1 00:00:05,760 --> 00:00:08,880 >>I'M WARREN LEONARD IN 2 00:00:08,880 --> 00:00:10,520 THE NHLBI AND ON 3 00:00:10,520 --> 00:00:12,200 BEHALF OF THE CYTOKINE INTEREST 4 00:00:12,200 --> 00:00:14,280 GROUP I'M DELIGHTED TO WELCOME 5 00:00:14,280 --> 00:00:16,880 TODAY'S SPEAKER CHRIS GARCIA 6 00:00:16,880 --> 00:00:19,840 FROM STANFORD WHO IS A 7 00:00:19,840 --> 00:00:20,360 WORLD-RENOWNED ENGINEER 8 00:00:20,360 --> 00:00:22,720 INTERESTED IN SIGNALING AND 9 00:00:22,720 --> 00:00:23,960 MAKING IMMUNO THERAPEUTICS. 10 00:00:23,960 --> 00:00:25,720 I'M DELIGHTED THAT 11 00:00:25,720 --> 00:00:27,520 WE'RE HOSTING CHRIS GARCIA A 12 00:00:27,520 --> 00:00:29,360 FRIEND WITH WHOM I HAD THE 13 00:00:29,360 --> 00:00:30,360 PLEASURE OF COLLABORATING. 14 00:00:30,360 --> 00:00:34,320 HE IS PROFESSOR OF MOLECULAR AND 15 00:00:34,320 --> 00:00:37,400 CELLULAR PHYSIOLOGY AND YOUNGER 16 00:00:37,400 --> 00:00:38,560 PROFESSOR STRUCTURAL BIOLOGY AT 17 00:00:38,560 --> 00:00:40,280 STANFORD AND INVESTIGATOR TO THE 18 00:00:40,280 --> 00:00:41,720 SHOW ARD HUGHES MEDICAL 19 00:00:41,720 --> 00:00:42,200 INSTITUTE. 20 00:00:42,200 --> 00:00:44,120 HE'S INTERESTED IN CELL SURFACE 21 00:00:44,120 --> 00:00:46,840 RECEPTORS AND THEIR LIGANDS WITH 22 00:00:46,840 --> 00:00:47,960 EXTRAORDINARY WOORK ON CYTOKINES 23 00:00:47,960 --> 00:00:50,400 IN THE T-CELL RECEPTOR AND USING 24 00:00:50,400 --> 00:00:51,160 INNOVATIVE APPROACHES TO 25 00:00:51,160 --> 00:00:54,000 UNDERSTAND HOW CELL SURFACE 26 00:00:54,000 --> 00:00:56,920 RECEPTORS ENGAGE LIGANDS AND 27 00:00:56,920 --> 00:00:57,680 TRANSDUCE SIGNALS. 28 00:00:57,680 --> 00:01:00,720 HE HAS DETERMINED THE STRUCTURE 29 00:01:00,720 --> 00:01:03,360 OF CYTOKINE FAMILY MEMBERS, 30 00:01:03,360 --> 00:01:05,840 COMPLEX RECEPTORS INCLUDING 31 00:01:05,840 --> 00:01:10,600 COMMA GAMMA CHAIN CYTOKINES, 32 00:01:10,600 --> 00:01:13,320 GP10, IL12, AND INTERFERONS. 33 00:01:13,320 --> 00:01:15,480 HE ALSO DETERMINED THE FIRST 34 00:01:15,480 --> 00:01:18,160 RECEPTOR FOR A JACK CYTOKINE 35 00:01:18,160 --> 00:01:18,960 RECEPTOR COMPLEX [INDISCERNIBLE] 36 00:01:18,960 --> 00:01:20,040 STRUCTURE AND MUCH MORE. 37 00:01:20,040 --> 00:01:24,040 HE CREATED IL2 AND IL4 38 00:01:24,040 --> 00:01:27,080 SUPERKINES DEVELOPED A WIDELY 39 00:01:27,080 --> 00:01:28,960 USED ORTHOGONAL IL2 SYSTEM AND 40 00:01:28,960 --> 00:01:32,240 GENERATED A BROAD RAINCHL OF 41 00:01:32,240 --> 00:01:33,200 CYTOKINE AGONISTS AND SERIES 42 00:01:33,200 --> 00:01:37,560 POINTSIGATE AGONIST AS WELL AS A 43 00:01:37,560 --> 00:01:41,200 CIRC ALPHA VARIANT WITH ENHANCED 44 00:01:41,200 --> 00:01:44,200 AFFINITY TO ANTAGONIZE CD47. 45 00:01:44,200 --> 00:01:46,040 HE FOUNDED SYNTHA SIGN A BIOTECH 46 00:01:46,040 --> 00:01:50,840 WITH A NEW FOCUS ON THERAPIES. 47 00:01:50,840 --> 00:01:52,440 CHRIS RECEIVED HIS MD. FROM 48 00:01:52,440 --> 00:01:54,120 TULANE AND Ph.D. FROM JOHNS 49 00:01:54,120 --> 00:01:54,360 HOPKINS. 50 00:01:54,360 --> 00:02:00,080 HE WAS A POST DOC AT GENENTECH 51 00:02:00,080 --> 00:02:04,120 AND THEN AT SCRIPS WITH IAN 52 00:02:04,120 --> 00:02:05,720 WILSON AND ON FACULTY AT SCRIPTS 53 00:02:05,720 --> 00:02:06,920 BEFORE MOVING TO STANFORD WHERE 54 00:02:06,920 --> 00:02:07,720 HE'S BEEN EVER SINCE. 55 00:02:07,720 --> 00:02:11,800 HE'S A MEMBER OF THE NATIONAL 56 00:02:11,800 --> 00:02:13,080 ACADEMY OF SCIENCES, NATIONAL 57 00:02:13,080 --> 00:02:17,040 ACADEMY OF MEDICINE AND RECEIVED 58 00:02:17,040 --> 00:02:19,600 THE 2021 WILLIAM POLE AWARD FROM 59 00:02:19,600 --> 00:02:21,240 THE CYTOKINE AND INTERFERON 60 00:02:21,240 --> 00:02:21,560 SOCIETY. 61 00:02:21,560 --> 00:02:25,920 FIRST SLIDE PLEASE AND ONLY 62 00:02:25,920 --> 00:02:26,440 SLIDE. 63 00:02:26,440 --> 00:02:28,840 FINALLY, I WOULD BE REMISS IF I 64 00:02:28,840 --> 00:02:32,640 DIDN'T MENTION HIS ATHLETIC 65 00:02:32,640 --> 00:02:33,680 PROWESS INCLUDING SWIMMING, 66 00:02:33,680 --> 00:02:37,560 BICYCLE, AND RUNNING WITH MANY, 67 00:02:37,560 --> 00:02:38,560 MANY ULTRA MARATHONS. 68 00:02:38,560 --> 00:02:40,120 SO IT'S A PLEASURE TO WELCOME 69 00:02:40,120 --> 00:02:42,200 YOU, CHRIS, HIS TITLE IS 70 00:02:42,200 --> 00:02:44,600 IMMUNITY THROUGH LIGAND-RECEPTOR 71 00:02:44,600 --> 00:02:45,480 ENGINEERING. 72 00:02:45,480 --> 00:02:47,880 >>THANKS WARREN AND CHRIS FOR 73 00:02:47,880 --> 00:02:50,160 FOR ORGANIZING THIS, IT'S A REAL 74 00:02:50,160 --> 00:02:52,600 HONOR TO GIVE ANOTHER WALS 75 00:02:52,600 --> 00:02:54,240 LECTURE, I GAVE 1 SEVERAL YEARS 76 00:02:54,240 --> 00:02:55,320 AGO AND FRANCIS COLLINS 77 00:02:55,320 --> 00:02:57,200 INTRODUCED ME IN THE BIG 78 00:02:57,200 --> 00:02:58,680 AUDITORIUM AND THIS IS A BIG 79 00:02:58,680 --> 00:03:00,200 THRILL BUT THIS WILL SUFFICE, 80 00:03:00,200 --> 00:03:04,800 TODAY, I HOPE TO BE BACK IN 81 00:03:04,800 --> 00:03:05,200 PERSON SOON. 82 00:03:05,200 --> 00:03:07,360 Y SOPHISTICATED THAT PICTURE 83 00:03:07,360 --> 00:03:09,520 THAT DOES BRING BACK MEMORIES 84 00:03:09,520 --> 00:03:13,920 THAT WAS THE CASCADE CREST 100 85 00:03:13,920 --> 00:03:16,120 MILLER IN THE CASCADE MOUNTAINS 86 00:03:16,120 --> 00:03:17,520 EVEN THOUGH I LOOK VERY 87 00:03:17,520 --> 00:03:19,160 COMFORTABLE, I WAS VERY 88 00:03:19,160 --> 00:03:20,560 UNCOMFORTABLE AT THE TIME IT WAS 89 00:03:20,560 --> 00:03:20,800 TAKEN. 90 00:03:20,800 --> 00:03:21,960 SO WHY DON'T WE GET ON WITH THE 91 00:03:21,960 --> 00:03:24,560 TALK HERE 92 00:03:24,560 --> 00:03:26,720 JUST TO GET A BIT OF A 93 00:03:26,720 --> 00:03:31,920 BACKGROUND, I THINK MY INTEREST 94 00:03:31,920 --> 00:03:33,720 CAN BE SUMMARIZED AS THINGS THAT 95 00:03:33,720 --> 00:03:39,240 HAPPEN AT THE CELL FUR FASMOSTLY 96 00:03:39,240 --> 00:03:40,280 LIGAND REMEDIATED RECEPTOR 97 00:03:40,280 --> 00:03:42,680 EVENTS AND HOW PROTEINS ENGAGE 98 00:03:42,680 --> 00:03:44,200 RECEPTORS AND HOW THEY 99 00:03:44,200 --> 00:03:44,920 REACTIVATE SIGNALING AND USING 100 00:03:44,920 --> 00:03:46,560 THAT INFORMATION AND USING THE 101 00:03:46,560 --> 00:03:47,600 ACTIONABLE VALUE FROM THAT 102 00:03:47,600 --> 00:03:49,240 INFORMATION TO TRY AND PERTURB 103 00:03:49,240 --> 00:03:50,520 THE PHYSIOLOGY OF THE CELL. 104 00:03:50,520 --> 00:03:54,040 AND THAT'S KIND OF WHAT WE'RE 105 00:03:54,040 --> 00:04:00,000 INTO HERE, ON MANY DIFFERENT 106 00:04:00,000 --> 00:04:00,720 LEVELS AND SYSTEMS. 107 00:04:00,720 --> 00:04:03,000 LET ME GET MY LASER POINTER 108 00:04:03,000 --> 00:04:03,200 HERE. 109 00:04:03,200 --> 00:04:05,440 AN INTERPLAY OF STRUCTURAL 110 00:04:05,440 --> 00:04:08,680 BIOLOGY WITH PROTEIN ENGINEERING 111 00:04:08,680 --> 00:04:10,720 TO UNDERSTAND MECHANISM AND THEN 112 00:04:10,720 --> 00:04:12,280 USE THE TERM ACTIONABLE VALUE 113 00:04:12,280 --> 00:04:15,520 AND THATIA REALLY MY INTEREST IN 114 00:04:15,520 --> 00:04:17,200 MECHANISM IS EXTRACTING 115 00:04:17,200 --> 00:04:19,840 INFORMATION THAT WE CAN USE FOR 116 00:04:19,840 --> 00:04:20,720 TRANSLATION TO POSSIBLY MAKE 117 00:04:20,720 --> 00:04:20,920 DRUGS. 118 00:04:20,920 --> 00:04:25,160 AND THE SYSTEMS IN THE LAB TO 119 00:04:25,160 --> 00:04:27,040 KIND OF NAME SORT OF THE 120 00:04:27,040 --> 00:04:28,600 HIGHLIGHTS HERE, I'VE WORKED IN 121 00:04:28,600 --> 00:04:31,120 IMMUNITY INFECTION FOR A LONG 122 00:04:31,120 --> 00:04:33,800 TIME, REALLY GO WAY BACK WITH 123 00:04:33,800 --> 00:04:35,400 THE T-CELL RECEPTOR AND THEN, 124 00:04:35,400 --> 00:04:38,480 YOU KNOW THROUGH MY EXPERIENCE 125 00:04:38,480 --> 00:04:40,720 AS A GENENTECH, I DEVELOPED AN 126 00:04:40,720 --> 00:04:42,080 INTEREST IN CYTOKINE SIGNALING. 127 00:04:42,080 --> 00:04:43,640 SO THOSE ARE THE TWIN POLES AT 128 00:04:43,640 --> 00:04:48,000 THE LAB BUT WE ALSO HAVE A BIG 129 00:04:48,000 --> 00:04:48,920 PROGRAM IN REGENERATIVE MEDICINE 130 00:04:48,920 --> 00:04:50,320 LOOKING AT THE NOTCH PATHWAYS 131 00:04:50,320 --> 00:04:53,440 AND THEN ALSO, MOST OF THE 132 00:04:53,440 --> 00:04:55,080 RECEPTOR SYSTEMS IN THE LAB ARE 133 00:04:55,080 --> 00:04:57,240 ACTIVATED BY SOME TYPE OF 134 00:04:57,240 --> 00:04:59,000 INDUCED PROXIMITY SO WE'RE 135 00:04:59,000 --> 00:05:00,840 REALLY DIGGING INTO THAT NOW AS 136 00:05:00,840 --> 00:05:03,120 AN ENGINEERING PLATFORM TO 137 00:05:03,120 --> 00:05:04,200 INDUCE PROXIMITY BETWEEN 138 00:05:04,200 --> 00:05:06,000 PROTEINS ON CELLS THAT DON'T 139 00:05:06,000 --> 00:05:07,040 NORMALLY COME TOGETHER AND I'LL 140 00:05:07,040 --> 00:05:09,200 TALK SOME ABOUT THAT TODAY. 