WEBVTT 00:00:00.000 --> 00:00:05.000 So, we're going to finish now by just talking more about this amazing 00:00:05.000 --> 00:00:11.000 immune system we have, the adaptive immune system. 00:00:11.000 --> 00:00:17.000 As I said on Friday, this is really an astonishing recognition system 00:00:17.000 --> 00:00:23.000 that just plays a key role in us being able to survive in this world 00:00:23.000 --> 00:00:29.000 that's full of bacteria, and yeast, and fungi, and viruses, 00:00:29.000 --> 00:00:34.000 parasites. There are things just all the time 00:00:34.000 --> 00:00:38.000 trying to do us in, and the reason we don't succumb is 00:00:38.000 --> 00:00:42.000 because we have this amazing immune system. And there are several 00:00:42.000 --> 00:00:47.000 features about it which I summarized the other day. 00:00:47.000 --> 00:00:51.000 One is its diversity. It has this incredible ability to 00:00:51.000 --> 00:00:55.000 recognize entities, including things that are 00:00:55.000 --> 00:01:00.000 synthesized in a lab that had never been seen on Earth before. 00:01:00.000 --> 00:01:05.000 It's amazing in terms of that side of it. Coupled with this is this 00:01:05.000 --> 00:01:10.000 incredible specificity. As I indicated the other day, 00:01:10.000 --> 00:01:16.000 for example, if it was seeing a benzene ring with a methyl on it, 00:01:16.000 --> 00:01:21.000 it might be able to recognize this, but it could tell the difference 00:01:21.000 --> 00:01:27.000 from having the methyl over here. It's got that level of 00:01:27.000 --> 00:01:31.000 sophistication. In spite of that, 00:01:31.000 --> 00:01:34.000 in spite of the fact that it can recognize everything else, 00:01:34.000 --> 00:01:37.000 it's able to avoid self recognition, 00:01:37.000 --> 00:01:46.000 which is a bit of a trick if you 00:01:46.000 --> 00:01:49.000 think about it, that you have a system that's able 00:01:49.000 --> 00:01:51.000 to see essentially anything, including things that never existed 00:01:51.000 --> 00:01:54.000 before. And how does it avoid seeing all of our molecules, 00:01:54.000 --> 00:01:57.000 and all the many, many things that makes us up? So, 00:01:57.000 --> 00:02:00.000 it has to be able to tell self from non-self. 00:02:00.000 --> 00:02:04.000 And then, I also talked about this memory aspects of the immune system, 00:02:04.000 --> 00:02:09.000 that if you get exposed to a virus or bacterium or something, 00:02:09.000 --> 00:02:14.000 but the first immune response is relatively weak. 00:02:14.000 --> 00:02:19.000 But then if you get subsequently exposed, you get a very powerful 00:02:19.000 --> 00:02:24.000 response. And that's the principle of a vaccine. If you think someone 00:02:24.000 --> 00:02:29.000 is going to be exposed to chickenpox but they haven't had it, 00:02:29.000 --> 00:02:34.000 if you could somehow elicit the initial response without making them 00:02:34.000 --> 00:02:39.000 sick by using a killed virus or something like that; 00:02:39.000 --> 00:02:42.000 polio is one of the examples you hear about in the paper right at the 00:02:42.000 --> 00:02:46.000 moment. Then, if someone does encounter that virus 00:02:46.000 --> 00:02:50.000 or that bacterium, because that's second response, 00:02:50.000 --> 00:02:54.000 it's very quick and it's very powerful, and that's what vaccines 00:02:54.000 --> 00:02:58.000 are all about. So, the issue, 00:02:58.000 --> 00:03:02.000 I guess, today is how does that happen? And this is one of these 00:03:02.000 --> 00:03:06.000 amazing insights into biology that's come by an application of all these 00:03:06.000 --> 00:03:10.000 tools, recombinant DNA, and sequencing, and all the fancy 00:03:10.000 --> 00:03:14.000 sort of things we've been talking about in the past few lectures. 00:03:14.000 --> 00:03:20.000 So, the first part I need to let you know, is there are two parts to this 00:03:20.000 --> 00:03:26.000 immune response, or two kinds of responses. 00:03:26.000 --> 00:03:40.000 One's called the humoral response 00:03:40.000 --> 00:03:46.000 and one's called the cellular response. And this takes place in 00:03:46.000 --> 00:03:52.000 the plasma of your blood. So, in the liquid part of the blood 00:03:52.000 --> 00:03:58.000 if you spin down the red cells and the white cells, 00:03:58.000 --> 00:04:04.000 what you're left with is the plasma. 00:04:04.000 --> 00:04:09.000 And, what this humoral response response does, 00:04:09.000 --> 00:04:14.000 it's able to target bacteria, viruses, proteins. 00:04:14.000 --> 00:04:30.000 And the recognition is done by a 00:04:30.000 --> 00:04:37.000 special kind of protein called antibodies. And I'll tell you about 00:04:37.000 --> 00:04:45.000 that in just a moment because they're a very important class of 00:04:45.000 --> 00:04:52.000 protein in this Earth. And the cellular immune response is 00:04:52.000 --> 00:05:00.000 carried out by a special kind of white blood cell. 00:05:00.000 --> 00:05:15.000 For this lecture I think I'll just 00:05:15.000 --> 00:05:21.000 abbreviate those as WBC if I need it. What this targets is not the actual 00:05:21.000 --> 00:05:26.000 pathogen itself. But it targets cells that are 00:05:26.000 --> 00:05:32.000 infected with a virus or a bacterium, etc. and that might seem to be even 00:05:32.000 --> 00:05:38.000 a little bit more of a trick. It's hard enough probably to figure 00:05:38.000 --> 00:05:43.000 out how to take something that's an entity like a virus that's floating 00:05:43.000 --> 00:05:49.000 around your blood and figure out how to find something that binds to it. 00:05:49.000 --> 00:05:54.000 What do you do if the thing's gone into one of your own cells and it's 00:05:54.000 --> 00:06:00.000 hiding out in their replicating in the same way that, 00:06:00.000 --> 00:06:06.000 let's say, a phage does or something like that 00:06:06.000 --> 00:06:13.000 How do you see one of your own cells that's been infected by something 00:06:13.000 --> 00:06:20.000 like that? And there is a special type of cells called cytotoxic T 00:06:20.000 --> 00:06:27.000 cell that's very important. It's often abbreviated as that. 00:06:27.000 --> 00:06:33.000 So let me first say a word about antibodies. These are proteins that 00:06:33.000 --> 00:06:40.000 consist of four polypeptide chains. Two of the chains are bigger. So 00:06:40.000 --> 00:06:47.000 they're called heavy chains. There's two of those. And there 00:06:47.000 --> 00:06:54.000 are two chains that are smaller, so those are usually called light 00:06:54.000 --> 00:07:01.000 chains. So, there's four of them altogether. 