1 00:00:16,790 --> 00:00:18,640 BARBARA IMPERIALI: OK, I want to walk us 2 00:00:18,640 --> 00:00:23,200 through a bit of an exercise to understand 3 00:00:23,200 --> 00:00:28,120 what happens when people become resistant to an antibiotic. 4 00:00:28,120 --> 00:00:31,180 What's the molecular basis for resistance? 5 00:00:31,180 --> 00:00:33,170 It's nothing magical. 6 00:00:33,170 --> 00:00:35,080 It's really things that you can understand 7 00:00:35,080 --> 00:00:38,350 based on what you've learned during various parts 8 00:00:38,350 --> 00:00:39,290 of the course. 9 00:00:39,290 --> 00:00:42,790 But I just want to remind you about this dreadful schematic 10 00:00:42,790 --> 00:00:46,750 here, which shows how rapidly resistance 11 00:00:46,750 --> 00:00:51,670 emerges to different antibiotics by showing you the year 12 00:00:51,670 --> 00:00:55,810 that the drugs are introduced and the year that resistances 13 00:00:55,810 --> 00:00:56,930 develop. 14 00:00:56,930 --> 00:01:01,475 One of the newest antibiotics to be introduced-- 15 00:01:01,475 --> 00:01:03,850 people thought, oh, it's a different mechanism of action. 16 00:01:03,850 --> 00:01:05,680 It should be pretty resilient. 17 00:01:05,680 --> 00:01:06,880 It should last for a while. 18 00:01:06,880 --> 00:01:08,380 It should be useful with daptomycin. 19 00:01:08,380 --> 00:01:13,060 It's a cyclic peptide antibiotic, 20 00:01:13,060 --> 00:01:15,280 which has a particular structure that doesn't 21 00:01:15,280 --> 00:01:16,900 look like a lot of the others. 22 00:01:16,900 --> 00:01:19,300 And honestly, it was two to three years 23 00:01:19,300 --> 00:01:21,190 before resistance emerged. 24 00:01:21,190 --> 00:01:24,160 So what I want to do is think together 25 00:01:24,160 --> 00:01:29,440 about what are the ways in which a bacterium could evolve 26 00:01:29,440 --> 00:01:32,870 to develop resistance against an antibiotic? 27 00:01:32,870 --> 00:01:36,430 So here we've got the target. 28 00:01:36,430 --> 00:01:38,770 We know that the antibiotic is very 29 00:01:38,770 --> 00:01:41,260 effective against the target. 30 00:01:41,260 --> 00:01:44,350 What types of things could happen in the bacterium 31 00:01:44,350 --> 00:01:48,330 to make it manage to just ignore the antibiotic 32 00:01:48,330 --> 00:01:50,320 and resist the antibiotic? 33 00:01:50,320 --> 00:01:51,850 Any suggestions? 34 00:01:51,850 --> 00:01:53,120 So it's very simple. 35 00:01:53,120 --> 00:01:55,030 There's a molecular target. 36 00:01:55,030 --> 00:01:57,190 It could be topoisomerase. 37 00:02:01,730 --> 00:02:05,480 It could be in fact the ribosome and the machinery 38 00:02:05,480 --> 00:02:07,850 for synthesizing proteins. 39 00:02:07,850 --> 00:02:12,270 It could be the machinery that cross-links peptidoglycan. 40 00:02:16,340 --> 00:02:20,090 What sorts of approaches and what sorts of strategies 41 00:02:20,090 --> 00:02:23,840 might evolve to make that antibiotic stop working? 42 00:02:23,840 --> 00:02:25,520 OK, fire. 43 00:02:25,520 --> 00:02:26,420 Yes. 44 00:02:26,420 --> 00:02:28,340 AUDIENCE: When two hydrogen-holding enzymes 45 00:02:28,340 --> 00:02:31,692 at-- create things that are not [INAUDIBLE] absorbing. 46 00:02:31,692 --> 00:02:32,900 BARBARA IMPERIALI: OK, right. 47 00:02:32,900 --> 00:02:35,000 So antibiotic gets in. 48 00:02:38,670 --> 00:02:46,230 The enzyme breaks up the antibiotic, so evolution 49 00:02:46,230 --> 00:02:48,580 to destroy the antibiotic. 50 00:02:52,810 --> 00:02:56,160 And that's very much what happens with penicillin. 51 00:02:56,160 --> 00:02:59,460 The key aspect of the structure that's so useful 52 00:02:59,460 --> 00:03:03,300 suddenly becomes invalidated through a degradation 53 00:03:03,300 --> 00:03:04,710 of the beta-lactam bond. 54 00:03:04,710 --> 00:03:05,690 So that's one of them. 55 00:03:05,690 --> 00:03:07,180 What's next? 56 00:03:07,180 --> 00:03:07,680 Yeah. 57 00:03:07,680 --> 00:03:10,015 AUDIENCE: [INAUDIBLE] 58 00:03:12,350 --> 00:03:13,950 BARBARA IMPERIALI: Ah, so maybe there 59 00:03:13,950 --> 00:03:25,050 could be uptake decreased, so that's quite hard, 60 00:03:25,050 --> 00:03:30,360 but there could be some evolution of the cell wall 61 00:03:30,360 --> 00:03:34,320 to make it less permeable to the antibiotic 62 00:03:34,320 --> 00:03:38,550 because we're usually relying on antibiotics to diffuse 63 00:03:38,550 --> 00:03:39,810 in passively. 64 00:03:44,690 --> 00:03:46,830 So if the membrane-- 65 00:03:46,830 --> 00:03:50,740 this could be in a membrane of a Gram-negative bacterium, 66 00:03:50,740 --> 00:03:53,930 or the outer membrane of a Gram-negative bacterium that 67 00:03:53,930 --> 00:03:55,820 has a slightly different composition, 68 00:03:55,820 --> 00:03:58,110 could physically change its structure. 69 00:03:58,110 --> 00:04:00,810 These are tough things to evolve all at once, 70 00:04:00,810 --> 00:04:02,840 but it's certainly a possibility. 71 00:04:02,840 --> 00:04:04,160 We've talked about uptake. 72 00:04:04,160 --> 00:04:05,660 What about-- what else could happen? 73 00:04:05,660 --> 00:04:06,160 Yes. 74 00:04:06,160 --> 00:04:08,325 AUDIENCE: When you get a [INAUDIBLE] out, 75 00:04:08,325 --> 00:04:12,063 such that they have oxygen [INAUDIBLE].. 76 00:04:12,063 --> 00:04:12,980 BARBARA IMPERIALI: OK. 77 00:04:12,980 --> 00:04:15,530 So this guy could just-- 78 00:04:15,530 --> 00:04:18,470 we've got a circular antibiotic usually, 79 00:04:18,470 --> 00:04:21,410 but this just changes-- 80 00:04:21,410 --> 00:04:22,910 the target just changes. 81 00:04:22,910 --> 00:04:25,380 It can't bind anymore, through mutation, 82 00:04:25,380 --> 00:04:28,090 so that the antibiotic simply doesn't bind. 83 00:04:28,090 --> 00:04:31,850 It gets in, but it's changed, and that happens a lot. 84 00:04:31,850 --> 00:04:34,460 It also happens a lot-- 85 00:04:34,460 --> 00:04:36,860 one can think of antibiotic resistance 86 00:04:36,860 --> 00:04:40,340 very much along the same veins as one thinks of resistance 87 00:04:40,340 --> 00:04:42,590 to chemotherapeutic agents. 88 00:04:42,590 --> 00:04:44,540 You're targeting a kinase. 89 00:04:44,540 --> 00:04:46,460 Your drug works great. 90 00:04:46,460 --> 00:04:48,800 A year later, the cancer comes back 91 00:04:48,800 --> 00:04:51,530 because there's a single mutation in your target. 92 00:04:51,530 --> 00:04:57,380 This happens a lot with the EGF, kinase, RAS's and so on. 93 00:04:57,380 --> 00:04:59,360 There's a dramatic change. 94 00:04:59,360 --> 00:05:02,030 So this change would be a change in the target. 95 00:05:02,030 --> 00:05:04,250 You mentioned two things, right? 96 00:05:04,250 --> 00:05:04,820 I thought. 97 00:05:04,820 --> 00:05:05,950 Maybe not. 98 00:05:05,950 --> 00:05:07,367 AUDIENCE: Well, like I said, there 99 00:05:07,367 --> 00:05:08,659 were some for that [INAUDIBLE]. 100 00:05:08,659 --> 00:05:09,600 BARBARA IMPERIALI: Ah. 101 00:05:09,600 --> 00:05:10,230 On the surface. 102 00:05:10,230 --> 00:05:12,030 AUDIENCE: A couple of days you're going back, so. 103 00:05:12,030 --> 00:05:13,697 BARBARA IMPERIALI: OK, so there could be 104 00:05:13,697 --> 00:05:16,600 some kind of import strategy. 105 00:05:16,600 --> 00:05:19,320 So some antibiotics just diffuse. 106 00:05:19,320 --> 00:05:22,010 Some go in through targeted import, 107 00:05:22,010 --> 00:05:24,780 and that might change so that the antibiotic can't 108 00:05:24,780 --> 00:05:26,075 get in anymore. 109 00:05:26,075 --> 00:05:26,700 Other thoughts? 110 00:05:29,370 --> 00:05:32,230 There's a couple of other sneaky ways. 111 00:05:32,230 --> 00:05:34,660 I mean, you've got to sort of give these bacteria credit 112 00:05:34,660 --> 00:05:38,210 for maximum sneakiness. 113 00:05:38,210 --> 00:05:42,110 So if influx is an issue, what about efflux? 114 00:05:45,350 --> 00:05:48,320 The biggest problem with antibiotics 115 00:05:48,320 --> 00:05:52,550 against Gram-negatives is that they way upregulate 116 00:05:52,550 --> 00:05:54,050 efflux pumps. 117 00:05:54,050 --> 00:05:57,267 They just, like, cover their cells with pumps that just go, 118 00:05:57,267 --> 00:05:58,850 you're going to give me an antibiotic? 119 00:05:58,850 --> 00:06:01,400 I'm just going to lob it straight back out to you. 120 00:06:01,400 --> 00:06:08,630 So the efflux pumps increase. 121 00:06:08,630 --> 00:06:12,860 So their molecules, we have a lot of efflux pumps 122 00:06:12,860 --> 00:06:16,240 to just kick out things that are not-- 123 00:06:16,240 --> 00:06:18,500 that we don't want in our cells. 124 00:06:18,500 --> 00:06:20,940 The bacteria have similar things. 125 00:06:20,940 --> 00:06:23,900 They will-- they're fairly promiscuous, 126 00:06:23,900 --> 00:06:26,450 exporting pumps that will bind to things 127 00:06:26,450 --> 00:06:29,150 that don't look like things that should be in a cell, 128 00:06:29,150 --> 00:06:32,170 and literally bind to them on the inside of the membrane, 129 00:06:32,170 --> 00:06:33,680 [MAKES SQUIRT SOUND] send them back 130 00:06:33,680 --> 00:06:35,580 to the outside of the membrane. 