DNA

Let’s talk about DNA. The genetic code is the blueprint used to build our bodies and that of every living being. At the very beginning of the 20th century, it was already known to scientist that the code was in genes, which in turn resided in chromosomes. In this series of articles I want to get through the incredible history and see how this most interesting of molecules works.

• Discovering the Genetic Code: We today know that chromosomes are made of DNA, but how that became a known fact? We must begin by going back to the earlier part of the 20th century, to the work of an English physician named Frederick Griffith. This experiment that I am about to describe really provided the first insight into the chemical nature of genetic information.
  
  
• 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.
  
  
• The Code is in DNA: In the early 1950’s, Hershey and Chase took a novel approach in trying to found out what the genetic material might be made of, by looking at how a particular kind of virus worked.

How it Works

• The Building Blocks: The building blocks of nucleic acids are called nucleotides. There are only four types of nucleotides. This is one of the reasons why nucleic acids seem relatively simple compared to proteins. Each nucleotide has a sugar that forms a ring.
  
  
• The DNA Structure: After the work of Hershey and Chase, biologists in the early 1950’s became convinced that DNA was what they needed to look at to understand the genetic code. They actually had no idea how DNA could possibly act as a mechanism for genetic inheritance.
  
  
• Watson and Crick’s Double Helix: James Watson was a young American, who had just completed his PhD. He was interested in protein structure. He moved to Cambridge, England, and began working with Francis Crick, who was a physicist familiar with x-ray crystallography and how to interpret it. The story goes that Watson happened to visit London for a seminar, and saw the x-ray diffraction patterns that Rosalind Franklin had obtained from Maurice Wilkins’ purified DNA. Watson made some notes, rushed back to Cambridge and told Crick what he had seen.

Understanding Replication

• Theories of Replication: The first alternative suggested that the DNA double helix must remain completely intact when it is replicated. That is, the two strands do not separate. The entire molecule is somehow used as a template for making more DNA. A second alternative suggested that the original DNA molecule becomes completely broken down during replication, with the newly copied DNA assembled by some unknown mechanism. In other words, the DNA double helix would actually be irrelevant. The mechanism that Watson and Crick proposed became known as the semi-conservative model of DNA replication. This was called semi-conservative because it predicts that during replication, the double helix unzips and the new daughter helixes would both have one strand of the old helix.
  
  
• Watson and Crick had it right: Watson and Crick’s semi-conservative model contrasted with a couple of other possibilities for how DNA could possibly replicate. There is the conservative model, which suggests that both strands in the original DNA double helix stay together during replication. Then there is the dispersive model, which suggests that both strands are not only separated, but even broken up into smaller pieces during replication. Deciding which of these models was the correct one seemed to be pretty easy, because they make very different predictions. It was not obvious how to prove it in the laboratory, however.
  
  
• The Process of Replication: In 1957, Arthur Kornberg made a really interesting discovery. He showed that DNA can be replicated outside of a cell, in a laboratory test tube. Kornberg wasn’t much interested in which model of replication was right. Instead, he was interested in specifically how replication occurred. Watson and Crick had suggested that the replication of DNA may not actually require an enzyme. If you could somehow unzip DNA, they thought that new DNA might just self-assemble, because the complimentary base-pairing would bring in all the appropriate nucleotides. Kornberg thought, though, that there must be some enzyme involved. He set out to figure out what that enzyme was.

The DNA Structure, Part II

James Watson was a young American, who had just completed his PhD. He was interested in protein structure. He moved to Cambridge, England, and began working with Francis Crick, who was a physicist familiar with x-ray crystallography and how to interpret it. The story goes that Watson happened to visit London for a seminar, and saw the x-ray diffraction patterns that Rosalind Franklin had obtained from Maurice Wilkins’ purified DNA. Watson made some notes, rushed back to Cambridge and told Crick what he had seen.

