WEBVTT 00:00:06.196 --> 00:00:09.496 >> So now what we understand is that all bacteria can talk to each other. 00:00:09.836 --> 00:00:14.556 They make chemical words, they recognize those words, and they turn on group behaviors 00:00:14.556 --> 00:00:18.916 that are only successful when all of the cells participate in unison. 00:00:19.206 --> 00:00:21.016 And so now we have a fancy name for this. 00:00:21.156 --> 00:00:22.526 We call it "quorum sensing". 00:00:22.746 --> 00:00:24.476 They vote with these chemical votes. 00:00:24.786 --> 00:00:27.916 The vote gets counted, and then everybody responds to the vote. 00:00:28.656 --> 00:00:32.546 And what's important for today's talk is that we know that there are hundreds of behaviors 00:00:32.546 --> 00:00:35.376 that bacteria carry out in these collective fashions, 00:00:35.426 --> 00:00:38.706 but the one that's probably the most important to you is virulence. 00:00:39.116 --> 00:00:43.106 So it's not like a couple bacteria get in you, and then they start secreting some toxins. 00:00:43.106 --> 00:00:44.046 You're enormous. 00:00:44.236 --> 00:00:45.896 That would have no effect on you. 00:00:45.896 --> 00:00:46.796 You're huge. 00:00:46.796 --> 00:00:51.006 But what they do, we now understand, is they get in you; they wait. 00:00:51.216 --> 00:00:52.196 They start growing. 00:00:52.196 --> 00:00:55.156 They count themselves with these little molecules, and they recognize, 00:00:55.206 --> 00:00:56.556 when they have the right cell number, 00:00:56.786 --> 00:01:00.226 that if all of the bacteria launch their virulence attack together, 00:01:00.446 --> 00:01:03.786 they're going to be successful at overcoming an enormous host. 00:01:06.516 --> 00:01:09.756 [ Applause ] 00:01:10.256 --> 00:01:13.186 >> Hi! I'm delighted to be back to give you a little progress 00:01:13.186 --> 00:01:15.486 about what we've been doing in quorum sensing. 00:01:15.816 --> 00:01:19.886 And so today, I want to tell you one story about how we're taking what we learned 00:01:19.886 --> 00:01:24.606 about these bacteria talking together and trying to interfere with that conversation, 00:01:24.836 --> 00:01:27.616 to make a fundamentally new kind of antibiotic. 00:01:27.736 --> 00:01:32.736 And so the story I'll tell you about concerns this pathogen, Pseudomonas aeruginosa. 00:01:33.236 --> 00:01:36.486 This is the bacterium that kills people who have cystic fibrosis. 00:01:36.816 --> 00:01:40.576 It kills immune-compromised people, and it causes infections 00:01:40.576 --> 00:01:43.686 when you get a catheter, a stent or a breathing tube. 00:01:43.946 --> 00:01:47.496 And the reason Pseudomonas is so virulent is 00:01:47.496 --> 00:01:50.646 because of this chemical communication, this quorum sensing. 00:01:51.026 --> 00:01:56.176 What Pseudomonas does is that as it grows, it makes and releases small molecules, 00:01:56.176 --> 00:01:58.266 which are the red triangles on this slide. 00:01:58.636 --> 00:02:01.686 And so as the cells grow, these molecules that are outside 00:02:01.686 --> 00:02:04.516 of the cells increase in proportion to cell number. 00:02:04.816 --> 00:02:09.106 And as you heard on the clip, when the bacteria detect that those molecules are there, 00:02:09.396 --> 00:02:12.386 they interpret that that means there's other cells around. 00:02:12.686 --> 00:02:16.936 And then, as a collective, all of the bacteria together make a biofilm, 00:02:16.936 --> 00:02:19.976 which is how they sit on surfaces and cure to tissue. 00:02:20.286 --> 00:02:24.756 And then the group together secretes the poisons, the toxins that make us sick. 00:02:25.126 --> 00:02:26.436 So that's quorum sensing. 00:02:27.346 --> 00:02:30.146 And so we want to be able to interfere with that conversation. 00:02:30.836 --> 00:02:34.076 And so we know what the molecule is that Pseudomonas talks with. 00:02:34.256 --> 00:02:36.796 It's the one that's on the left side of this slide. 00:02:37.236 --> 00:02:41.516 And so what we did, using chemistry, is we changed the structure of that molecule 00:02:41.666 --> 00:02:43.026 to make the one that's on the right. 00:02:43.616 --> 00:02:47.256 And so what that chemistry did was it changed the signal molecule, 00:02:47.426 --> 00:02:49.286 the word, into an inhibitor. 00:02:49.596 --> 00:02:52.466 So we changed the molecule that turns on quorum sensing 00:02:52.656 --> 00:02:55.236 into a molecule that shuts down quorum sensing. 00:02:55.626 --> 00:02:57.936 So what happens if you have such a molecule? 00:02:58.326 --> 00:03:00.186 So first, I'll talk about biofilms. 00:03:00.446 --> 00:03:04.386 So in this petri plate, what we've done is we've put Pseudomonas in the middle 00:03:04.386 --> 00:03:06.576 of the petri plate, and what I hope you can see is 00:03:06.576 --> 00:03:09.136 that the bacteria have spread out to the edges. 