1 00:00:03,215 --> 00:00:06,418 I think we can all pretty much agree 2 00:00:06,418 --> 00:00:09,934 that germs are really annoying. 3 00:00:11,063 --> 00:00:14,434 You can take my word for this because I'm kind of an expert. 4 00:00:14,434 --> 00:00:16,788 Not only because I work with viruses for a living, 5 00:00:16,788 --> 00:00:18,197 which I do, 6 00:00:18,197 --> 00:00:21,628 but mainly because I have two young sons at home. 7 00:00:21,628 --> 00:00:22,878 They're four and two, 8 00:00:22,878 --> 00:00:25,786 and I swear they are germ factories. 9 00:00:25,786 --> 00:00:28,985 It seems like every single week they are sick with something. 10 00:00:28,985 --> 00:00:31,137 They have some upper respiratory, 11 00:00:31,137 --> 00:00:33,240 lower respiratory, diarrhea, vomiting, 12 00:00:33,240 --> 00:00:35,939 you name it, they've been infected. 13 00:00:35,939 --> 00:00:39,790 What that means is I am constantly sick. 14 00:00:41,073 --> 00:00:43,948 So, yes, germs are a real big pain. 15 00:00:43,948 --> 00:00:46,196 But luckily if it's a bacterial infection 16 00:00:46,196 --> 00:00:49,183 you can treat it with antibiotics, 17 00:00:49,183 --> 00:00:50,662 but if it's a viral infection 18 00:00:50,662 --> 00:00:52,563 you just kind of wait it out, right? 19 00:00:52,563 --> 00:00:55,675 But luckily most of the infections are not that bad 20 00:00:55,675 --> 00:00:59,118 and my kids will cure them in a couple of weeks. 21 00:00:59,118 --> 00:01:01,694 But we also know that there are a lot of other viruses 22 00:01:01,694 --> 00:01:03,693 that lead to more significant problems. 23 00:01:03,693 --> 00:01:07,456 It can range from maybe having life-long cold sores 24 00:01:07,456 --> 00:01:12,331 to something more serious like debilitation or even death. 25 00:01:12,331 --> 00:01:15,169 So in general viruses are something 26 00:01:15,169 --> 00:01:17,264 I want to stay away from. 27 00:01:17,264 --> 00:01:19,713 They're nasty. 28 00:01:20,016 --> 00:01:22,338 But now let me introduce you to my mom. 29 00:01:22,338 --> 00:01:25,315 This picture was taken in December 2008. 30 00:01:25,315 --> 00:01:26,811 We were visiting my brother, 31 00:01:26,811 --> 00:01:28,557 who lived in Hawaii at that time. 32 00:01:28,557 --> 00:01:32,558 My mom loves golf, her family and warm weather. 33 00:01:33,198 --> 00:01:34,931 Probably in that order. 34 00:01:34,931 --> 00:01:38,262 So Hawaii is really her paradise. 35 00:01:38,442 --> 00:01:41,702 We had a really great time, it was really fun. 36 00:01:42,215 --> 00:01:45,195 Unfortunately, when I took this picture, 37 00:01:45,486 --> 00:01:48,263 I didn't realize that my mom's body 38 00:01:48,263 --> 00:01:51,159 was in the process of betraying her. 39 00:01:51,159 --> 00:01:55,972 Because just six months later she was diagnosed with breast cancer. 40 00:01:56,289 --> 00:01:58,002 When she was diagnosed, 41 00:01:58,002 --> 00:01:59,887 I was pregnant with my first son. 42 00:01:59,887 --> 00:02:04,212 So it became this big emotionally confusing time for me. 43 00:02:04,212 --> 00:02:06,557 Because there I was, 44 00:02:06,557 --> 00:02:08,961 growing life in my body, 45 00:02:08,961 --> 00:02:10,783 and there she was, 46 00:02:10,783 --> 00:02:12,796 growing what could potentially 47 00:02:12,796 --> 00:02:14,822 be her death. 