Using Franklin’s data, Watson and Crick were able to deduce a number of key structural elements about how DNA must be shaped. These are things they figured out by looking at those dots on the x-ray crystallograph. First, they learned that the molecule had to form some kind of helix. It had to have a kind of spiral structure, similar to the alpha helix that is characteristic of many parts of proteins. Second, they figured out that the width of this helix was about two nanometers. The interesting thing about this is that, this width was twice the width of what you would have expected if there was only a single helix. That gave them the idea that there had to be more than one helix. A double helix, perhaps.

Another thing they learned was what the regular spacing of the repeated patterning along the length of the molecule is. They saw that there was a repeating pattern at about 0.3 nanometers. This corresponded to the size of one nucleotide. Then there was a larger repeating pattern that was ten times that size. From this they inferred that the number of nucleotides that would occur when the spiral went around just once and returned to the same point in the spiral had to be about ten nucleotides.

That isn’t a lot of information. If I gave you that information you couldn’t tell me the structure of DNA. What Watson and Crick did was to use that data and set out to figure out the structure of DNA the old-fashioned way. They made physical models of the molecule with metal rods. They made large-scale models of DNA several feet tall.

They built many models and asked each time: when we have this model, does it all fit together? They tried over and over again. Eventually they came up with a model that fit. The trickiest part of the modeling was to figure out how the nitrogenous bases fit into the picture. Remember, a polymer of DNA is a repeating pattern of sugars and phosphates, with different nitrogenous bases hanging off the side (the guanines, the adenines and so forth). Where did they fit? If you had two, or even more molecules of DNA that were spiraling together, where do the nitrogenous bases go?

Well, after a couple of failed attempts putting the nitrogenous bases on the outside, Watson and Crick realized they had to go on the inside. Why they might want to put them on the outside? It is the nitrogenous bases that vary along the length of the molecule. It is the variation of the different kinds of nucleotides that must somehow involve the code. If we’re going to get access to that code, we’ve got to make what’s different about that code available to the outside world. They couldn’t get the backbones to work together in any way that made sense with the nitrogenous bases on the outside.

If they turned those nitrogenous bases in, and had the nitrogenous bases connecting with each other, forming kind of stairs, with the backbones of these molecules forming the stringers that are holding the steps; the molecule began to fit together. This actually made sense, because these nitrogenous bases are chemical repelled by water. They want to be on the inside of the molecule because of that.

There was one interesting additional problem. This is actually the most interesting part of the story. That is, how did the bases fit together? If the put the nitrogenous bases on the inside, they could get a double helical structure that began to fit the data, but there was still a problem remaining, there are two kinds of bases, the pyrimidines and the purines, and they are of different sizes. Purines have two rings, and pyrimidines only have one.

If you just try to put these stair steps across the two sides of the double helix, you’ll have some steps that are wider, and some that are narrower. For example, if you got two purines together, you’ll have a relatively narrow step. The outside of this spiral would be going in and out, which is not structurally stable. That’s were Chargaff's rule came in. They realized the implications of Chargaff's rule, which says that the amount of the base adenine (A), always equals the amount of thymine (T). Similarly, the amount of guanine (G), always equals the amount of cytosine (C). This suggested that it may be that one always pairs up with the other when they are matching together on the inside of the helix.

It turns out that when they looked at how these kinds of nitrogenous bases would match up, they found that those peculiar combinations (A and T, C and G) would always maximize that potential weak bonding that occurs between the bases. With this, they actually solved two problems. They figured out how you can have a regular distance along the whole length of the staircase. Also, they figured out what could hold the staircase together. If you always match A with T and G with C, the bonding that holds two sides together is maximized.


In April, 1953, which is only a year after people became convinced that DNA was the information molecule, Watson and Crick published a one-page paper in the journal Nature, which described the double helix. They described the molecular structure and how they thought it would all fit together. The real significance of this work was not simply to describe the 3D structure of DNA, but to show how that 3D structure might actually say something about replication.

