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.