141 00:05:09,200 --> 00:05:10,960 SO OF ALL THESE DIFFERENT KIND 142 00:05:10,960 --> 00:05:13,200 OF PROJECTS IN THE LAB, I WILL 143 00:05:13,200 --> 00:05:15,400 MAINLY FOCUS ON CYTOKINES TODAY 144 00:05:15,400 --> 00:05:16,240 AND REALLY ADDRESS SOMETHING 145 00:05:16,240 --> 00:05:21,440 THAT I REALLY GOD INTERESTED IN 146 00:05:21,440 --> 00:05:24,120 READING WARREN LEONARD'S PAPERS 147 00:05:24,120 --> 00:05:26,400 AND USING THIS WORD PLEOTROPY, 148 00:05:26,400 --> 00:05:28,640 HE WAS 1 OF THE FIRST PEOPLE TO 149 00:05:28,640 --> 00:05:31,560 PUT THIS WORD OUT THERE AND IT'S 150 00:05:31,560 --> 00:05:34,040 AN APT WORD BECAUSE CYTOKINES 151 00:05:34,040 --> 00:05:37,160 ARE PLEOTROAPIC IN THAT THEY ACT 152 00:05:37,160 --> 00:05:38,960 ON MULTIPLE DIFFERENT CELL 153 00:05:38,960 --> 00:05:39,240 TYPES. 154 00:05:39,240 --> 00:05:41,200 CELLS HAVE COUNTER VAILING 155 00:05:41,200 --> 00:05:42,280 ACTIONS, THEY HAVE SPECIFIC 156 00:05:42,280 --> 00:05:46,920 ACTIONS AND IT'S A VERY 157 00:05:46,920 --> 00:05:47,760 DIFFICULT ISSUE IN CYTOKINE 158 00:05:47,760 --> 00:05:50,240 BIOLOGY TO UNDERSTAND WHAT THE 159 00:05:50,240 --> 00:05:51,560 SPECIFIC FUNCTIONS OF DIFFERENT 160 00:05:51,560 --> 00:05:55,240 CYTOKINES ARE IN THE FACE OF 161 00:05:55,240 --> 00:05:56,120 THIS PLEIOTROPY. 162 00:05:56,120 --> 00:05:58,560 BUT IT'S ALSO BEEN A HUGE 163 00:05:58,560 --> 00:05:59,840 BARRIER TO GETTING CYTOKINES IN 164 00:05:59,840 --> 00:06:02,560 THE CLINIC OTHER THAN OTHER 165 00:06:02,560 --> 00:06:03,880 PARTICULAR EXAMPLES SUCH AS EFO 166 00:06:03,880 --> 00:06:06,320 AND A FEW OTHERS THAT HAVE VERY 167 00:06:06,320 --> 00:06:09,200 RESTRICTED EXPRESSION OF THEIR 168 00:06:09,200 --> 00:06:09,800 RECEPTORS. 169 00:06:09,800 --> 00:06:11,640 IMMUNE CYTOKINES LIKE IL2 AND 170 00:06:11,640 --> 00:06:12,560 OTHERS HAVE BEEN VERY DIFFICULT 171 00:06:12,560 --> 00:06:14,600 TO IMPLEMENT IN THE CLINIC IN AN 172 00:06:14,600 --> 00:06:15,720 AGONIST MOST AND THAT'S 173 00:06:15,720 --> 00:06:18,000 SOMETHING I'VE BEEN VERY 174 00:06:18,000 --> 00:06:21,440 INTERESTED IN BASED ON THE 175 00:06:21,440 --> 00:06:22,440 MECHANISM OF HOW CYTOKINE 176 00:06:22,440 --> 00:06:22,680 SIGNAL. 177 00:06:22,680 --> 00:06:24,240 SO TO THE RIGHT HERE WHAT I'M 178 00:06:24,240 --> 00:06:28,120 SHOWING YOU HERE IS THE KIND OF 179 00:06:28,120 --> 00:06:30,920 CLASSIC PARADIGM OF HOW CYTOKINE 180 00:06:30,920 --> 00:06:33,480 SIGNAL, BINDS WITH HIGH AFFINITY 181 00:06:33,480 --> 00:06:35,560 TO 1 RECEPTOR WHICH RECRUITS IN 182 00:06:35,560 --> 00:06:37,720 THE SECOND RECEPTOR THAT CAUSES 183 00:06:37,720 --> 00:06:40,360 THE JANUS KINASES WHICH ARE 184 00:06:40,360 --> 00:06:42,320 ASSOCIATED WITH THE 185 00:06:42,320 --> 00:06:43,120 INTERRACELLULAR DOMAINS TO 186 00:06:43,120 --> 00:06:44,280 PHOSPHORYLATE AND THEN THE STATS 187 00:06:44,280 --> 00:06:46,720 WITH THAT THEY GO INTO THE 188 00:06:46,720 --> 00:06:46,960 NUCLEUS. 189 00:06:46,960 --> 00:06:49,160 AND THIS 2 STEP MECHANISM 190 00:06:49,160 --> 00:06:55,000 AFFORDS A LOT OF ENGINEERING 191 00:06:55,000 --> 00:06:56,240 PLEIOTROPY AGONIST TO BRENG 192 00:06:56,240 --> 00:06:57,840 THESE 2 TOGETHER IN DIFFERENT 193 00:06:57,840 --> 00:07:00,240 WAYS THAT COULD MODULATE 194 00:07:00,240 --> 00:07:00,480 SIGNALING. 195 00:07:00,480 --> 00:07:02,400 AND WE'VE RELIED A LOT ON 196 00:07:02,400 --> 00:07:04,840 STRUCTURAL BIOLOGY TO PROVIDE 197 00:07:04,840 --> 00:07:07,720 BLUEPRINTS OF CYTOKINE RECEPTOR 198 00:07:07,720 --> 00:07:09,560 COMPLEXES, THIS A SELECTION, AN 199 00:07:09,560 --> 00:07:11,640 INCOMPLETE SELECTION FROM OVER 200 00:07:11,640 --> 00:07:16,600 THE YEARS STARTING WITH IL1 AND 201 00:07:16,600 --> 00:07:18,360 YOU'LL SEE PROBABLY SOME OF 202 00:07:18,360 --> 00:07:19,560 YOUR--1 OF YOUR FAVORITE 203 00:07:19,560 --> 00:07:22,880 MOLECULES UP HERE, WE PROBABLY 204 00:07:22,880 --> 00:07:24,400 LOOKED AT IT AND YOU KNOW WE 205 00:07:24,400 --> 00:07:26,000 REALLY TRY TO INNOVATE FROM THE 206 00:07:26,000 --> 00:07:27,680 STRUCTURES OF THE EXTRA CELLULAR 207 00:07:27,680 --> 00:07:33,960 COMPLEXES AND THEN 208 00:07:33,960 --> 00:07:41,440 RECENTLY--SORRY, I THINK I WILL 209 00:07:41,440 --> 00:07:42,920 KEEP MY POINTER--WELL, HOW DO I 210 00:07:42,920 --> 00:07:45,800 GET THIS THING GOING HERE. 211 00:07:45,800 --> 00:07:46,760 PLAYER OPTIONS, LET'S GO OFF 212 00:07:46,760 --> 00:07:49,040 THERE, THERE WE GO. 213 00:07:49,040 --> 00:07:49,560 OKAY. 214 00:07:49,560 --> 00:07:53,120 SO WE RECENTLY LAST YEAR A GROUP 215 00:07:53,120 --> 00:07:56,320 IN MY LAB, CALEB, 216 00:07:56,320 --> 00:08:00,000 [INDISCERNIBLE] AND OTHERS NOW 217 00:08:00,000 --> 00:08:03,200 NATHANIEL DAB NET WE DETERMINED 218 00:08:03,200 --> 00:08:05,440 THE FULL LENGTH KINASE OF A 219 00:08:05,440 --> 00:08:06,240 CYTOKINE RECEPTOR AND I WILL 220 00:08:06,240 --> 00:08:08,760 TALK MORE ABOUT THAT LATER BUT 221 00:08:08,760 --> 00:08:11,080 THE REASON I SHOWED THIS NOW IS 222 00:08:11,080 --> 00:08:13,480 TO COMPARE AND CONTRAST HOW WE 223 00:08:13,480 --> 00:08:15,480 THINKING ABOUT CYTOKINE 224 00:08:15,480 --> 00:08:18,720 ENGINEERING WHICH IS IN THE 225 00:08:18,720 --> 00:08:21,920 CONTEXT OF NOW GPC Rs ARE 226 00:08:21,920 --> 00:08:24,120 ACTIVATED AND THAT THEY'RE VERY 227 00:08:24,120 --> 00:08:26,720 PLASTIC MOLECULES AND YOU KNOW 228 00:08:26,720 --> 00:08:30,040 KIND OF THE WHOLE FOUNDATION OF 229 00:08:30,040 --> 00:08:31,200 THE GPCR DRUG DISCOVERY INDUSTRY 230 00:08:31,200 --> 00:08:35,040 IS THIS IDEA THAT YOU CAN MAKE 231 00:08:35,040 --> 00:08:36,800 BIASED AGONISTS AND PARTIAL 232 00:08:36,800 --> 00:08:39,360 AGONISTS, THIS IS A CLASSICAL 233 00:08:39,360 --> 00:08:40,880 PHARMAICOLOGICAL DOSE RESPONSE 234 00:08:40,880 --> 00:08:44,480 GROUP FOR GPCR LIGANDS THAT HAS 235 00:08:44,480 --> 00:08:46,040 REALLY BEEN LIMITED TO G-PROTEIN 236 00:08:46,040 --> 00:08:47,320 RECEPTORS AND ION CHANNELS AND 237 00:08:47,320 --> 00:08:49,160 WE'RE THINKING ABOUT THIS KIND 238 00:08:49,160 --> 00:08:50,560 OF ENGINE, THIS SIGNALING ENGINE 239 00:08:50,560 --> 00:08:52,760 IN THE CONTEXT OF THESE 240 00:08:52,760 --> 00:08:54,040 PHARMAICOLOGICAL PRINCIPLES AND 241 00:08:54,040 --> 00:08:55,120 THAT'S REALLY DRIVEN A LOT WITH 242 00:08:55,120 --> 00:08:57,640 WHAT I WILL SHOW YOU TODAY, SORT 243 00:08:57,640 --> 00:08:59,800 OF ENGINEERING THE PROTEIN TO 244 00:08:59,800 --> 00:09:03,920 ACHIEVE THE SAME TYPE OF 245 00:09:03,920 --> 00:09:05,480 BEHAVIORS THAT SMALL MOLECULE 246 00:09:05,480 --> 00:09:11,240 AGONIST FOR GPC Rs WORK. 247 00:09:11,240 --> 00:09:12,640 AND ALSO NOT JUST ENGINEERING 248 00:09:12,640 --> 00:09:16,760 THE CYTOKINE BUT ALSO MAKING 249 00:09:16,760 --> 00:09:19,600 MOLECULES THAT CAN CHANGE THE 250 00:09:19,600 --> 00:09:20,960 GEOMETRY OF THE CYTOKINE 251 00:09:20,960 --> 00:09:21,400 RECEPTOR DIMER. 252 00:09:21,400 --> 00:09:23,240 SO I WILL JUST REALLY GET 253 00:09:23,240 --> 00:09:25,000 STARTED HERE WITH A FEW EXAMPLES 254 00:09:25,000 --> 00:09:28,040 OF HOW WE'RE DOING THIS AND 255 00:09:28,040 --> 00:09:29,960 STARTING OFF ON IL2 AND WE 256 00:09:29,960 --> 00:09:32,440 DETERMINE THE STRUCTURE OF THIS 257 00:09:32,440 --> 00:09:33,560 HIGH AFFINITY COMPLEX QUITE A 258 00:09:33,560 --> 00:09:36,400 FEW YEARS AGO NOW BUT IT'S JUST 259 00:09:36,400 --> 00:09:38,680 CONTINUED TO REALLY YIELD 260 00:09:38,680 --> 00:09:41,000 INFORMATION THAT HAS ALLOWED US 261 00:09:41,000 --> 00:09:44,240 TO ENGINEER A WHOLE SLEW OF 262 00:09:44,240 --> 00:09:45,680 INTERESTING IL2 VARIANTS EXPW I 263 00:09:45,680 --> 00:09:49,320 WON'T SUMMARIZE A LOT OF THAT 264 00:09:49,320 --> 00:09:50,480 JUST FOCUSING ON THE MORE RECENT 265 00:09:50,480 --> 00:09:51,680 DATA AND REALLY THE INTEREST HAS 266 00:09:51,680 --> 00:09:56,720 BEEN TO ASK IF WE CAN MAKE IL2 267 00:09:56,720 --> 00:09:59,720 VARIANTS THAT MIGHT SKEW T-CELLS 268 00:09:59,720 --> 00:10:01,560 TOWARDS REGULATORY T-CELLS OR 269 00:10:01,560 --> 00:10:02,640 EFFECTOR T-CELLS AND SO HAVE A 270 00:10:02,640 --> 00:10:05,200 LOT OF OTHER GROUPS AND THAT'S 271 00:10:05,200 --> 00:10:10,840 TO MAKE DRUGS FOR AUTOIMMUNITY 272 00:10:10,840 --> 00:10:13,680 OR CANCER IMMUNOTHERAPY AND 1 273 00:10:13,680 --> 00:10:16,280 RECENT SERIES OF STUDIES WE'VE 274 00:10:16,280 --> 00:10:20,480 DONE IS WE'VE MADE A SERIES OF 275 00:10:20,480 --> 00:10:23,160 PARTIAL STAT AGONIST BY MUTATING 276 00:10:23,160 --> 00:10:24,520 THE COMMON GAMMA CHAIN BINDING 277 00:10:24,520 --> 00:10:26,400 FACE OF IL2 WHERE WE ESSENTIALLY 278 00:10:26,400 --> 00:10:33,320 BEEN ABLE TO TITRATE STATED 5 IN 279 00:10:33,320 --> 00:10:36,360 INCREMENTS AND WE SYSTEMATICALLY 280 00:10:36,360 --> 00:10:37,680 CHARACTERIZED THESE INVITRO BUT 281 00:10:37,680 --> 00:10:40,200 ALSO ADMINISTER THEM TO MICE TO 282 00:10:40,200 --> 00:10:41,920 OBSERVE THE IMMUNE CELL 283 00:10:41,920 --> 00:10:45,160 PROFILING BEHAVIOR