Watson and Crick’s paper ends with the following sentence: “It had not escaped our attention that the specific pairing we have postulated immediately suggests a possible copying mechanism for the genetic material.”

The fact that A and T, G and C were always paired together, meant that if you took the two sides of the molecule apart, you would always know what the other side has to be. That’s called complementary base-pairing. It was this fact that suggested that mechanism by which DNA was replicated. I’m very excited about this subject, but I will leave it to another article.

The DNA Structure, Part I

After the work of Hershey and Chase, biologists in the early 1950’s became convinced that DNA was what they needed to look at to understand the genetic code. They actually had no idea how DNA could possibly act as a mechanism for genetic inheritance. Let’s step back and remind ourselves of what this molecule has to accomplish. It needs to do two things. First, it needs to have some way of providing a code that can store information about proteins.

The linear structure of DNA, with variable bases along the chain was consistent with the idea that could provide such a code. Proteins also are linear chains. So, you can imagine that there could be some sort of mapping of the pattern of one molecule in the pattern of the other. It wasn’t clear what this mapping could be, but they thought they could figure that out. I will talk about that code in another article.

Second, the molecule had to be able to replicate. If we are going to transmit genetic information, from one generation to the next, it won’t work unless we make duplicate copies of the code, so we can handle one copy of the blueprint to the offspring. The real problem was that it wasn’t clear how DNA could be replicated. The linear structure of DNA offer some hope for a code, but it didn’t offer a clue about how replication might occur.

This is where the race, literally a race, for discovering the three-dimensional structure of DNA began. Scientists were convinced they needed to know the three dimensional structure of DNA to understand replication. It was this impetus that led to the discovery of the now famous DNA double-helix, by Watson and Crick. This was arguably the most important finding in biology in the 20th century.

Why biologists should be interested in the three-dimensional structure of DNA? Biochemists had begun to understand, in the 1950’s, that the function of proteins could be understood by figuring out something about their structure. So, it was hoped that some aspect of the function of DNA, specifically how it was replicated, could be understood by deducing its structure.

What kind of evidence could you use to deduce the three-dimensional structure? The first kind of evidence came from a procedure known as x-ray crystallography. The positions of atoms in a crystal can be inferred from the pattern that they create when you shoot a beam of x-rays through that substance. The x-rays would bend around those atoms, and then, when you look at the pattern on the other side, you see lines and dots in particular orientations and spacing. From them, if you’re familiar with the procedure and very clever, you’ll able to deduce something about the relative positions and orientations of the atoms that make up that structure.

If you shoot an x-ray through a relatively simple crystal, you’ll get a very regular pattern. If you shoot an x-ray through a more complex material, like an organic molecule, you’ll get a much more complex pattern. It is pretty difficult to pull information form that pattern, and infer something about the way the molecule must be structured.

You may be asking, what are we talking about here, crystals or organic molecules? Well, even the most complex organic molecules, in the hands of a good biochemist, can be crystallized. In fact, that’s where the story starts. Maurice Wilkins, a biochemist working at King’s College in London, was able to produce a remarkably pure crystal of DNA. Working with Wilkins was a woman named Rosalind Franklin. She was an expert x-ray crystallographer. She took Wilkins’ purified DNA crystal and was able to get what was to that point the most clear and accurate x-ray crystallograph of DNA that had yet been obtained.

As I said, these patterns are quite hard to interpret. Nowadays we can use computers and algorithms to deduce the structure of proteins from this kind of data, but back then was pretty much painstaking hand calculation and educated guesswork. As it turns out, Wilkins and Franklin puzzled over their x-ray crystallograph trying to deduce something about the structure of DNA. They didn’t quite figure it out. By the time, another person arrived on the scene, James Watson.