131 00:06:35,580 --> 00:06:38,450 So Gram-negative bacteria can massively 132 00:06:38,450 --> 00:06:40,520 upregulate the production of a pump 133 00:06:40,520 --> 00:06:44,640 that they already have, but they just make much more of them. 134 00:06:44,640 --> 00:06:48,080 So in many cases, you can hardly test a new compound 135 00:06:48,080 --> 00:06:51,530 because it's getting pumped out as fast as it gets pumped in. 136 00:06:51,530 --> 00:06:55,790 What could be a strategy when this happens? 137 00:06:55,790 --> 00:06:59,050 Because people are doing this. 138 00:06:59,050 --> 00:07:00,650 You inhibit the pump. 139 00:07:00,650 --> 00:07:02,500 So you make your antibiotic-- 140 00:07:02,500 --> 00:07:05,440 it works great, but you stop the pump working. 141 00:07:05,440 --> 00:07:09,190 So you have to give two drugs, the drug that's 142 00:07:09,190 --> 00:07:12,430 the antibiotic to the target and the drug that inhibits 143 00:07:12,430 --> 00:07:14,980 the pump, and that happens. 144 00:07:14,980 --> 00:07:19,480 Similarly, with this mechanism, where the antibiotic gets 145 00:07:19,480 --> 00:07:24,610 destroyed, you can recover from this 146 00:07:24,610 --> 00:07:29,850 by inhibiting the destroying enzyme, 147 00:07:29,850 --> 00:07:32,200 and then your antibiotic doesn't get destroyed 148 00:07:32,200 --> 00:07:34,130 when it gets into the cells. 149 00:07:34,130 --> 00:07:36,910 So there's one extremely important formulation 150 00:07:36,910 --> 00:07:38,980 of antibiotic that is used. 151 00:07:38,980 --> 00:07:40,285 It's called Augmentin. 152 00:07:46,190 --> 00:07:52,350 And what it is is a penicillin plus 153 00:07:52,350 --> 00:07:54,550 a beta-lactamase inhibitor. 154 00:07:54,550 --> 00:07:58,950 It's the drug that works plus a drug that 155 00:07:58,950 --> 00:08:01,890 inhibits the enzyme that destroys the drug. 156 00:08:01,890 --> 00:08:03,420 People get this all the time. 157 00:08:03,420 --> 00:08:06,340 Every day of the week, this stuff is prescribed. 158 00:08:06,340 --> 00:08:09,510 It's a two-compound cocktail that 159 00:08:09,510 --> 00:08:12,480 has something to overcome the resistance so that your drug 160 00:08:12,480 --> 00:08:13,950 still works in a cell. 161 00:08:13,950 --> 00:08:14,790 All right? 162 00:08:14,790 --> 00:08:17,130 And there's one more key mechanism, 163 00:08:17,130 --> 00:08:20,370 and what bacteria will just do is they say, well, you know, 164 00:08:20,370 --> 00:08:23,430 I'm getting dosed with this much antibiotic. 165 00:08:23,430 --> 00:08:29,920 What's a good way around it is to massively upregulate 166 00:08:29,920 --> 00:08:33,520 the biosynthesis of the target to a state where you just 167 00:08:33,520 --> 00:08:35,320 can't saturate it all. 168 00:08:35,320 --> 00:08:39,440 So upregulation of the target is a very, very common thing. 169 00:08:39,440 --> 00:08:41,770 So you-- this should have just increased the number 170 00:08:41,770 --> 00:08:43,419 of transcripts being made. 171 00:08:43,419 --> 00:08:46,960 You increase the amount of target being made so 172 00:08:46,960 --> 00:08:51,370 that, even if antibiotics are flooding into cells, 173 00:08:51,370 --> 00:08:55,120 there's just not enough to inhibit all of the target 174 00:08:55,120 --> 00:08:59,270 because it's been upregulated by 10 or 100-fold. 175 00:08:59,270 --> 00:09:02,050 So what I think is cool about all these mechanisms 176 00:09:02,050 --> 00:09:03,143 is they all make sense. 177 00:09:03,143 --> 00:09:04,810 You just kind of have to think of them-- 178 00:09:04,810 --> 00:09:06,280 do I stop the drug getting in? 179 00:09:06,280 --> 00:09:08,350 Do I stop it getting pumped out? 180 00:09:08,350 --> 00:09:10,420 Do I stop it getting degraded? 181 00:09:10,420 --> 00:09:12,340 Do I make more target? 182 00:09:12,340 --> 00:09:14,380 All of those things are very viable, 183 00:09:14,380 --> 00:09:17,380 and they are strategies that are used quite commonly. 184 00:09:17,380 --> 00:09:23,710 So very commonly, both in bacteria and in viruses, 185 00:09:23,710 --> 00:09:25,960 we seldom give one compound. 186 00:09:25,960 --> 00:09:29,820 We commonly give multiple compounds 187 00:09:29,820 --> 00:09:32,740 to sort of hit multiple targets, because if you 188 00:09:32,740 --> 00:09:36,790 gave a two-drug cocktail to a bacterium, 189 00:09:36,790 --> 00:09:40,030 but you knew there was going to be upregulation of a target, 190 00:09:40,030 --> 00:09:43,540 you could hope that the other enzyme is still a target. 191 00:09:43,540 --> 00:09:48,150 So you give cocktails of drugs, as opposed to single drugs. 192 00:09:48,150 --> 00:09:50,590 And you're going to see that very relevantly when 193 00:09:50,590 --> 00:09:54,430 we talk about the HIV virus because it's only 194 00:09:54,430 --> 00:09:57,880 been that HIV has become-- 195 00:09:57,880 --> 00:10:01,450 HIV-AIDS has become a treatable condition 196 00:10:01,450 --> 00:10:04,750 because of drug cocktails, not because of singular drugs that 197 00:10:04,750 --> 00:10:06,280 inhibit one step. 198 00:10:06,280 --> 00:10:08,470 And you'll see it very, very commonly there. 199 00:10:08,470 --> 00:10:11,240 Any questions about this stuff? 200 00:10:11,240 --> 00:10:11,803 OK. 201 00:10:11,803 --> 00:10:13,345 So we're going to move on to viruses. 202 00:10:26,530 --> 00:10:31,330 And so I will actually update the slides that are on the web 203 00:10:31,330 --> 00:10:33,790 to give you this set of information 204 00:10:33,790 --> 00:10:36,520 so you can see it in one place. 205 00:10:36,520 --> 00:10:37,160 OK, viruses. 206 00:10:47,480 --> 00:10:51,350 Viruses are fascinating organisms. 207 00:10:51,350 --> 00:10:53,300 They don't have the right to be alive 208 00:10:53,300 --> 00:10:56,720 because they don't have the machinery to be alive, 209 00:10:56,720 --> 00:10:59,690 but they exploit the host's mechanisms 210 00:10:59,690 --> 00:11:01,950 for completing their viability. 211 00:11:01,950 --> 00:11:05,030 So viruses, more or less, I think 212 00:11:05,030 --> 00:11:11,120 we like to think of them as living a borrowed life. 213 00:11:14,900 --> 00:11:23,000 And they only survive if they have spent 214 00:11:23,000 --> 00:11:25,430 some time inside a host cell. 215 00:11:45,090 --> 00:11:48,440 So we will see with viruses, some viruses specifically 216 00:11:48,440 --> 00:11:50,510 target humans. 217 00:11:50,510 --> 00:11:54,050 Other viruses may spend some time in different organisms, 218 00:11:54,050 --> 00:11:56,960 and then target humans, and be carried around 219 00:11:56,960 --> 00:11:59,430 amongst different organisms. 220 00:11:59,430 --> 00:12:02,270 But the key thing is that viruses can only 221 00:12:02,270 --> 00:12:05,750 actually replicate once they're inside a host cell 222 00:12:05,750 --> 00:12:08,780 because they basically exploit all of the host cell's 223 00:12:08,780 --> 00:12:10,520 machinery to do that. 224 00:12:10,520 --> 00:12:13,850 So viruses don't make many of their own enzymes. 225 00:12:13,850 --> 00:12:16,670 They don't have their own amino acid supplies 226 00:12:16,670 --> 00:12:19,520 or all the metabolic enzymes that 227 00:12:19,520 --> 00:12:23,550 are required for life, all the replication, transcription, 228 00:12:23,550 --> 00:12:25,370 translation machinery. 229 00:12:25,370 --> 00:12:27,590 They just borrow the host's machinery, 230 00:12:27,590 --> 00:12:31,160 but there are occasionally individual components 231 00:12:31,160 --> 00:12:33,960 that the virus will bring along with it 232 00:12:33,960 --> 00:12:37,850 to cover certain things that are not provided by the hosts. 233 00:12:37,850 --> 00:12:39,890 But viral genomes are tiny. 234 00:12:39,890 --> 00:12:43,130 They may comprise maybe eight genes. 235 00:12:43,130 --> 00:12:45,010 Some of them are a lot-- are bigger, 236 00:12:45,010 --> 00:12:48,000 but they are very, very small genomes. 237 00:12:48,000 --> 00:12:51,890 They're very, what we call, parsimonious genomes, 238 00:12:51,890 --> 00:12:54,320 so there's overlapping genes, so you can keep 239 00:12:54,320 --> 00:12:56,960 the genome tiny by having-- 240 00:12:56,960 --> 00:12:59,720 compacting the size of the genome. 241 00:12:59,720 --> 00:13:01,890 And then there are bigger viruses. 242 00:13:01,890 --> 00:13:05,570 Some of the biggest viruses approach the sizes of bacteria, 243 00:13:05,570 --> 00:13:07,820 like the mimiviruses, and they may 244 00:13:07,820 --> 00:13:11,150 have been an intermediate step from virus 245 00:13:11,150 --> 00:13:14,420 to more elaborated organisms. 246 00:13:14,420 --> 00:13:17,240 And those viruses have a bit more machinery 247 00:13:17,240 --> 00:13:18,740 within their contexts. 