0:00:06.221,0:00:07.217 Good evening. 0:00:07.217,0:00:08.218 (Applause) 0:00:08.218,0:00:11.443 Tonight I want to talk to you[br]about a new area of nanotechnology; 0:00:11.443,0:00:13.755 that is nanomedicines. 0:00:13.755,0:00:14.736 And this is an area 0:00:14.736,0:00:19.306 where nanotechnology is enabling[br]new and exciting biotechnology. 0:00:19.721,0:00:21.740 Now, over the past few decades, 0:00:21.740,0:00:23.745 deaths due to heart disease[br]have plummeted, 0:00:23.745,0:00:25.744 as you can see[br]from the data on this slide, 0:00:25.744,0:00:27.833 and that's a really good story. 0:00:27.833,0:00:30.875 But unfortunately with cancer, [br]we can't say the same. 0:00:30.875,0:00:32.432 And so today, 0:00:32.432,0:00:37.622 cancer is now the number one disease[br]that kills Americans under the age of 85. 0:00:38.076,0:00:41.278 And as you might expect,[br]this is not just a US problem; 0:00:41.278,0:00:42.522 it's a worldwide problem. 0:00:42.522,0:00:45.672 And from these data, you can see [br]that the death rate due to cancer 0:00:45.672,0:00:50.922 exceeds that from tuberculosis, [br]malaria, and HIV all combined. 0:00:50.922,0:00:54.550 And unfortunately, it's predicted[br]to continue to increase in the future. 0:00:55.302,0:00:59.541 So if you look, cancer has[br]a massive cost to society right now 0:00:59.541,0:01:04.311 in the loss of productivity that we have[br]from people expiring at an early age, 0:01:04.311,0:01:06.286 but also in the cost of the therapies, 0:01:06.286,0:01:10.489 as these therapies are increasing in price[br]at rates that are just not sustainable 0:01:10.489,0:01:13.219 when we have to treat[br]so many people worldwide. 0:01:13.774,0:01:16.259 And, of course, [br]you've probably all witnessed 0:01:16.259,0:01:18.760 that many patients[br]that are on current therapies 0:01:18.760,0:01:22.317 really suffer through poor quality of life[br]while they're on treatment 0:01:22.317,0:01:24.754 and even after the treatment's over. 0:01:24.754,0:01:29.744 So there's a real strong reason[br]to try to develop new cancer therapeutics 0:01:29.744,0:01:33.009 that are efficacious,[br]that have reasonable costs, 0:01:33.009,0:01:36.326 and, of course, can give patients[br]high quality of life. 0:01:36.326,0:01:39.312 And these issues motivate us[br]every day of our life. 0:01:39.312,0:01:41.713 We get up, go to the lab,[br]go to the hospital 0:01:41.713,0:01:45.613 to try to see if we can make[br]an impact on these issues. 0:01:45.613,0:01:48.595 Now, if we really want to have[br]an impact on the death rate, 0:01:48.595,0:01:51.502 we're going to have to treat[br]what's called metastatic disease. 0:01:51.502,0:01:55.797 That's where you have multiple tumors[br]throughout the body at the same time, 0:01:55.797,0:01:59.518 and this implies that your therapy has[br]to treat the whole body at the same time 0:01:59.518,0:02:01.978 or it's called systemic treatments. 0:02:02.750,0:02:04.307 Now, what are nanomedicines? 0:02:04.307,0:02:07.708 Well, these are small particles[br]that are therapeutics, 0:02:07.708,0:02:09.267 and they have the potential 0:02:09.267,0:02:12.604 to try to change the way[br]that we treat cancer patients. 0:02:12.604,0:02:15.945 Now, the National Cancer Institute[br]defines these particles 0:02:15.945,0:02:18.979 as particles between[br]one and 100 nanometers, 0:02:18.979,0:02:22.011 and they're composites[br]between therapeutic agents 0:02:22.011,0:02:24.571 and other carrier molecules,[br]like polymers. 0:02:25.320,0:02:27.558 Now, why is the size important? 0:02:27.558,0:02:29.810 This is real nanotechnology. 0:02:29.810,0:02:31.800 These particles are small. 0:02:31.800,0:02:35.290 So if you take 100-nanometer particle [br]and increase it to a soccer ball, 0:02:35.290,0:02:39.281 that's the same increase in size [br]from the soccer ball to the planet Earth. 