Before I introduce Watson, I want to introduce another kind of clue. There was a scientist working at Columbia University named Erwin Chargaff, who discovered a peculiar thing about DNA. He found that if you took the DNA from any organism, and decomposed it into its component nucleotides, you always found a quite interesting relationship. You always found that the amount of the base adenine (A), always equals the amount of thymine (T). Similarly, the amount of guanine (G), always equals the amount of cytosine (C). So, if you take apart the DNA of any organism, you always will find that the amount of A equals the amount T, and the amount of G equals the amount of C.

This was a very curious relationship that became known as Chargaff’s rule. Next time we’re going to talk about James Watson and his codiscovery of the double-helix with Francis Crick.

The Building Blocks of DNA: What Is DNA Made Of?

The building blocks of nucleic acids are called nucleotides. There are only four types of nucleotides. This is one of the reasons why nucleic acids seem relatively simple compared to proteins. Each nucleotide has a sugar that forms a ring. Bonded to one part of this sugar is something called a phosphate group. This phosphate group is just a phosphorus atom with a bunch of oxygen around it. Bonded to another part of the sugar is a nitrogenous base. It is the nitrogenous base that differs from nucleotide to nucleotide. There are four different kinds of nitrogenous bases.

Organic chemists like to number carbons. They actually love carbons because organic chemistry is all about carbons, so they don’t even write them down when they are drawing structures of molecules. If there is a line between two elements, you must assume that there is a carbon there. Instead of writing them, they number the carbons in the sugar around the ring counter-clockwise from one to six. Like this:

There are four kinds of nitrogenous bases. These can be classed into two different groups which differ in size. The pyrimidines have a single six-element ring that’s made of carbons and nitrogens. There are two kinds of pyrimidines, we call them cytosine and thymine. The details aren’t important but these are two kinds of pyrimidines. Here we have drawings of them in order: cytosine and thymine.

The purines, the second kind of nitrogenous bases, are bigger. They are composed of two rings. In addition to the six-element ring that the pyrimidines are made of there is an additional five-element ring that is attached on the side. There are two kinds of purines: adenine and guanine.

We usually refer to the different nucleotides that we find in nucleic acids by the single letter which designates the type of base that it has. We have:

A: adenine.
G: guanine.
C: cytosine.
T: thymine.

Next time we’ll begin to see how this relatively simple polymer, with phosphates and sugars, could serve as a code.

A History Of DNA, Part III: The Code is in DNA

In my last post we saw how Avery and his colleagues demonstrated (but not conclusively to the scientific community) that the molecule which holds the genetic material in living things is DNA. Now I want to look at a very interesting experiment that really changed the minds of biologist in the matter. In the early 1950’s, Hershey and Chase took a novel approach in trying to found out what the genetic material might be made of, by looking at how a particular kind of virus worked.

Let me give you some background. Viruses are not true cells. They are made of an outer coat of protein with an inner core of nucleic acid. Viruses are made of just two things. The way a virus makes its living is by attaching to a cell, say a bacteria cell, injecting something into that cell and taking over the machinery of the cell. Here is a great introduction to viruses by Salman Khan(Sal), I really recomend you to watch it to understand viruses better.



Hershey and Chase were working with a particular kind of virus, called the T2 phage. This is a bacteria-eating virus, which makes its living by taking over a bacteria and using the protein-synthesizing machinery of the bacteria to make more viruses. Viruses can’t replicate themselves, they have to take over another cell. Clearly, then, what a virus must be doing, is injecting some information. It’s the information that would cause the cell to be taken over. What Hershey and Chase set out to do was to ask, what is it that these T2 viruses are actually putting inside the bacteria? There were only two candidates, proteins and nucleic acids.

The trick was to figure out how to determine which part was being injected. It is a very simple experiment to propose conceptually, but like many experiments in science, the devil is in the details. Hershey and Chase developed a very clever way to figure that out. They did this by radioactively labeling the proteins and the DNA that the virus was made of. In proteins, sulfur is a fairly common element. There is a radioactive form of sulfur (S-35). So, they could grow some T2 viruses in a medium that had a lot of this radioactive sulfur in it. What would happen is that as the viruses reproduce, they would incorporate sulfur into their protein codes. That meant that you could ask not where did the protein go, but where did the radioactivity go.