48 00:02:15,434 --> 00:02:17,873 And in addition, since I was pregnant, 49 00:02:17,873 --> 00:02:20,153 I was starting to appreciate 50 00:02:20,153 --> 00:02:21,980 the female breasts as something 51 00:02:21,980 --> 00:02:23,915 that provides sustenance, right? 52 00:02:23,915 --> 00:02:26,422 They're supposed to support life. 53 00:02:26,422 --> 00:02:31,535 But hers may ultimately be the source of her demise. 54 00:02:32,266 --> 00:02:35,227 So it was a very difficult time. 55 00:02:35,227 --> 00:02:37,805 In a couple months after her diagnosis, 56 00:02:37,805 --> 00:02:39,989 she started her cancer treatment. 57 00:02:39,989 --> 00:02:43,303 Chemo, surgery, radiation. 58 00:02:43,974 --> 00:02:46,366 It was a very difficult time. 59 00:02:46,366 --> 00:02:48,379 And all the things that you hear 60 00:02:48,379 --> 00:02:52,403 about cancer treatment, especially chemo being horrible, 61 00:02:52,403 --> 00:02:55,208 it's true, it is really horrible. 62 00:02:55,208 --> 00:02:57,697 And this is something that you will not appreciate 63 00:02:57,697 --> 00:03:01,606 unless you or someone you love goes through it. 64 00:03:01,814 --> 00:03:03,174 But we've made it. 65 00:03:03,174 --> 00:03:05,333 We made it through that long, intense year 66 00:03:05,333 --> 00:03:06,907 and at her cancer hospital 67 00:03:06,907 --> 00:03:09,229 there's this bell that they hung on the wall 68 00:03:09,229 --> 00:03:12,387 and at the end of the year you can go and ring that bell, 69 00:03:12,387 --> 00:03:15,500 telling everyone you're done with treatment, 70 00:03:15,500 --> 00:03:17,295 you're done with cancer. 71 00:03:17,295 --> 00:03:19,496 So we were very happy that day, 72 00:03:19,496 --> 00:03:21,403 but that happiness and that relief 73 00:03:21,403 --> 00:03:24,812 was extremely short-lived. 74 00:03:25,567 --> 00:03:27,823 And the worry starts to creep in. 75 00:03:27,823 --> 00:03:29,848 The source of that worry 76 00:03:29,848 --> 00:03:31,954 is because of this one word. 77 00:03:31,954 --> 00:03:33,868 This one word has so much power. 78 00:03:33,868 --> 00:03:35,874 Metastasis. 79 00:03:35,874 --> 00:03:37,661 Metastasis is where the cancer 80 00:03:37,661 --> 00:03:40,231 that originated in one part of the body 81 00:03:40,231 --> 00:03:43,118 spreads and moves to different parts of your body, 82 00:03:43,118 --> 00:03:46,417 to set up tumors elsewhere. 83 00:03:46,837 --> 00:03:49,921 According to the American Cancer Society, 84 00:03:49,921 --> 00:03:53,227 if the cancer cells are found just in your breasts, 85 00:03:53,227 --> 00:03:56,542 your 5-year relative survival rate is 99 percent. 86 00:03:56,542 --> 00:03:57,972 Which is great. 87 00:03:59,507 --> 00:04:01,554 But you can see that if cancer cells 88 00:04:01,554 --> 00:04:04,428 are found at distant metastatic sites, 89 00:04:04,428 --> 00:04:08,695 your survival rate drops to 24 percent. 90 00:04:09,906 --> 00:04:11,772 That is scary. 91 00:04:12,949 --> 00:04:15,903 Hence, we have one of the greatest challenges 92 00:04:15,903 --> 00:04:18,233 to modern medicine. 93 00:04:18,857 --> 00:04:21,812 Which is, how do we deliver these toxic drugs, 94 00:04:21,813 --> 00:04:24,019 these messages of death, if you will, 95 00:04:24,019 --> 00:04:26,450 just to those metastatic cancer cells? 