248 00:13:18,740 --> 00:13:23,720 People-- obviously, there's no fossil record for viruses. 249 00:13:23,720 --> 00:13:27,800 It's not like we can go, you know, go exploring 250 00:13:27,800 --> 00:13:29,690 and find a fossil record. 251 00:13:29,690 --> 00:13:31,580 But where these viruses are being found 252 00:13:31,580 --> 00:13:34,310 is in the permafrost, so they're frozen. 253 00:13:34,310 --> 00:13:37,160 They've been frozen there for centuries. 254 00:13:37,160 --> 00:13:39,740 So people are finding really sort of scary things 255 00:13:39,740 --> 00:13:42,680 in the Siberian permafrost because the viruses are 256 00:13:42,680 --> 00:13:44,300 preserved there. 257 00:13:44,300 --> 00:13:47,000 And some of these giant viruses are being 258 00:13:47,000 --> 00:13:49,130 discovered in those locations. 259 00:13:49,130 --> 00:13:53,120 And if that's not the subject for wonderful sci-fi books, 260 00:13:53,120 --> 00:13:56,060 I don't know what is, because there are-- and I 261 00:13:56,060 --> 00:13:58,850 tend to read those things because my favorite thing is 262 00:13:58,850 --> 00:14:01,610 finding mistakes in them. 263 00:14:01,610 --> 00:14:04,620 So there's a lot out there about those kinds of things. 264 00:14:04,620 --> 00:14:08,642 So let me just show you a tiny bit about-- 265 00:14:08,642 --> 00:14:11,710 you know, this is that boring old "learn genetics" thing 266 00:14:11,710 --> 00:14:15,280 right from the beginning, but what I want to take you back to 267 00:14:15,280 --> 00:14:16,210 is sizes. 268 00:14:16,210 --> 00:14:17,380 So we know all this stuff. 269 00:14:17,380 --> 00:14:20,535 We've learned it to death, hemoglobin, antibodies, 270 00:14:20,535 --> 00:14:22,030 and ribosome. 271 00:14:22,030 --> 00:14:25,870 But what I really want to point out on this slide is that 272 00:14:25,870 --> 00:14:29,170 the smallest viruses, like the rhinovirus-- 273 00:14:29,170 --> 00:14:30,730 that's the common cold-- 274 00:14:30,730 --> 00:14:34,120 or the hepatitis virus are not barely any bigger 275 00:14:34,120 --> 00:14:36,250 than the ribosome. 276 00:14:36,250 --> 00:14:39,370 So obviously, there's not much in the virus, 277 00:14:39,370 --> 00:14:41,680 but all the components of the virus 278 00:14:41,680 --> 00:14:48,130 have evolved to enable them to sneakily get into host cells, 279 00:14:48,130 --> 00:14:52,030 exploit the host cell machinery, and then replicate 280 00:14:52,030 --> 00:14:55,330 inside host cell, and then get out of the host cell 281 00:14:55,330 --> 00:14:58,940 and ready to infect another host cell. 282 00:14:58,940 --> 00:15:02,030 So I want you to really notice these sizes. 283 00:15:02,030 --> 00:15:05,650 So the rhinovirus is similar to a ribosome, 284 00:15:05,650 --> 00:15:08,980 but some viruses, which we will talk about, 285 00:15:08,980 --> 00:15:13,840 the influenza virus and the HIV virus are a little bigger, 286 00:15:13,840 --> 00:15:17,820 but none of them compete up to the size of a bacterium. 287 00:15:17,820 --> 00:15:22,900 And just to get you into that mode, there are the bacteria, 288 00:15:22,900 --> 00:15:25,030 and there's the mitochondria, and remember 289 00:15:25,030 --> 00:15:28,690 endosymbiotic theory, bacteria, similar size to mitochondria, 290 00:15:28,690 --> 00:15:32,880 and much, much bigger than any typical virus. 291 00:15:32,880 --> 00:15:37,060 But giant viruses approach some of these bigger sizes. 292 00:15:37,060 --> 00:15:38,790 They're a different ballgame altogether. 293 00:15:38,790 --> 00:15:41,890 And we won't talk about them, apart from the fact 294 00:15:41,890 --> 00:15:44,396 that they're really cool, and they're in the permafrost. 295 00:15:53,080 --> 00:15:56,680 All right, so another impressive thing 296 00:15:56,680 --> 00:16:01,300 about viruses, as they look-- some of them like this. 297 00:16:01,300 --> 00:16:05,110 Phage, a bacterial virus, they look like things, 298 00:16:05,110 --> 00:16:09,530 lunar landers, for example, or sort of other kinds of things. 299 00:16:09,530 --> 00:16:11,110 Some of them are linear. 300 00:16:11,110 --> 00:16:13,510 Some of them are different kinds of shapes. 301 00:16:13,510 --> 00:16:15,760 A lot of viruses are icosahedra. 302 00:16:15,760 --> 00:16:19,320 We'll talk about that in a moment. 303 00:16:19,320 --> 00:16:22,330 But the fact sheet about viruses is first of all sizes. 304 00:16:26,230 --> 00:16:29,980 And the typical viral size, if there is something typical, 305 00:16:29,980 --> 00:16:35,710 expand from 20 to 400 nanometers in diameter. 306 00:16:39,080 --> 00:16:41,810 So remember, the ribosome sits right 307 00:16:41,810 --> 00:16:47,030 at this end with respect to size, but bacteria-- 308 00:16:47,030 --> 00:16:52,090 oh, yellow, I can't do a yellow lecture here-- 309 00:16:55,130 --> 00:16:59,060 remember, are 1 to 10 micrometers in length, 310 00:16:59,060 --> 00:17:01,730 depending on what dimension you're measuring, 311 00:17:01,730 --> 00:17:05,030 so considerably smaller, nanometer scale, 312 00:17:05,030 --> 00:17:07,589 micrometer scale for bacteria. 313 00:17:07,589 --> 00:17:10,910 So that's the first thing that it's important to know. 314 00:17:10,910 --> 00:17:13,760 They're very small. 315 00:17:13,760 --> 00:17:17,420 The next critical thing is what's in a virus? 316 00:17:17,420 --> 00:17:21,109 What is its-- what's the blood and guts of a virus? 317 00:17:21,109 --> 00:17:28,860 And it's either DNA or RNA, and it 318 00:17:28,860 --> 00:17:32,940 can be single-stranded or double-stranded. 319 00:17:32,940 --> 00:17:35,690 So it has its genetic material. 320 00:17:35,690 --> 00:17:38,910 Its genetic material is usually dedicated 321 00:17:38,910 --> 00:17:41,170 to making more copies of itself. 322 00:17:41,170 --> 00:17:45,180 So if the virus has a coat, a coat of proteins, 323 00:17:45,180 --> 00:17:47,460 the virus has to have a gene for that 324 00:17:47,460 --> 00:17:50,460 because the host isn't going to have a coat for a virus. 325 00:17:50,460 --> 00:17:53,820 So the virus has to have certain specialized things that 326 00:17:53,820 --> 00:17:58,950 complete itself that can't be borrowed from the host cell. 327 00:17:58,950 --> 00:18:02,280 And they can be-- 328 00:18:02,280 --> 00:18:07,420 let's see-- they can be what are called capsid viruses 329 00:18:07,420 --> 00:18:08,350 or enveloped. 330 00:18:12,730 --> 00:18:16,480 Capsid viruses just have a protein coat. 331 00:18:16,480 --> 00:18:20,260 The enveloped viruses have a membrane surrounding them 332 00:18:20,260 --> 00:18:22,420 with proteins stuck into them. 333 00:18:22,420 --> 00:18:31,400 So the enveloped viruses have an outer membrane 334 00:18:31,400 --> 00:18:32,995 which is studded with proteins. 335 00:18:35,860 --> 00:18:37,570 But what is cool about the virus is 336 00:18:37,570 --> 00:18:39,100 it never makes its own membranes. 337 00:18:39,100 --> 00:18:41,320 It doesn't make its phospholipids. 338 00:18:41,320 --> 00:18:44,470 It just, as it emerges from a host cell, 339 00:18:44,470 --> 00:18:47,690 pinches a piece of the cell surface. 340 00:18:47,690 --> 00:18:50,500 It steals the cellular membrane with it, 341 00:18:50,500 --> 00:18:52,660 as it's emerging from a cell. 342 00:18:52,660 --> 00:18:55,630 And you'll see this in a video, how cool that 343 00:18:55,630 --> 00:18:59,890 is, all the proteins that-- all the components of the virus 344 00:18:59,890 --> 00:19:02,500 cluster near the surface of a membrane, 345 00:19:02,500 --> 00:19:05,560 and then you have this wonderful endocytosis 346 00:19:05,560 --> 00:19:07,190 using the host membrane. 347 00:19:07,190 --> 00:19:11,232 So the virus never has to make it own membrane. 348 00:19:11,232 --> 00:19:14,960 And not all viruses are enveloped, just some of them, 349 00:19:14,960 --> 00:19:17,540 and you'll see examples of each. 350 00:19:17,540 --> 00:19:19,400 So the definition really is that they're 351 00:19:19,400 --> 00:19:22,270 small, infectious agents, that they only 352 00:19:22,270 --> 00:19:25,870 replicate inside living cells because they 353 00:19:25,870 --> 00:19:30,040 have to exploit a lot of the machinery of living cells. 354 00:19:30,040 --> 00:19:34,150 And they can infect humans, other animals. 355 00:19:34,150 --> 00:19:35,860 There are plant viruses. 356 00:19:35,860 --> 00:19:37,450 Bacteria have viruses. 357 00:19:37,450 --> 00:19:42,100 So all living organisms have viruses that infect them. 358 00:19:42,100 --> 00:19:46,630 But viruses are usually targeted very specifically to the cells 359 00:19:46,630 --> 00:19:47,950 that they infect. 360 00:19:47,950 --> 00:19:50,530 And, in fact, you will see with HIV, 361 00:19:50,530 --> 00:19:54,100 it's not just a virus that infects a human host. 362 00:19:54,100 --> 00:19:56,140 It infects specifically, and that 363 00:19:56,140 --> 00:20:00,830 was why it was so terrifying, this-- actually T cells. 