AND HAD SOME 284 00:10:45,160 --> 00:10:47,560 INTERESTING RESULTS HERE. 285 00:10:47,560 --> 00:10:53,440 FOR INSTANCE, THIS 1 MOLECULE 286 00:10:53,440 --> 00:10:54,480 CALLED HLINT, WHICH WE 287 00:10:54,480 --> 00:10:56,080 COLLABORATED WITH ON THIS, IT'S 288 00:10:56,080 --> 00:10:58,920 A VERY SMALL, A PARTIAL AGONIST 289 00:10:58,920 --> 00:11:00,720 THAT'S BARELY, VERY SLIGHTLY 290 00:11:00,720 --> 00:11:03,200 ATTENUATE IN THE STAT 5 BUT YET 291 00:11:03,200 --> 00:11:04,920 WARREN TOOK THIS MOLECULE AND HE 292 00:11:04,920 --> 00:11:07,360 AND HIS GROUP FOUND SOME VERY 293 00:11:07,360 --> 00:11:09,280 INTERESTING PROPERTIES THAT IT'S 294 00:11:09,280 --> 00:11:12,040 VERY IL2 LIKE IN ITS ABILITY TO 295 00:11:12,040 --> 00:11:15,320 EXPAND T-CELLS BUT THERE'S A 296 00:11:15,320 --> 00:11:17,440 REDUCTION AND ACTIVATION OF 297 00:11:17,440 --> 00:11:18,920 EXHAUSTIAN MARKERS LIKE TIM 3 298 00:11:18,920 --> 00:11:23,720 AND LAG, AND IT ALSO HAS THESE 299 00:11:23,720 --> 00:11:26,040 STEM LIKE PROCESSES LIKE THE 300 00:11:26,040 --> 00:11:26,680 TRANSCRIPTION FACTOR AND 301 00:11:26,680 --> 00:11:29,080 RESPONSE WHICH IS REDUCED DPLI 302 00:11:29,080 --> 00:11:31,080 COLSIS WHICH IS HALLMARKS OF 303 00:11:31,080 --> 00:11:38,600 STEMNESS, AND IN WORKING WITH 304 00:11:38,600 --> 00:11:39,920 NICK RESTIFO, THEY FOUND THAT 305 00:11:39,920 --> 00:11:42,040 PRECONDITIONING CELLS PRIOR TO 306 00:11:42,040 --> 00:11:44,520 ADOPTED TRANSFER IN A FEMALE 307 00:11:44,520 --> 00:11:45,560 MODEL SIGNIFICANTLY DELAYED 308 00:11:45,560 --> 00:11:47,360 TUMOR GROWTH COMPARED TO IL2 OR 309 00:11:47,360 --> 00:11:49,960 SUPER 2 ASK ALSO LED TO ENHANCED 310 00:11:49,960 --> 00:11:50,600 PERSISTENCE. 311 00:11:50,600 --> 00:11:53,840 SO THAT WAS REALLY JUST THE 312 00:11:53,840 --> 00:11:56,640 SLIGHTEST ATTENUATION OF STAT 5 313 00:11:56,640 --> 00:11:57,960 SIGNALING REALLY SIGNIFICANTLY 314 00:11:57,960 --> 00:12:02,000 CHANGEDLET IN VIVO ACTIVITY OF 315 00:12:02,000 --> 00:12:04,480 THIS MOLECULE WHICH REALLY SHOWS 316 00:12:04,480 --> 00:12:06,240 HOW TUNEABLE THESE CYTOKINE ARE. 317 00:12:06,240 --> 00:12:08,920 HERE'S ANOTHER EXAMPLE THAT'S A 318 00:12:08,920 --> 00:12:11,720 BIT MORE ATTENUATE IN STAT 5 319 00:12:11,720 --> 00:12:15,120 WHICH WE CALL REH AND CALEB 320 00:12:15,120 --> 00:12:16,400 GLASSMAN IN MY LAB AND WE WORK 321 00:12:16,400 --> 00:12:18,960 WIDE WARREN ON THIS, FOUND IT 322 00:12:18,960 --> 00:12:21,280 HAS HIGH SELECTIVITY FOR 323 00:12:21,280 --> 00:12:22,720 REGULATORY T-CELLS VERSUS 324 00:12:22,720 --> 00:12:26,320 CONVENTIONAL T-CELLS AND WE DID 325 00:12:26,320 --> 00:12:28,720 SOME RNA SEQ WITH WARREN AND 326 00:12:28,720 --> 00:12:32,960 FOUND THAT IN T-CONS WE SAW A 327 00:12:32,960 --> 00:12:34,480 REDUCTION IN THE TRANSCRIPTION 328 00:12:34,480 --> 00:12:36,480 OF CERTAINLY THESE 329 00:12:36,480 --> 00:12:37,120 PROINFLAMMATORY MOLECULES 330 00:12:37,120 --> 00:12:39,200 WHEREAS THAT WAS LESS SO IN THE 331 00:12:39,200 --> 00:12:41,680 REGULATORY T-CELLS SO HERE 332 00:12:41,680 --> 00:12:43,400 AGAIN, THIS SLIGHT ATTENUATION 333 00:12:43,400 --> 00:12:45,800 OF THE MEMBRANE PROAKS 334 00:12:45,800 --> 00:12:46,920 MALSIGNALING ADAPTOR REALLY LED 335 00:12:46,920 --> 00:12:48,560 TO THESE DIFFERENT CHANGES IN 336 00:12:48,560 --> 00:12:51,160 DIFFERENT CELL SUBSETS OF 337 00:12:51,160 --> 00:12:54,960 T-CELLS AND WE ALSO SHOWED THAT 338 00:12:54,960 --> 00:13:01,040 THERE WAS THIS MOLECULE SHOWED 339 00:13:01,040 --> 00:13:04,680 IMPROVED TREATMENT OF A 340 00:13:04,680 --> 00:13:05,440 DSS INTESTINAL INFLAMMATION 341 00:13:05,440 --> 00:13:07,880 COMPARED TO IL2 AND THAT IS MOST 342 00:13:07,880 --> 00:13:09,600 LIKELY DUE TO THE T-REG 343 00:13:09,600 --> 00:13:12,240 EXPANSION BUT WE ALSO HAD AN 344 00:13:12,240 --> 00:13:13,480 INTERESTING EXPERIENCE WITH THIS 345 00:13:13,480 --> 00:13:15,120 MOLECULE THAT, YOU KNOW IT 346 00:13:15,120 --> 00:13:25,640 LOOKED INITIALLY TO US LIKE A 347 00:13:27,240 --> 00:13:37,720 TREG POTENTIATOR BUT SO THIS AN 348 00:13:52,200 --> 00:13:53,240 MP38 TUMOR MOLLEDLE--IT EXPANDS 349 00:13:53,240 --> 00:13:58,680 THEM IN THE TUMOR AND LESS TOXIN 350 00:13:58,680 --> 00:14:00,320 THAT WE'VE LOOK TD AT SO THIS 351 00:14:00,320 --> 00:14:07,640 WAS QUITE A SURPRISE AND COUNTER 352 00:14:07,640 --> 00:14:09,840 ENTUMOR SPECTRUMMATIVE AND 353 00:14:09,840 --> 00:14:11,840 REALLY KIND OF TURNS THIS IDEA 354 00:14:11,840 --> 00:14:13,400 IN THE FIELD THAT IT'S REFERRED 355 00:14:13,400 --> 00:14:16,080 TO AS THE ALPHA PROBLEM BECAUSE 356 00:14:16,080 --> 00:14:18,160 IT'S HIGH ON TREGS WELL HERE WE 357 00:14:18,160 --> 00:14:21,160 HAVE A CD25 VERSION OF IL2 THAT 358 00:14:21,160 --> 00:14:26,280 EXHIBITS VERY PROFOUND ANTITUMOR 359 00:14:26,280 --> 00:14:27,000 EFFECTS AND LESS TOXICITY. 360 00:14:27,000 --> 00:14:29,200 SO ALPHA MAY NOT BE THE PROBLEM, 361 00:14:29,200 --> 00:14:31,080 IT MAY ACTUALLY BE AN 362 00:14:31,080 --> 00:14:31,960 OPPORTUNITY TO SELECTIVELY 363 00:14:31,960 --> 00:14:33,120 TARGET THE DETAILS IN THE 364 00:14:33,120 --> 00:14:37,680 ACTIVATED TAILS IN THE TUMOR. 365 00:14:37,680 --> 00:14:41,120 NOW MOVING ON TO ANOTHER 366 00:14:41,120 --> 00:14:43,600 CYTOKINE HERE, IL12, IT'S 367 00:14:43,600 --> 00:14:48,680 ANOTHER VERY POTENT T-CELL 368 00:14:48,680 --> 00:14:51,680 CYTOKINE THAT HAS REALLY BEEN A 369 00:14:51,680 --> 00:14:52,680 TANTALIZING THERAPEUTIC TARGET 370 00:14:52,680 --> 00:14:54,440 EXCEPT IT'S EXTREMELY TOXIC EVEN 371 00:14:54,440 --> 00:14:58,440 MORE SO THAN IL12. 372 00:14:58,440 --> 00:15:00,520 CALEB GLASSMAN IN MY LAB, A 373 00:15:00,520 --> 00:15:02,160 STUDENT HERE DETERMINED THE 374 00:15:02,160 --> 00:15:06,680 STRUCTURE OF THE IL12 375 00:15:06,680 --> 00:15:07,280 [INDISCERNIBLE] COMPLEX BY 376 00:15:07,280 --> 00:15:10,000 CRYOEM AND I WILL NOT DWELL ON 377 00:15:10,000 --> 00:15:10,640 THE STRUCTURAL DETAILS HERE 378 00:15:10,640 --> 00:15:14,640 OTHER THAN TO SHOW YOU THAT THE 379 00:15:14,640 --> 00:15:17,120 INTERACTION OF THE IL12 R-BETA 1 380 00:15:17,120 --> 00:15:20,400 WITH THE CYTOKINE IS RATHER 381 00:15:20,400 --> 00:15:23,680 UNUSUAL IN THAT SO THE GREEN 382 00:15:23,680 --> 00:15:27,920 MOLECULE HERE IS IL12 RBETTA 1 383 00:15:27,920 --> 00:15:30,440 AND P40 IS THE RECEPTOR SUBUNIT 384 00:15:30,440 --> 00:15:33,160 OF THE CYTOKINE AND IT'S 385 00:15:33,160 --> 00:15:36,680 INTERACTING WITH THE IG-DOMAINS 386 00:15:36,680 --> 00:15:42,000 OF THE CYTOKINE RATHER THAN THE 387 00:15:42,000 --> 00:15:43,040 HELICAL BUNDLE LIKE MOST 388 00:15:43,040 --> 00:15:43,360 CYTOKINE DO. 389 00:15:43,360 --> 00:15:45,640 SO THAT LED TO AN INTERESTING 390 00:15:45,640 --> 00:15:46,320 OPPORTUNITY OPPORTUNITY HERE TO 391 00:15:46,320 --> 00:15:48,600 ASK IF WE COULD DECOUPLE THE 392 00:15:48,600 --> 00:15:51,480 ACTIVITY OF IL12 FROM NK CELLS 393 00:15:51,480 --> 00:15:53,560 WHICH SECRETE A LOT OF GAMMA 394 00:15:53,560 --> 00:15:55,680 INTERFERON WHICH IS MOST LIKELY 395 00:15:55,680 --> 00:15:58,080 DUE TO THE--MOST LIKELY LEADS TO 396 00:15:58,080 --> 00:16:01,960 THE TOXICITY OF IL12, AND 397 00:16:01,960 --> 00:16:05,520 SELECTIVELY ACTIVATE T-CELLS. 398 00:16:05,520 --> 00:16:07,640 SO, WHAT CALEB DID IS HE DID 399 00:16:07,640 --> 00:16:10,080 STAINING OF ACTIVATED T-CELLS 400 00:16:10,080 --> 00:16:12,160 VERSUS NK CELLS AND FOUND THAT 401 00:16:12,160 --> 00:16:15,320 IL12 R-BETA 1 IS VERY HIGH ON 402 00:16:15,320 --> 00:16:18,600 CD8 T-CELL BLASTS, MUCH LESS 1 403 00:16:18,600 --> 00:16:21,680 ON NK CELLS SO WHAT ABOUT WITH 404 00:16:21,680 --> 00:16:23,960 WITH THE STRATEGY, IF WE COULD 405 00:16:23,960 --> 00:16:26,400 WEAKEN THE INTERACTION OF IL12 406 00:16:26,400 --> 00:16:29,000 WITH OUR BETA 1, WE MIGHT GET 407 00:16:29,000 --> 00:16:30,000 SELECTIVITY FOR THE CD8 T-CELLS 408 00:16:30,000 --> 00:16:31,960 SO HE MADE A SERIES OF PARTIAL 409 00:16:31,960 --> 00:16:34,320 AGONISTS BY MUTATING THE P40 410 00:16:34,320 --> 00:16:36,720 SUBUNIT OF IL12, NOT THE HELICAL 411 00:16:36,720 --> 00:16:39,120 SUBUNIT AND YOU CAN SEE THIS 2 412 00:16:39,120 --> 00:16:45,480 XL OR 3 XL OR 4 XL, NOW STAT 4 413 00:16:45,480 --> 00:16:46,800 PARTIAL AGONISTS. 