Alternatively, they could label the DNA. They could grow the same kind of virus in a medium that had radioactive phosphorus (P-32). Phosphorus is not found in proteins, but it is a major chemical constituent of DNA.

So, they grew viruses in a medium that either had radioactive sulfur or radioactive phosphorus. This resulted in some viruses having their proteins radioactively labeled, and others their DNA radioactively labeled.

In separate experiments, they added either the radioactively labeled sulfur viruses (with the radioactive protein), or the radioactively labeled phosphorus viruses (with the radioactively labeled DNA). In both cases they would give these viruses just a couple of minutes. Enough time for them to attach to bacteria and inject whatever they are injecting. Then they would stop the whole process. They were given enough time to inject but not enough time to take over the cell and cause it to build more viruses.

They gave the viruses just 20 minutes, and then they would put the solution in a blender. Then they put this solution in a centrifuge, which spins it around. Because of the action of the centrifuge, the heavier stuff would go down to the bottom of the tube. This would be the relatively large bacterial cell bodies. The lighter stuff, which would be the outer coats of the tiny viruses, would remain up in the solution. If you centrifuge them just right, you’ll get a little lump of stuff at the bottom of the tube, that’s going to be all the bacteria. Then you’ll have the rest of the fluid in the tube, which would include the viral coats.

They then would ask, where is the radioactivity? Is the radioactivity at the bottom, or at the rest of the fluid? What they found was that if they radioactively labeled the sulfur, marking the proteins, the radioactivity was found in the fluid, where the viral coats were. If you radioactively labeled the DNA with phosphorus, the radioactivity was found at the bottom, where the bacteria were. This was a very simple result but took the world by storm, because it showed incontrovertibly that what these viruses were injecting in the bacteria (and happened to be the genetic material), was DNA.

Hershey and Chase published these results in 1952, and it really caused a lot of interest. Biologists began to take a closer look at nucleic acids. That is what I want to do in my next post, look at the structure of DNA.

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.

A History Of DNA, Part I: Before the Discovery

Proteins are the biological molecules that make things work in living systems. We could say that they are involved in every process in the cell. They are controllers of biochemical reactions, structural elements that hold parts of the cell together, motors that make things move, signals, and so forth. The function of a protein depends almost entirely on its shape. Its three dimensional shape determines its physical and chemical properties, which in turn allow the protein to serve its unique function. The three dimensional shape of a protein, in turn, depends almost entirely on the linear sequence of the building blocks of life, the amino-acids.

There are 20 kinds of amino-acids. An average protein might have a few hundred amino-acids. So, proteins are the work horses, and their function is determined by its chemical sequence of amino-acids. Now, how do we get a protein of a particular sequence built? To answer this question we need to address two things. First, what is the blueprint that is used to build proteins? Second, how does that molecule actually work?

It is the first question that I want to talk about today. Before we can understand how the code works, we need to understand what the code is made of. I think that we all know the answer today: DNA. Interestingly, though, that was one of the questions that defined molecular biology in the 20th century.

At the very beginning of the 20th century, it was already known to scientist that the code was in genes, which in turn resided in chromosomes. This was known from the work of early cell biologists, Walter Sutton and Theodor Boveri being the most important, who discovered that the particular movement of chromosomes that occurs when cells divide corresponded to patterns of transmission of traits between parents and their offspring. These patters of trait transmission had actually been discovered earlier by the Austrian monk Gregor Mendel.

Cell biologists knew about Mendel’s work, how chromosomes moved, and they developed what now is called the chromosomal theory of inheritance. This theory basically says that the way chromosomes move is somehow related to the way that inheritance occurs, therefore, chromosomes are related to information in cells.

We today know that chromosomes are made of DNA, but how that became a known fact? We must begin by going back to the earlier part of the 20th century, to the work of an English physician named Frederick Griffith. This experiment that I am about to describe really provided the first insight into the chemical nature of genetic information.