364 00:20:00,830 --> 00:20:04,720 That's the one cell type in the host that it goes after. 365 00:20:04,720 --> 00:20:10,210 So viruses very often target to particular organs 366 00:20:10,210 --> 00:20:13,810 within their hosts, and that's why 367 00:20:13,810 --> 00:20:15,250 we know some of the viruses. 368 00:20:15,250 --> 00:20:17,770 And you'll see that the names of the viruses 369 00:20:17,770 --> 00:20:22,300 are related to the organs that they may infect. 370 00:20:22,300 --> 00:20:24,970 So I want to just briefly describe the terms. 371 00:20:24,970 --> 00:20:30,100 We talk about these with all infectious diseases, 372 00:20:30,100 --> 00:20:35,440 that they may be endemic, epidemic, and pandemic. 373 00:20:35,440 --> 00:20:38,710 Endemic is the term that we use for, there's 374 00:20:38,710 --> 00:20:41,830 a very low level of an infectious agent 375 00:20:41,830 --> 00:20:43,420 in the population. 376 00:20:43,420 --> 00:20:45,760 It's completely out of-- 377 00:20:45,760 --> 00:20:47,230 within control. 378 00:20:47,230 --> 00:20:49,710 There's a few cases, but there's not 379 00:20:49,710 --> 00:20:53,200 a transfer from person to person or animal to animal. 380 00:20:53,200 --> 00:20:57,550 We would call that endemic, a very, very low level of virus 381 00:20:57,550 --> 00:20:59,920 that doesn't cause any threat. 382 00:20:59,920 --> 00:21:04,390 As soon as the virus or bacterial infectious agents 383 00:21:04,390 --> 00:21:08,390 starts spreading amongst a local population, 384 00:21:08,390 --> 00:21:11,920 we would call that a local epidemic, so 385 00:21:11,920 --> 00:21:15,280 all of a community, all of a country, 386 00:21:15,280 --> 00:21:17,890 so very much defined geographically 387 00:21:17,890 --> 00:21:22,660 into a particular space where there's transmission of viruses 388 00:21:22,660 --> 00:21:26,980 from person to person or animal to person within a community. 389 00:21:26,980 --> 00:21:29,530 There has to be direct contact. 390 00:21:29,530 --> 00:21:34,480 But now, with travel, many viruses 391 00:21:34,480 --> 00:21:38,170 reach pandemic stages, which means worldwide. 392 00:21:38,170 --> 00:21:42,220 So plane travel really caused enormous trouble 393 00:21:42,220 --> 00:21:48,220 because you can have a virus in Africa or Asia. 394 00:21:48,220 --> 00:21:51,280 Somebody gets on a plane and ends up somewhere else, 395 00:21:51,280 --> 00:21:55,210 and the virus has been moved to a new country. 396 00:21:55,210 --> 00:22:00,430 I made the terrible mistake of reading Hot Zone on a plane one 397 00:22:00,430 --> 00:22:03,550 time, which is about Marburg virus, which 398 00:22:03,550 --> 00:22:07,820 is where people basically just start bleeding out in the spot. 399 00:22:07,820 --> 00:22:09,430 And I'm reading this book, and it's 400 00:22:09,430 --> 00:22:12,010 describing the steps of someone who 401 00:22:12,010 --> 00:22:15,310 had Marburg and was just sort of bleeding out next to them 402 00:22:15,310 --> 00:22:16,090 on the plane. 403 00:22:16,090 --> 00:22:19,450 And I'm like, are you crazy, reading this book on a plane? 404 00:22:19,450 --> 00:22:22,360 Because they were describing how Marburg was just 405 00:22:22,360 --> 00:22:26,770 moved from its country of origin to New York City, 406 00:22:26,770 --> 00:22:28,240 or something like that. 407 00:22:28,240 --> 00:22:32,410 So you remember when we had the Ebola concerns. 408 00:22:32,410 --> 00:22:35,260 There was a real, genuine worry that Ebola 409 00:22:35,260 --> 00:22:38,400 would jump through flight travel, 410 00:22:38,400 --> 00:22:40,590 through people coming in at airports, 411 00:22:40,590 --> 00:22:43,740 and end up with a pandemic of Ebola. 412 00:22:43,740 --> 00:22:50,070 When there was a real problem with the avian flu in Asia, 413 00:22:50,070 --> 00:22:54,030 Singapore, that's very, very protective of its territory, 414 00:22:54,030 --> 00:22:57,930 had sensors that would-- you would go into Singapore, 415 00:22:57,930 --> 00:23:00,960 and you'd go down these two huge escalators. 416 00:23:00,960 --> 00:23:03,750 And they had sensors measuring people's temperature 417 00:23:03,750 --> 00:23:08,220 at a distance as they came down the escalator, and hauling 418 00:23:08,220 --> 00:23:11,880 people over, and sort of interrogating them, 419 00:23:11,880 --> 00:23:13,140 where have you been?-- 420 00:23:13,140 --> 00:23:16,260 to see whether they would be allowed to enter Singapore, 421 00:23:16,260 --> 00:23:19,500 because the flight travel, people getting on planes, 422 00:23:19,500 --> 00:23:22,230 spreading a very contagious virus to a new country 423 00:23:22,230 --> 00:23:24,780 is very, very realistic. 424 00:23:24,780 --> 00:23:29,460 The issue with spreading to pandemic situations 425 00:23:29,460 --> 00:23:33,600 is very, very important when one thinks of history, 426 00:23:33,600 --> 00:23:39,030 because when the Europeans were conquering the Americas, 427 00:23:39,030 --> 00:23:42,210 in particular South America and Central America, 428 00:23:42,210 --> 00:23:45,070 they brought with them a lot of viruses. 429 00:23:45,070 --> 00:23:47,220 But there was an innate sort of resistance 430 00:23:47,220 --> 00:23:50,220 to-- because of years and years of exposure. 431 00:23:50,220 --> 00:23:53,520 But these communities have never seen these viruses, 432 00:23:53,520 --> 00:23:56,910 so millions of people died because they were suddenly 433 00:23:56,910 --> 00:24:01,110 exposed to a human virus that they had never seen before, 434 00:24:01,110 --> 00:24:04,650 through transmission from a country where there wasn't 435 00:24:04,650 --> 00:24:06,700 such a problem with the virus. 436 00:24:06,700 --> 00:24:11,430 So the indigenous peoples of the Americas, Australia, 437 00:24:11,430 --> 00:24:15,810 and New Zealand had terrible consequences there. 438 00:24:15,810 --> 00:24:18,690 Some of you have probably heard of the Spanish flu, 439 00:24:18,690 --> 00:24:23,460 and that was towards the tail end of World War I 440 00:24:23,460 --> 00:24:27,010 and is thought to have killed as many as 100 million people. 441 00:24:27,010 --> 00:24:29,760 And that, in fact, is quite interesting. 442 00:24:29,760 --> 00:24:32,910 It's called the Spanish flu, but there's some evidence 443 00:24:32,910 --> 00:24:35,670 that it might have originated in the Americas, 444 00:24:35,670 --> 00:24:39,300 in the boats that took troops over to Europe 445 00:24:39,300 --> 00:24:41,740 to help at the tail end of the First World War. 446 00:24:41,740 --> 00:24:45,330 And there's a really interesting book about that whole story, 447 00:24:45,330 --> 00:24:48,780 that the Spanish flu may not have originated in Spain. 448 00:24:48,780 --> 00:24:51,510 And that's a-- it's definitely a worthwhile read. 449 00:24:51,510 --> 00:24:56,370 So that tells you a lot about the statistics of viruses. 450 00:24:56,370 --> 00:25:01,050 I just want to highlight here, we talk about HIV 451 00:25:01,050 --> 00:25:03,420 as a very serious virus. 452 00:25:03,420 --> 00:25:08,790 It emerged in the early '80s to this current-- 453 00:25:08,790 --> 00:25:13,320 well, in 2011, there were 35 million people infected. 454 00:25:13,320 --> 00:25:17,040 There's about 2 and 1/2 million new cases a year. 455 00:25:17,040 --> 00:25:20,190 But what's fascinating about HIV-- 456 00:25:20,190 --> 00:25:23,010 there was a stage before the really good antivirals 457 00:25:23,010 --> 00:25:26,520 were available that, if the mother had HIV, 458 00:25:26,520 --> 00:25:28,920 the baby would get HIV. 459 00:25:28,920 --> 00:25:31,950 But now, if there's treatment of the mother, 460 00:25:31,950 --> 00:25:36,330 and the baby is delivered, often by a Caesarean section, 461 00:25:36,330 --> 00:25:39,390 the baby can escape being infected 462 00:25:39,390 --> 00:25:41,760 with the virus due to the new antivirals. 463 00:25:41,760 --> 00:25:44,220 So that's really important, that the-- 464 00:25:44,220 --> 00:25:46,920 originally, there were a lot of cases of newborns who 465 00:25:46,920 --> 00:25:50,280 simply got HIV during birth. 466 00:25:50,280 --> 00:25:53,520 But now that can be-- there's escape from that, 467 00:25:53,520 --> 00:25:54,840 which is really, really cool. 468 00:25:54,840 --> 00:25:57,450 The viral load can be brought really low 469 00:25:57,450 --> 00:26:00,570 with the common antivirals against HIV, 470 00:26:00,570 --> 00:26:05,700 and that next generation doesn't have that sentence. 471 00:26:05,700 --> 00:26:08,310 So I mentioned to you that a lot of viruses 472 00:26:08,310 --> 00:26:12,720 are basically named after the organs that they hit. 473 00:26:12,720 --> 00:26:14,820 So I've just got a human being here 474 00:26:14,820 --> 00:26:18,020 with a lot of different viruses that hit different places, 475 00:26:18,020 --> 00:26:21,480 and I just want to point out a few points. 