In our last article, we left off with the race to understand the molecular basis of heredity. Protein molecules were thought to be complex enough to encode genetic information, but no one could quite figure out how that information could be copied and passed on from cell to cell. DNA was a big enough molecule, but, seemingly, too simple to hold the information. Clearly, there was still a lot to learn about DNA. Most of what people knew about DNA was that it was a nuisance when you were trying to study cells. Depending on what you are studying, one of the things cell biologists do a lot is grind up cells to study what is inside them. Basically, you take a big chunk of tissue, put it in a big test tube-looking thing called, oddly enough, a tissue grinder, and mash it all up until you rupture all the cells and release the contents so you can study them. One annoying thing that always happens when you homogenize cells is that this big wad of sticky, snot-like mess floats to the top of your cell preparation and gums everything up. You have to go to a lot of trouble to get rid of it before you can do anything else. That big wad, as it turns out, is DNA. Like I said, there is a LOT of DNA in a cell.
Anyway, people started to wonder what all that DNA was doing in the cells. One of the most wonderful things about Biology is how efficient it is. Very seldom does anything exist or happen in Biology without a good reason, because making things is energetically expensive, and nature is conservative. Organisms generally don’t waste energy making things they don’t need. All cells make a ton of DNA, so there must be a reason, and people started looking into it. One of the first things they discovered was what it was made of. Like we went over last week, DNA is made of a sugar (deoxyribose), some phosphate, and some nitrogen-containing parts, called nucleotides, adenine (A), thymine (T), cytosine (C) and guanine (G). They also discovered that the amount of A in a particular DNA molecule always equaled the amount of T and the amount of C always equaled the amount of G. That was an incredibly important piece of information. Think on why that might be before we get to the end of the story and see if you’re right. The next step in the study of DNA was to figure out the shape of the molecule. Doing the experimental work to do that was not, and still is not, an easy task. You can’t just look at a molecule under a microscope, because even really big ones, like DNA, are still much too small to see at a structural level under a microscope. To study the shape of big molecules like proteins and DNA, we turn to physics and a process called x-ray diffraction. Everyone is familiar with x-rays, in respect to how they are used in medicine and dentistry to look at things inside other things. This is actually a really good topic for another article, but for now, let’s say that in x-ray diffraction, x-rays work a lot like light casting a shadow—you focus x-rays on a structure, like a molecule, and depending on the shape of the molecule, it will cast a “shadow” with a particular shape.
There are a relative few basic shapes found in molecules, particularly in the macromolecules (“macro” just means “big”) common in Biology. There are straight chains; there are spirals (helices [“helices” is the plural of “helix”]); folds, or “pleats”, like you see in curtains hanging in a window; globs with irregular shapes; and a few others. If you pass an x-ray beam through molecules of these various shapes, you will see a particular diffraction pattern associated with each one. For instance, if you subject a helical molecule to x-ray diffraction, the pattern you will see looks sort of like the wi-fi symbol on your phone, with the arcs fanning out. This would be a really good time to look up “DNA x-ray diffraction” on the internet. When people tried x-ray diffraction on DNA, however, what they got was TWO of those patterns, oriented in opposite directions, and nobody really knew what to make of that.
Rosalind Franklin
Now, there is an important side story here. In order to do x-ray diffraction, you first have to prepare a crystallized sample of the molecule you want to look at. It is INCREDIBLY tedious, difficult work to prepare a large enough, pure sample of a crystal to do diffraction studies. The group in England who were working on DNA included a woman named Rosalind Franklin who was among the first people to successfully crystalize DNA for diffraction studies. Two of the other people who were working on DNA were two young scientists by the name of Francis Crick and James Watson (an American). They were not doing a lot of the actual work like diffraction studies and chemical analysis, but they were trying to put all the pieces together. Watson and Crick found out about the diffraction study results, and they knew that the amount of A was always equal to T and C to G. They knew what A, T, C and G looked like. They knew that there was also the sugar and the phosphate in the DNA molecule. What they did next made them among the most famous scientists in history. They, without actually doing many of the long, tedious studies, uncovering small bits of the story, took everything that was known and put in together. It seems simple, even obvious, now, looking back, but it wasn’t at all obvious at the time. Watson and Crick made little cardboard cutout models of adenine, thymine, cytosine and guanine molecules and started trying to fit them together like pieces of a puzzle. Eventually, they discovered that the adenine molecules would fit perfectly with the thymine molecules and the cystosines fit with the guanines. That is why there is always the same amount of A as there is of T, and the same amount of C as G. A is always PAIRED with T and C is always paired with G in DNA molecules. If you take that information, and then you look at the weird diffraction pattern, that looks like what you would get from TWO helical-shaped molecules, it is possible to make the leap that DNA is a DOUBLE HELIX. A double helix is what you would get if you took a ladder and twisted it into a spiral. In a DNA molecule, the upright parts of the ladder are the “backbone” of the molecule, composed of the sugars and phosphates. The “rungs” of the ladder are pairs of nucleotides-either A paired with T or C paired with G. This all seems nice, but why was it such a big deal? The big deal was that it explained how the genetic information could be copied. If you take the double helix and split it down the middle, both halves would be perfect templates to make a copy. Everywhere there is an A, the other side has to be a T. Everywhere there is a G, the other side has to be a C. That is the secret to how genetic information is passed from one cell to the next and one generation to the next—you split the DNA, use each half as a template to make a new copy and then you have TWO perfect copies of the original molecule, one for each new cell. It is a magnificent, elegant process—one of the most amazing processes in all of science.
Juanyi Yu, Jr-Shin Li, Tzyh-Jong Tarn – Juanyi Yu et. al. & quot;Optimal Control of Gene Mutation in DNA Replication & quot; , Journal of Biomedicine and Biotechnology doi:10.1155/2012/743172
Watson and Crick published their findings in a short, two-page paper in the science journal Nature in 1953. They and the leader of the DNA research group in England, Maurice Wilkins, won the Nobel Prize for the discovery in 1962. The fact that Rosalind Franklin did not receive a share of the prize is often cited as an example of the sexism that permeated scientific research back in the day (and is still does, to a lesser extent). While the contributions of women were (and are) often underappreciated, in this case, bias wassn’t a factor. By the time the Nobel was awarded, Rosalind Franklin had died of cancer, and Nobel Prizes are not awarded posthumously.
One last little note: I was at the Salk Institute for Biological Studies in La Jolla, California (Google this place—it’s gorgeous!), participating in a joint research project some years ago. Francis Crick was a past president of the Salk Institute and still had a lab there at the time. One evening, as I was walking across the parking lot, I saw a nice Mercedes with the license plate AT-CG. I can say, in a brush with greatness, that I have placed my hand, with no slight reverence, on the trunk lid of Francis Crick’s car.