00:07:01.000 --> 00:07:05.000 And, ignoring secondary structure and stuff for the moment, 00:07:05.000 --> 00:07:09.000 let me just sort of give you an idea of how these are laid out. 00:07:09.000 --> 00:07:23.000 These are the two heavy chains. 00:07:23.000 --> 00:07:28.000 And these are joined together by disulfide bridges. 00:07:28.000 --> 00:07:34.000 You remember disulfide bridges? If you had two cystines they can 00:07:34.000 --> 00:07:39.000 form a covalent bond between them under oxidizing conditions. 00:07:39.000 --> 00:07:45.000 So, those heavy chains are locked together. They're actually 00:07:45.000 --> 00:07:50.000 physically covalently joined. In fact, there's the light chains 00:07:50.000 --> 00:07:56.000 here. So, this is the light. And this part up here is highly 00:07:56.000 --> 00:08:02.000 variable between different antibodies. 00:08:02.000 --> 00:08:07.000 And the part down here is constant between antibodies. 00:08:07.000 --> 00:08:13.000 And it's this huge amount of variability that the body produces 00:08:13.000 --> 00:08:19.000 many, many, many types of antibodies, and then figures out which ones will 00:08:19.000 --> 00:08:25.000 work to find the particular entity it's trying to recognize. 00:08:25.000 --> 00:08:31.000 And I'll come back and tell you in a moment how that is done. 00:08:31.000 --> 00:08:36.000 There is a diagram of what I showed you, but of course these are 00:08:36.000 --> 00:08:41.000 proteins. They have three-dimensional structures, 00:08:41.000 --> 00:08:46.000 and so if you were to look at them with the secondary structure showing, 00:08:46.000 --> 00:08:51.000 you can see the different, especially here, a lot of beta 00:08:51.000 --> 00:08:57.000 sheets should be leaping out at you. 00:08:57.000 --> 00:09:01.000 Now, the part where the recognition is done is up at this end. 00:09:01.000 --> 00:09:05.000 So, it's essentially right here. And here's a little movie. You 00:09:05.000 --> 00:09:10.000 could see how the thing looks in three dimensional space. 00:09:10.000 --> 00:09:14.000 You see the part that's over on the left at the moment; that's the light 00:09:14.000 --> 00:09:19.000 chain and the blue chain is that part of the heavy chain complex with 00:09:19.000 --> 00:09:23.000 the light chain. And here is the, 00:09:23.000 --> 00:09:27.000 it's been tilted up this way so this is the yellow and blue part 00:09:27.000 --> 00:09:32.000 you were looking at And the recognition pocket is right 00:09:32.000 --> 00:09:36.000 at the end of that. And at this picture, 00:09:36.000 --> 00:09:40.000 it's showing how a particular protein was shown in red. 00:09:40.000 --> 00:09:44.000 This is an anti-body that can very, very precisely recognize that 00:09:44.000 --> 00:09:48.000 particular protein. You can't really tell it from the 00:09:48.000 --> 00:09:52.000 three-dimensional shape shown on the left because it just shows the 00:09:52.000 --> 00:09:56.000 secondary structure. But, if you could see the full 00:09:56.000 --> 00:10:00.000 space filling model, you'd be amazed. The surfaces are 00:10:00.000 --> 00:10:05.000 absolutely complementary. It goes back to one of those 00:10:05.000 --> 00:10:11.000 principles I've said over and over and over again that so much of 00:10:11.000 --> 00:10:16.000 biology works by having complementary surfaces. 00:10:16.000 --> 00:10:22.000 And there's a little movie you could see how this thing is setting 00:10:22.000 --> 00:10:27.000 up there at the top. So, these antibodies are produced 00:10:27.000 --> 00:10:33.000 by a special type of what are called B cells. 00:10:33.000 --> 00:10:46.000 These are cells that play roles in the humoral part of the immune 00:10:46.000 --> 00:10:59.000 system. And they're called plasma cells. And each plasma cell makes 00:10:59.000 --> 00:11:08.000 one particular antibody. And that's it. 00:11:08.000 --> 00:11:12.000 So you have many different types of plasma cells, but each one only 00:11:12.000 --> 00:11:17.000 expresses one particular gene that encodes one particular antibody. 00:11:17.000 --> 00:11:21.000 So, for years, this is something that people struggled with just 00:11:21.000 --> 00:11:25.000 conceptually. They could sort of calculate that there were so many 00:11:25.000 --> 00:11:30.000 antibodies that if your entire genome was nothing but antibody 00:11:30.000 --> 00:11:34.000 genes, we still wouldn't have enough DNA to account for all this ability 00:11:34.000 --> 00:11:39.000 to recognize things. So, some other principle had to be 00:11:39.000 --> 00:11:44.000 involved. And there are all sorts of speculations about what it was. 00:11:44.000 --> 00:11:49.000 I had shown you, I'd managed to not get Bob Horvitz's thing on here, 00:11:49.000 --> 00:11:54.000 but this then, who is our fourth Nobel laureate, 00:11:54.000 --> 00:12:00.000 I've been sort of working through these. 