The discovery of the double helix structure of DNA

In 1865, Mendel, often considered the father of modern genetics, comes up with a structured way of thinking about these inheritable factors, which we now call genes. Then, as we go into the early 1900s, his work was rediscovered, and people started to say, "Okay, we see how some of these traits get passed on in these somewhat predictable ways. We can put some structure around it." But what is the actual biological mechanism for that? How are these traits encoded at a cellular or at a molecular level?

In 1902, and we talked about this in a previous video, Boveri and Sutton come up with the chromosome theory based on seeing how chromosomes separate and pair during cell division. They said, "Hey, those seem to map up quite well to what Mendel described by these heritable factors." Then we start having a lot more evidence for this. Morgan is able to show that this mutant eye color trait seems to be passed on in a way that shows that it is on the X sex chromosome. He and his team start doing a lot more work, especially with fruit flies, to show that, "Hey, chromosomes are the basis for where these heritable factors are."

But then, even within the chromosomes, people weren't sure if chromosomes were made up of proteins or made up of DNA. What was the molecule or the set of molecules that actually encoded for these heritable traits? At first, most of the weight was on the protein side, because proteins were these complex molecules that had all of this variety that seemed like it could code for these heritable traits. While DNA, at least early on, seemed like a kind of boring molecule, people assumed that there wasn't a lot of diversity in DNA. They assumed that even if you go from one species to another, the DNA molecule was fundamentally the same.

So early on, people actually were more on the side of the proteins. But then, more and more evidence came the way of the DNA side. You had Griffith's experiment, where he was able to show, "Hey, I could take this heat-killed bacteria, but if I mix it with some other living bacteria, somehow there's some transformation principle that transforms the living bacteria into the type of species that I had in the heat-killed." Then you go to 1944, and Avery, MacCarthy, and MacLeod are able to show some pretty good evidence that the actual principle, that the thing that was left in that heat-killed bacteria, was probably DNA.

We get even more conclusive evidence with the experiments of Hershey and Chase, and we have a whole video on this, where they say, "Hey, what is it that viruses inject into bacteria to hijack their genetic system?" They say, "Hey, it's not proteins; it is DNA that does this." So they provide much more conclusive evidence on the side of DNA. But even at that point, we as a community, as a civilization, still didn't know what the actual structure of DNA was. We also did not know how that structure actually coded for all of these heritable factors.

The work culminates with Watson and Crick, but it was dependent on all of the people I mentioned and more. One person who should get special credit for providing a little bit more evidence on the side of DNA and helping Watson and Crick actually—there are several people, but in particular Chargaff and Rosalind Franklin—who probably does not get as much credit as she deserves. Chargaff's the one that showed that, "Hey, DNA actually is more interesting than people appreciated." He noticed that the frequencies of the nitrogenous bases of adenine, guanine, cytosine, and thymine in DNA vary across species. If something is somehow coding for what makes a species a species, well, it would have to vary across species, so that makes DNA interesting.

The other thing that he noticed—this was key for Watson and Crick's work—is that the frequency of guanine is equal to the frequency of cytosine in DNA, and the frequency of adenine is equal to the frequency of thymine in DNA. So it's a clue that these somehow are associated with each other; they somehow pair with each other.

We get to the early 50s with all this evidence that DNA is the molecular basis. You have Chargaff with his rules called Chargaff's rules, and then you have Rosalind Franklin, and she's doing imaging X-ray diffraction patterns from X-rays beamed into crystals of DNA. What I mean by a crystal of DNA is that a crystal is taking a bunch of molecules in a ring and arranging them in a regular pattern.

So a crystal of DNA means having one DNA molecule, then another DNA molecule, and then another DNA molecule, and then you beam X-rays. X-rays are key because their wavelength is small enough to capture features at an atomic level. You beam X-rays, and then the X-rays diffract, and you capture the pattern of that diffraction. Depending on the structures in the actual molecules, you'll have different diffraction patterns. Franklin's famous diffraction pattern is shown right over here, and when she immediately saw this, they had some of the telltale cues for a helical structure.

Now, I wouldn't read too much into this if you're not an expert reader of X-ray diffraction patterns; this isn't a direct image of a DNA molecule. However, they already knew— in fact, people in this community already knew—that this X pattern was a telltale sign for a helical structure of some kind. They were also able to look at the different clues to think about what's the spacing between different molecules and even the spacing between the different turns of the helix structure.

Once again, this diffraction pattern is not a direct image, and it takes a lot of well-developed expertise to backwards map how things would diffract into the thing that actually caused the diffraction. They would take measurements from multiple different angles to get a better understanding of it. Actually, today, you have computers doing this, taking a diffraction pattern and constructing what the electron clouds of the actual molecule look like.

This was painstaking work, and she already had a sense that it was probably a helical structure, but she was waiting to get a little more evidence before she published her work. Now, at the same time, you have Watson and Crick who were trying to solve the structure. They got hold of Franklin's work with the help of Maurice Wilkins, who Franklin worked with. They were able to establish that it wasn't a single helix but a double helix.

You actually had these base pairs forming the rungs of the double helix, and that was really interesting because that showed how DNA could replicate itself, how it could contain actual information. We go into much more depth in future videos.

Now, the sad part about this story is that Wilkins, Watson, and Crick won a Nobel Prize. Franklin, unfortunately, died very young, and you’re not allowed to receive a Nobel Prize if you’ve passed away. So she’s very deserving of it. This work, which many people consider to be one of the biggest discoveries in science, was based on what she did. Arguably, had Watson and Crick not had access to her work, they would not have been able to figure it out. And if she just stuck to what she was doing, without other people having access to her work, she might have been able to get to that same conclusion.

So she is one of the people who sometimes the history of science overlooks. But this isn't to not give credit to Watson and Crick either. There were still a lot of very powerful intuitive leaps that they had to make to come up with this double helix structure—this anti-parallel double helix structure where they go in opposite directions but bridge with these nitrogenous bases pairing with each other.

This is a big, big, big deal. Throughout most of human history, we knew that traits were passed on, but traits seemed like this magical, mystical thing. How do I encode my, you know, I know my laugh is like my dad's, but how is that actually encoded in my DNA? Now we’re able to see that a lot of what we consider about ourselves to be us is encoded in these molecules and encoded in these base pairs.

So it’s beautiful, it’s incredible, it’s shedding light on one of the biggest mysteries of what makes humans—actually, all life—life.