0:02:39.281,0:02:43.004 So these very, very small particles,[br]we can put into the blood of a patient, 0:02:43.004,0:02:45.224 and they will circulate[br]throughout your body. 0:02:45.789,0:02:48.762 Now, it's interesting[br]that it's nanotechnology, 0:02:48.762,0:02:52.982 but it's actually large relative[br]to these chemotherapeutic drugs 0:02:52.982,0:02:55.492 that are less than a nanometer in size. 0:02:55.492,0:02:58.355 And so the analogy[br]is that the drug is the soccer ball; 0:02:58.355,0:03:01.094 the nanoparticle is actually[br]the Goodyear blimp. 0:03:01.094,0:03:03.144 So it's a very large entity, 0:03:03.144,0:03:07.224 and because of that, it's restricted[br]from certain areas in your body. 0:03:07.656,0:03:10.364 It also can carry a large payload of drug. 0:03:10.364,0:03:14.135 Think about how many soccer balls you[br]might be able to put in the Goodyear blimp 0:03:14.135,0:03:18.395 and how other multiple functions[br]can be put onto these larger entities. 0:03:19.030,0:03:21.270 Now, my group and others[br]throughout the world 0:03:21.270,0:03:22.798 have spent the last decade or so 0:03:22.798,0:03:27.368 trying to figure out how to design[br]and engineer these multifunctional systems 0:03:27.368,0:03:29.840 to treat patients with solid tumors. 0:03:29.840,0:03:33.903 And the field as a whole is converging[br]to this area of about 50 nanometers, 0:03:33.903,0:03:35.623 plus or minus 20. 0:03:35.623,0:03:38.820 And think of 50 nanometers[br]as, like, half the Goodyear blimp, 0:03:38.820,0:03:40.540 rather than the full Goodyear blimp. 0:03:40.540,0:03:45.600 And I've given you two illustrations[br]on this slide of those types of particles. 0:03:45.600,0:03:49.619 And so we're trying to design the size[br]and what's on the surface 0:03:49.619,0:03:52.939 and what kind of functions[br]that we can place into these particles. 0:03:53.371,0:03:55.311 And the reason is as follows - 0:03:55.311,0:03:57.589 now, the one panel's not showing up - 0:03:57.589,0:04:01.185 is that when you[br]infuse these into a patient 0:04:01.185,0:04:03.095 they can circulate in the blood system, 0:04:03.095,0:04:08.058 but they can't access certain areas[br]that chemotherapeutic drugs access, 0:04:08.058,0:04:09.798 like healthy tissues. 0:04:09.798,0:04:12.700 For example, those drugs[br]can go into your bone marrow, 0:04:12.700,0:04:15.810 that makes all of your cells[br]for your immune system, and kill them 0:04:15.810,0:04:18.808 and the molecules of your hair[br]that make your hair fall out. 0:04:18.808,0:04:21.057 With a nanoparticle, they can't go there, 0:04:21.057,0:04:25.537 and so they're much safer therapies[br]than the chemotherapeutic drugs. 0:04:25.537,0:04:29.178 But tumors grow new vessels, and so[br]those vessels are not completed yet, 0:04:29.178,0:04:33.688 and they'll allow these nanoparticles[br]to actually access that region. 0:04:33.688,0:04:36.786 And so we decorate[br]the surface of these particles 0:04:36.786,0:04:40.083 with molecules that allow them[br]to preferentially act 0:04:40.083,0:04:43.741 and interact with surface molecules[br]on the cancer cells 0:04:43.741,0:04:47.062 that then take these particles [br]inside the cell. 0:04:47.062,0:04:50.185 The ones we make at Caltech,[br]we try to make somewhat intelligent; 0:04:50.185,0:04:52.152 we put chemical sensors on them that say, 0:04:52.152,0:04:54.320 "Okay. I'm inside the cell now. 0:04:54.320,0:04:56.873 Give off my therapeutic payload." 0:04:56.873,0:05:00.598 And we make, by design, [br]the remnants of this particle small enough 0:05:00.598,0:05:03.719 that when it disassembles,[br]those remnants go out into your urine, 0:05:03.719,0:05:07.289 so there's no trace of it left[br]after the administration. 0:05:08.128,0:05:13.596 So normal cells grow, they divide,[br]and they die in an orderly fashion. 