00:03:09.446 --> 00:03:11.066 That's this biofilm formation. 00:03:11.326 --> 00:03:15.656 As a group, they move out over the plate, and that could be like your tissues. 00:03:16.456 --> 00:03:18.116 But we have this inhibitor. 00:03:18.326 --> 00:03:21.556 So now if we do the experiment, and we put the Pseudomonas in the plate, 00:03:21.716 --> 00:03:25.956 and we add the inhibitor, what you can see is that the Pseudomonas can't move. 00:03:26.116 --> 00:03:26.746 So that's good. 00:03:26.746 --> 00:03:28.176 That's step one in the infection. 00:03:28.176 --> 00:03:31.696 It seems like our inhibitor can shut down biofilm formation. 00:03:32.206 --> 00:03:34.766 The next question for us is, what about these poisons, 00:03:34.766 --> 00:03:37.016 these toxins, that Pseudomonas secretes? 00:03:37.356 --> 00:03:39.056 So now you're looking at an experiment, 00:03:39.056 --> 00:03:42.646 and in the lefthand test tube, that's wild-type Pseudomonas. 00:03:43.056 --> 00:03:46.436 It's doing quorum sensing, and it's secreted these toxins. 00:03:46.676 --> 00:03:49.816 And when it secretes those toxins, the bacteria turn green. 00:03:50.116 --> 00:03:53.256 In the middle test tube, that's a mutant that we've made, 00:03:53.256 --> 00:03:55.676 where we've knocked out its quorum-sensing system. 00:03:55.896 --> 00:03:57.956 So that mutant has no communication. 00:03:58.216 --> 00:04:00.496 And what you can see is that the bacteria are colorless. 00:04:00.896 --> 00:04:03.666 They can't secrete the toxin, so they don't turn green. 00:04:04.376 --> 00:04:09.456 The righthand test tube shows you wild-type Pseudomonas that we've added our inhibitor. 00:04:09.646 --> 00:04:14.026 And what I hope you can see is that the inhibitor greatly decreases the ability 00:04:14.026 --> 00:04:16.886 of Pseudomonas to secrete that green poison. 00:04:17.246 --> 00:04:18.246 So now we're in business. 00:04:18.246 --> 00:04:20.836 It looks like at least in the lab, we can shut down biofilms, 00:04:20.836 --> 00:04:23.016 and we can shut down toxin secretion. 00:04:23.286 --> 00:04:24.796 So what about in an infection? 00:04:25.326 --> 00:04:29.346 So in this experiment, you're looking at an animal model system that we have 00:04:29.346 --> 00:04:31.236 for Pseudomonas infection in the lab, 00:04:31.546 --> 00:04:34.716 and all we do is measure whether the animals are alive or dead. 00:04:35.166 --> 00:04:37.376 And so on the line that you looking at, obviously, 00:04:37.376 --> 00:04:40.436 if we don't add pseudomonas, the animals are perfectly fine. 00:04:41.096 --> 00:04:45.976 If we give a Pseudomonas infection, now what you can see is that all of the animals die 00:04:46.026 --> 00:04:48.946 within the first day after the infection starts. 00:04:49.326 --> 00:04:53.976 But if we do that, we give the Pseudomonas infection, and we give that inhibitor molecule 00:04:53.976 --> 00:04:56.556 that I showed you, what you can see with the third line is 00:04:56.556 --> 00:04:59.566 that we can greatly improve the outcome for the animal. 00:04:59.896 --> 00:05:04.326 So in fact, we think now that there must be merit to this idea of interfering 00:05:04.326 --> 00:05:08.416 with chemical communication, and that maybe this could form the foundation 00:05:08.686 --> 00:05:10.556 of a new type of therapeutic. 00:05:11.086 --> 00:05:15.486 And so what we're doing in the lab, right now, is we're taking the molecule that I showed you, 00:05:15.486 --> 00:05:19.316 and we have to make it more medicine-like we have to build in potency, 00:05:19.316 --> 00:05:21.276 and we have to make that molecule safe. 00:05:21.926 --> 00:05:25.986 The second thing is that we got inspired by that biofilm experiment that I showed you, 00:05:25.986 --> 00:05:27.926 and we're working with engineers now to try, 00:05:27.926 --> 00:05:31.736 to try to embed those inhibitor molecules into materials. 00:05:31.816 --> 00:05:37.016 And the idea is that maybe we could make infection-resistant catheters, 00:05:37.016 --> 00:05:38.616 or stents or breathing tubes. 00:05:39.106 --> 00:05:42.316 And then finally, I'm just telling you one little vignette that's about Pseudomonas. 00:05:42.316 --> 00:05:45.436 We work on lots of globally-important pathogens in my lab, 00:05:45.706 --> 00:05:50.306 and we're having similar success doing these kinds of strategies in other bacteria as well. 00:05:50.516 --> 00:05:54.966 And then to finish, I just want to show you the two students who did the work, Colina Loflin 00:05:54.966 --> 00:05:55.916 and [inaudible] Drescher [phonetic]. 00:05:55.946 --> 00:05:58.946 They both work in the lab, and I'm lucky to get to work with them every day. 00:05:59.256 --> 00:05:59.946 Thanks for having me back. 00:06:00.186 --> 00:06:02.186 [ Applause ] 00:06:02.356 --> 00:06:02.716 >> So interesting.