00:12:00.000 --> 00:12:05.000 Susumu Tonegawa, who is in the cancer center, 00:12:05.000 --> 00:12:10.000 he's in the biology department. He's also heading, now, this 00:12:10.000 --> 00:12:15.000 Picower Center of learning and memory. So, since doing this work 00:12:15.000 --> 00:12:20.000 I'm telling you about on the immune system, he's gone to do some 00:12:20.000 --> 00:12:25.000 wonderful stuff more on the big problem of how we learn, 00:12:25.000 --> 00:12:30.000 and trying to get more molecular insights into that process. 00:12:30.000 --> 00:12:36.000 But what Susumu managed to figure out was that this variation and 00:12:36.000 --> 00:12:42.000 diversity in the immune system was, at its roots, a combinatorial sort 00:12:42.000 --> 00:12:48.000 of process. So, if you look in the DNA of a zygote, 00:12:48.000 --> 00:12:54.000 so that's the fertilized egg. We're just getting started with one of our 00:12:54.000 --> 00:13:00.000 cells. You've got a single cell. We're looking in the DNA to see 00:13:00.000 --> 00:13:06.000 what would happen. We come to the part of the DNA 00:13:06.000 --> 00:13:10.000 that's involved in producing antibodies. What he found was that 00:13:10.000 --> 00:13:15.000 if you looked along the DNA, there were sequences that looked 00:13:15.000 --> 00:13:19.000 like part of the stuff that you'd find in antibodies, 00:13:19.000 --> 00:13:24.000 but there were a whole series of them. So, he called this particular 00:13:24.000 --> 00:13:28.000 segment V1, V2, V3, up to VN. There were a whole 00:13:28.000 --> 00:13:33.000 set of these basically side by side by side by side. 00:13:33.000 --> 00:13:42.000 There are about 300 of these in humans. And then down the DNA a 00:13:42.000 --> 00:13:51.000 little bit he found another set of sequences that are all variations of 00:13:51.000 --> 00:14:01.000 each other. And these were given D1, D2, D3, D4, up to DN. 00:14:01.000 --> 00:14:07.000 And there are many of these. And then down the DNA a little 00:14:07.000 --> 00:14:13.000 farther, there were three other sections that were called joining 00:14:13.000 --> 00:14:20.000 segments. They were called J1, J2, J3. And a little bit farther 00:14:20.000 --> 00:14:26.000 down there was a block of DNA coding the constant part of this 00:14:26.000 --> 00:14:33.000 polypeptide chain that goes into an antibody. 00:14:33.000 --> 00:14:37.000 And what Susumu Tonegawa was able to show, and this led to the Nobel 00:14:37.000 --> 00:14:42.000 Prize. So, what happens during the development of these B cells is 00:14:42.000 --> 00:14:47.000 there are rearrangements. And a lot of DNA is thrown around. 00:14:47.000 --> 00:14:52.000 And the basic strategy is to take, if you think this as being column A, 00:14:52.000 --> 00:14:57.000 you take one from column A, one from column B, just picking them randomly, 00:14:57.000 --> 00:15:02.000 one from column C over here, and throw away everything else. 00:15:02.000 --> 00:15:11.000 So you might have, for example, in one B cell, 00:15:11.000 --> 00:15:21.000 you might have V32, D15, J2, and then the constant region. 00:15:21.000 --> 00:15:31.000 And, what's in between is an intron that will be spliced out at the time 00:15:31.000 --> 00:15:45.000 that the gene's expressed. In another B cell, you might 00:15:45.000 --> 00:15:58.000 have V11, D22, J3. So, this rearrangement is random in 00:15:58.000 --> 00:16:05.000 the sense of which V segment is chosen, which D segment is chosen, 00:16:05.000 --> 00:16:12.000 and which J segment. I don't mean that it all just joins together in a 00:16:12.000 --> 00:16:19.000 completely uncontrolled way. And then the rest of the DNA is 00:16:19.000 --> 00:16:34.000 deleted. 00:16:34.000 --> 00:16:47.000 So a consequence of this, is each B cell expresses only one 00:16:47.000 --> 00:17:00.000 antibody. It's true that they're diploid, but only one chromosome 00:17:00.000 --> 00:17:11.000 is expressed. So that's how they avoid, 00:17:11.000 --> 00:17:19.000 you can imagine they might make to two. But they only make one. 00:17:19.000 --> 00:17:27.000 In the process, as you can see, that part is random. Furthermore, 00:17:27.000 --> 00:17:36.000 the joining events are what I think you could call sloppy. 00:17:36.000 --> 00:17:42.000 And this leads to even more variation than you would have 00:17:42.000 --> 00:17:48.000 imagined simply looking at the number of segments. 00:17:48.000 --> 00:17:54.000 So, what this part of the process does is it explains why the system 00:17:54.000 --> 00:18:00.000 can be has the diversity it has, because it's using this 00:18:00.000 --> 00:18:04.000 combinatorial process. If you know the number you can 00:18:04.000 --> 00:18:08.000 calculate how many possible combinations there are. 00:18:08.000 --> 00:18:12.000 But then there's much more variation because when it joins 00:18:12.000 --> 00:18:16.000 together a little segments that are joined are done in a sloppy way so 00:18:16.000 --> 00:18:20.000 that the DNA sequence that shows up where the joints occur doesn't look 00:18:20.000 --> 00:18:24.000 like anything that was in the DNA at all. It was something like a 00:18:24.000 --> 00:18:28.000 polymerase that wasn't very faithful copying and making mistakes 00:18:28.000 --> 00:18:31.000 as it went along. So what the system does, 00:18:31.000 --> 00:18:35.000 is it doesn't get you a response. It just explains why there is so 00:18:35.000 --> 00:18:39.000 much diversity, and why it is that I can go into the 00:18:39.000 --> 00:18:43.000 lab and synthesize a compound that's never been on this earth before, 00:18:43.000 --> 00:18:47.000 inject a rabbit to it, and the rabbit will probably produce an 00:18:47.000 --> 00:18:51.000 antibody that's able to recognize that. That's because it's made this 00:18:51.000 --> 00:18:55.000 whole set of them. And they all are going to have 00:18:55.000 --> 00:18:59.000 somewhat different surfaces. And they make so many that one of 00:18:59.000 --> 00:19:03.000 those surfaces is going to fit the molecule that I'm testing. 