476 00:26:21,480 --> 00:26:26,520 Viruses may be targets nowadays of childhood vaccinations, 477 00:26:26,520 --> 00:26:27,450 and many of you-- 478 00:26:27,450 --> 00:26:29,280 I hope all of you-- 479 00:26:29,280 --> 00:26:33,540 have had vaccinations to many of these common viruses. 480 00:26:33,540 --> 00:26:37,980 There is a concern now with communities that are deciding 481 00:26:37,980 --> 00:26:41,700 not to vaccinate children. 482 00:26:41,700 --> 00:26:45,960 That's a huge social problem that may, initially, sort of, 483 00:26:45,960 --> 00:26:48,750 people can get away with it because there's 484 00:26:48,750 --> 00:26:50,820 community vaccination. 485 00:26:50,820 --> 00:26:53,130 You're in a community where a lot of people 486 00:26:53,130 --> 00:27:00,420 have a resistance or some sort of immunity to a virus. 487 00:27:00,420 --> 00:27:04,440 But as communities become less and less vaccinated, 488 00:27:04,440 --> 00:27:06,390 than later generations will start 489 00:27:06,390 --> 00:27:08,400 to get the disease seriously. 490 00:27:08,400 --> 00:27:10,860 And that's actually happening in parts of the world where 491 00:27:10,860 --> 00:27:11,440 there's-- 492 00:27:11,440 --> 00:27:14,280 there used to be no polio, and now there's 493 00:27:14,280 --> 00:27:18,630 polio emerging because the community immunity has 494 00:27:18,630 --> 00:27:20,280 been-- is fading away. 495 00:27:20,280 --> 00:27:25,530 So we hope that people get vaccinated. 496 00:27:25,530 --> 00:27:26,970 That's for sure. 497 00:27:26,970 --> 00:27:28,800 The vaccinations work. 498 00:27:28,800 --> 00:27:32,310 Several vaccinations-- several viruses 499 00:27:32,310 --> 00:27:34,410 were pretty much eradicated. 500 00:27:34,410 --> 00:27:39,360 Smallpox and polio were two of the real poster examples 501 00:27:39,360 --> 00:27:42,300 of childhood vaccinations that worked 502 00:27:42,300 --> 00:27:44,400 and worked amazingly well. 503 00:27:44,400 --> 00:27:46,590 But now, there's a problem with failure 504 00:27:46,590 --> 00:27:49,900 to vaccinate in certain parts of the world. 505 00:27:49,900 --> 00:27:51,420 So that's a concern. 506 00:27:51,420 --> 00:27:55,080 And then, another interesting thing is that some viruses-- 507 00:27:55,080 --> 00:27:58,070 whoops, oops, go back. 508 00:27:58,070 --> 00:27:58,570 Sorry. 509 00:27:58,570 --> 00:27:59,690 Go back, back, back, back. 510 00:27:59,690 --> 00:28:01,023 Don't now-- that's all a secret. 511 00:28:01,023 --> 00:28:02,560 You can't see that just yet. 512 00:28:02,560 --> 00:28:06,910 Some viruses lead to cancer, so human papilloma virus, 513 00:28:06,910 --> 00:28:11,800 where there is a vaccine, the people who have HIV-- 514 00:28:11,800 --> 00:28:15,730 some of the types of hepatitis and Epstein-Barr 515 00:28:15,730 --> 00:28:19,630 are all associated with later cases of cancer. 516 00:28:19,630 --> 00:28:21,040 That's important to know. 517 00:28:21,040 --> 00:28:25,090 So often cancers are named by the organ that they attach, 518 00:28:25,090 --> 00:28:27,100 so even though the three-- 519 00:28:27,100 --> 00:28:32,020 the five hepatitises all attack the liver, they're not related. 520 00:28:32,020 --> 00:28:35,210 They're just five viruses that go off to the liver. 521 00:28:35,210 --> 00:28:38,060 So if you've had a vaccination against Hep A, 522 00:28:38,060 --> 00:28:41,892 It doesn't protect you from Hep B or C by a relationship. 523 00:28:41,892 --> 00:28:43,600 They're very, very different, so you have 524 00:28:43,600 --> 00:28:45,860 to have different vaccinations. 525 00:28:45,860 --> 00:28:49,610 So this just gives you a nice view of human viruses, 526 00:28:49,610 --> 00:28:52,510 what their names are, what organs they may attack, 527 00:28:52,510 --> 00:28:55,450 what sorts of things they might be associated with. 528 00:28:55,450 --> 00:28:58,360 But the trouble is, this nomenclature doesn't get you 529 00:28:58,360 --> 00:29:02,780 anywhere towards understanding the mechanism of a virus. 530 00:29:02,780 --> 00:29:07,210 So what we will focus on is a much better system 531 00:29:07,210 --> 00:29:10,060 for describing viruses that's based 532 00:29:10,060 --> 00:29:15,010 on whether they have DNA or RNA within the genomes 533 00:29:15,010 --> 00:29:17,430 that they import into host cells, 534 00:29:17,430 --> 00:29:20,980 and whether that DNA or RNA is single-stranded or 535 00:29:20,980 --> 00:29:24,100 double-stranded, because that truly tells us 536 00:29:24,100 --> 00:29:27,280 a lot more about the virus and maybe the steps that 537 00:29:27,280 --> 00:29:30,880 could be inhibited to prevent the viral infections. 538 00:29:30,880 --> 00:29:33,050 But first of all, just a few pictures-- 539 00:29:33,050 --> 00:29:36,350 here's some-- so viruses can be rod-shaped. 540 00:29:36,350 --> 00:29:37,510 They can look like-- 541 00:29:37,510 --> 00:29:39,640 they can be icosahedra. 542 00:29:39,640 --> 00:29:41,860 They can just have a capsid. 543 00:29:41,860 --> 00:29:44,380 So I mentioned they may just have a protein 544 00:29:44,380 --> 00:29:49,600 coat, the sets of repeating proteins that 545 00:29:49,600 --> 00:29:54,010 pack into a beautiful structure, very commonly an icosahedron, 546 00:29:54,010 --> 00:29:56,290 and I'll show you why that is. 547 00:29:56,290 --> 00:29:59,290 Or they may be enveloped viruses, 548 00:29:59,290 --> 00:30:04,180 like, influenza has a membranous surface around where 549 00:30:04,180 --> 00:30:05,560 the DNA is packaged. 550 00:30:05,560 --> 00:30:08,800 All of these have nucleic acids packaged within them, 551 00:30:08,800 --> 00:30:12,070 DNA or RNA, single or double-stranded. 552 00:30:12,070 --> 00:30:15,240 And in the case of the enveloped viruses, 553 00:30:15,240 --> 00:30:18,070 that membrane-- it's a normal membrane. 554 00:30:18,070 --> 00:30:19,600 It's just like your membrane. 555 00:30:19,600 --> 00:30:22,070 In fact, it is your membrane-- 556 00:30:22,070 --> 00:30:24,730 will have proteins dotted within it 557 00:30:24,730 --> 00:30:28,750 that's actually-- serve as recognition to the host cells. 558 00:30:28,750 --> 00:30:32,680 They'll grab onto host cells and be the source of the infection 559 00:30:32,680 --> 00:30:34,405 into the host cells. 560 00:30:34,405 --> 00:30:39,037 And this is a bacterial virus, and as I said, 561 00:30:39,037 --> 00:30:40,120 I just love the way they-- 562 00:30:40,120 --> 00:30:41,650 I mean, they really look like this. 563 00:30:41,650 --> 00:30:43,748 You know, the cartoon is really the cartoon 564 00:30:43,748 --> 00:30:45,790 of what the thing looks like, and they're sort of 565 00:30:45,790 --> 00:30:46,810 pretty amazing. 566 00:30:46,810 --> 00:30:48,220 And they kind of-- 567 00:30:48,220 --> 00:30:51,970 they keep their nucleic acid in the head here. 568 00:30:51,970 --> 00:30:56,320 They land on their sort of feet, and they shoot the nucleic acid 569 00:30:56,320 --> 00:30:58,580 material into the host cells. 570 00:30:58,580 --> 00:31:00,590 So that's very interesting. 571 00:31:00,590 --> 00:31:02,330 Of course, this thing is-- 572 00:31:02,330 --> 00:31:02,830 OK. 573 00:31:02,830 --> 00:31:08,450 So why are many viruses that are capsid viruses icosahedra? 574 00:31:08,450 --> 00:31:13,120 So it ends up being a problem of geometry. 575 00:31:13,120 --> 00:31:18,640 So how can you make a perfect coat around something 576 00:31:18,640 --> 00:31:21,820 with very, very few building blocks of different types? 577 00:31:21,820 --> 00:31:25,220 Like, if every building block in that coat was different, 578 00:31:25,220 --> 00:31:28,150 the virus would have to have genes for all of them. 579 00:31:28,150 --> 00:31:30,370 What viruses can do is they can have 580 00:31:30,370 --> 00:31:34,540 genes for, like, three pieces of a module of the virus. 581 00:31:34,540 --> 00:31:38,020 So I'm going to show you how these capsid viruses get 582 00:31:38,020 --> 00:31:39,640 assembled. 583 00:31:39,640 --> 00:31:44,260 So here, color-coded, is an icosahedral virus, 584 00:31:44,260 --> 00:31:49,330 where I've coded in the red, green, and blue, 585 00:31:49,330 --> 00:31:52,510 a triangular component-- this is really cool-- 586 00:31:52,510 --> 00:31:57,970 that is a single sort of panel on that icosahedral virus that 587 00:31:57,970 --> 00:32:00,310 comes together as a triangle through 588 00:32:00,310 --> 00:32:05,110 noncovalent interactions between three proteins. 589 00:32:05,110 --> 00:32:07,210 You see that panel there. 590 00:32:07,210 --> 00:32:10,510 What you can then do is see how that panel would 591 00:32:10,510 --> 00:32:14,920 fit into a pentagon with an extra triangle stuck onto it, 592 00:32:14,920 --> 00:32:20,290 and you can fit that triangle into the pentagon 593 00:32:20,290 --> 00:32:22,700 and also into the additional piece. 