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DNA as the "transforming principle"

How Griffith and later Avery, McCarty and MacLeod found strong evidence that DNA is the "transforming principle" that encodes genetic information.

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Video transcript

- [Voiceover] So to review how we got at least to this video, in 1865, Mendel first shares his laws of inheritance. He observes that there are these heritable factors, these discrete heritable factors that would be passed down from parent to offspring according to certain rules. And he came up with the laws of inheritance, law of segregation, law of independent assortment, law of dominance. But as we've said multiple times, that work at the time that it was for shared wasn't taken that seriously. In fact, a lot of people didn't pay attention to it and it wasn't until the early 1900s that it was rediscovered. But even when it was first rediscovered around 1900, people did not know what the molecular basis for these heritable factors that Mendel talked about, what the basis of these factors were. And in 1902, we have the first really solid theory for what the molecular basis for those inheritable factors actually could be. This is when Boveri and Sutton come up and they independently did their work, but they both came to the same theory at around the same time. They came up with the chromosome theory, now called the Boveri-Sutton chromosome theory. Their work was based on observing how cells divide, especially meiosis, and in seeing how these chromosomes seem to pair up then segregate then independently assort and get passed on to their offspring. And they said hey, these chromosomes, on a physical level, on a molecular level, seem to be behaving in ways that are very similar to the heritable factors that Mendel talked about. So it was a very strong theory. And then we get to 1911 where that theory gets some more evidence put behind it. Thomas Hunt Morgan, we talked about it, he used his fruit flies to see how that mutant trait that would pass on from one generation to another and the only plausible explanation that he could come up with is that it was being passed on, on the X sex chromosome. And him and his team continued to do more and more work to establish that chromosomes indeed seem to be the basis, the physical location for these heritable factors that Mendel first talked about in 1865. But even Morgan and his team, when they looked at chromosomes, a lot of times now when we think of chromosomes we think of chromosomes as being made up of DNA, and that is true; but chromosomes are also made up of other things, including proteins. And in the early days, when people said hey, it looks like chromosomes are really the basis or the location for these heritable factors, for these genes. When people look at these two different molecules, they said hey, it's probably the proteins that are actually responsible for encoding the information of inheritance. Proteins, people knew, were these complex molecules that in some ways you could say encoded information. Well, at the time, they thought that DNA were these kind of boring molecules that surely this couldn't encode information. And so the first evidence, strong evidence, that DNA is actually where the genetic information is encoded doesn't happen for several more decades. And we start along that path with Griffith right over here, famous for Griffith's experiment, where he does something really interesting. And he by himself, his experiments in 1920 or that he publishes in 1920 or he actually he conducts and publishes in 1928, they aren't responsible in and of themselves for establishing DNA to be the molecule that's actually the basis of inheritance, but they start an interesting path of inquiry where these gentlemen in 1944 are finally able to establish that DNA is where these heritable factors are actually encoded. So what was Griffith's experiment? Well, he was studying strains of bacteria, and he saw that the same, the two variants on a certain strain or two variants of bacteria, you had the rough strain and the smooth strain, if he injected the rough strain into a mouse, the mouse lived. If he injected the smooth strain into a mouse, the mouse died. And it was because the smooth strain had this protective coating on it that made it harder to attack by the mouses immune system. So that by itself, well, that's interesting, this is the virulent strain, this is the one that's actually going to kill the mice. Now if he took this smooth strain, the virulent strain and he heated up so those bacteria were killed and then he injected those, so this is the heat-killed smooth strain, if he injected those into the mouse, the mouse still lived because those bacteria were dead. But then he did something very, very, very interesting. He took this, the heat-killed smooth strain, he took some of that and he took some of the live rough strain put together. Now common sense would tell you is like okay, this blue stuff, that's not going to kill the mouse, and this killed smooth strain, that's not going to kill the mouse either. So if mix it up, that shouldn't kill the mouse, but it did kill the mouse, which was fascinating. And so he came up with this theory of a transformation principle. Even though he killed the smooth strain here, there must've been some type of materials, some type of molecule that still got transferred from the dead bacteria to the live bacteria and essentially transformed the live bacteria into the smooth strain, allowing them to kill the mouse. And so he came up with this idea of some kind of transformation principle. And so you can imagine, and look, it took some time, over 10 years, now almost two decades, Avery, McCarty and McLeod said hey, what is this transformation principle? Why don't we use Griffith's experiment and let's keep, instead of just taking you know the whole heat-killed smooth strain, let's try to break it up into its components and let's try to isolate the different components and keep doing the experiment until we have an isolated molecule or an isolated component that seems to do the trick. So they were trying to isolate the transformation principle. And they did just as what I described. They took the heat-killed smooth strain, they would try to separate the different constituents out. You can separate them out physically, you could use certain washes that would wash away certain components. You could use enzymes that would destroy certain components. And eventually, and this is very meticulous work, so you can imagine they take the stuff, the whole dead heat-killed smooth strain and they start to separated it out into its various components. So that might be one component right over there, this is another, let me do it in these different colors, this is another component right over there, this is another component right over there. They're using different chemical techniques to separate all of the constituents that were in that original heat-killed smooth strain. And then instead of running this last phase of the experiment with the entire heat killed smooth strain, they do it with the rough strain mixed with each of these components separately. And then they kept running the experiment and they would say, hey, look, when we have this component right over here and we tried to run the experiment, the mouse still lives. The mouse still lives. So this one did not transform the rough strain. And maybe this one also did not transform the rough strain. But then eventually, they were able to isolate something that did transform the rough strain. So the mouse dies, and so it did transform the rough strain into the smooth strain. And so they took this material and they start applying all sorts of test to it. They could look at the molecular components of it. And when they looked at the ratios of nitrogen and phosphorus, they said hey, this seems to have ratios that are consistent with DNA, which is a molecule they already knew about. And it was not ratios that would've been consistent with proteins. They ran chemical tests and said hey, it doesn't look like there's a lot of protein in this thing that we isolated, or even RNA, which is another molecule that they new. Enzymes that would've degraded proteins or RNA did not degrade this stuff, but the enzyme that degraded DNA did degrade this stuff. And so they were able to come up with the idea that DNA was the transformation principle. And this is a really, really, really big deal. Think about this quest that we've been going through for the better part of a hundred years. Inheritable factors, well, where are they located? Hey, it looks like they're on the chromosomes. We start having evidence that they're on the chromosomes. But chromosomes are made up of DNA and proteins, and it wasn't until the start with Griffith's experiments and then Avery, McCarty and McLeod come along and said hey, let's identify what was it exactly about the heat-killed smooth strain What's the component in it that actually transformed the other strain? And it was DNA. And what was fascinating is when you mixed that DNA from the heat-killed smooth strain with the rough strain, that DNA was able to mix in with the DNA of the rough strain and allows it to start producing these smooth protein coats that allowed it to be more virulent. So the mouse's immune system couldn't attack it as well. So it's really fascinating on a lot of levels. You know, the whole takeaway from this one is how did we get to DNA being the important part of the chromosomes, at least in terms of encoding the actual genetic information, but it's also a cool way to think about just almost how magical DNA is, that if you mix it in, if you mix it in the DNA of one strain with a live version of another strain, you actually might be able to transform that strain. In some ways, they were doing very, very basic genetic engineering here.