96 00:04:26,450 --> 00:04:28,417 When we're talking about delivery, 97 00:04:28,417 --> 00:04:31,437 there are really two factors that you must consider. 98 00:04:31,437 --> 00:04:33,663 One is efficiency. 99 00:04:33,663 --> 00:04:36,582 How well can you get these drugs, these messages of death, 100 00:04:36,582 --> 00:04:38,242 just to the cancer cells, right? 101 00:04:38,242 --> 00:04:40,011 And the second is specificity. 102 00:04:40,011 --> 00:04:41,724 That's where you want those drugs 103 00:04:41,724 --> 00:04:43,878 delivered just to the cancer cells, 104 00:04:43,878 --> 00:04:45,510 those metastatic cancer cells, 105 00:04:45,510 --> 00:04:48,918 but leave all the other healthy tissues alone. 106 00:04:48,918 --> 00:04:52,521 And that will decrease those horrible side effects. 107 00:04:52,800 --> 00:04:55,251 The question is, how? 108 00:04:56,406 --> 00:05:00,235 In my work, the answer lies with the virus. 109 00:05:01,223 --> 00:05:05,337 Viruses are nature's nano-cell machines 110 00:05:05,337 --> 00:05:08,007 that have evolved to deliver genes, 111 00:05:08,007 --> 00:05:09,680 or deliver messages 112 00:05:09,680 --> 00:05:11,999 into those cells. 113 00:05:11,999 --> 00:05:14,709 They are incredibly good at their job. 114 00:05:14,709 --> 00:05:16,330 So what we're trying to do 115 00:05:16,330 --> 00:05:19,523 is engineer viruses to treat cancer. 116 00:05:21,962 --> 00:05:23,231 Let me introduce you now 117 00:05:23,231 --> 00:05:24,714 to the virus that we work on. 118 00:05:24,714 --> 00:05:27,400 It's called the adeno-associated virus, 119 00:05:27,400 --> 00:05:28,900 it's a very benign virus, 120 00:05:28,900 --> 00:05:31,368 it is not linked to any disease. 121 00:05:31,368 --> 00:05:33,967 Actually most of us, 80 to 90 percent of us 122 00:05:33,967 --> 00:05:35,084 sitting here today, 123 00:05:35,084 --> 00:05:37,728 we've already been infected by this virus. 124 00:05:38,541 --> 00:05:42,928 So I'm showing you here the outside shell of this virus. 125 00:05:42,928 --> 00:05:44,726 It is empty on the inside, 126 00:05:44,726 --> 00:05:47,658 so that it could carry a very small piece of DNA 127 00:05:47,658 --> 00:05:49,851 that encodes for that message 128 00:05:49,851 --> 00:05:53,634 that you would want to deliver to the cancer cells. 129 00:05:54,147 --> 00:05:58,322 And so when I look at images like this, of the virus, 130 00:05:58,924 --> 00:06:02,532 I am convinced that Mother Nature is an artist. 131 00:06:03,329 --> 00:06:07,148 Not only that, she is a proficient designer. 132 00:06:08,055 --> 00:06:11,519 The tight interlock between form and function 133 00:06:12,303 --> 00:06:15,013 is fundamental for design. 134 00:06:15,362 --> 00:06:18,578 This virus is only 25 nanometers in diameter, 135 00:06:19,417 --> 00:06:23,857 which is 4,000 times smaller than the width of your hair. 136 00:06:24,202 --> 00:06:26,742 So, in this tiny little package, 137 00:06:27,301 --> 00:06:30,017 Nature doesn't really have a lot of wiggle room 138 00:06:30,017 --> 00:06:32,003 to include things that are not important 139 00:06:32,003 --> 00:06:34,054 for the ultimate function of the virus. 