594 00:32:22,700 --> 00:32:24,850 And then you can start to visualize 595 00:32:24,850 --> 00:32:29,200 how you could build an icosahedron from those pieces 596 00:32:29,200 --> 00:32:34,120 because they represent each of those faces within the virus. 597 00:32:34,120 --> 00:32:40,210 So you can go from this, which is a set of building blocks 598 00:32:40,210 --> 00:32:41,660 that I just showed you-- 599 00:32:41,660 --> 00:32:43,840 then you can assemble them like this. 600 00:32:43,840 --> 00:32:48,070 And one of these would be this part of the icosahedron, 601 00:32:48,070 --> 00:32:52,570 and then you just have a bunch of copies of it. 602 00:32:52,570 --> 00:32:54,810 And you can see how you would assemble that. 603 00:32:54,810 --> 00:32:58,710 And years ago, I decided to decorate my Christmas tree 604 00:32:58,710 --> 00:33:00,370 with icosahedra. 605 00:33:00,370 --> 00:33:03,450 So I went through this geometrical thing, 606 00:33:03,450 --> 00:33:05,320 and believe me, it works really nicely. 607 00:33:05,320 --> 00:33:08,220 You can put together an icosahedron 608 00:33:08,220 --> 00:33:09,880 and build an icosahedron. 609 00:33:09,880 --> 00:33:12,330 You could spray it gold and put it on your Christmas tree. 610 00:33:12,330 --> 00:33:14,550 It's kind of fanatical, but it really-- it's 611 00:33:14,550 --> 00:33:17,670 highly recommended. 612 00:33:17,670 --> 00:33:20,670 All right, so let's now get down to something a little bit more 613 00:33:20,670 --> 00:33:23,820 serious than Christmas trees and things. 614 00:33:23,820 --> 00:33:30,450 All right, so I told you that the classification of viruses 615 00:33:30,450 --> 00:33:35,240 by what organ they attack or who discovered them or anything 616 00:33:35,240 --> 00:33:36,060 is just-- 617 00:33:36,060 --> 00:33:39,960 is a vagary that's not so useful to the non-physicians 618 00:33:39,960 --> 00:33:41,950 because you can't immediately know, 619 00:33:41,950 --> 00:33:45,300 oh, this is how the virus gets into the host cell. 620 00:33:45,300 --> 00:33:48,930 This is how the virus uses its genetic material 621 00:33:48,930 --> 00:33:50,760 to make new viruses. 622 00:33:50,760 --> 00:33:53,280 So what was developed by Baltimore-- 623 00:33:53,280 --> 00:33:55,540 David Baltimore used to be at-- 624 00:33:55,540 --> 00:33:56,880 it was kind of interesting. 625 00:33:56,880 --> 00:34:00,220 David Baltimore, a very famous person and Nobel laureate, 626 00:34:00,220 --> 00:34:04,020 used to be at MIT when I was at Caltech, 627 00:34:04,020 --> 00:34:05,880 and we moved in opposite directions. 628 00:34:05,880 --> 00:34:07,830 I'm not sure it was a great trade for MIT, 629 00:34:07,830 --> 00:34:10,150 but it was a great trade for Caltech. 630 00:34:10,150 --> 00:34:13,409 So I ended up with David Baltimore's labs in Building 68 631 00:34:13,409 --> 00:34:18,270 because we did that swap in 1999 or something like that. 632 00:34:18,270 --> 00:34:20,219 So I thought that was pretty interesting. 633 00:34:20,219 --> 00:34:23,310 Anyway, so what Baltimore decided 634 00:34:23,310 --> 00:34:26,940 is-- was much better to classify viruses 635 00:34:26,940 --> 00:34:31,568 by the type of genetic material, like, are they DNA or RNA? 636 00:34:31,568 --> 00:34:34,530 Is that DNA or RNA single-stranded or 637 00:34:34,530 --> 00:34:35,850 double-stranded? 638 00:34:35,850 --> 00:34:39,989 Because, depending on what the genetic material in the virus 639 00:34:39,989 --> 00:34:44,370 is, once that gets unloaded into a host cell, 640 00:34:44,370 --> 00:34:47,219 certain steps have to happen in order for the virus 641 00:34:47,219 --> 00:34:50,159 to be able to replicate that genetic material, 642 00:34:50,159 --> 00:34:53,310 to convert it ultimately into the proteins 643 00:34:53,310 --> 00:34:59,340 it needs, and then to package up new viral genetic material 644 00:34:59,340 --> 00:35:02,940 into viral capsids so that they can then 645 00:35:02,940 --> 00:35:06,760 be sprung out of the cell and go infect another cell. 646 00:35:06,760 --> 00:35:11,050 So the classification basically went this way. 647 00:35:11,050 --> 00:35:17,070 So if you think of it, what the major goal in the infected cell 648 00:35:17,070 --> 00:35:20,850 is to get the virus to a stage where the virus has 649 00:35:20,850 --> 00:35:22,920 plus-messenger RNA. 650 00:35:22,920 --> 00:35:27,960 It has RNA that can be read by the host's ribosomes 651 00:35:27,960 --> 00:35:29,950 and convert it into proteins. 652 00:35:29,950 --> 00:35:32,130 So the overall goal of the virus, 653 00:35:32,130 --> 00:35:36,930 if we give it sort of some conscience, shall we say, 654 00:35:36,930 --> 00:35:41,710 is to make its viral material into messenger RNA. 655 00:35:41,710 --> 00:35:44,580 Now, the virus doesn't include messenger RNA. 656 00:35:44,580 --> 00:35:47,070 That's just what is made transiently, 657 00:35:47,070 --> 00:35:50,550 but the virus may have single-stranded DNA. 658 00:35:50,550 --> 00:35:53,490 It may have plus-sense RNA. 659 00:35:53,490 --> 00:35:55,890 It may have negative-sense RNA. 660 00:35:55,890 --> 00:35:58,440 It could have double-stranded DNA, 661 00:35:58,440 --> 00:36:01,560 or it could even have double-stranded RNA. 662 00:36:01,560 --> 00:36:04,290 And depending on what that genetic material, 663 00:36:04,290 --> 00:36:07,170 is what the Baltimore classification of a virus 664 00:36:07,170 --> 00:36:07,920 would be. 665 00:36:07,920 --> 00:36:10,200 So depending on what's inside the virus, 666 00:36:10,200 --> 00:36:12,090 then they can be classified. 667 00:36:12,090 --> 00:36:15,540 And what we're going to go through today and on Friday 668 00:36:15,540 --> 00:36:22,020 is examples of class I, class V, and class VI viruses, 669 00:36:22,020 --> 00:36:26,130 so we can see how that genetic material ultimately 670 00:36:26,130 --> 00:36:28,310 becomes a new viral-- 671 00:36:28,310 --> 00:36:32,160 a new virus within a host cell, or at least the components 672 00:36:32,160 --> 00:36:36,070 thereof ready to be sprung out of a virus. 673 00:36:36,070 --> 00:36:44,040 And there's one important point that I want to also address-- 674 00:36:44,040 --> 00:36:49,740 oops-- budding or lytic. 675 00:36:49,740 --> 00:36:52,890 All right, there are two ways in which 676 00:36:52,890 --> 00:36:56,160 viruses escape their host cell. 677 00:36:56,160 --> 00:36:59,190 They may be budding. 678 00:36:59,190 --> 00:37:02,280 So here you have a host cell. 679 00:37:02,280 --> 00:37:04,740 The viral components all congregate 680 00:37:04,740 --> 00:37:08,970 near the surface of the membrane from the inside, 681 00:37:08,970 --> 00:37:12,710 and then the host cell buds off. 682 00:37:12,710 --> 00:37:17,790 The viral components go with it, and the bud splits off. 683 00:37:17,790 --> 00:37:20,370 So the host cell has its nucleus. 684 00:37:20,370 --> 00:37:21,840 It's still intact. 685 00:37:21,840 --> 00:37:23,970 HIV is such a virus. 686 00:37:23,970 --> 00:37:26,190 HIV doesn't kill its hosts. 687 00:37:26,190 --> 00:37:27,820 That's the best sign of a parasite. 688 00:37:27,820 --> 00:37:31,650 It wants the host to stick around, so it just buds off. 689 00:37:31,650 --> 00:37:37,410 The other types of viruses are lytic, 690 00:37:37,410 --> 00:37:42,720 and, basically, the cell just bursts open and throws out 691 00:37:42,720 --> 00:37:43,260 the virus. 692 00:37:43,260 --> 00:37:45,290 So they're in two categories. 693 00:37:45,290 --> 00:37:48,413 Some of them are budding, though the enveloped viruses 694 00:37:48,413 --> 00:37:49,830 have to be budding because they're 695 00:37:49,830 --> 00:37:53,250 going to take with them the membrane of the host cell. 696 00:37:53,250 --> 00:37:53,910 All right? 697 00:37:53,910 --> 00:37:56,980 So that's another important difference. 698 00:37:56,980 --> 00:37:59,350 So what have we got here? 699 00:37:59,350 --> 00:38:04,050 So ultimately, the goal is to be able to make a plus-strand mRNA 700 00:38:04,050 --> 00:38:06,010 for protein synthesis. 701 00:38:06,010 --> 00:38:10,320 So we really need to have the appropriate sense of the RNA 702 00:38:10,320 --> 00:38:13,420 that will dictate the protein synthesis. 703 00:38:13,420 --> 00:38:16,520 So let's first of all look at one of the simple versions, 704 00:38:16,520 --> 00:38:18,930 a double-stranded DNA virus. 705 00:38:18,930 --> 00:38:23,280 And this is represented by the smallpox virus. 706 00:38:23,280 --> 00:38:27,900 So everybody's heard of that, and herpes simplex. 707 00:38:27,900 --> 00:38:30,090 And these are both enveloped viruses, 708 00:38:30,090 --> 00:38:33,305 so that means they have a membrane shell. 709 00:38:33,305 --> 00:38:34,680 And so I'm just going to walk you 710 00:38:34,680 --> 00:38:37,920 through the steps of going from the double-stranded DNA 711 00:38:37,920 --> 00:38:39,420 to make a new virus. 