00:19:03.000 --> 00:19:07.000 You can sort of see, that's only part of the trick. 00:19:07.000 --> 00:19:11.000 So, how do you now get an immune response? Because you've got 00:19:11.000 --> 00:19:15.000 millions of these things. But what you now need is a whole 00:19:15.000 --> 00:19:20.000 lot of one particular antibody that's going to recognize the 00:19:20.000 --> 00:19:24.000 pathogen that you are being exposed to. And the principle of that is 00:19:24.000 --> 00:19:29.000 really cute. It's a process called clonal selection. 00:19:29.000 --> 00:19:44.000 And the idea is that each 00:19:44.000 --> 00:20:01.000 B cell displays 00:20:01.000 --> 00:20:05.000 a sample of its antibody on its surface. So, we might think of it 00:20:05.000 --> 00:20:10.000 this sort of way, that after this process is through 00:20:10.000 --> 00:20:15.000 we have one B cell. Of course, these are way out of 00:20:15.000 --> 00:20:20.000 proportion. The cells would be huge, and these would be molecules. 00:20:20.000 --> 00:20:24.000 So, they're small. But here would be an antibody that can recognize 00:20:24.000 --> 00:20:29.000 squares, say, this one would have an antibody that could recognize 00:20:29.000 --> 00:20:34.000 triangle. This one would have an antibody that 00:20:34.000 --> 00:20:38.000 could recognize a semicircle and so on, millions and millions of 00:20:38.000 --> 00:20:42.000 different shapes. And these cells don't divide, 00:20:42.000 --> 00:20:46.000 though. They've been made, and they just sit there. 00:20:46.000 --> 00:20:50.000 And then, when you stimulate them with an antigen, 00:20:50.000 --> 00:20:54.000 and I used that word the other day, an antigen is just anything that 00:20:54.000 --> 00:20:58.000 will elicit an immune response. It could be a piece of a foreign 00:20:58.000 --> 00:21:02.000 protein, carbohydrate, just about anything that's a small 00:21:02.000 --> 00:21:09.000 molecule you've made in the lab. But let's say we exposed now this 00:21:09.000 --> 00:21:19.000 individual to an antigen, which in this case can fit into that 00:21:19.000 --> 00:21:30.000 receptor. And what happens, then, this one becomes stimulated to 00:21:30.000 --> 00:21:40.000 divide. So what we have now is this B cell 00:21:40.000 --> 00:21:49.000 that has this antigen stuck into its binding pocket on the sample of its 00:21:49.000 --> 00:21:59.000 antibody. And then, the cells divide and they give rise 00:21:59.000 --> 00:22:08.000 to two populations. They give rise to the plasma cells, 00:22:08.000 --> 00:22:17.000 which are very short-lived, on the order of a few days. 00:22:17.000 --> 00:22:26.000 And what these do, so they would look like this, 00:22:26.000 --> 00:22:35.000 what they do is secrete antibodies into the plasma. 00:22:35.000 --> 00:22:40.000 So what you end up with, then, are a lot of these antibodies 00:22:40.000 --> 00:22:45.000 that have exactly the specificity that the original sample had on the 00:22:45.000 --> 00:22:50.000 outside of that particular B cell. This takes a few days. So back 00:22:50.000 --> 00:22:55.000 when we were talking about the discovery of DNA, 00:22:55.000 --> 00:23:00.000 I was telling you about Streptococcus pneumonia, 00:23:00.000 --> 00:23:05.000 and you get infected by the Streptococcus. 00:23:05.000 --> 00:23:09.000 And there would be this period of five or six days where this person 00:23:09.000 --> 00:23:13.000 was very sick, and then either they'd survive or 00:23:13.000 --> 00:23:17.000 they didn't survive. If they survived, they'd been able 00:23:17.000 --> 00:23:22.000 to mount an immune response and make these antibodies before they got 00:23:22.000 --> 00:23:26.000 killed by the bacteria. And the reason it takes a few days 00:23:26.000 --> 00:23:30.000 is when you start out there could be just one B cell that's able with an 00:23:30.000 --> 00:23:35.000 antibody, makes an antibody that is capable of recognizing the capsule. 00:23:35.000 --> 00:23:39.000 Maybe there are a few. Anyway, but they were very, 00:23:39.000 --> 00:23:43.000 very tiny number, and there were probably a lot of bacteria. 00:23:43.000 --> 00:23:47.000 So what had to happen, then, is that the original cell or small 00:23:47.000 --> 00:23:51.000 number of cells that could recognize the Streptococcus had to be 00:23:51.000 --> 00:23:55.000 amplified. They had to make a lot of plasma cells that have the 00:23:55.000 --> 00:23:59.000 potential to make the antibody, and then they had to secrete the 00:23:59.000 --> 00:24:03.000 antibody into the plasma. And I'll tell you in just a minute 00:24:03.000 --> 00:24:08.000 some of the strategies that that uses to help kill the pathogen. 00:24:08.000 --> 00:24:14.000 And the other population, just before I go on there, 00:24:14.000 --> 00:24:19.000 are what are called memory cells. There's not as many of these made, 00:24:19.000 --> 00:24:24.000 but they're very long-lived. And so, what they have is exactly the same 00:24:24.000 --> 00:24:30.000 capacity to make the same antibody, but they're not actively dividing. 00:24:30.000 --> 00:24:37.000 They'll just sit there, 00:24:37.000 --> 00:24:45.000 float around in your bloodstream, and then if you get a second 00:24:45.000 --> 00:24:54.000 exposure to the antigen, you get a very fast and strong 00:24:54.000 --> 00:25:03.000 response because the selection for finding the cells that had 00:25:03.000 --> 00:25:12.000 antibodies that can recognize the antigen has already been done. 00:25:12.000 --> 00:25:15.000 And there's already a few of them around, and then after you do that 00:25:15.000 --> 00:25:19.000 then you're able to make, once again, the binding of the 00:25:19.000 --> 00:25:22.000 antigen stimulates these guys to start dividing. 