0:05:13.596,0:05:16.565 And there are many[br]regulatory systems that are used 0:05:16.565,0:05:19.286 that are turned on[br]and turned off to control this. 0:05:19.286,0:05:21.504 In cancer, some of these are altered, 0:05:21.504,0:05:23.236 and so what can happen, for example, 0:05:23.236,0:05:26.026 is the pathways that allow[br]these cells to grow and divide 0:05:26.026,0:05:27.867 get turned on permanently. 0:05:27.867,0:05:32.057 So if you really want to make an effective[br]therapy that has minimal side effects, 0:05:32.057,0:05:36.090 you'd like to attack [br]just at those altered positions. 0:05:36.090,0:05:40.142 And there's some new biotechnology[br]that may help us do this job, 0:05:40.142,0:05:44.326 and this is called RNA interference,[br]and it's a method to silence genes, 0:05:44.326,0:05:49.696 where the drug, now, is a small piece[br]of what's called a duplex of RNA - 0:05:49.696,0:05:52.229 two strands of RNA together. 0:05:52.229,0:05:54.175 And Craig Mello and Andy Fire 0:05:54.175,0:05:57.929 got the Nobel Prize in Physiology[br]or Medicine in 2006 0:05:57.929,0:06:00.559 for figuring out how this works in worms. 0:06:01.461,0:06:04.144 But when Andy gave his Nobel address, 0:06:04.144,0:06:07.671 he said, "Well, what could happen[br]if we have a patient that has a tumor 0:06:07.671,0:06:10.628 and there's a gene [br]that's causing that tumor to grow? 0:06:10.628,0:06:13.718 Could we, in fact, [br]make one of these small RNAs 0:06:13.718,0:06:17.008 and, in fact, give it to the patient[br]and stop the growth of the tumor? 0:06:17.671,0:06:19.674 If you could get that RNA to the target, 0:06:19.674,0:06:21.856 you could have some[br]really cool therapeutics." 0:06:21.856,0:06:24.162 I like that term, "cool therapeutics." 0:06:24.162,0:06:25.691 And delivery is the major issue: 0:06:25.691,0:06:28.961 How do you get these to the right place[br]and to do the right job? 0:06:29.483,0:06:32.022 So, about a year or so ago, 0:06:32.022,0:06:34.032 my colleagues and I were the first to show 0:06:34.032,0:06:36.937 that you could translate this[br]from a worm to a human, 0:06:36.937,0:06:40.330 and as you might expect,[br]that's a big translation. 0:06:40.330,0:06:41.334 But just last year, 0:06:41.334,0:06:44.384 we were able to show that you can, [br]in fact, do this in patients, 0:06:44.384,0:06:47.298 and so I'll try to illustrate[br]a few points for you now. 0:06:47.298,0:06:50.361 So what is so interesting[br]about this technology 0:06:50.361,0:06:54.345 is, unlike most drugs[br]that attack at the protein level - 0:06:54.345,0:06:56.309 and proteins do many different functions, 0:06:56.309,0:06:58.928 so you have to have drugs[br]that do many different things, 0:06:58.928,0:07:02.073 and there are lots of protein functions[br]that you just can't attack, 0:07:02.073,0:07:04.183 and those are called undruggable targets. 0:07:04.731,0:07:08.754 But RNA interference attacks[br]at what's called the messenger RNA, 0:07:08.754,0:07:12.422 and all we have to do there[br]is just change the sequence of the letters 0:07:12.422,0:07:15.672 that we can attack and eliminate[br]any of those messenger RNAs, 0:07:15.672,0:07:18.859 and so any gene, now, [br]is druggable by this technology, 0:07:18.859,0:07:21.839 just by changing[br]the letters on our duplex RNA. 0:07:22.682,0:07:24.211 So what my colleagues and I did 0:07:24.211,0:07:27.895 is we developed a nanoparticle[br]that carried these small RNAs, 0:07:27.895,0:07:31.086 and we infused these into cancer patients. 0:07:31.086,0:07:34.653 And these particles would circulate[br]through the body of the cancer patients. 0:07:34.653,0:07:36.062 And we were able to show 0:07:36.062,0:07:40.682 that they would, in fact, go to tumors [br]in metastatic melanoma patients, 0:07:40.946,0:07:44.247 and, in fact, they would do it[br]in a dose-dependent fashion, 0:07:44.247,0:07:45.246 and what that means 0:07:45.246,0:07:48.198 is the more nanoparticles[br]that we actually put into the body, 0:07:48.198,0:07:51.205 the more we saw ending up in the tumors. 