Griffith’s Experiment

Griffith was a physician and he wasn’t interested in the molecular basis of inheritance. Instead, he was working on a much more applied problem. He was studying Streptococcus pneumoniae, which is a bacteria that causes pneumonia in humans. What Griffith wanted to do was to develop a vaccine against this particular organism, because the pneumonia caused by it often proved fatal. This was before the advent of antibiotics, of course.

As often it is the case for disease-causing bacteria, there were different strains that varied in their virulence. They varied in how likely they were to induce the disease and cause death. Griffith was working with two strains of Streptococcus pneumoniae. He was working with what we call the S strain on the one hand. This was a very virulent strain. It is called S because if you grow it in a colony, it actually looks kind of shiny and smooth. He had another strain, which he called the R strain, which was non-virulent. If you got the R strain, you might be a little sick but you wouldn’t die. It is called the R strain because the bacteria look kind of rough on the surface.

The important thing to note is that these strains did breed true. In other words, as they reproduced, their offspring had the same properties. S strain bacteria gave rise to more S strain bacteria and so on. It is inferred from that, that the difference between the S strain and the R strain bacteria somehow must be genetically encoded.

What did Griffith do? Griffith was using the approach pioneered by Louis Pasteur, which was to take the organism that you want to develop a vaccine for and kill it. This organism could no longer harm you, but nonetheless, would perhaps induce some sort of immune response if injected in a subject. The idea was to take S strain bacteria, kill them by heating them up, and then take these dead S strain bacteria and inject them into a laboratory mouse, and see if that mouse develops immunity. The mouse wouldn’t die if you injected dead S strain bacteria, but the parts of the bacteria that are injected might nonetheless induce an immune response.

This is a great idea, but it didn’t work. It often doesn’t work. There wasn’t enough left of these dead S strain bacteria to induce an immune response. If you injected these in a mouse, and then injected live S strain bacteria, the mouse would die.

Another common technique that was used then and now to develop vaccines was to eject not only the dead offending organism, but some related organism that was less virulent. In this case, we are talking about the R strain bacteria. The idea is that the live R strain bacteria, because they are alive, would induce the organism to develop a full immune response. That development of a full immune response would somehow pickup some immunity to the dead S strain bacteria. This is a common technique and it often works.

What Griffith did then? He killed some S strain bacteria and injected them in with living R strain bacteria. What he hoped would happen is that the mouse would develop immunity to the S strain, but what happened instead was unexpected, and unfortunate for the mouse, the mouse died. This is a surprising result. What’s being injected into the mouse are dead S strain bacteria, that wouldn’t kill the mouse; and live R strain bacteria, that wouldn’t kill the mouse neither. Nothing was injected in the mouse that should kill it, and yet the mouse died.

What Griffith found out when he dissected the poor dead mouse was that inside it were living S strain bacteria. He injected dead S strain, and when he took the mouse apart, he found living S strain. What Griffith concluded from this work, and correctly, was that somehow the living R strain bacteria had taken up something from the dead S strain bacteria, and incorporated it into them. That somehow transformed the R strain into the S strain.

Griffith later showed that he didn’t need the mouse. You can do this in a beaker. If you put dead S strain and live R strain bacteria in a beaker, some of the live R strain would become transformed into live S strain.

What’s really interesting from this experiment, in my opinion, is that the material that they incorporated must somehow be genetic material. It must somehow have information in it. How else could the R strain bacteria now become virulent like an S strain bacteria? The difference between S and R had to have something to do with genetically transmitted information. What Griffith did was he left it there. It was only 1929 when he was doing this work. He said that he had discovered what he called the transforming principle.

Our interest in this, and of scientist interested in genetics, is that somehow this transforming stuff must involve genetic material. In my next post we will see how this experiment helped in discovering that DNA is the molecule that holds genetic material in living things.

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.

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