00:25:22.000 --> 00:25:26.000 They make a lot of plasma cells. And going back to the principal of 00:25:26.000 --> 00:25:30.000 vaccination, your first response is fairly modest. 00:25:30.000 --> 00:25:34.000 But if you get a second response, what you're doing now is the memory 00:25:34.000 --> 00:25:39.000 cells are already there. They have the specificity for 00:25:39.000 --> 00:25:43.000 recognizing the antigen in question. And you can make a whole lot of 00:25:43.000 --> 00:25:48.000 them. So, if you had chickenpox when you were little, 00:25:48.000 --> 00:25:52.000 you have memory cells that know how to recognize the chickenpox virus. 00:25:52.000 --> 00:25:57.000 And then when your kid gets chickenpox like mine did, 00:25:57.000 --> 00:26:01.000 I didn't get sick because I had memory cells that were able 00:26:01.000 --> 00:26:07.000 to recognize that. OK, so what happens if you get an 00:26:07.000 --> 00:26:14.000 antibody? How does this help the organism, or in our case someone 00:26:14.000 --> 00:26:22.000 like you or me, avoid getting sick? 00:26:22.000 --> 00:26:29.000 So there are a couple of strategies. One we might think of 00:26:29.000 --> 00:26:35.000 is bind and block. For example, you are a virus and you 00:26:35.000 --> 00:26:40.000 get covered by antibodies. Viruses: it's exactly the same 00:26:40.000 --> 00:26:46.000 logic as bacteriophage, except that instead of affecting a 00:26:46.000 --> 00:26:51.000 bacterial cell a virus would be infecting one of our cells. 00:26:51.000 --> 00:26:56.000 And as the virus has receptors or something, it has to recognize 00:26:56.000 --> 00:27:02.000 something on my cell, in order to attach and then to 00:27:02.000 --> 00:27:08.000 inject its DNA. So if we've got an antibody sitting 00:27:08.000 --> 00:27:15.000 here, then it can't find its way to the host cell. 00:27:15.000 --> 00:27:22.000 And then, there are a couple of other ways. They can target for 00:27:22.000 --> 00:27:29.000 destruction. And there's basically two ways. There's something called 00:27:29.000 --> 00:27:36.000 the complement system, that if it is able to recognize, 00:27:36.000 --> 00:27:44.000 say, the bacterial cell and their antibodies are sticking to the 00:27:44.000 --> 00:27:52.000 outside, what the complement system does is it's able to make little 00:27:52.000 --> 00:28:00.000 pores in the membrane of the pathogen. 00:28:00.000 --> 00:28:03.000 And I think one of the things I hope you will remember is that one of the 00:28:03.000 --> 00:28:07.000 secrets of life is that we have to keep that membrane around there. 00:28:07.000 --> 00:28:10.000 We have to keep all of our insides in, and the rest of the world 00:28:10.000 --> 00:28:14.000 outside. We have hydrogen ion gradients across the membrane. 00:28:14.000 --> 00:28:18.000 So, if you want to kill a cell and you, say, insert a protein that has 00:28:18.000 --> 00:28:21.000 a little hole and it, and that thing sits and sticks in 00:28:21.000 --> 00:28:25.000 the membrane, that cell is dead. It can't maintain an ion gradient, 00:28:25.000 --> 00:28:29.000 and things can leak out through the hole. 00:28:29.000 --> 00:28:35.000 So that's one of the ways of killing it. The other ways are macrophages. 00:28:35.000 --> 00:28:42.000 These are a type of white blood cell, as well, 00:28:42.000 --> 00:28:48.000 are very good at recognizing bacteria that have antibodies stuck 00:28:48.000 --> 00:28:55.000 to the outside. And in fact, that was the principle 00:28:55.000 --> 00:29:02.000 of that. We have the Streptococcus, and we have the capsule. 00:29:02.000 --> 00:29:06.000 And you may remember that little movie I showed of a white blood cell 00:29:06.000 --> 00:29:10.000 that was trying to eat it, and it couldn't get hold of the 00:29:10.000 --> 00:29:14.000 thing, whereas we saw another example where a bacterium without a 00:29:14.000 --> 00:29:18.000 capsule, there was sort of principle I said is that the white blood cell 00:29:18.000 --> 00:29:22.000 was able to recognize the bacterium and then it pinches it off inside of 00:29:22.000 --> 00:29:26.000 a membrane bubble. And I sort of said at least in 00:29:26.000 --> 00:29:30.000 principle that there is another little bubble with poisons, 00:29:30.000 --> 00:29:35.000 and it brings it together so that you have the bacterium and the 00:29:35.000 --> 00:29:40.000 poison together inside of some intracellular compartment, 00:29:40.000 --> 00:29:45.000 so that macrophages know how to kill a bacterium if they bring it inside. 00:29:45.000 --> 00:29:50.000 The problem in the case of something like Streptococcus was 00:29:50.000 --> 00:29:55.000 being able to recognize it because it couldn't get hold of that capsule. 00:29:55.000 --> 00:30:01.000 So, those antibodies that guy made during that five day thing decorate 00:30:01.000 --> 00:30:06.000 the outside of the capsule because their specificity is to recognize 00:30:06.000 --> 00:30:11.000 the capsule and bind to it. But a macrophage, 00:30:11.000 --> 00:30:15.000 even if it couldn't get hold of the bacterium with a capsule is able to 00:30:15.000 --> 00:30:20.000 ingest something that has antibodies stuck on the outside. 00:30:20.000 --> 00:30:24.000 And once it gets inside, it can kill the bacterium. 