414 00:16:46,800 --> 00:16:50,360 AND WHEN CALEB LOOKED AT A MOUSE 415 00:16:50,360 --> 00:16:53,200 AT THEIR ABILITY TO ACTIVATE 416 00:16:53,200 --> 00:16:55,040 T-CELLS VERSUS NK CELLS YOU SEE 417 00:16:55,040 --> 00:16:58,680 THEY LARGELY RETAIN THE ABILITY 418 00:16:58,680 --> 00:17:00,440 ON T-CELLS TO MAKE GAMMA 419 00:17:00,440 --> 00:17:02,640 INTERFERON BUT THE NK-CELLS 420 00:17:02,640 --> 00:17:04,280 THERE'S MUCH LESS ACTIVITY TO 421 00:17:04,280 --> 00:17:07,840 THE NK-CELLS SO WE TOOK THIS 422 00:17:07,840 --> 00:17:11,680 ENDOTUMOR MODEL AND THIS MC 38 423 00:17:11,680 --> 00:17:16,000 TUMOR MODEL AGAIN AND FOUND THAT 424 00:17:16,000 --> 00:17:18,200 WHILE WILD-TYPE IL2 IS EXTREMELY 425 00:17:18,200 --> 00:17:19,640 TOXIC, EACH AT 1 MICROGRAM, MICE 426 00:17:19,640 --> 00:17:21,600 GET VERY SICK UNTIL THEY 427 00:17:21,600 --> 00:17:25,000 RECOVER, AND THEN AT HIGHER 428 00:17:25,000 --> 00:17:27,640 DOSES, IT'S LETHAL, OUR PARTIAL 429 00:17:27,640 --> 00:17:29,040 AGONIST HAD NO TOXICITY 430 00:17:29,040 --> 00:17:29,960 WHATSOEVER. 431 00:17:29,960 --> 00:17:33,440 BUT THEY MAINTAINED THE SAME 432 00:17:33,440 --> 00:17:37,120 ABILITY TO REDUCE TUMOR GROWTH 433 00:17:37,120 --> 00:17:38,640 AND ENHANCE SURVIVAL. 434 00:17:38,640 --> 00:17:42,080 SO ESSENTIALLY WE DECOUPLED THE 435 00:17:42,080 --> 00:17:43,720 TOXICITY OF IL12 FROM THE 436 00:17:43,720 --> 00:17:45,320 ANTITUMOR EFFECTS AND JUST IN 437 00:17:45,320 --> 00:17:54,760 FULL DISCLOSURE, I STARTED A 438 00:17:54,760 --> 00:17:57,400 COMPANY CALLED SYNTHYKINE TO 439 00:17:57,400 --> 00:17:59,280 TEST THIS IN HUMANS. 440 00:17:59,280 --> 00:18:02,440 NOW LET'S SAY FROM A CANCER 441 00:18:02,440 --> 00:18:05,640 IMMUNO THERAPEUTIC CYTOKINES AND 442 00:18:05,640 --> 00:18:06,920 IMMUNOSUPPRESSIVE, IL10, THIS IS 443 00:18:06,920 --> 00:18:09,880 A NICE STORY DONE BY BOBBY 444 00:18:09,880 --> 00:18:12,680 SAXTON IN MY LAB WHO IS NOW AN 445 00:18:12,680 --> 00:18:15,560 ASSIST ABT PROFESSOR AT UC 446 00:18:15,560 --> 00:18:19,840 BERKELEY SO IL10 IS A WELL KNOWN 447 00:18:19,840 --> 00:18:21,280 IMMUNOSUPPRESSIVE ESPECIALLY ON 448 00:18:21,280 --> 00:18:24,440 MONOCYTES, MACROPHAGES BUT IT 449 00:18:24,440 --> 00:18:26,080 ALSO DOES HAVE SOME ACTIVATING 450 00:18:26,080 --> 00:18:29,920 EFFECTS ON T-CELLS AND THAT'S 451 00:18:29,920 --> 00:18:32,240 LARGELY DUE TO THESE ACTIVITIES 452 00:18:32,240 --> 00:18:34,720 ARE LARGELY CAN BE SEPARATED, 453 00:18:34,720 --> 00:18:38,320 THE STAT 3 IS THE 454 00:18:38,320 --> 00:18:39,280 ANTIINFLAMMATORY EFFECT, DOWN 455 00:18:39,280 --> 00:18:42,360 STREAM OF IL10 RECEPTOR AND STAT 456 00:18:42,360 --> 00:18:44,560 1 IS THE PROINFLAMMATORY SO 457 00:18:44,560 --> 00:18:46,680 BOBBY TOOK A SIMILAR STRATEGY ON 458 00:18:46,680 --> 00:18:49,480 IL10 THAT I'VE SHOWN YOU 459 00:18:49,480 --> 00:18:50,720 ALREADY, HE DETERMINED THE 460 00:18:50,720 --> 00:18:53,640 CRYOEM STRUCTURE OF THE IL10 461 00:18:53,640 --> 00:18:55,240 RECEPTOR COMPLEX, AND IT'S THIS 462 00:18:55,240 --> 00:18:56,880 INTERESTING DISCIPLINARY MERRIC 463 00:18:56,880 --> 00:18:58,760 STRUCTURE SO INSTEAD OF 2 464 00:18:58,760 --> 00:19:03,520 RECEPTORS AND 1 CYTOKINE, YOU'VE 465 00:19:03,520 --> 00:19:04,200 GOT A 2-2-2. 466 00:19:04,200 --> 00:19:06,760 SO IT SORT OF DEPARTS FROM THE 467 00:19:06,760 --> 00:19:08,960 IL2 TYPE OF MODEL I SHOWED YOU 468 00:19:08,960 --> 00:19:12,160 EARLIER BUT WHAT BOBBY DID WAS 469 00:19:12,160 --> 00:19:17,480 HE ALSO--HE FOUND ON MONOCYTES 470 00:19:17,480 --> 00:19:19,280 THAT IL10 RBETTA IS HIGH AND SO 471 00:19:19,280 --> 00:19:21,280 WHAT WE DID WAS HE CREATED A 472 00:19:21,280 --> 00:19:23,520 SERIES OF PARTIAL AGONISTS ON 473 00:19:23,520 --> 00:19:25,800 IL10 TO WEAKEN THE INTERACTION 474 00:19:25,800 --> 00:19:27,320 WITH IL10 R BETA AND THEN FOUND 475 00:19:27,320 --> 00:19:31,720 WHEN HE LOOKED AT DIFFERENT CELL 476 00:19:31,720 --> 00:19:33,280 TYPES THAT HE WAS ABLE TO 477 00:19:33,280 --> 00:19:36,040 PRESERVE STAT 3 INDUCTION ON 478 00:19:36,040 --> 00:19:38,080 MONOCYTES, BUT SIGNIFICANTLY 479 00:19:38,080 --> 00:19:41,680 DIMINISH IT ON T-CELLS, B-CELLS 480 00:19:41,680 --> 00:19:44,080 AND NK-CELLS AND ESSENTIALLY 481 00:19:44,080 --> 00:19:45,440 ERASE STAT 1 SIGNALING FROM 482 00:19:45,440 --> 00:19:45,920 T-CELLS. 483 00:19:45,920 --> 00:19:48,920 SO THAT PREDICTS WE WOULD HAVE 484 00:19:48,920 --> 00:19:52,080 PRESERVED THE ANTIINFLAMMATORY 485 00:19:52,080 --> 00:19:53,680 EFFECTS AND ELIMINATED THE 486 00:19:53,680 --> 00:19:55,040 PROINFLAMMATORY EFFECTS AND THAT 487 00:19:55,040 --> 00:19:56,680 WAS WORN OUT BY THE GENE 488 00:19:56,680 --> 00:19:59,680 SIGNATURES HERE WHEN WE DID IN 489 00:19:59,680 --> 00:20:01,840 RNA SEQ, THESE PROINFLAMMATORY 490 00:20:01,840 --> 00:20:03,960 CYTOKINES WERE REALLY 491 00:20:03,960 --> 00:20:05,920 SIGNIFICANTLY REDUCED WITH A 492 00:20:05,920 --> 00:20:09,000 PARTIAL AGONIST, AND WE ALSO 493 00:20:09,000 --> 00:20:09,840 LOOKEDDA THE ACTUAL CYTOKINES 494 00:20:09,840 --> 00:20:11,800 THEMSELVES AND YOU CAN SEE 495 00:20:11,800 --> 00:20:14,760 COMPARED TO WILD-TYPE, THE 496 00:20:14,760 --> 00:20:17,480 PARTIAL AGONIST OR SIGNIFICANTLY 497 00:20:17,480 --> 00:20:22,280 REDUCED BUT IN A MODEL AT THIS 498 00:20:22,280 --> 00:20:23,120 LPS ACTIVATION MODEL, MONOCYTES 499 00:20:23,120 --> 00:20:26,920 WHERE THEY DUMP OUT TNF AND IL6 500 00:20:26,920 --> 00:20:28,040 AND OTHER PROINFLAMMATORY 501 00:20:28,040 --> 00:20:29,760 CYTOKINES, THE PARTIAL AGONIST 502 00:20:29,760 --> 00:20:31,160 MAINTAINS ITS ACTIVITY AND 503 00:20:31,160 --> 00:20:32,560 INHIBITING THE SECRETION OF 504 00:20:32,560 --> 00:20:38,120 THESE CYTOKINES JUST AS WELL AS 505 00:20:38,120 --> 00:20:38,360 IL10. 506 00:20:38,360 --> 00:20:41,640 AND HE ALSO WENT ON AND DID A 507 00:20:41,640 --> 00:20:43,080 MOUSE SEPSIS MODEL WHERE HE 508 00:20:43,080 --> 00:20:44,800 SHOWED WE WERE ABLE TO PROTECT 509 00:20:44,800 --> 00:20:48,720 THESE MICE FROM THE IL6 AND TNF 510 00:20:48,720 --> 00:20:50,400 CYTOKINE STORM WHEN THE MICE ARE 511 00:20:50,400 --> 00:20:52,080 INFECTED WITH SEPSIS AS WELL AS 512 00:20:52,080 --> 00:20:53,560 WILD-TYPE 10. 513 00:20:53,560 --> 00:20:56,480 SO HERE AGAIN WE'VE SHOWN WE CAN 514 00:20:56,480 --> 00:20:57,880 DECOUPLE THE ACTIVITIES OF THE 515 00:20:57,880 --> 00:21:00,280 CYTOKINES IN GETTING BACK TO THE 516 00:21:00,280 --> 00:21:01,480 NOTION OF PLEIOTROPY THAT I 517 00:21:01,480 --> 00:21:03,400 TALKED ABOUT IN THE BEGINNING, 518 00:21:03,400 --> 00:21:04,480 IT SEEMS THAT CYTOKINE ENGINEER 519 00:21:04,480 --> 00:21:05,720 SUGGEST AN EFFECTIVE WAY OF 520 00:21:05,720 --> 00:21:06,760 ADDRESSING THAT PROBLEM AND 521 00:21:06,760 --> 00:21:11,160 HERE'S 1 LAST PIECE OF DATA ON 522 00:21:11,160 --> 00:21:13,800 IL10 IN A COLITIS MODEL AT IL10S 523 00:21:13,800 --> 00:21:18,400 HAVE A LOT OF INTEREST IN THE 524 00:21:18,400 --> 00:21:19,800 CLINIC ARE INFLAMMATORY BOWEL 525 00:21:19,800 --> 00:21:21,200 DISEASE BUT THERE'S BEEN IN 526 00:21:21,200 --> 00:21:23,160 PROBLEM WITH THIS 527 00:21:23,160 --> 00:21:24,200 PROINFLAMMATORY ASSPECS OF 528 00:21:24,200 --> 00:21:25,040 WILD-TYPE IL10 AND HERE WE 529 00:21:25,040 --> 00:21:31,160 SHOWED THAT WE CAN PROTECT MICE 530 00:21:31,160 --> 00:21:33,280 FROM DSS AS WELL AS CYTOKINE 531 00:21:33,280 --> 00:21:39,000 TYPE HERE AND THIS IS ALSO ON A 532 00:21:39,000 --> 00:21:42,320 CLINICAL PATH THROUGH 533 00:21:42,320 --> 00:21:44,800 SYNTHECOIN, AND FINALLY I WANT 534 00:21:44,800 --> 00:21:47,680 TO FINISH UP ON 535 00:21:47,680 --> 00:21:50,240 INTERFERON-GAMMA, AND WHICH IS 536 00:21:50,240 --> 00:21:53,400 REALLY THE PREMIER MASTER 537 00:21:53,400 --> 00:21:55,360 REGULATOR AND MORE PLEIOTROPIC 538 00:21:55,360 --> 00:21:57,240 THAN IL2 AND IT ACTIVATES ON 539 00:21:57,240 --> 00:22:00,240 MOST TYPES OF IMMUNE SELLS, SO, 540 00:22:00,240 --> 00:22:03,040 WHEN WE STARTED THERE WAS NOT A 541 00:22:03,040 --> 00:22:04,560 STRUCTURURE KNOWN OF THIS 542 00:22:04,560 --> 00:22:05,600 RECEPTOR COMPLEX AND JUAN MEN 543 00:22:05,600 --> 00:22:09,480 DOZA IN MY LAB WHO'S A JUNIOR 544 00:22:09,480 --> 00:22:10,880 FACULTY AT UNIVERSITY OF CHICAGO 545 00:22:10,880 --> 00:22:12,920 TOOK ON THIS CHALLENGE AND 546 00:22:12,920 --> 00:22:14,680 REALLY IT'S SORT OF A BIG VISION 547 00:22:14,680 --> 00:22:16,880 WE HAD FOR THIS, THE RATIONAL 548 00:22:16,880 --> 00:22:18,800 FOR GETTING INTO THIS WOULD BE 549 00:22:18,800 --> 00:22:22,400 TO ASK, COULD WE UNCOUPLE THE 550 00:22:22,400 --> 00:22:23,680 IMMUNOSTIMULATORY FROM THE 551 00:22:23,680 --> 00:22:25,360 IMMUNEUE O SUPPRESS ANT ACTIONS 552 00:22:25,360 --> 00:22:27,080 OF GAMMA INTERFERON, I MEAN THE 553 00:22:27,080 --> 00:22:28,400 PRINCIPAL ACTION OF GAMMA 554 00:22:28,400 --> 00:22:29,200 INTERFERON WHICH MOST PEOPLE 555 00:22:29,200 --> 00:22:31,240 KNOW ABOUT IS THAT IT 556 00:22:31,240 --> 00:22:32,440 UPREGULATES CLASS 1 EXPRESSION, 557 00:22:32,440 --> 00:22:34,760 BUT IT ALSO UPREGULATES CHECK 558 00:22:34,760 --> 00:22:36,320 POINT LIGANDS, SO IT'S 559 00:22:36,320 --> 00:22:37,840 IMMUNOSUPPRESSIVE IN THE TUMOR 560 00:22:37,840 --> 00:22:38,240 MICROENVIRONMENT. 