0:07:51.205,0:07:54.885 And we could do this where patients[br]would have very high quality of life. 0:07:55.405,0:07:58.692 In the few patients[br]that we were able to get biopsies, 0:07:58.692,0:08:00.519 we were able to look more closely, 0:08:00.519,0:08:02.728 and I've shown two pictures[br]here on this slide: 0:08:02.728,0:08:05.751 the first is, the light areas [br]that are in the tumor area, 0:08:05.751,0:08:07.956 those are actually the nanoparticles. 0:08:07.956,0:08:11.676 And so we were actually able to show[br]that these nanoparticles go into the tumor 0:08:11.676,0:08:13.464 and into the tumor cells, 0:08:13.464,0:08:16.417 but they didn't localize at all[br]into the healthy tissue 0:08:16.417,0:08:19.548 that was around the tumor,[br]as we're trying to do. 0:08:19.548,0:08:23.808 Now, we were able to eliminate[br]this individual messenger RNA. 0:08:23.808,0:08:27.343 We were able to show that it was[br]by this RNA interference mechanism. 0:08:27.343,0:08:30.338 And so, it would stop[br]the production of a protein, 0:08:30.338,0:08:32.440 which I'm showing on this slide as well - 0:08:32.440,0:08:34.459 that we eliminated this protein, 0:08:34.459,0:08:37.759 and this caused the tumors[br]not to grow in these patients. 0:08:39.144,0:08:42.570 So, what I've shown you[br]is at least one example 0:08:42.570,0:08:46.468 where, in fact, the nanoparticle[br]can enable this new biotechnology 0:08:46.468,0:08:50.528 to try to create new cancer therapeutics[br]with the right type of properties. 0:08:50.908,0:08:54.694 And so we hope that[br]the potential for these is high 0:08:54.694,0:08:57.056 and mainly to be able[br]to give cancer patients 0:08:57.056,0:09:00.206 treatment options[br]with high quality of life. 0:09:00.206,0:09:02.969 Now, what about the future? 0:09:02.969,0:09:04.689 So what we've been able to do so far 0:09:04.689,0:09:08.391 is to take these nanoparticles,[br]infuse them in the patient, 0:09:08.391,0:09:13.411 and actually inhibit an individual gene[br]in the tumor of these patients 0:09:13.411,0:09:15.619 while they're having high quality of life. 0:09:15.619,0:09:16.701 Now, there's no reason 0:09:16.701,0:09:19.862 that we couldn't put multiple types [br]of RNAs into these particles 0:09:19.862,0:09:22.872 so we could attack[br]multiple genes simultaneously. 0:09:23.383,0:09:27.132 So, our vision is that[br]we start to treat patients 0:09:27.132,0:09:30.597 and that we use, then, [br]a fingerprick of blood 0:09:30.597,0:09:34.294 and analyze a variety[br]of biomolecules in blood 0:09:34.294,0:09:37.569 through a variety of other techniques[br]that people have talked about - 0:09:37.569,0:09:39.486 various arrays and so forth. 0:09:39.486,0:09:40.736 We take that information - 0:09:40.736,0:09:43.833 probably what will happen in the future[br]is you'll do this at home; 0:09:43.833,0:09:45.358 you'll plug it into your iPhone, 0:09:45.358,0:09:47.354 and your iPhone[br]will call up your physician 0:09:47.354,0:09:48.957 and say, "Here are the results" 0:09:48.957,0:09:51.447 so that the next time [br]you go to the doctor's office, 0:09:51.447,0:09:52.716 they're going to say, 0:09:52.716,0:09:55.380 "Here's the new therapy[br]that we're going to give to you." 0:09:55.380,0:10:00.290 So not only in a personalized sense [br]can you change for these therapies, 0:10:00.290,0:10:04.664 but we're hoping that you can[br]actually change in a dynamic sense 0:10:04.664,0:10:08.647 for an individual person to actually[br]follow the course of the disease 0:10:08.647,0:10:12.009 and eradicate it[br]in the best manner you can. 0:10:12.009,0:10:15.936 So that's the vision for cancer,[br]and it probably would happen that way - 0:10:15.936,0:10:18.464 and then hopefully[br]with other diseases as well. 0:10:18.464,0:10:19.460 Thank you. 0:10:19.460,0:10:21.360 (Applause)