selectively breaking down different classes of biological molecules. We have four major classes of molecules: proteins, nucleic acids, carbohydrates and lipids.

If you could take a beaker of transforming principle from experiments similar to Griffith’s, and selectively break down each of these classes of biological molecules, then you could ask which molecule, when it is broken down, causes the transforming principle to no longer work. You have some S strain and R strain bacteria, you extract some substance which you would call transforming principle, and then you treat that solution to selectively knock out the proteins, or the nucleic acids, or the other molecules. Then you ask, which one when it is broken down ends up the transforming principle to no longer transform?

They did that, and this is what they found. They could break the carbohydrates, no problem. They could break down the lipids, no problem, still got transformation. They could break down the proteins, and there was no problem. If they broke down the nucleic acids, however, the transforming stopped. They concluded from that, that the transforming principle Griffith discovered must be some kind of nucleic acid.

To me that is pretty good evidence, but interestingly, in the 1940’s, that result wasn’t widely accepted. This was for a couple of reasons. First of all, there was growing interest in protein biochemistry, and a lot of people were still focusing on the importance of proteins. There was a bias against believing it could possibly not be proteins that hold the code. The other reason that people were critical is that they biochemical techniques that these researchers were using were relatively novel. There was some argument that maybe they may not had destroyed all of the class of molecules they thought they had destroyed.

So, there was no way for Avery and his colleagues to prove otherwise at the time and the issue stood. This is where the work of two other researchers came in about a decade later: Alfred Hershey and Martha Chase. In my post I will talk about their clever experiment that shaped modern biochemistry.

The Origin of Life, Part IV: Genetic Code

Ok. We’ve shown that it is possible for cell-like structures to spontaneously generate in certain conditions. How do we get from protobionts to all the enormously complicated and diverse stuff that we see today? We don’t know the answer to that question and we probably never will. We do know, however, part of the answer. Part of the answer has to do with reproduction.

How does a living system reproduce? What minimally do we need to get reproduction? How reproduction arose is an especially tricky problem. It is the problem that is most debated today in the area of the origin of life.

To understand what is needed for reproduction, let’s imagine we’re back in time. Let’s imagine we have some proto-cells that are functioning. Let’s say that by chance, one of these protobionts just happens to come up with some unique new trait. This trait could be anything. For example, it could be a new kind of molecule that makes this cell more durable. It could be a new kind of molecule that increases its ability to take up material from the outside.

This protobiont is different from the rest. It is somehow more efficient, better at doing its job. The problem is that we have only one of them. That individual won’t last forever. Even if it does, there will only be one of them. This issue leads us to reproduction. This problem would be solved if our protobiont could reproduce itself in a way that would pass that useful trait on to its progeny. How does it do that? Well, cells split into two. We have one cell, it grows a little larger and splits into two. In essence, that’s reproduction. This is not enough, however.

The Genetic Code and the Problem of Replication

If the trait we are talking about is a molecule, which of the daughter cells gets the molecule? Even if there is a lot of these molecules and each daughter cell gets a half of it, and the daughters of these cells get the half again, eventually this property will fade away. What we need instead is for these primitive cells to somehow be able to make completely new and accurate copies of themselves. They have to be able to store information about the structure of the molecule and transfer that information to its offspring.

How such a mechanism for storing and transmitting this kind of information came about is one of the unresolved questions about the origin of life. We know, however, that there is such a molecule in modern cells. This is a cell that accesses a blueprint for making more molecules. This molecule is called Deoxyribonucleic acid, or DNA.

DNA passes its information onto another kind of nucleic acid, RNA, and then the information goes from RNA into proteins. This is the way information works in modern cells. In this system, DNA acts as some kind of blueprint, RNA as the translator and proteins are the product of that blueprint. Proteins do much of the real work in modern cells.

Here we encounter a really serious problem, however. DNA could not have been the storage molecule that first arose in early life. Why not? The reason is that DNA can’t replicate itself. DNA requires a huge number of other proteins acting as enzymes to replicate. DNA in modern cells can be replicated but only if there are proteins to do the replication job. Proteins that could do that replication job might have arisen sometime in the early history of life on Earth, but they couldn’t have arisen before there was DNA to store their code. We need to postulate simultaneously the appearance of DNA that could store information about proteins and proteins that could replicate that DNA. Which came first, the chicken or the egg?

Neither could have come first because DNA and proteins can’t exist without each other in modern cells. Also, it is unbelievably improbable to think that just the right kind of proteins and just the right kind of DNA happened to arise spontaneously sometime in the early history of life.

What was need, instead, is for some kind of molecule that could do both of these things. A molecule that could replicate itself and it could do other useful things in the cell. Today we’re beginning to think that when life arose the molecule that did that was the nucleic acid RNA, or some early form of what we know today as RNA. Why we think that?

The RNA World

At the beginning of the 1960’s researchers have begun to suspect that RNA might have acted as the first blueprint or genetic material. In the laboratory, it is possible to put in some kind of RNA and then some building blocks, and under the right conditions the RNA replicates itself. RNA in the solution somehow acts as a template that helps the monomers come together in the right way and also polymerize.

A second breakthrough that led people to think that RNA might be the first information processing molecule came in 1983, when Thomas Cech actually discovered that, in modern cells, there are some kinds of RNA that do act as catalysts the way protein enzymes do. That is, they perform some important biochemical tasks in the cell. They are generally called ribozymes.

The important point is that these rybozymes are functioning as catalytic molecules just like protein enzymes. We’ve got two things now. We’ve got evidence that RNA can replicate itself and also evidence that RNA can have some sort of catalytic function. Taken together, these two sets of results suggest that in the very early stages of life, that magical point where a non-living protobiont somehow slipped over the edge into the state that we might want to call a living cell, happened in what we now call an RNA world. RNA actually dominated as the key biological molecule.

At some point after the RNA world, things changed. RNA had gotten the system rolling, but eventually DNA and proteins took over. DNA took over the job of being the information-bearing molecule. Proteins took over the job of doing all of the catalytic and other kinds of work in the cell. RNA became relegated to just an intermediate in the process.

Why this would happen is fairly obvious. Proteins are extraordinarily versatile molecules. They do an enormous number of tasks. Their versatility comes from the fact that they can assume all sorts of complicated shapes in a way that RNA can’t. Proteins clearly took over doing the real work in the cell because they were really good at it. DNA assumes a particular kind of chemical configuration that makes it really good at storing information in a way that RNA is not particularly good. Once we have DNA, it is much better than RNA at making more copies of itself and storing that information. So, it took over that job. RNA became just an intermediate.

I think that with this we have what is basically needed to the appearance of life. We’ve explained the origin of life, at least in part. Quite an accomplishment, eh? How do we get from these simple cells to platypuses and other things is another subject, and don’t worry, I’ll try to tackle it.

Return from Genetic Code to The Origin of Life