140 00:06:34,054 --> 00:06:36,572 Which is to infect cells. 141 00:06:37,446 --> 00:06:39,698 The other thing I want to point out 142 00:06:39,698 --> 00:06:42,794 is that viruses are old technology. 143 00:06:44,298 --> 00:06:47,641 I mean, it's really, really old technology. 144 00:06:48,140 --> 00:06:49,910 Billions of years. 145 00:06:49,910 --> 00:06:51,738 What we're trying to do 146 00:06:51,738 --> 00:06:53,585 is to simply piggy-back 147 00:06:53,585 --> 00:06:56,497 on Mother Nature's work. 148 00:06:56,761 --> 00:06:59,878 To program these viruses to kill cancer. 149 00:07:03,108 --> 00:07:05,682 Our over-arching strategy, in our lab, 150 00:07:05,682 --> 00:07:08,050 is to program synthetic algorithms 151 00:07:08,050 --> 00:07:09,827 into the virus structure, 152 00:07:09,827 --> 00:07:11,546 in order to train it to pick out 153 00:07:11,546 --> 00:07:14,669 those cancer cells and to destroy them. 154 00:07:15,830 --> 00:07:18,281 Now, it turns out, that you can already 155 00:07:18,281 --> 00:07:22,016 think of viruses as nanoscopic computers. 156 00:07:22,888 --> 00:07:25,321 They have evolved to detect 157 00:07:25,321 --> 00:07:26,919 biomolecular signals 158 00:07:26,919 --> 00:07:28,324 in their environment, 159 00:07:28,324 --> 00:07:29,931 which could include 160 00:07:29,931 --> 00:07:32,041 biomolecular cues in our bodies, 161 00:07:32,041 --> 00:07:34,985 in order to have productive infections 162 00:07:34,985 --> 00:07:38,561 that lead to self-replication ultimately. 163 00:07:40,088 --> 00:07:43,468 In every step of the virus infectious process 164 00:07:43,468 --> 00:07:46,512 the virus detects biomolecular signals 165 00:07:46,512 --> 00:07:48,723 that allow the virus to do the next step 166 00:07:48,723 --> 00:07:50,959 of that infection, 167 00:07:50,959 --> 00:07:52,649 and t's actually very fascinating, 168 00:07:52,649 --> 00:07:54,595 because it turns out that every 169 00:07:54,595 --> 00:07:58,109 biomolecular signal acts upon the capsid, 170 00:07:58,109 --> 00:08:01,529 changing it, sometimes just a little bit, 171 00:08:01,529 --> 00:08:04,281 and sometimes quite dramatically. 172 00:08:05,314 --> 00:08:06,901 So you can think of viruses 173 00:08:06,901 --> 00:08:10,192 as some of the most primitive shape-shifters. 174 00:08:12,419 --> 00:08:15,109 In our work, we're basically taking 175 00:08:15,109 --> 00:08:18,234 these intrinsic properties of viruses 176 00:08:18,234 --> 00:08:21,493 as inspiration and we want to re-write 177 00:08:21,493 --> 00:08:25,042 or re-program what the virus 178 00:08:25,042 --> 00:08:28,898 detects and computes as biomolecular input. 179 00:08:31,239 --> 00:08:32,680 Here are some of the viruses 180 00:08:32,680 --> 00:08:35,568 that we have re-programmed in the laboratory. 181 00:08:35,568 --> 00:08:36,879 Just by looking at them, 182 00:08:36,879 --> 00:08:39,334 you actually won't be able to tell the difference 183 00:08:39,334 --> 00:08:40,762 between our engineered viruses 184 00:08:40,762 --> 00:08:43,574 and the ones that exist in Nature. 185 00:08:43,574 --> 00:08:45,347 But these are different. 186 00:08:45,347 --> 00:08:47,554 These have algorithms 187 00:08:47,554 --> 00:08:50,283 programmed into their structure 188 00:08:50,283 --> 00:08:53,546 that turns them into cancer-seeking assassins. 