00:30:24.000 --> 00:30:29.000 In fact, immunologists call this process opsinization, 00:30:29.000 --> 00:30:33.000 which is derived from the Greek words for seasoning, 00:30:33.000 --> 00:30:38.000 like putting salt on your food. And the idea was that when they were 00:30:38.000 --> 00:30:42.000 giving that word, with these macrophages, 00:30:42.000 --> 00:30:46.000 which liked to eat bacteria, they have a little seasoning that 00:30:46.000 --> 00:30:50.000 they have these little antibodies decorating their outsides. 00:30:50.000 --> 00:30:54.000 So here you can see it least in the humoral response how you generate a 00:30:54.000 --> 00:30:59.000 whole lot of diversity. Then this principle of what's called 00:30:59.000 --> 00:31:03.000 clonal selection identifies a B cell that's able to make an antibody that 00:31:03.000 --> 00:31:07.000 can recognize the particular pathogen or molecule that you're 00:31:07.000 --> 00:31:12.000 being exposed to amplify that, make a lot of antibodies, and then 00:31:12.000 --> 00:31:16.000 it can either just stick to the pathogen like a virus and mess it up 00:31:16.000 --> 00:31:21.000 that way, or it can decorate it if it's something like a bacterium, 00:31:21.000 --> 00:31:25.000 and then pull in a couple of other systems that are capable of killing 00:31:25.000 --> 00:31:30.000 the pathogen. I mean, it's an absolutely amazing system. 00:31:30.000 --> 00:31:33.000 It sounded like science fiction when I first heard about it. 00:31:33.000 --> 00:31:36.000 When I heard people talking about it, everyone could see there was an 00:31:36.000 --> 00:31:40.000 information theory problem. How do you encode all that 00:31:40.000 --> 00:31:43.000 information with just this amount of DNA in a cell? 00:31:43.000 --> 00:31:47.000 Now we understand. And there's even another part that 00:31:47.000 --> 00:31:50.000 I'm leaving out here. But once this whole thing has been 00:31:50.000 --> 00:31:54.000 selected, there's another whole round of sort of refinement where 00:31:54.000 --> 00:31:57.000 the cells do kind of a very kind of localized mutagenesis one base pair 00:31:57.000 --> 00:32:01.000 at a time in the vicinity of this binding pocket. 00:32:01.000 --> 00:32:07.000 And they're able to make, if they're given more time and more 00:32:07.000 --> 00:32:13.000 exposure to the antigen, they can make a better and better 00:32:13.000 --> 00:32:19.000 binding surface until you begin to approach sort of the theoretical 00:32:19.000 --> 00:32:25.000 maximum. Now, the T cell, in this case this 00:32:25.000 --> 00:32:34.000 involves the cytotoxic T cells, and they have a specific recognition 00:32:34.000 --> 00:32:47.000 molecule on their surface. It's called the T cell receptor. 00:32:47.000 --> 00:33:00.000 And in this case, it's attached. 00:33:00.000 --> 00:33:04.000 So, this is the membrane of the T cell. And this is the cytoplasm 00:33:04.000 --> 00:33:08.000 down on this side. There's a little bit of the protein 00:33:08.000 --> 00:33:12.000 that goes into that. And then there's an alpha helix 00:33:12.000 --> 00:33:17.000 that goes through, and then a segment that comes up 00:33:17.000 --> 00:33:21.000 like this. And there's another chain that does the same thing. 00:33:21.000 --> 00:33:25.000 So, there are two segments that span the membrane. 00:33:25.000 --> 00:33:30.000 This thing is anchored in the membrane. 00:33:30.000 --> 00:33:34.000 And then it's essentially the same principle as with antibodies. 00:33:34.000 --> 00:33:39.000 There's a variable region, and there's a constant region. 00:33:39.000 --> 00:33:44.000 And to a first approximation anyway the logic by which the cell 00:33:44.000 --> 00:33:49.000 generates a huge, diverse set of T cell receptors is 00:33:49.000 --> 00:33:54.000 the same logic that underlies the generation of a whole lot of 00:33:54.000 --> 00:33:59.000 different antibodies by taking segments, joining them, 00:33:59.000 --> 00:34:04.000 picking them randomly out of column A, column B, and then joining them 00:34:04.000 --> 00:34:09.000 together, sloppy joining all the other processes to increase the pool 00:34:09.000 --> 00:34:19.000 of diversity. Now, what these B cells are able to 00:34:19.000 --> 00:34:33.000 do, then, these T cells are able to do is something quite remarkable. 00:34:33.000 --> 00:34:38.000 We have on our cells, this is, say, one of my cells, 00:34:38.000 --> 00:34:43.000 little sort of proteins that function as sort of display cases or 00:34:43.000 --> 00:34:48.000 something. And what they do is they show samples of all of the different 00:34:48.000 --> 00:34:53.000 proteins that are inside us at any given moment. Proteins are turned 00:34:53.000 --> 00:34:59.000 over, and chopped up, and things are recycled and so on. 00:34:59.000 --> 00:35:07.000 So there are always little peptides, little pieces of proteins around. 00:35:07.000 --> 00:35:16.000 And, the display case, if you will, has got a major 00:35:16.000 --> 00:35:25.000 histocompatibility complex, which is usually abbreviated as MHC 00:35:25.000 --> 00:35:32.000 because it's such an unwieldy name. And there are many, 00:35:32.000 --> 00:35:36.000 many alleles of MHC in the population, which means that we each 00:35:36.000 --> 00:35:40.000 have, for the most part, a sort of individually designed 00:35:40.000 --> 00:35:44.000 display case for showing these peptides. The property of these 00:35:44.000 --> 00:35:49.000 display cases, they take some little piece of a 00:35:49.000 --> 00:35:53.000 protein just a few amino acids long, it binds into the display case, and 00:35:53.000 --> 00:35:57.000 that sticks on the outside of our cell. And so we have 00:35:57.000 --> 00:36:02.000 a lot of these. And so on the surface of our cells 00:36:02.000 --> 00:36:07.000 are these little individualized MHC display cases showing little samples 00:36:07.000 --> 00:36:12.000 of the peptides of the proteins from