712 00:38:39,420 --> 00:38:40,950 So here's the virus. 713 00:38:40,950 --> 00:38:46,500 It has a capsid, as well as a membrane envelope. 714 00:38:46,500 --> 00:38:50,310 And there's recognition between the virus and the host cell. 715 00:38:50,310 --> 00:38:54,090 And we'll talk very specifically about what that recognition is 716 00:38:54,090 --> 00:38:58,530 when we talk about HIV, because that's very well categorized. 717 00:38:58,530 --> 00:39:01,380 Once the virus gets into the host cell, 718 00:39:01,380 --> 00:39:05,340 it sort of spills off all the coat and dumps 719 00:39:05,340 --> 00:39:10,140 out its double-stranded DNA, the viral DNA, into the host cell. 720 00:39:10,140 --> 00:39:12,750 And then that DNA can-- 721 00:39:12,750 --> 00:39:15,570 in the nucleus, can replicate into more copies 722 00:39:15,570 --> 00:39:20,880 of the viral DNA, or it can be transcribed 723 00:39:20,880 --> 00:39:24,000 into messenger RNA, which is then 724 00:39:24,000 --> 00:39:28,830 the coat for all those capsid proteins that the virus needs. 725 00:39:28,830 --> 00:39:32,550 And then these start to self-assemble within the host 726 00:39:32,550 --> 00:39:37,170 cell where the capsid proteins wrap around 727 00:39:37,170 --> 00:39:39,450 the viral genetic material. 728 00:39:39,450 --> 00:39:42,870 They accumulate near the surface of the cell, 729 00:39:42,870 --> 00:39:45,520 and then they bud off from the cell. 730 00:39:45,520 --> 00:39:48,120 So that's how you go from simple DNA. 731 00:39:48,120 --> 00:39:51,450 So these processes are completely 732 00:39:51,450 --> 00:39:56,790 based on the human enzymes that do those processes. 733 00:39:56,790 --> 00:39:59,400 Replication, we've got to replicate DNA. 734 00:39:59,400 --> 00:40:01,553 We're going to have to do that in the nucleus. 735 00:40:01,553 --> 00:40:02,970 Transcription, we're going to have 736 00:40:02,970 --> 00:40:07,650 to ship out part of the DNA from the nucleus to the cytoplasm 737 00:40:07,650 --> 00:40:09,300 and make-- 738 00:40:09,300 --> 00:40:12,240 we're going to have to make a copy of the messenger RNA 739 00:40:12,240 --> 00:40:14,010 and ship it out to the nucleus. 740 00:40:14,010 --> 00:40:17,520 And then we're going to use the host ribosomes, the host's 741 00:40:17,520 --> 00:40:20,130 amino acids, the building blocks in everything, 742 00:40:20,130 --> 00:40:24,850 to make a new protein that is not a host's cell protein. 743 00:40:24,850 --> 00:40:26,610 It's the capsid protein. 744 00:40:26,610 --> 00:40:28,230 Obviously, the human cell isn't going 745 00:40:28,230 --> 00:40:30,310 to be making a capsid protein. 746 00:40:30,310 --> 00:40:34,050 So that's the main thing that the virus had to encode. 747 00:40:34,050 --> 00:40:36,300 It had to have the DNA to make that. 748 00:40:36,300 --> 00:40:38,460 So that all looks sort of fairly simple, 749 00:40:38,460 --> 00:40:40,240 and the steps make sense. 750 00:40:40,240 --> 00:40:43,710 This is why we cover this virus first because it really-- 751 00:40:43,710 --> 00:40:46,790 it's kind of the most transparent to understand, 752 00:40:46,790 --> 00:40:50,470 so this transient stage of sort of borrowing machinery. 753 00:40:50,470 --> 00:40:53,730 And as I mentioned here, the virus 754 00:40:53,730 --> 00:40:55,710 can spring out of the host cell. 755 00:40:55,710 --> 00:40:57,396 Yes. 756 00:40:57,396 --> 00:41:00,584 AUDIENCE: So all it means is-- one's that don't kill the host 757 00:41:00,584 --> 00:41:05,513 cells, how do they, like, on the body, or the cells that they-- 758 00:41:05,513 --> 00:41:08,055 BARBARA IMPERIALI: They start to just be too much of a burden 759 00:41:08,055 --> 00:41:10,080 onto the body, so they're just-- 760 00:41:10,080 --> 00:41:13,650 you know, if they're inside cells and exploiting 761 00:41:13,650 --> 00:41:17,040 the resources of the cell, they're basically-- 762 00:41:17,040 --> 00:41:19,830 they're harming it, but they're not destroying it instantly 763 00:41:19,830 --> 00:41:20,980 every life cycle. 764 00:41:20,980 --> 00:41:25,860 They're just using resources to replicate, and then go-- 765 00:41:25,860 --> 00:41:28,140 get spread to another cell, and another cell, 766 00:41:28,140 --> 00:41:29,710 where they'll keep using resources. 767 00:41:29,710 --> 00:41:31,890 So it's really just an overload of the system. 768 00:41:31,890 --> 00:41:34,050 It's a very good point. 769 00:41:34,050 --> 00:41:36,670 But they can stick around a long time, 770 00:41:36,670 --> 00:41:38,610 and with HIV, you're going to see 771 00:41:38,610 --> 00:41:40,380 what really sneaky thing they do is 772 00:41:40,380 --> 00:41:43,420 because they put their genome into the host genome. 773 00:41:43,420 --> 00:41:46,860 And that's sort of really pretty terrifying. 774 00:41:46,860 --> 00:41:49,560 I always ask this question, but it's kind of a silly one. 775 00:41:49,560 --> 00:41:51,570 You know, what is life? 776 00:41:51,570 --> 00:41:53,280 A virus is alive. 777 00:41:53,280 --> 00:41:56,040 Well, they're kind of alive, but they're not really alive 778 00:41:56,040 --> 00:41:58,110 unless they have some place to live. 779 00:41:58,110 --> 00:41:59,850 But aren't we all like that? 780 00:41:59,850 --> 00:42:01,290 So that's very philosophical. 781 00:42:01,290 --> 00:42:03,660 So we'll move right on here. 782 00:42:03,660 --> 00:42:05,940 So when you think of a virus, this 783 00:42:05,940 --> 00:42:08,310 is the original central dogma, all 784 00:42:08,310 --> 00:42:10,920 the moving parts of the central dogma. 785 00:42:10,920 --> 00:42:13,230 And note-- so that when you think of a virus, 786 00:42:13,230 --> 00:42:17,190 what double-- what does double-stranded DNA need 787 00:42:17,190 --> 00:42:19,440 from the host? 788 00:42:19,440 --> 00:42:21,060 It's got all of these things. 789 00:42:21,060 --> 00:42:24,090 It's got the-- the host has the polymerase. 790 00:42:24,090 --> 00:42:27,400 It has the DNA-dependent RNA polymerase. 791 00:42:27,400 --> 00:42:29,580 It's got all the ribosomal machinery. 792 00:42:29,580 --> 00:42:31,920 So the only thing that the virus needs 793 00:42:31,920 --> 00:42:35,010 is the gene for its capsid proteins. 794 00:42:35,010 --> 00:42:38,060 So you can peel out from that entire life cycle 795 00:42:38,060 --> 00:42:40,630 the one unique thing about the virus. 796 00:42:40,630 --> 00:42:43,380 So that's a double-stranded DNA. 797 00:42:43,380 --> 00:42:46,650 Let's now move to a different type of V, 798 00:42:46,650 --> 00:42:50,370 which is a negative-stranded RNA virus. 799 00:42:50,370 --> 00:42:52,560 And these are quite important because these 800 00:42:52,560 --> 00:42:55,020 form the basis for-- 801 00:42:55,020 --> 00:42:56,950 let me just go to the diseases. 802 00:42:56,950 --> 00:42:59,940 This is the influenza virus, and I'm 803 00:42:59,940 --> 00:43:01,770 going to mention some very important points 804 00:43:01,770 --> 00:43:04,290 relative to influenza virus. 805 00:43:04,290 --> 00:43:10,395 So influenza virus is what's known as a segmented virus. 806 00:43:17,480 --> 00:43:20,470 And what that means is that its genome-- 807 00:43:20,470 --> 00:43:24,630 in this case, it's negative-stranded RNA-- 808 00:43:24,630 --> 00:43:25,375 is in pieces. 809 00:43:36,730 --> 00:43:45,280 A lot of other viruses just have a single strand of genome, 810 00:43:45,280 --> 00:43:49,240 a single nucleic acid strand. 811 00:43:52,130 --> 00:44:00,740 So it's just one piece, where portions of that nucleic acid 812 00:44:00,740 --> 00:44:03,830 code for different proteins, and they'll often 813 00:44:03,830 --> 00:44:07,710 code for initially polyproteins that get broken up. 814 00:44:07,710 --> 00:44:10,400 And we'll see a virus with a single strand 815 00:44:10,400 --> 00:44:12,140 when we look at HIV. 816 00:44:12,140 --> 00:44:17,630 But the influenza virus has a segmented genome. 817 00:44:17,630 --> 00:44:20,270 And that's very relevant for its lifestyle 818 00:44:20,270 --> 00:44:24,980 because we'll see in a moment how influenza virus can cause 819 00:44:24,980 --> 00:44:28,820 more damage than we anticipate because of recombination 820 00:44:28,820 --> 00:44:31,580 of different copies of the segmented virus 821 00:44:31,580 --> 00:44:32,610 through differences. 822 00:44:32,610 --> 00:44:34,610 But let's first of all take a look 823 00:44:34,610 --> 00:44:36,830 at the life cycle of this virus, and then we'll 824 00:44:36,830 --> 00:44:40,550 move on to dealing with the issue of the segmentation. 825 00:44:40,550 --> 00:44:45,740 So here's a typical enveloped virus with a capsid. 826 00:44:45,740 --> 00:44:50,300 Inside, there's the negative-stranded RNA that gets 827 00:44:50,300 --> 00:44:52,850 into the host cell, and you make-- 828 00:44:52,850 --> 00:44:58,130 and you dump into the host cell the viral genomic RNA. 829 00:44:58,130 --> 00:45:00,230 That can get copied. 