189 00:08:53,546 --> 00:08:55,737 Let me explain. 190 00:08:56,475 --> 00:08:57,573 The basic idea 191 00:08:57,573 --> 00:09:00,047 is that we want to create viruses that will be able 192 00:09:00,047 --> 00:09:01,610 to travel throughout the body 193 00:09:01,610 --> 00:09:03,702 in an inert fashion, 194 00:09:03,702 --> 00:09:06,645 or in a locked configuration, if you will. 195 00:09:06,645 --> 00:09:08,293 In this locked configuration 196 00:09:08,293 --> 00:09:10,530 the virus cannot deliver the message 197 00:09:10,530 --> 00:09:12,530 that it's carrying 198 00:09:12,530 --> 00:09:16,255 until it comes across some biomolecular cue, 199 00:09:16,255 --> 00:09:19,940 signal, represented by the key here, 200 00:09:19,940 --> 00:09:22,079 and that key will open up the capsid 201 00:09:22,079 --> 00:09:25,109 and now, in this open configuration, 202 00:09:25,109 --> 00:09:27,550 the virus can deliver that message 203 00:09:27,550 --> 00:09:30,114 to the cancer cells. 204 00:09:30,301 --> 00:09:32,382 The other way that I like to conceptualize 205 00:09:32,382 --> 00:09:34,266 our design strategy is thinking of it 206 00:09:34,266 --> 00:09:36,645 as if we were programming encryption 207 00:09:36,645 --> 00:09:38,715 into these viruses. 208 00:09:39,015 --> 00:09:41,441 So, the message cannot be read 209 00:09:41,441 --> 00:09:45,445 unless it is deciphered by the appropriate key. 210 00:09:47,594 --> 00:09:51,284 The next natural question is, what key? 211 00:09:52,300 --> 00:09:55,043 Luckily, advances in biomedical research 212 00:09:55,043 --> 00:09:58,007 has been answering that question for us. 213 00:09:58,007 --> 00:10:00,171 It turns out that if you look at tumor cells, 214 00:10:00,171 --> 00:10:02,601 tumor masses, there are a lot 215 00:10:02,601 --> 00:10:05,655 of biochemical signals, these cues, 216 00:10:05,655 --> 00:10:07,987 that are present at higher concentrations 217 00:10:07,987 --> 00:10:12,438 in the tumor, either outside of the cancer cells 218 00:10:12,438 --> 00:10:15,247 or within the cancer cells themselves. 219 00:10:15,247 --> 00:10:17,854 You can imagine all of these cues 220 00:10:17,854 --> 00:10:19,699 can act as the key 221 00:10:19,699 --> 00:10:22,450 that will open up our virus. 222 00:10:23,540 --> 00:10:25,590 This is a demonstration of how 223 00:10:25,590 --> 00:10:27,416 one of our devices work. 224 00:10:27,416 --> 00:10:29,496 In this black part, you don't see anything 225 00:10:29,496 --> 00:10:32,713 but there's an entire lawn of cells 226 00:10:33,159 --> 00:10:35,487 and onto this lawn we've added these viruses 227 00:10:35,487 --> 00:10:37,485 that we have in here, and in this case 228 00:10:37,485 --> 00:10:40,750 the virus is still in its locked state, 229 00:10:40,750 --> 00:10:42,854 its encrypted state, 230 00:10:42,854 --> 00:10:46,219 and as a demonstration this virus is delivering a message 231 00:10:46,219 --> 00:10:49,074 that, if read properly by that cell, 232 00:10:49,074 --> 00:10:50,925 would turn that cell green. 233 00:10:50,925 --> 00:10:53,534 It's a green message. 234 00:10:53,534 --> 00:10:56,280 You can see there's really not many cells 235 00:10:56,280 --> 00:10:59,039 that are able to read that green message. 