561 00:22:38,240 --> 00:22:39,840 SO WE WANTED TO ASK BY STRUCTURE 562 00:22:39,840 --> 00:22:43,200 IF WE COULD POSSIBLY DECOUPLE 563 00:22:43,200 --> 00:22:43,920 THESE ACTIONS. 564 00:22:43,920 --> 00:22:45,720 SO 1 DETERMINE THE STRUCTURE OF 565 00:22:45,720 --> 00:22:48,440 THE GAMMA INTERFERON RECEPTOR 566 00:22:48,440 --> 00:22:52,400 COMPLEX AND YOU CAN SEE HERE 567 00:22:52,400 --> 00:22:54,160 GAMMA INTERFERON BEAR 568 00:22:54,160 --> 00:22:56,240 RESEMBLANCE TO IL10, IT'S A 569 00:22:56,240 --> 00:22:58,160 TIMER AND DECORATED BY THE 4 570 00:22:58,160 --> 00:23:00,680 RECEPTORS, 2 GAMMA R1S, 2 GAMMA 571 00:23:00,680 --> 00:23:02,240 R2s AND I WILL NOT GET INTO 572 00:23:02,240 --> 00:23:06,160 THE DETAILS OF THIS 1 EITHER BUT 573 00:23:06,160 --> 00:23:09,680 JUST TO SHOW YOU WHAT UPON JUAN 574 00:23:09,680 --> 00:23:13,800 DID HE, HE SELECTIVELY APLATED 575 00:23:13,800 --> 00:23:15,800 THE DIFFERENT BINDING SITES LIKE 576 00:23:15,800 --> 00:23:17,200 GAMMA INTERFERON AND IN SO DOING 577 00:23:17,200 --> 00:23:18,960 CREATED A SERIES OF PARTIAL 578 00:23:18,960 --> 00:23:21,160 AGONISTS, THIS IS PSTAT 1 WE'RE 579 00:23:21,160 --> 00:23:21,880 LOOKING AT HERE. 580 00:23:21,880 --> 00:23:26,800 THIS WAS A BEAUTIFUL CALIBRATION 581 00:23:26,800 --> 00:23:30,600 OF THE MAX RANGE OF GAMMA 582 00:23:30,600 --> 00:23:31,680 INTERFERON. 583 00:23:31,680 --> 00:23:33,440 AND SO, SO WITH THESE PARTIAL 584 00:23:33,440 --> 00:23:37,680 AGONIST THEN, WE WENT AND DID IN 585 00:23:37,680 --> 00:23:38,640 GENE--RNA SEEK EXPERIMENTS TO 586 00:23:38,640 --> 00:23:41,280 LOOK AT GENE EXPRESSION AND 587 00:23:41,280 --> 00:23:43,400 FOUND SOMETHING RATHER 588 00:23:43,400 --> 00:23:45,640 UNEXPECTED WHICH IS THAT MOST OF 589 00:23:45,640 --> 00:23:49,880 THE GENES UPREGULATED BY GAMMA 590 00:23:49,880 --> 00:23:51,120 INTERFERON WERE UPREGULATED TO 591 00:23:51,120 --> 00:23:53,320 ROUGHLY THE SAME EXTENT BY 592 00:23:53,320 --> 00:23:55,000 WILD-TYPE GAMMA VERSUS THE 593 00:23:55,000 --> 00:23:56,160 PARTIAL AGONIST. 594 00:23:56,160 --> 00:23:58,760 WE CALL THOSE STABLE GENES BUT 595 00:23:58,760 --> 00:24:00,560 THERE WAS A MUCH SMALLER STABLE 596 00:24:00,560 --> 00:24:03,400 SUBSET WHERE THE PARTIAL 597 00:24:03,400 --> 00:24:04,760 AGONISTS UPREGULATED GENES TO A 598 00:24:04,760 --> 00:24:07,000 LOWER DEGREE THAN THE WORLD TYPE 599 00:24:07,000 --> 00:24:09,440 AND AMONGST THE STABLE 1S WAS 600 00:24:09,440 --> 00:24:12,440 CLASS 1 MHC, AND AMONGST THE 601 00:24:12,440 --> 00:24:16,000 TUNEABLE 1S WAS PDL 1, THE CHECK 602 00:24:16,000 --> 00:24:17,480 POINT LIGAND. 603 00:24:17,480 --> 00:24:20,320 SO WITH THAT INFORMATION, JUAN 604 00:24:20,320 --> 00:24:21,840 AND [INDISCERNIBLE] IN MY LAB 605 00:24:21,840 --> 00:24:24,320 AND COLLABORATING WITH 606 00:24:24,320 --> 00:24:25,320 [INDISCERNIBLE] STARTED STAINING 607 00:24:25,320 --> 00:24:26,200 CANCER CELL LINES. 608 00:24:26,200 --> 00:24:27,840 HERE'S AN EXAMPLE OF LUNG CANCER 609 00:24:27,840 --> 00:24:31,360 CELL LYNN WHERE THE UPREGULATION 610 00:24:31,360 --> 00:24:33,680 OF HRA 1 CLASS 1 IS EQUIVALENT 611 00:24:33,680 --> 00:24:35,800 BETWEEN WILD-TYPE AND THE 612 00:24:35,800 --> 00:24:37,920 PARTIAL AGONIST WHERE THE PDL1 613 00:24:37,920 --> 00:24:41,680 IS ATTENUATE SIGNIFICANTLY BY 614 00:24:41,680 --> 00:24:42,440 THE PARTIAL AGONISTS. 615 00:24:42,440 --> 00:24:45,080 AND JUAN WENT ON TO STAIN AND DO 616 00:24:45,080 --> 00:24:46,360 THIS EXPERIMENT WITH MANY 617 00:24:46,360 --> 00:24:48,120 DIFFERENT TYPES OF CANCER CELL 618 00:24:48,120 --> 00:24:49,440 LINES AND THERE'S BIAS TO 619 00:24:49,440 --> 00:24:51,360 DIFFERENT DEGREES, SOME MORE, 620 00:24:51,360 --> 00:24:52,560 SOME LESS, SOME NONEXISTENT BUT 621 00:24:52,560 --> 00:24:54,200 WE DO SEEM TO BE ABLE TO TILT 622 00:24:54,200 --> 00:24:57,760 THE BALANCE TOWARDS CLASS 1 OVER 623 00:24:57,760 --> 00:24:59,760 PDL 1 GENERALLY AND SO, WHAT 624 00:24:59,760 --> 00:25:03,960 WE'RE DOING NOW IN MY LAB, 625 00:25:03,960 --> 00:25:05,360 [INDISCERNIBLE] IN MY LAB NOW 626 00:25:05,360 --> 00:25:08,880 MADE SOME MOUSE GAMMA INTERFERON 627 00:25:08,880 --> 00:25:11,320 PARTIAL AGONIST TO ALLOW US TO 628 00:25:11,320 --> 00:25:13,440 PROPERLY EXPLORE THE PROPERTIES 629 00:25:13,440 --> 00:25:17,480 OF THESE BIAS IN TUMOR MODELS IN 630 00:25:17,480 --> 00:25:17,840 IN VIVO. 631 00:25:17,840 --> 00:25:20,600 SO JUST TO SUMMARIZE WHAT I 632 00:25:20,600 --> 00:25:22,160 SHOWED YOU, WHAT HAVE WE 633 00:25:22,160 --> 00:25:25,480 LEARNED, CELLS HAVE INTRINSIC 634 00:25:25,480 --> 00:25:36,000 RESPONSE THRESHOLDS TO CYTOKINES 635 00:25:38,960 --> 00:25:42,160 THAT CAN BE--IT'S A MULTILEVEL 636 00:25:42,160 --> 00:25:44,000 CONTROL OF THESE HARD WIRED 637 00:25:44,000 --> 00:25:47,040 RESPONSE THRESHOLDS BUT THE 638 00:25:47,040 --> 00:25:48,800 BOTTOM LINE IS THAT BUT BY 639 00:25:48,800 --> 00:25:50,040 MAKING PARTIAL AGONIST AND 640 00:25:50,040 --> 00:25:52,440 CYTOKINE WE CAN IN MANY CASES 641 00:25:52,440 --> 00:25:53,880 PHASE OUT ACTIONS ON DIFFERENT 642 00:25:53,880 --> 00:25:56,920 CELL TYPES AND SIGNIFICANTLY 643 00:25:56,920 --> 00:25:58,040 NARROW THE PLEIOTROPY IN THIS 644 00:25:58,040 --> 00:25:59,840 CASE FOR EXAMPLE, BOBBY SAXON 645 00:25:59,840 --> 00:26:01,880 WAS ABLE TO NARROW THE ACTIVITY 646 00:26:01,880 --> 00:26:04,400 OF IL10 TO ESSENTIALLY ONLY 647 00:26:04,400 --> 00:26:07,240 MONOCYTES AND SO REALLY I THINK 648 00:26:07,240 --> 00:26:09,880 THE PATH FORWARD FOR GETTING 649 00:26:09,880 --> 00:26:11,120 CYTOKINES INTO THE CLINIC IS 650 00:26:11,120 --> 00:26:14,120 GOING TO INCORPORATE THIS 651 00:26:14,120 --> 00:26:18,280 CONCEPT HERE OF TUNING DOWN THE 652 00:26:18,280 --> 00:26:23,160 AGANISM AND GETTING BETTER CELL 653 00:26:23,160 --> 00:26:23,640 SET SELECTIVITY. 654 00:26:23,640 --> 00:26:27,880 SO UNTIL NOW WHAT I'VE SHOWN YOU 655 00:26:27,880 --> 00:26:31,680 IS ENGINEERING THE CYTOKINE 656 00:26:31,680 --> 00:26:32,160 ITSELF? 657 00:26:32,160 --> 00:26:35,360 SORT OF TUNING IT DOWN, LOWERING 658 00:26:35,360 --> 00:26:36,320 ACTIVITY, BUT THERE ARE A LOT I 659 00:26:36,320 --> 00:26:37,680 WAS TO DO THIS AND IF YOU GET 660 00:26:37,680 --> 00:26:39,280 ASHES WAY FROM THE CYTOKINE, AND 661 00:26:39,280 --> 00:26:41,800 THE CYTOKINE RIGHT HERE TO THE 662 00:26:41,800 --> 00:26:44,120 RIGHT HERE'S A 4 HELIX CLASSICAL 663 00:26:44,120 --> 00:26:46,960 SYSTEM, TO THE 2 RECEPTORS, AND 664 00:26:46,960 --> 00:26:49,680 ALSO HERE WE NOW HAVE A GBCR AND 665 00:26:49,680 --> 00:26:51,960 I'M SHOWING YOU THE 666 00:26:51,960 --> 00:26:53,320 CONFIRMATIONAL CHANGES THAT GPC 667 00:26:53,320 --> 00:26:55,240 Rs UNDERGO WITH THE G-PROTEIN 668 00:26:55,240 --> 00:26:57,160 IN RESPONSE TO DIFFERENT 669 00:26:57,160 --> 00:26:57,480 LIGANDS. 670 00:26:57,480 --> 00:26:58,600 AND WE TOOK ANOTHER APPROACH 671 00:26:58,600 --> 00:27:01,560 HERE WHICH IS TO ASK INSTEAD OF 672 00:27:01,560 --> 00:27:03,280 JUST DOWN TUNING THE BINDING OF 673 00:27:03,280 --> 00:27:06,680 THE SECOND RECEPTOR, COULD WE 674 00:27:06,680 --> 00:27:08,520 REORIENT THE DIMER 675 00:27:08,520 --> 00:27:09,160 DEO--METABOLIZEDETRY TO 676 00:27:09,160 --> 00:27:10,320 ACCOMPLISH SOMETHING ANALOGOUS 677 00:27:10,320 --> 00:27:14,080 TO THE SHAPE CHANGES THE GPC 678 00:27:14,080 --> 00:27:16,040 Rs UNDERGO WHEN THEY BIND 679 00:27:16,040 --> 00:27:16,360 THEIR LIGANDS. 680 00:27:16,360 --> 00:27:18,560 BUT TO DO THAT, THE SCAFFOLD 681 00:27:18,560 --> 00:27:19,480 ITSELF WAS NOT SUITABLE. 682 00:27:19,480 --> 00:27:21,240 THERE WAS NOT A LOT OF 683 00:27:21,240 --> 00:27:23,280 OPPORTUNITIES TO REORIENT THE 684 00:27:23,280 --> 00:27:24,600 DIMER GERONTOLOGYSTS OHMETRY 685 00:27:24,600 --> 00:27:25,160 WITH THE SCAFFOLD. 686 00:27:25,160 --> 00:27:27,880 SO WHAT WE DID, SO WHAT WE WOULD 687 00:27:27,880 --> 00:27:30,120 LIKE TO DO AND WE WOULD LIKE TO 688 00:27:30,120 --> 00:27:33,280 HAVE A SCAFFOLD THAT WE COULD 689 00:27:33,280 --> 00:27:35,040 CHANGE THE DIMER GEOMETRY AND 690 00:27:35,040 --> 00:27:37,000 CHANGE IT TO THE JACK TO 1 691 00:27:37,000 --> 00:27:38,760 ANOTHER TO TUNE THE SIGNALING UP 692 00:27:38,760 --> 00:27:41,000 IN THE WAY THE WAY THE CHEMISTRY 693 00:27:41,000 --> 00:27:43,760 IS ABLE TO MAKE SMALL MOLECULES 694 00:27:43,760 --> 00:27:45,760 THAT CAN CHANGE THE SHAPE OF GPC 695 00:27:45,760 --> 00:27:48,200 Rs, SO THAT WAS THE OVERALL 696 00:27:48,200 --> 00:27:51,800 CONCEPT AND WE WENT ABOUT THIS, 697 00:27:51,800 --> 00:27:55,360 BY USING A DIFFERENT BINDING 698 00:27:55,360 --> 00:27:56,560 SCAFFOLD WHICH IS CALLED A 699 00:27:56,560 --> 00:28:03,120 DARKEN AND THE DARKEN IS A 700 00:28:03,120 --> 00:28:03,720 PROFESSIONAL BINDING SCAFFOLD, 701 00:28:03,720 --> 00:28:07,800 THAT WAS CREATED FOR THE SOLE 702 00:28:07,800 --> 00:28:09,920 PURPOSE OF SELECTING SCAFFOLDS 703 00:28:09,920 --> 00:28:11,080 FROM LIBRARIES. 