830 00:45:00,230 --> 00:45:04,700 The minus-strand RNA gets copied to the plus-strand RNA, 831 00:45:04,700 --> 00:45:09,120 which becomes the messenger for protein synthesis in the cell. 832 00:45:09,120 --> 00:45:10,700 So you've gone in with minus strand. 833 00:45:10,700 --> 00:45:13,090 You've made the plus strand, which is the messenger, 834 00:45:13,090 --> 00:45:16,430 and that encodes all the proteins that 835 00:45:16,430 --> 00:45:19,170 are needed for a new virus. 836 00:45:19,170 --> 00:45:23,900 And some of those proteins may have signal sequences. 837 00:45:23,900 --> 00:45:26,900 They may be shipped to the surface of the cell, 838 00:45:26,900 --> 00:45:30,980 and they may be planted in the outside cellular membrane 839 00:45:30,980 --> 00:45:32,420 of the host cells. 840 00:45:32,420 --> 00:45:36,050 And what you see here is copies of those proteins 841 00:45:36,050 --> 00:45:38,970 actually in the surface of a cell. 842 00:45:38,970 --> 00:45:42,170 So what happens with this virus is, once all the moving 843 00:45:42,170 --> 00:45:46,490 parts are made, they congregate at the surface of a cell, 844 00:45:46,490 --> 00:45:50,010 get packaged, and then bud off from the cell. 845 00:45:50,010 --> 00:45:53,990 So remember all the rules you learned about where proteins 846 00:45:53,990 --> 00:45:57,110 end up in the cell are all good still here 847 00:45:57,110 --> 00:46:01,580 because the capsid proteins have to get to a cell membrane, 848 00:46:01,580 --> 00:46:04,220 so they're translated with a signal sequence. 849 00:46:04,220 --> 00:46:08,150 They congregate-- I don't know how this self-assembly occurs, 850 00:46:08,150 --> 00:46:12,020 but it's a fascinating process, so that ultimately you 851 00:46:12,020 --> 00:46:16,370 bud off an intact virion from the host cell. 852 00:46:16,370 --> 00:46:19,220 But the key thing that the virus has to have 853 00:46:19,220 --> 00:46:23,930 is something that will copy negative-stranded RNA 854 00:46:23,930 --> 00:46:27,840 to plus-stranded RNA, which is going to be the messenger. 855 00:46:27,840 --> 00:46:31,760 So the virus also has to code for a particular protein that's 856 00:46:31,760 --> 00:46:33,890 unique to its lifestyle. 857 00:46:33,890 --> 00:46:38,360 So it has an RA-dependent RNA polymerase. 858 00:46:38,360 --> 00:46:41,900 We don't use an RNA-dependent RNA polymerase, 859 00:46:41,900 --> 00:46:45,890 but the virus needs it to take its negative-strand RNA 860 00:46:45,890 --> 00:46:48,590 to a plus-strand RNA, which will be the messenger. 861 00:46:48,590 --> 00:46:49,760 So does that make sense? 862 00:46:49,760 --> 00:46:51,920 So obviously, that's a moving part 863 00:46:51,920 --> 00:46:54,690 that it needs to provide to the host. 864 00:46:54,690 --> 00:46:58,700 Now, what's this about segmented viruses that's quite important? 865 00:47:01,220 --> 00:47:03,740 Oh, and I just want to underscore here, 866 00:47:03,740 --> 00:47:06,500 what defines the destination of these proteins, 867 00:47:06,500 --> 00:47:09,380 whether they're capsid proteins or proteins that 868 00:47:09,380 --> 00:47:11,930 are going to be packaged within the virus, 869 00:47:11,930 --> 00:47:14,210 is basically just the same rules that 870 00:47:14,210 --> 00:47:16,460 apply that we talked about when we talked 871 00:47:16,460 --> 00:47:19,790 about protein trafficking. 872 00:47:19,790 --> 00:47:22,820 So every year, there's a whole panic. 873 00:47:22,820 --> 00:47:24,480 Did you get your flu shot? 874 00:47:24,480 --> 00:47:26,000 Is it going to work this year? 875 00:47:26,000 --> 00:47:28,370 Oh my god, millions of people are going to get sick. 876 00:47:28,370 --> 00:47:29,390 Go get your flu shot. 877 00:47:29,390 --> 00:47:32,490 It's tetravalent, it's trivalent, and so on. 878 00:47:32,490 --> 00:47:35,300 So what we're trying to do every year 879 00:47:35,300 --> 00:47:38,430 is predict what the virus is going to look like. 880 00:47:38,430 --> 00:47:39,440 So we have to-- 881 00:47:39,440 --> 00:47:42,770 there are teams of people, who sometimes get it wrong, 882 00:47:42,770 --> 00:47:47,170 who predict the variation in these genes. 883 00:47:47,170 --> 00:47:50,780 And they look at winter in the Southern Hemisphere, 884 00:47:50,780 --> 00:47:52,610 because that precedes us, and try 885 00:47:52,610 --> 00:47:55,520 to guess what's going to happen in winter in the Northern 886 00:47:55,520 --> 00:47:56,420 Hemisphere. 887 00:47:56,420 --> 00:48:01,190 And we get to try and put together a vaccination package. 888 00:48:01,190 --> 00:48:04,940 But the problem with the viral influenza virus 889 00:48:04,940 --> 00:48:10,190 is that there can be not just a drift, like mutations, 890 00:48:10,190 --> 00:48:13,100 small mutations happening a little bit at a time, 891 00:48:13,100 --> 00:48:16,850 but there can be recombination of the genes, 892 00:48:16,850 --> 00:48:21,770 because they are segmented, into totally new virus particles 893 00:48:21,770 --> 00:48:23,960 that have different properties. 894 00:48:23,960 --> 00:48:28,700 So viruses don't just drift in their genomic sequence. 895 00:48:28,700 --> 00:48:33,130 They can have dramatic shifts in their sequences that occur-- 896 00:48:33,130 --> 00:48:37,310 whoops-- through combinations of viruses that come-- that 897 00:48:37,310 --> 00:48:39,450 have infected different animals. 898 00:48:39,450 --> 00:48:41,300 So some of the common strains, when 899 00:48:41,300 --> 00:48:44,360 we talk about certain strains that have been very, very 900 00:48:44,360 --> 00:48:48,710 troublesome to humans, may result from such a combination. 901 00:48:48,710 --> 00:48:54,170 So this would be the Eurasian pig flu, the classic pig flu, 902 00:48:54,170 --> 00:48:56,810 the human flu, the bird flu. 903 00:48:56,810 --> 00:49:00,370 If, in certain communities where people often 904 00:49:00,370 --> 00:49:03,040 live with their livestock, a cell 905 00:49:03,040 --> 00:49:06,430 gets infected with viruses, a human virus 906 00:49:06,430 --> 00:49:11,200 and the swine virus, they can mix and match together. 907 00:49:11,200 --> 00:49:14,620 And you can make a totally different viral composition, 908 00:49:14,620 --> 00:49:18,520 where you've got one piece of genetic information 909 00:49:18,520 --> 00:49:22,880 from the swine flu and seven more from the human flu. 910 00:49:22,880 --> 00:49:24,910 And what that can suddenly mean is 911 00:49:24,910 --> 00:49:28,630 that the-- first of all, the vaccines don't work at all, 912 00:49:28,630 --> 00:49:31,690 but that they may have very, very different properties 913 00:49:31,690 --> 00:49:33,910 for infectivity. 914 00:49:33,910 --> 00:49:37,780 The protein that is expressed that may cause 915 00:49:37,780 --> 00:49:40,870 that very first attack of the virus on your cells 916 00:49:40,870 --> 00:49:44,440 in the upper lungs may be very different to the type-- 917 00:49:44,440 --> 00:49:46,720 to the protein that comes from the swine flu 918 00:49:46,720 --> 00:49:50,590 and may give you much more serious lung infections 919 00:49:50,590 --> 00:49:52,870 because they can go deeper into the lungs. 920 00:49:52,870 --> 00:49:56,050 So it can be very small changes by pulling 921 00:49:56,050 --> 00:50:00,840 an enzyme, a piece of gene, from a completely different organism 922 00:50:00,840 --> 00:50:03,640 and matching it up with the rest of the genes 923 00:50:03,640 --> 00:50:07,480 from the human virus that makes for dramatic shifts 924 00:50:07,480 --> 00:50:10,990 in viral infections that cause these sorts 925 00:50:10,990 --> 00:50:13,870 of sudden tectonic shifts where we've really 926 00:50:13,870 --> 00:50:15,880 got to deal with a virus. 927 00:50:15,880 --> 00:50:17,560 There are two terms up here. 928 00:50:17,560 --> 00:50:20,740 There's H and N. These are hemagglutinin and 929 00:50:20,740 --> 00:50:22,120 neuraminidase. 930 00:50:22,120 --> 00:50:25,240 They are two proteins that are in the viral coat, 931 00:50:25,240 --> 00:50:30,400 so you'll often hear viruses referred to as H1N1, H3N3, 932 00:50:30,400 --> 00:50:33,430 and it's just the variant of those proteins that 933 00:50:33,430 --> 00:50:34,330 are in the viruses. 934 00:50:34,330 --> 00:50:35,980 See these little terms here-- 935 00:50:35,980 --> 00:50:39,370 that's what that means, what type of hemagglutinin, 936 00:50:39,370 --> 00:50:42,790 what type of neuraminidase, is on the surface of the virus. 937 00:50:42,790 --> 00:50:45,700 So I am done for today, and next class 938 00:50:45,700 --> 00:50:49,660 will be exclusively about the AIDS-HIV virus, where we'll 939 00:50:49,660 --> 00:50:52,450 go into that life cycle and also talk 940 00:50:52,450 --> 00:50:55,780 about resistance to therapeutic agents and combination 941 00:50:55,780 --> 00:50:57,630 therapies.