the proteins that are inside us. 00:36:12.000 --> 00:36:17.000 So, if everything is fine, all of the peptides that are in the display 00:36:17.000 --> 00:36:22.000 cases are our own. And I'll tell you in a minute why 00:36:22.000 --> 00:36:27.000 that doesn't cause a problem. But then if you get infected by a 00:36:27.000 --> 00:36:32.000 virus, and it injects DNA or its RNA inside of you and then starts to 00:36:32.000 --> 00:36:37.000 replicate, now you have some virus proteins that don't belong to you. 00:36:37.000 --> 00:36:43.000 They get chopped into pieces, and they begin to appear on these 00:36:43.000 --> 00:36:49.000 major histocompatibility display cases. So if you think here, 00:36:49.000 --> 00:36:56.000 this could be, perhaps, a little piece of, let's call it self protein, 00:36:56.000 --> 00:37:02.000 it could be a little piece of my own DNA polymerase or something 00:37:02.000 --> 00:37:09.000 like that. And over in this one, 00:37:09.000 --> 00:37:17.000 let's say we have a little piece of a viral protein. 00:37:17.000 --> 00:37:25.000 So that's something that would not be normally there. 00:37:25.000 --> 00:37:33.000 So what this T-cell receptor does is it recognizes, so this 00:37:33.000 --> 00:37:40.000 is non-self or foreign. What the T-cell receptor does is it 00:37:40.000 --> 00:37:46.000 recognizes these foreign peptides. But it does it in the context of 00:37:46.000 --> 00:37:53.000 the display case. Otherwise the peptides would be 00:37:53.000 --> 00:37:59.000 floating around. So, in essence, the T-cell receptor, 00:37:59.000 --> 00:38:06.000 if this is a cytotoxic T cell it's able to see the individual display 00:38:06.000 --> 00:38:13.000 case with a bit of viral protein in it. 00:38:13.000 --> 00:38:17.000 And then it knows that it should kill that cell because it's got 00:38:17.000 --> 00:38:21.000 something in it that shouldn't be there. I mean, 00:38:21.000 --> 00:38:25.000 it's a brutal but very effective strategy. If we applied it here, 00:38:25.000 --> 00:38:29.000 I go around if I found any of you had a cold, I could just take a gun 00:38:29.000 --> 00:38:33.000 and shoot you and it would cut down on the number of sick days for the 00:38:33.000 --> 00:38:38.000 rest of us because it wouldn't spread the infection. 00:38:38.000 --> 00:38:42.000 But in essence, at a molecular level, 00:38:42.000 --> 00:38:46.000 that's the strategy. Try to identify a cell that's got something 00:38:46.000 --> 00:38:50.000 inside it that shouldn't be there, and then the cytotoxic T cells kill 00:38:50.000 --> 00:38:54.000 that. And let me just show you a couple of quick movies of this. 00:38:54.000 --> 00:38:58.000 At this point, these will be the last protein structures you're going 00:38:58.000 --> 00:39:03.000 to see from me, I think. Here's a representation of that T 00:39:03.000 --> 00:39:07.000 cell just as a cartoon as you see it in a textbook. 00:39:07.000 --> 00:39:11.000 Here it is. This is the binding pocket up here. 00:39:11.000 --> 00:39:15.000 And there's a little tiny peptide, nine and amino acids from the HIV 00:39:15.000 --> 00:39:19.000 virus bound in here. Somebody did a crystal structure, 00:39:19.000 --> 00:39:23.000 and was able to work that out. And, if you look at it in three 00:39:23.000 --> 00:39:27.000 dimensions, you'll see how beautifully this little binding 00:39:27.000 --> 00:39:31.000 pocket and the peptide lies in there. 00:39:31.000 --> 00:39:35.000 So that red part is the piece of chalk, and the other part is what 00:39:35.000 --> 00:39:39.000 I'm describing as my hand. It's not a bad analogy, actually, 00:39:39.000 --> 00:39:44.000 even on a structural level. And then, here's another representation. 00:39:44.000 --> 00:39:48.000 This is sort of showing the hand with a piece of peptide in it. 00:39:48.000 --> 00:39:53.000 And then the T cell is able to see this whole thing in recognize it. 00:39:53.000 --> 00:39:57.000 And, if you look at it in a structural form, here's 00:39:57.000 --> 00:40:02.000 the little peptide. This is the part, 00:40:02.000 --> 00:40:07.000 the display case you're looking at. And here's the T cell receptor now 00:40:07.000 --> 00:40:11.000 fitting down in seeing the peptide in the context of this major 00:40:11.000 --> 00:40:16.000 histocompatibility antigen. And again, these things are all 00:40:16.000 --> 00:40:21.000 beautifully complementary a three dimensional level. 00:40:21.000 --> 00:40:26.000 Again, at the heart of this is the principle of complementary surfaces 00:40:26.000 --> 00:40:31.000 fitting together that underlies so much biology. What's this? 00:40:31.000 --> 00:40:36.000 This is a tumor cell. These are cytotoxic T cells that 00:40:36.000 --> 00:40:41.000 have recognized this tumor cell is doing something it shouldn't that a 00:40:41.000 --> 00:40:46.000 normal cell wouldn't do. And it's attacking it, and it's 00:40:46.000 --> 00:40:52.000 killing them. So, not only does the cellular immune 00:40:52.000 --> 00:40:57.000 response help us against things like infections from virus and bacteria, 00:40:57.000 --> 00:41:03.000 it also will help prevent cancer. So obviously there must be some 00:41:03.000 --> 00:41:10.000 trick here to why we don't see our own peptides. This is the self 00:41:10.000 --> 00:41:17.000 versus non-self And it's a relatively simple principle. 00:41:17.000 --> 00:41:24.000 So, distinguishing self versus non-self is a problem throughout 00:41:24.000 --> 00:41:32.000 this whole part of the immune system. 00:41:32.000 --> 00:41:41.000 And here's the principle. During embryogenesis, the cell 00:41:41.000 --> 00:41:50.000 makes, the organism I guess, makes the assumption. I mean 00:41:50.000 --> 00:42:00.000 obviously it's not thinking about it. 00:42:00.000 --> 00:42:10.000 This is a way of understanding what's happening. 