704 00:28:11,080 --> 00:28:13,120 SO [INDISCERNIBLE] IN MY LAB 705 00:28:13,120 --> 00:28:19,400 MADE A DARPIN LIBRARY AND MADE A 706 00:28:19,400 --> 00:28:20,920 CRISTTAL STRUCTURE OF THE 707 00:28:20,920 --> 00:28:23,800 COMPLEX WITH EPO RECEPTOR. 708 00:28:23,800 --> 00:28:25,760 AND THEN WE COLLABORATED WITH 709 00:28:25,760 --> 00:28:27,960 DAVID BAKER'S LAB TO SEE IF WE 710 00:28:27,960 --> 00:28:29,840 COULD DIMERIZE THE DARPINS AND 711 00:28:29,840 --> 00:28:33,400 BRING IN A SECOND RECEPTOR TO 712 00:28:33,400 --> 00:28:34,320 MAYBE ACTIVATE SIGNALING AND WE 713 00:28:34,320 --> 00:28:38,080 ARE ABLE TO DO THAT. 714 00:28:38,080 --> 00:28:40,880 WE DESIGNED WITH THE BAKER LAB, 715 00:28:40,880 --> 00:28:42,760 THESE MUTATIONS IN THE DIMER 716 00:28:42,760 --> 00:28:43,880 INTERFACE THAT COMPELLED THE 717 00:28:43,880 --> 00:28:45,640 DIMERIZATION OF THE DARPIN AND 718 00:28:45,640 --> 00:28:46,760 THAT BROUGHT 2 RECEPTORS 719 00:28:46,760 --> 00:28:57,240 TOGETHER AND THAT HAS BEEN A 720 00:29:06,920 --> 00:29:12,720 FANTASTIC YOU CAN CHANGE THEM 721 00:29:12,720 --> 00:29:14,240 AND WE DID SO AND YOU CAN SEE 722 00:29:14,240 --> 00:29:20,480 HOW THEY MEASURE THE STAT 5 OF 723 00:29:20,480 --> 00:29:21,680 THE ERK SIGNALING, AS WE 724 00:29:21,680 --> 00:29:23,080 INCREASE THE DIMER ANGLE WE 725 00:29:23,080 --> 00:29:24,920 PHASE OUT SIGNALING SO AS THE 726 00:29:24,920 --> 00:29:26,240 RECEPTORS START TO LIE FLATOT 727 00:29:26,240 --> 00:29:26,960 EMPLOYMENT PROGRAMS BRAIN, THE 728 00:29:26,960 --> 00:29:28,720 JACKS SEEM TO BE UNABLE TO 729 00:29:28,720 --> 00:29:29,720 COMMUNICATE WITH EACH OTHER 730 00:29:29,720 --> 00:29:31,000 ANYMORE AND WE DON'T GET 731 00:29:31,000 --> 00:29:36,600 ACTIVATION OF THE RECEPTOR. 732 00:29:36,600 --> 00:29:37,440 AND THEN ANOTHER--THERE'S 733 00:29:37,440 --> 00:29:40,200 ANOTHER WAY OF INSERTING THESE 734 00:29:40,200 --> 00:29:44,040 INTO THE DARPINS THAT GIVES YOU 735 00:29:44,040 --> 00:29:45,720 A CHANGE IN THE DISTANCE BETWEEN 736 00:29:45,720 --> 00:29:48,000 THE MONITOR MERS RATHER THAN THE 737 00:29:48,000 --> 00:29:49,840 CURVEATURE, SO THAT ALLOWS THE 738 00:29:49,840 --> 00:29:50,720 PURE SEPARATION FORT RECEPTORS 739 00:29:50,720 --> 00:29:52,560 WHICH YOU CAN MEASURE AND IN 740 00:29:52,560 --> 00:29:54,240 THAT SERIES, RATHER THAN A IMRAD 741 00:29:54,240 --> 00:29:57,880 Y'ALL PHASING DOWN OF THE EMAX 742 00:29:57,880 --> 00:29:59,720 WE GOT PRETTY MUCH MAINTAINED 743 00:29:59,720 --> 00:30:02,160 WITH INCREASING DISTANCE, THE 744 00:30:02,160 --> 00:30:03,560 EMAX OF SIGNALING THROUGH STAT 5 745 00:30:03,560 --> 00:30:05,200 AND THEN AT SOME THRESHOLD 746 00:30:05,200 --> 00:30:06,760 DISTANCE, IT BROKE OFF AND 747 00:30:06,760 --> 00:30:08,280 CLEARLY THE JAX AT THAT POINT 748 00:30:08,280 --> 00:30:09,480 WERE NOT ABLE TO TALK TO EACH 749 00:30:09,480 --> 00:30:11,640 OTHER SO WE HAVE 2 DIFFERENT 750 00:30:11,640 --> 00:30:13,040 KIND OF RECEPTOR TUNING THROUGH 751 00:30:13,040 --> 00:30:14,320 THIS IS A GERONTOLOGYSTS 752 00:30:14,320 --> 00:30:16,840 O--METABOLIZEDETRY AND THIS IS 753 00:30:16,840 --> 00:30:17,200 DISTANCE. 754 00:30:17,200 --> 00:30:20,040 AND WE WENT ON TO ASK ABOUT THE 755 00:30:20,040 --> 00:30:22,200 PHYSIOLOGICAL RELEVANCE OF THIS 756 00:30:22,200 --> 00:30:26,240 KIND OF APPROACH WORKING 757 00:30:26,240 --> 00:30:28,880 [INDISCERNIBLE] AT THE BROAD, WE 758 00:30:28,880 --> 00:30:32,080 HAD THIS ASSAY FROM 759 00:30:32,080 --> 00:30:33,720 HEMATOPOIETIC STEM CELLS TO 760 00:30:33,720 --> 00:30:36,280 RECELLS WHERE YOU FOLLOW CD31 761 00:30:36,280 --> 00:30:39,200 AND 235 AND THEY MAKE THIS 762 00:30:39,200 --> 00:30:39,960 STEREO TYPICAL U-SHAPED CURVE 763 00:30:39,960 --> 00:30:40,960 OVER THE COURSE OF THE 764 00:30:40,960 --> 00:30:43,720 DEVELOPMENT AND THIS IS SHOWING 765 00:30:43,720 --> 00:30:45,360 YOU WHAT EPO LOOKS LIKE AFTER 766 00:30:45,360 --> 00:30:47,760 THE 14th DAY OR SO. 767 00:30:47,760 --> 00:30:49,160 WELL WE FOUND BY USING THESE 768 00:30:49,160 --> 00:30:52,600 DARPINSINS, WE USE THE RECEPTOR 769 00:30:52,600 --> 00:30:55,280 IN DIFFERENT INCASULAR GEOMETRYS 770 00:30:55,280 --> 00:30:57,520 WE CAN ABORD RED BLOOD CELL 771 00:30:57,520 --> 00:31:01,760 DEVELOPMENT AT DIFFERENT STAGES 772 00:31:01,760 --> 00:31:04,680 FROM ESSENTIALLY EARLY STAGE TO 773 00:31:04,680 --> 00:31:07,720 UPRIGHT ANGLES WHICH COPIES EFO, 774 00:31:07,720 --> 00:31:09,960 SO THIS IS AN EXAMPLE WHERE 775 00:31:09,960 --> 00:31:13,760 CHANGING THE ORIENTATION REALLY 776 00:31:13,760 --> 00:31:14,920 HAD PROFOUND EFFECTS ON CELL 777 00:31:14,920 --> 00:31:16,720 FATE DETEARM NATIONS AND THAT'S 778 00:31:16,720 --> 00:31:22,160 SOMETHING THAT I REMAIN VERY 779 00:31:22,160 --> 00:31:22,640 INTERESTED IN. 780 00:31:22,640 --> 00:31:25,360 BUT IN DOING IT IN A SLIGHTLY 781 00:31:25,360 --> 00:31:26,680 DIFFERENT WAY. 782 00:31:26,680 --> 00:31:27,520 SO THE DARPINSINS ARE 783 00:31:27,520 --> 00:31:29,880 INTERESTING BUT THEY DON'T HAVE 784 00:31:29,880 --> 00:31:31,280 DRUG LIKE PROPERTIES, THEY ARE 785 00:31:31,280 --> 00:31:32,800 KIND OF A SYNTHETIC TOOL 786 00:31:32,800 --> 00:31:34,520 COMPOUND WHICH YOU CAN DO VERY 787 00:31:34,520 --> 00:31:35,320 INTERESTING PROTEIN ENGINEERING 788 00:31:35,320 --> 00:31:36,800 THINGS WITH THEM BUT THE STEP 789 00:31:36,800 --> 00:31:39,000 TOWARDS PUTTING THISEM INTO 790 00:31:39,000 --> 00:31:42,280 HUMANS IN SYSTEMIC CIRCULATION 791 00:31:42,280 --> 00:31:44,120 IS REALLY NOT BEEN PROVE KNOW 792 00:31:44,120 --> 00:31:46,440 YET THAT'S POSSIBLE SO WE WANT 793 00:31:46,440 --> 00:31:48,280 TO ACHIEVE WHAT I JUST SHOWED 794 00:31:48,280 --> 00:31:51,040 YOU WHICH IS THIS GEOMETRIC 795 00:31:51,040 --> 00:31:52,480 REORIENTATION OF THE EXTRA 796 00:31:52,480 --> 00:31:55,920 CELLULAR DOMAINS BUT NOT USING A 797 00:31:55,920 --> 00:31:58,000 DARPINS SCAFFOLD SO FOR THIS WE 798 00:31:58,000 --> 00:32:00,240 TURN TO A NANO BODY DIMER 799 00:32:00,240 --> 00:32:02,240 SCAFFOLD, EITHER 2 NANO BODIES 800 00:32:02,240 --> 00:32:05,040 TOGETHER AS A STRING LIKE A NANO 801 00:32:05,040 --> 00:32:07,280 BODY OR SEFB, ESSENTIALLY SMALL 802 00:32:07,280 --> 00:32:09,080 BINDING DOMAINS THAT WILL 803 00:32:09,080 --> 00:32:10,920 HOPEFULLY DIMERIZE 2 RECEPTORS 804 00:32:10,920 --> 00:32:13,480 HERE LIKE IN THIS CASE IL2 805 00:32:13,480 --> 00:32:23,840 BRINGS TOGETHER IT'S 2 806 00:32:44,560 --> 00:32:44,760 RECEPTORS. 807 00:32:44,760 --> 00:32:47,480 AND SO THAT WHEN WE LINK THEM 808 00:32:47,480 --> 00:32:49,480 TOGETHER THEY WILL BRING THE 2 809 00:32:49,480 --> 00:32:51,440 RECEPTORS TOGETHER IN DIFFERENT 810 00:32:51,440 --> 00:32:52,840 GEOMETRYS BY VIRTUE OF THE FACT 811 00:32:52,840 --> 00:32:53,800 THAT THEY'RE BINDING TO 812 00:32:53,800 --> 00:32:57,160 DIFFERENT PARTS OF THE EXTRA 813 00:32:57,160 --> 00:32:57,560 CELLULAR DOMAIN. 814 00:32:57,560 --> 00:32:59,400 IS IT WE CAN MAKE A MATRIX THEN 815 00:32:59,400 --> 00:33:02,240 OF THE NANO BODIES, THE BETA 816 00:33:02,240 --> 00:33:03,800 BINDERS VERSUS THE GAMMA BINDERS 817 00:33:03,800 --> 00:33:06,800 IN 2 DIFFERENT ORIENTATIONS, A 818 00:33:06,800 --> 00:33:08,200 FORWARD AND REVERSE ORIENTATION 819 00:33:08,200 --> 00:33:11,080 AND IN THAT WAY WE GET THIS 820 00:33:11,080 --> 00:33:13,280 MATRIX OF GEOMETRYS THAT WE CAN 821 00:33:13,280 --> 00:33:16,920 VERY EASILY TEST ON MOLECULES ON 822 00:33:16,920 --> 00:33:18,920 CELLS FOR STAFF 5 ACTIVATION AND 823 00:33:18,920 --> 00:33:23,680 WHEN MICHELLE DID THIS SHE FOUND 824 00:33:23,680 --> 00:33:26,560 A REAL DIVERSITY OF ACTIVATION 825 00:33:26,560 --> 00:33:27,800 STRENGTHS OF BINDERS THAT HAVE 826 00:33:27,800 --> 00:33:30,720 THE SAME MAX AS IL2 TO SOME OF 827 00:33:30,720 --> 00:33:32,440 THEM SUPER AGONIST THAT WERE 828 00:33:32,440 --> 00:33:34,000 STRONGER THAN IL2 AND THIS 829 00:33:34,000 --> 00:33:39,640 WASN'T JUST AN ACTIVATION 830 00:33:39,640 --> 00:33:40,040 STRENGTH ISSUE. 