236 00:10:59,039 --> 00:11:02,595 That's mainly because the virus is encrypted. 237 00:11:04,039 --> 00:11:07,078 Conversely, when the virus sees 238 00:11:07,788 --> 00:11:10,657 these biomolecular keys, 239 00:11:11,265 --> 00:11:13,303 the viruses open, 240 00:11:13,303 --> 00:11:14,938 that message is decyphered 241 00:11:14,938 --> 00:11:17,214 and these cells can now read 242 00:11:17,214 --> 00:11:20,147 these green messages. 243 00:11:21,769 --> 00:11:24,522 Let's go back to the schematic here. 244 00:11:24,522 --> 00:11:27,691 I told you that there's a lot of keys 245 00:11:28,059 --> 00:11:30,269 within the tumor mass, 246 00:11:30,269 --> 00:11:32,444 greater concentration in the tumor, 247 00:11:32,444 --> 00:11:35,485 but you may have noticed that there are also keys, 248 00:11:35,490 --> 00:11:38,226 present at lower concentrations, 249 00:11:38,226 --> 00:11:40,277 elsewhere in the body. 250 00:11:40,277 --> 00:11:42,514 And that represents some problem. 251 00:11:42,514 --> 00:11:46,529 That could lead to these non-targeted side effects, 252 00:11:46,529 --> 00:11:49,023 that you want to run away from. 253 00:11:49,023 --> 00:11:51,219 Our answer to this is trying 254 00:11:51,219 --> 00:11:54,971 to make these viruses open 255 00:11:54,971 --> 00:11:57,899 only when it detects two, 256 00:11:57,899 --> 00:12:00,506 both the red and the green. 257 00:12:00,506 --> 00:12:02,244 As shown here. 258 00:12:02,244 --> 00:12:04,162 And we have successfully generated 259 00:12:04,162 --> 00:12:07,045 one of these devices recently. 260 00:12:07,045 --> 00:12:09,109 Another way to think about this 261 00:12:09,109 --> 00:12:12,958 is to program an "AND" logic operator 262 00:12:12,958 --> 00:12:15,236 into this virus structure. 263 00:12:15,236 --> 00:12:18,991 I believe that the virus biotechnology community 264 00:12:18,991 --> 00:12:20,790 we are dreaming the same dream, 265 00:12:20,790 --> 00:12:22,970 we have the same vision. 266 00:12:22,970 --> 00:12:24,275 In the very near future, 267 00:12:24,275 --> 00:12:26,900 we want to be able to program viruses, 268 00:12:26,900 --> 00:12:30,169 real viruses, as we would computer programs. 269 00:12:30,169 --> 00:12:32,028 And we want this design process 270 00:12:32,028 --> 00:12:35,335 to be standardized, modular 271 00:12:35,335 --> 00:12:38,493 and lead to a predictable outcome. 272 00:12:40,761 --> 00:12:43,629 I leave you with a cliff-hanger. 273 00:12:44,030 --> 00:12:45,727 The big looming question is, 274 00:12:45,727 --> 00:12:49,102 how will these devices work in the human body? 275 00:12:50,511 --> 00:12:54,017 Will they actually do what we are proposing? 276 00:12:54,690 --> 00:12:57,880 We don't know the answers to these questions yet. 277 00:13:01,268 --> 00:13:04,103 But I work with a really great team, 278 00:13:04,687 --> 00:13:07,651 of very hard-working and passionate students 279 00:13:07,651 --> 00:13:09,613 on this research. 280 00:13:09,613 --> 00:13:11,664 So follow us and see our progress 281 00:13:11,664 --> 00:13:14,005 over the next several years. 282 00:13:14,005 --> 00:13:17,142 I invite you. Go viral with us. 283 00:13:17,848 --> 00:13:19,132 Thank you. 284 00:13:19,132 --> 00:13:21,379 (Applause)