00:42:10.000 --> 00:42:20.000 It makes the assumption that no pathogens are present. 00:42:20.000 --> 00:42:36.000 Any B or T cell recognizing something must be recognizing itself. 00:42:36.000 --> 00:42:52.000 And so, it deletes those B and T cells. This process is given a name. 00:42:52.000 --> 00:43:05.000 It's called education. And it happens in this organ called 00:43:05.000 --> 00:43:16.000 thymus. So, and then after birth, then it switches. And now B and T 00:43:16.000 --> 00:43:28.000 cells, if they recognize something, the body makes the assumption it 00:43:28.000 --> 00:43:36.000 must be a pathogen. And it goes after it. 00:43:36.000 --> 00:43:41.000 We have this huge human disease where that goes awry: rheumatoid 00:43:41.000 --> 00:43:45.000 arthritis, or multiple sclerosis are cases where the self versus non-self 00:43:45.000 --> 00:43:50.000 recognition has broken down. OK, so for example multiple 00:43:50.000 --> 00:43:55.000 sclerosis, a very difficult disease, because there's a gradual 00:43:55.000 --> 00:44:00.000 deterioration of the nervous system. 00:44:00.000 --> 00:44:04.000 And what happens is the body of the person with that mounts an immune 00:44:04.000 --> 00:44:08.000 response against the sheath that covers the nerves, 00:44:08.000 --> 00:44:12.000 and then that sheath gets destroyed, and that the nervous system, 00:44:12.000 --> 00:44:16.000 somebody with multiple sclerosis, starts to break down. And so, if 00:44:16.000 --> 00:44:20.000 you lose this self versus non-self you get what's called an autoimmune 00:44:20.000 --> 00:44:24.000 disease. You may have heard that phrase. It's very important. 00:44:24.000 --> 00:44:28.000 It's a very tough thing if you have one of these. But that's what lies 00:44:28.000 --> 00:44:31.000 at the heart of it. And people still don't know, 00:44:31.000 --> 00:44:35.000 but there is certainly some evidence for some of these that are triggered 00:44:35.000 --> 00:44:39.000 by a bacterial infection. So, it could be that perhaps maybe 00:44:39.000 --> 00:44:43.000 a bacterial protein looked close enough to one of your own proteins, 00:44:43.000 --> 00:44:47.000 that somehow you got antibodies against the bacterium, 00:44:47.000 --> 00:44:50.000 and then it turned out it could also recognize something in your body. 00:44:50.000 --> 00:44:54.000 There are some other immune diseases you probably heard of, 00:44:54.000 --> 00:44:58.000 the baby in a bubble kind of thing. There are a few people who were 00:44:58.000 --> 00:45:02.000 born who have no immune response at all because one of the basic pieces 00:45:02.000 --> 00:45:06.000 for doing those DNA gymnastics I talked about isn't there. 00:45:06.000 --> 00:45:10.000 Those people have no B cells or T cells. They die unless they are 00:45:10.000 --> 00:45:14.000 absolutely shielded from everything else. And that's one of those cases 00:45:14.000 --> 00:45:18.000 when gene therapy, if you could get that gene into that 00:45:18.000 --> 00:45:23.000 person, they'd have an immune system and they could live. 00:45:23.000 --> 00:45:27.000 There are other kinds of immune deficiencies that are less extreme, 00:45:27.000 --> 00:45:32.000 but nevertheless, people will be susceptible to infection. 00:45:32.000 --> 00:45:36.000 The other one which I've already talked about, but now you can see in 00:45:36.000 --> 00:45:40.000 another context is AIDS, Acquired Immune Deficiency Syndrome. 00:45:40.000 --> 00:45:44.000 And I told you what the HIV virus does is it injects its RNA. 00:45:44.000 --> 00:45:48.000 That makes a DNA copy. It goes into protein. The cells that it 00:45:48.000 --> 00:45:52.000 affects our special type of T cell called T helper cells. 00:45:52.000 --> 00:45:56.000 What they are doesn't matter so much, but what's important to know 00:45:56.000 --> 00:46:00.000 is they're needed for both branches of the immune system. 00:46:00.000 --> 00:46:04.000 They play roles in the humoral response and cellular response. 00:46:04.000 --> 00:46:08.000 So, someone who gets infected with HIV, what happens is the virus is 00:46:08.000 --> 00:46:12.000 replicating in these helper T cells. And so their immune system is 00:46:12.000 --> 00:46:16.000 slowly, slowly being knocked away. And the last thing, which I won't 00:46:16.000 --> 00:46:20.000 have time to talk about, but if you have an allergy, 00:46:20.000 --> 00:46:24.000 that's an overreaction of the immune system. So this is my last lecture. 00:46:24.000 --> 00:46:28.000 I've got to let you guys go. It's been a true pleasure to talk to you; 00:46:28.000 --> 00:46:32.000 A real honor to meet many of you. And many of you put a lot of effort 00:46:32.000 --> 00:46:36.000 into those little answers. I really, really appreciate that. 00:46:36.000 --> 00:46:41.000 For those who'd rather not be here, I hope that somewhere down the line 00:46:41.000 --> 00:46:46.000 when you're confronted with a medical situation dealing with your 00:46:46.000 --> 00:46:50.000 parents, your child, yourself, whatever it is, 00:46:50.000 --> 00:46:55.000 that some of the stuff that you heard will reemerge to help you with 00:46:55.000 --> 00:47:00.000 those decisions. And I wish you the best of luck for 00:47:00.000 --> 00:47:04.000 the rest of the course, and the rest of your careers at MIT 00:47:04.000 --> 00:47:09.000 and beyond. Thanks very much. And as I leave, 00:47:09.000 --> 00:47:13.000 too, I've had the pleasure of just having an incredible teaching staff. 00:47:13.000 --> 00:47:18.000 I don't think you guys know how hard they work behind the scenes, 00:47:18.000 --> 00:47:21.000 but thanks to all of you for being with me.