831 00:33:40,040 --> 00:33:42,680 WE SEE BIAS, TOO, SO WHEN 832 00:33:42,680 --> 00:33:45,160 MICHELLE LOOKED AT FOSTER NURSED 833 00:33:45,160 --> 00:33:46,200 FOCUSED ON STAT 5 AND FOSTER 834 00:33:46,200 --> 00:33:47,120 NURSED FOCUSED ON AKT, CAN YOU 835 00:33:47,120 --> 00:33:49,360 SEE THAT AS WE LOOK AT DIFFERENT 836 00:33:49,360 --> 00:33:51,720 VERSIONS OF THESE MOLECULES, WE 837 00:33:51,720 --> 00:33:53,520 CAN SEE DIFFERENT DEGREES OF 838 00:33:53,520 --> 00:33:55,800 BIAS OF STAT 5 OVER 839 00:33:55,800 --> 00:33:56,720 IEE, AUDIENCE KT. 840 00:33:56,720 --> 00:33:59,560 AND WHEN MICHELLE LOOKED AT THE 841 00:33:59,560 --> 00:34:00,760 FUNCTION, DID SOME FUNCTIONAL 842 00:34:00,760 --> 00:34:02,520 ASSAYS WITH THESE MOLECULES FOR 843 00:34:02,520 --> 00:34:06,760 EXAMPLE, LOOKING AT CD8 T-CELL 844 00:34:06,760 --> 00:34:08,120 DIFFERENTIATION FROM PBMCs, 845 00:34:08,120 --> 00:34:10,440 SHE FOUND THAT DIFFERENT 846 00:34:10,440 --> 00:34:12,160 SURROGATE AGONIST CAN BE BEND 847 00:34:12,160 --> 00:34:16,880 INTO EFFECTOR MEMORY BIAS, 848 00:34:16,880 --> 00:34:18,280 EFFECTOR CENTRAL MEMORY BIAS AND 849 00:34:18,280 --> 00:34:23,720 THIS JUST REALLY WAS JUST A 850 00:34:23,720 --> 00:34:24,560 REALLY FASCINATING RESULT, I 851 00:34:24,560 --> 00:34:26,520 THOUGHT BECAUSE THIS IS DUE IN 852 00:34:26,520 --> 00:34:28,080 LARGE PART TO SIMPLY THE FACT 853 00:34:28,080 --> 00:34:31,040 THAT COMPARED TO IL2, HERE'S THE 854 00:34:31,040 --> 00:34:33,440 NATIVE IL2 RECEPTOR GEOMETRY, 855 00:34:33,440 --> 00:34:35,640 THESE SURROGATE AGONISTS ARE 856 00:34:35,640 --> 00:34:36,880 DIMERIZING THE RECEPTORS IN 857 00:34:36,880 --> 00:34:40,280 DIFFERENT SHAPES AND DIFFERENT 858 00:34:40,280 --> 00:34:41,400 DISTANCES BETWEEN THE 859 00:34:41,400 --> 00:34:43,240 INTRACELLULAR DOMAINS IN VERY 860 00:34:43,240 --> 00:34:44,400 UNPREDICTABLE WAYS THAT HAVING 861 00:34:44,400 --> 00:34:46,240 THESE KINDS OF EFFECTS ON 862 00:34:46,240 --> 00:34:48,040 SIGNALING AND FUNCTION. 863 00:34:48,040 --> 00:34:49,640 SO EISN'TIALLY THIS A WAY OF 864 00:34:49,640 --> 00:34:51,280 TAKING A SINGLE CYTOKINE AND 865 00:34:51,280 --> 00:34:52,680 CREATING, YOU KNOW A HUGE NUMBER 866 00:34:52,680 --> 00:34:54,400 OF DIFFERENT FLAVORS OF THAT 867 00:34:54,400 --> 00:34:57,320 CYTOKINE THAT HAVE DIFFERENT 868 00:34:57,320 --> 00:34:57,600 FUNCTIONS. 869 00:34:57,600 --> 00:34:59,680 AND SO WE'RE DOING THIS IN A LOT 870 00:34:59,680 --> 00:35:02,080 OF DIFFERENT SYSTEMS NOW, EACH 871 00:35:02,080 --> 00:35:05,000 VARIANT MIGHT HAVE A DIFFERENT 872 00:35:05,000 --> 00:35:07,480 PLACE IN, IMMUNE DISEASE, A 873 00:35:07,480 --> 00:35:08,000 DIFFERENT THERAPEUTIC 874 00:35:08,000 --> 00:35:08,560 INDICATION. 875 00:35:08,560 --> 00:35:12,160 WE'VE ALSO DONE THIS WITH TYPE 1 876 00:35:12,160 --> 00:35:13,200 INTERFERON AGONISTS, WHERE AGAIN 877 00:35:13,200 --> 00:35:17,640 WE MADE NANO BODIES AGAINST THE 878 00:35:17,640 --> 00:35:19,360 EXTRA CELLULAR DOMAINS, 879 00:35:19,360 --> 00:35:20,280 [INDISCERNIBLE] AND DID A MATRIX 880 00:35:20,280 --> 00:35:22,480 AGAINST ALL AND HERE WE FOUND A 881 00:35:22,480 --> 00:35:24,720 MUCH LOWER HIT RATE OF AGONISTS 882 00:35:24,720 --> 00:35:26,240 SO INTERFERON RECEPTOR SEEMS TO 883 00:35:26,240 --> 00:35:29,120 BE MUCH MORE STRUCTURALLY 884 00:35:29,120 --> 00:35:30,560 RESTRICTIVE IN ITS ORIENTATION 885 00:35:30,560 --> 00:35:31,720 THAN IL2 RECEPTOR BUT 886 00:35:31,720 --> 00:35:34,800 NEVERTHELESS WE FOUND SOME HITS 887 00:35:34,800 --> 00:35:39,760 AND JUST SHOWING YOU HERE NOW, 888 00:35:39,760 --> 00:35:41,280 PARTIAL AGONISTS COMPARED TO 889 00:35:41,280 --> 00:35:43,800 TYPE 1 INTERFERON AND A459 CELLS 890 00:35:43,800 --> 00:35:45,200 AND EVEN THOUGH THEY'RE PARTIAL 891 00:35:45,200 --> 00:35:47,400 AGONISTS THEY'RE JUST AS POTENT 892 00:35:47,400 --> 00:35:49,560 AND TYPE 1 INTERFERON FOR 893 00:35:49,560 --> 00:35:51,040 EXAMPLE, IN INHIBITING 894 00:35:51,040 --> 00:35:52,800 SARS-COV-2 REPLICATION IN A549 895 00:35:52,800 --> 00:35:53,400 CELLS. 896 00:35:53,400 --> 00:35:56,640 THESE ARE DOSE RESPONSE CURVES 897 00:35:56,640 --> 00:35:57,480 FOR INHIBITING SARS-COV-2 898 00:35:57,480 --> 00:36:00,280 REPLICATION AND IN WORKING WITH 899 00:36:00,280 --> 00:36:01,800 THE [INDISCERNIBLE] LABS WE 900 00:36:01,800 --> 00:36:05,680 FOUND THEY INHIBIT OTHER TYPES 901 00:36:05,680 --> 00:36:08,640 OF VIRUSES, LIKE ZIKA VIRUS EVEN 902 00:36:08,640 --> 00:36:10,400 MORE POTENTLY THAN TYPE 1 903 00:36:10,400 --> 00:36:10,720 INTERFERON. 904 00:36:10,720 --> 00:36:13,080 BUT THE REAL PART OF THESE 905 00:36:13,080 --> 00:36:17,920 MOLECULES THAT I FIND 906 00:36:17,920 --> 00:36:20,400 INTERESTING IS THAT 1 OF THE 907 00:36:20,400 --> 00:36:21,640 LIMITATIONS OF USING TYPE 1 908 00:36:21,640 --> 00:36:22,720 INTERFERONS IN THE CLINIC THEY 909 00:36:22,720 --> 00:36:26,480 HAVE A LOT OF SIDE EFFECTS, 910 00:36:26,480 --> 00:36:28,320 CALLED FLU-LIKE SED EFFECTS THEY 911 00:36:28,320 --> 00:36:31,240 ACTIVATE A LOT OF 912 00:36:31,240 --> 00:36:32,120 PROINFLAMMATORY GENES. 913 00:36:32,120 --> 00:36:38,720 AND OUR SURROGATE ACTIVITIES 914 00:36:38,720 --> 00:36:41,160 BARELY AGGRAVATE THEM, THEY'RE 915 00:36:41,160 --> 00:36:42,120 BARELY ATTENUATE SO OUR 916 00:36:42,120 --> 00:36:48,680 PREDICTION IS THEY WILL HAVE 917 00:36:48,680 --> 00:36:51,880 MUCH LESS PRO INFLAMMATORY 918 00:36:51,880 --> 00:36:55,200 ACTIVATION, SO AND I STARTED A 919 00:36:55,200 --> 00:36:57,520 COMPANY TO STUDY THESE IN 920 00:36:57,520 --> 00:36:58,360 ANTIVIRALS WITH LESS SIDE 921 00:36:58,360 --> 00:36:58,720 EFFECTS. 922 00:36:58,720 --> 00:37:01,560 I WANT TO GO HERE FROM NOW, SO 923 00:37:01,560 --> 00:37:04,080 UNTIL NOW WE'VE BEEN TALKING 924 00:37:04,080 --> 00:37:08,040 ABOUT KNOWN CYTOKINE SIGNALING 925 00:37:08,040 --> 00:37:09,160 PATHWAYS, TUNING DOWN SYSTEMS 926 00:37:09,160 --> 00:37:11,240 WITH DIFFERENT KINDS OF 927 00:37:11,240 --> 00:37:11,520 MOLECULES. 928 00:37:11,520 --> 00:37:12,440 WE'RE ALSO THINKING ABOUT THIS 929 00:37:12,440 --> 00:37:14,720 IN A DIFFERENT KIND OF WAY, 930 00:37:14,720 --> 00:37:16,520 WHICH IS BRINGING TOGETHER 931 00:37:16,520 --> 00:37:18,320 CYTOKINE RECEPTORS THAT DON'T 932 00:37:18,320 --> 00:37:21,560 NORMALLY PAIR ON THE CELL 933 00:37:21,560 --> 00:37:22,360 SURFACE, THROUGH INDUCED 934 00:37:22,360 --> 00:37:24,760 PROXIMITY AND IF YOU THINK ABOUT 935 00:37:24,760 --> 00:37:27,960 IT, ALL THE PLEIOTROPY THAT 936 00:37:27,960 --> 00:37:30,280 WARREN HAS WRITTEN ABOUT AND 937 00:37:30,280 --> 00:37:33,440 PUBLISHED ON SO PROLIFICALLY IS 938 00:37:33,440 --> 00:37:37,720 ALSO AN OPPORTUNITY TO CREATE 939 00:37:37,720 --> 00:37:39,200 NEW CYTOKINE SIGNALINGAXIS THAT 940 00:37:39,200 --> 00:37:40,560 DON'T EXIST IN NATURE BECAUSE 941 00:37:40,560 --> 00:37:44,880 EVERY TYPE OF IMMUNE CELL HAS 942 00:37:44,880 --> 00:37:45,720 MULTIPLE DIFFERENT CYTOKINE 943 00:37:45,720 --> 00:37:46,520 RECEPT ONORS AND YOU CAN THINK 944 00:37:46,520 --> 00:37:48,640 OF THAT AS A MENU OF POSSIBLE 945 00:37:48,640 --> 00:37:49,520 WAYS TO BRING THEM TOGETHER AND 946 00:37:49,520 --> 00:37:51,200 YOU THINK OF IT, WE HAVE 947 00:37:51,200 --> 00:37:52,960 SOMETHING LIKE 30 OR 40 948 00:37:52,960 --> 00:37:54,560 DIFFERENT CYTOKINE RECEPTORS AND 949 00:37:54,560 --> 00:37:57,040 THAT THE KINASES ASSOCIATED WITH 950 00:37:57,040 --> 00:37:57,880 THE INTRACELLULAR DOMAINS HAVE 951 00:37:57,880 --> 00:37:59,520 THE ABILITY TO CROSS TALK WITH 1 952 00:37:59,520 --> 00:38:01,920 ANOTHER, IT REALLY OPENS UP A 953 00:38:01,920 --> 00:38:03,840 WHOLE NEW POSSIBILITY OF 954 00:38:03,840 --> 00:38:08,600 CREATING NEW CYTOKINE SIGNALING 955 00:38:08,600 --> 00:38:09,640 AXIS. 956 00:38:09,640 --> 00:38:10,680 SO HERE'S 1 EXAMPLE, PRINTS 957 00:38:10,680 --> 00:38:12,120 BEING DONE BY [INDISCERNIBLE] IN 958 00:38:12,120 --> 00:38:14,600 MY LAB WHERE WE TOOK THE IL2 959 00:38:14,600 --> 00:38:19,240 RECEPTOR COMPLEX AND THE IL10 960 00:38:19,240 --> 00:38:20,520 RECEPTOR COMPLEX AND WE BORROWED 961 00:38:20,520 --> 00:38:22,200 A CHAIN FROM EACH COMPLEX TO TRY 962 00:38:22,200 --> 00:38:25,400 TO MAKE A IL2 OR 10 USING THIS 963 00:38:25,400 --> 00:38:31,400 NANO BODY TYPE OF APPROACH. 964 00:38:31,400 --> 00:38:38,120 AND FOUND A NUMBER OF THITS THAT 965 00:38:38,120 --> 00:38:42,880 ACTIVATE THEM AND SOME EARLY 966 00:38:42,880 --> 00:38:44,200 FUNCTIONAL ASSAYS OF THIS HE 967 00:38:44,200 --> 00:38:45,040 FINDS THAT DIFFERENT VERSIONS 968 00:38:45,040 --> 00:38:49,320 ARE ABLE TO ACTIVATE CDHT-CELL 969 00:38:49,320 --> 00:38:53,280 ACTIVATION AND ALTHOUGH NOT AS 970 00:38:53,280 --> 00:38:53,880 POTENTLY AS IL2. 971 00:38:53,880 --> 00:38:55,280 SO WHAT WE REALLY HAVE HERE IS 972 00:38:55,280 --> 00:38:57,960 LIKE A NEW FLAVOR OF IL2. 973 00:38:57,960 --> 00:38:59,640 BECAUSE WE REPLACED COMMON GAMMA 974 00:38:59,640 --> 00:39:01,360 CHAIN WITH IL10 OR BETA, IT'S 975 00:39:01,360 --> 00:39:04,960 GOING TO HAVE ITS OWN UNIQUE 976 00:39:04,960 --> 00:39:05,960 CONSTELLATION OF SIGNALING 977 00:39:05,960 --> 00:39:07,200 ADAPTORS THAT WERE IN THE 978 00:39:07,200 --> 00:39:08,280 PROCESS OF EXPLORING BUT SHOW 979 00:39:08,280 --> 00:39:10,040 THIS IS A CYTOKINE THAT DOESN'T 980 00:39:10,040 --> 00:39:12,520 EXIST IN NATURE, BUT HAS 981 00:39:12,520 --> 00:39:16,720 ACTIVITY ON NATURAL CELLS AND 982 00:39:16,720 --> 00:39:18,160 SO, WE'RE LOOKING INTO THIS A 983 00:39:18,160 --> 00:39:20,000 LOT DEEPER AND REALLY TRYING TO 984 00:39:20,000 --> 00:39:23,000 UNDERSTAND WHAT NEW PROPERTIES 985 00:39:23,000 --> 00:39:23,960 THESE SYNTHETIC CYTOKINES HAVE. 986 00:39:23,960 --> 00:39:30,320 SO I WANT TO PIVOT A LITTLE BIT 987 00:39:30,320 --> 00:39:31,240 HERE FROM SYSTEMIC CYTOKINES 988 00:39:31,240 --> 00:39:33,000 WHICH OUR LAB IS MAINLY A 989 00:39:33,000 --> 00:39:34,760 PROTEIN LAB AND SO WE'RE MORE 990 00:39:34,760 --> 00:39:36,040 INTERESTED IN MAKING PROTEIN 991 00:39:36,040 --> 00:39:39,920 MOLECULES THAT DO THINGS ON 992 00:39:39,920 --> 00:39:41,200 CELLS, BUT CELL THERAPY IS ALSO 993 00:39:41,200 --> 00:39:44,280 A GREAT OPPORTUNITY FOR PROTEIN 994 00:39:44,280 --> 00:39:47,240 ENGINEERING AND I'M GOING TO 995 00:39:47,240 --> 00:39:49,000 SHOW YOU WHAT OUR CONTRIBUTION 996 00:39:49,000 --> 00:39:51,160 TO ADVANCING CELL THERAPY HAS 997 00:39:51,160 --> 00:39:55,120 BEEN AND THAT'S BEEN IN 998 00:39:55,120 --> 00:39:56,040 ORTHAGOREAN NOLL IL2 SYSTEM. 999 00:39:56,040 --> 00:39:59,520 SO WHAT I'M SHOWING YOU HERE IS 1000 00:39:59,520 --> 00:40:03,080 THE IL2 RECEPTOR COMPLEX AGAIN. 1001 00:40:03,080 --> 00:40:06,960 AND SO, YOU KNOW 1 OF THE 1002 00:40:06,960 --> 00:40:08,000 LIMITATIONS OF CELL THERAPY IS 1003 00:40:08,000 --> 00:40:10,320 THAT WHEN YOU GIVE PEOPLE 1004 00:40:10,320 --> 00:40:11,360 ENGINEERED T-CELLS THEY DON'T 1005 00:40:11,360 --> 00:40:13,000 EXPAND AS MUCH AS YOU WOULD LIKE 1006 00:40:13,000 --> 00:40:15,000 THEM TO AND YOU WOULD LIKE TO 1007 00:40:15,000 --> 00:40:16,760 GIVE THEM IL2 TO EXPABD THOSE 1008 00:40:16,760 --> 00:40:18,440 CELLS BUT IL2 IS VERY TOXIC. 1009 00:40:18,440 --> 00:40:21,000 SO IF WE COULD MAKE AN IL2 THAT 1010 00:40:21,000 --> 00:40:22,920 WAS SELECTIVE FOR IL2 RBETTA 1011 00:40:22,920 --> 00:40:27,280 THAT WOULD BE 1 POSSIBLE WAY OF 1012 00:40:27,280 --> 00:40:28,880 SOLVING THAT PROBLEM SO WHAT WE 1013 00:40:28,880 --> 00:40:32,120 DID WAS WE MADE A MUTANT IL2 1014 00:40:32,120 --> 00:40:35,440 THAT NO LONGER BOUND TO 1015 00:40:35,440 --> 00:40:37,160 WILD-TYPE IL2 RBETTA AND A 1016 00:40:37,160 --> 00:40:40,840 MUTANT BETA THAT NO LONG BOUND 1017 00:40:40,840 --> 00:40:42,360 TO ILR2, BUT THEY BOUND TO EACH 1018 00:40:42,360 --> 00:40:43,720 OTHER AND THE IDEA BEING THAT 1019 00:40:43,720 --> 00:40:46,160 YOU COULD INSTALL THAT INTO 1020 00:40:46,160 --> 00:40:48,000 ENGINEERED T-CELLS AND PUT THOSE 1021 00:40:48,000 --> 00:40:50,840 CELLS INTO PEOPLE OR MICE, DOSE 1022 00:40:50,840 --> 00:40:52,640 WITH THE MUTANT CYTOKINE AND GET 1023 00:40:52,640 --> 00:40:53,840 SELECTIVE EXPANSION OF THE 1024 00:40:53,840 --> 00:40:54,640 ENGINEERED T-CELLS. 1025 00:40:54,640 --> 00:40:58,160 AND IN FACT, IT'S WORKED 1026 00:40:58,160 --> 00:40:59,160 BEAUTIFULLY. 1027 00:40:59,160 --> 00:41:00,200 AND THESE ARE THE DIFFERENT 1028 00:41:00,200 --> 00:41:01,920 THINGS CAN YOU DO WITH IT. 1029 00:41:01,920 --> 00:41:04,720 YOU CAN EXPAND CELLS, WE CAN 1030 00:41:04,720 --> 00:41:07,000 TRANSPLANT WITHOUT HOST 1031 00:41:07,000 --> 00:41:09,360 PRECONDITIONING, THERE'S REDUCED 1032 00:41:09,360 --> 00:41:10,000 TOXICITY MITIGATING EXHAUSTION 1033 00:41:10,000 --> 00:41:12,760 AND A LOT OF REASONS WHY THIS IS 1034 00:41:12,760 --> 00:41:14,360 A VERY POWERFUL TECHNOLOGY AND 1035 00:41:14,360 --> 00:41:15,880 JUST TO SHOW YOU A LITTLE BIT 1036 00:41:15,880 --> 00:41:17,920 ABOUT HOW WE DID IT, THIS IS 1037 00:41:17,920 --> 00:41:19,880 ORIGINAL ENGINEERING WAS DONE BY 1038 00:41:19,880 --> 00:41:22,800 JONATHAN [INDISCERNIBLE] IN MY 1039 00:41:22,800 --> 00:41:24,800 LAB, AND THE WAY HE WENT ABOUT 1040 00:41:24,800 --> 00:41:32,280 IT WAS MAKING A MUTATION IN THE 1041 00:41:32,280 --> 00:41:34,080 RECEPTOR SO IT 1042 00:41:34,080 --> 00:41:34,760 ABNORMALITIESIGATED IL2 BINDING 1043 00:41:34,760 --> 00:41:35,600 AND THIS IS BASED ON THE 1044 00:41:35,600 --> 00:41:38,160 STRUCTURE AND THEN CREATING A 1045 00:41:38,160 --> 00:41:40,360 LIBRARY ON IL2 AND SELECTING 1046 00:41:40,360 --> 00:41:41,640 AGAINST THE MUTANT, SELECTING 1047 00:41:41,640 --> 00:41:44,440 FOR THE MUTANT AND AGAINST THE 1048 00:41:44,440 --> 00:41:44,880 WILD-TYPE RECEPTOR. 1049 00:41:44,880 --> 00:41:48,760 SO HERE'S WHAT THIS LOOKS LIKE, 1050 00:41:48,760 --> 00:41:52,200 BASICALLY, THIS IS NOW THE 1051 00:41:52,200 --> 00:41:55,760 LIBRARY BINDING TO IL2 R, THE 1052 00:41:55,760 --> 00:41:57,520 MUTANT RECEPTOR THAT DOESN'T 1053 00:41:57,520 --> 00:41:58,600 BIEBD TO IL2 AND YOU CAN SEE 1054 00:41:58,600 --> 00:41:59,800 NEITHER OF THEM ARE BINDING 1055 00:41:59,800 --> 00:42:01,280 REALLY WELL BUT AFTER THE 1056 00:42:01,280 --> 00:42:03,040 SELECTION, YOU GET SELECTIVITY 1057 00:42:03,040 --> 00:42:05,920 FOR THE MUTANT RECEPTOR. 1058 00:42:05,920 --> 00:42:07,200 VERSUS THE WILD-TYPE RECEPTOR SO 1059 00:42:07,200 --> 00:42:10,480 NOW WE HAVE, WHAT WE CALL AN 1060 00:42:10,480 --> 00:42:11,720 ORTHOGONAL IL2. 1061 00:42:11,720 --> 00:42:15,960 AND WHAT THIS LOOKS LIKE IS THAT 1062 00:42:15,960 --> 00:42:18,880 WHEN YOU UPON TRANSDUCE T-CELLS 1063 00:42:18,880 --> 00:42:22,800 WITH THE ORTHOBETTA RECEPTOR AND 1064 00:42:22,800 --> 00:42:24,520 THEN ADD THE ORTHOCYTOKINE YOU 1065 00:42:24,520 --> 00:42:27,960 GET A STAT 5 SIGNAL WHEREAS WHEN 1066 00:42:27,960 --> 00:42:33,040 YOU APPLY THE ORTHOGONAL 1067 00:42:33,040 --> 00:42:33,840 WILD-TYPE T-CELLS WE DON'T GET 1068 00:42:33,840 --> 00:42:36,080 ANY GROWTH IN THIS CASE. 1069 00:42:36,080 --> 00:42:38,960 WE DEMONSTRATED THIS IN VIVO, 1070 00:42:38,960 --> 00:42:40,600 JONATHAN AND LEON IN MY LAB HAVE 1071 00:42:40,600 --> 00:42:42,680 DONE EXPERIMENTS WHERE WE CAN 1072 00:42:42,680 --> 00:42:46,880 MIX THE ORTHO2 CELLS WITH THE 1073 00:42:46,880 --> 00:42:48,520 NORMAL T-CELLS AND WE GET VERY 1074 00:42:48,520 --> 00:42:50,760 SPECIFIC EXPANSION OF THE 1075 00:42:50,760 --> 00:42:53,040 ORTHOT-CELLS BY THE 1076 00:42:53,040 --> 00:42:53,560 ORTHOCYTOKINE. 1077 00:42:53,560 --> 00:42:57,000 AND THAT IS NOT--WE DO NOT SEE 1078 00:42:57,000 --> 00:43:00,360 EXPANSION OF CELLS THAT DO NOT 1079 00:43:00,360 --> 00:43:02,480 HAVE THE ORTHOGONAL RECEPTOR. 1080 00:43:02,480 --> 00:43:05,240 AND WE'VE SHOWN WITH MIKE MALONE 1081 00:43:05,240 --> 00:43:09,320 HERE, HERE'S 1 EXAMPLE IN A 1082 00:43:09,320 --> 00:43:13,000 CAR-T MODEL, IN A CD11 KARKS-T, 1083 00:43:13,000 --> 00:43:15,200 CELL AND WE PUT THEM INTO THE 1084 00:43:15,200 --> 00:43:19,160 CAR-T CELLS AND THEN WE SEE DOSE 1085 00:43:19,160 --> 00:43:20,320 DEPENDENT EXPANSION OF THE 1086 00:43:20,320 --> 00:43:23,640 T-CELLS AT DIFFERENT DOSES OF 1087 00:43:23,640 --> 00:43:24,680 THE ORTHOGONAL CYTOKINE, SO THIS 1088 00:43:24,680 --> 00:43:26,760 IS 2 LONG EXPANSION OF THESE 1089 00:43:26,760 --> 00:43:27,160 CELLS. 1090 00:43:27,160 --> 00:43:32,400 AND IN THIS EXPERIMENT, MIKE 1091 00:43:32,400 --> 00:43:37,720 SHOWED VERY NICELY THAT THE CAR 1092 00:43:37,720 --> 00:43:42,040 T WITHOUT THE ORTHOGONAL IS 1093 00:43:42,040 --> 00:43:45,040 CONTROLLING THE TUMORS BUT WHEN 1094 00:43:45,040 --> 00:43:47,520 YOU ADD THE ORTHOGONAL CYTOKINE, 1095 00:43:47,520 --> 00:43:50,920 YOU GET THE DOSE TO DOSE 1096 00:43:50,920 --> 00:43:51,680 SIGNIFICANTLY FEWER CELLS. 1097 00:43:51,680 --> 00:43:53,160 FOR EXAMPLE, THIS IS 200,000 1098 00:43:53,160 --> 00:43:55,040 CELLS, IT'S A BIT EFFECTIVE AND 1099 00:43:55,040 --> 00:43:58,360 IN HALF A MILLION CELLS WHICH 1100 00:43:58,360 --> 00:44:00,240 JUST AS EFFECTIVE AS A MILLION 1101 00:44:00,240 --> 00:44:03,000 CELLS, SO IT ALLOWS YOU TO PUT 1102 00:44:03,000 --> 00:44:04,280 IN MANY FEWER CELLS INTO THE 1103 00:44:04,280 --> 00:44:08,840 MICE AT ALL SO THE SURVIVAL 1104 00:44:08,840 --> 00:44:14,320 BENEFIT IS CLEAR AND THIS IS 1105 00:44:14,320 --> 00:44:15,200 ALSO ANOTHER MOLECULE WHICH IS 1106 00:44:15,200 --> 00:44:17,280 GOING INTO THE CLINIC THROUGH 1107 00:44:17,280 --> 00:44:17,560 SYNTH KINE. 1108 00:44:17,560 --> 00:44:22,600 NOW THERE'S BEEN A RECENT TWIST 1109 00:44:22,600 --> 00:44:23,320 WITH THIS ORTHOBETTA SYSTEM I 1110 00:44:23,320 --> 00:44:24,920 WANT TO TELL YOU ABOUT AND THIS 1111 00:44:24,920 --> 00:44:30,880 IS A COLLABORATION BETWEEN MY 1112 00:44:30,880 --> 00:44:32,960 LAB TONY, KARL, AND 1113 00:44:32,960 --> 00:44:34,200 [INDISCERNIBLE] WHO'S NOW HERE 1114 00:44:34,200 --> 00:44:36,000 AT STANFORD AND WHAT THIS SYSTEM 1115 00:44:36,000 --> 00:44:37,080 DOES, IT AFFORDS YOU THE 1116 00:44:37,080 --> 00:44:39,480 POSSIBILITY OF SWAPPING OUT THE 1117 00:44:39,480 --> 00:44:46,240 INTRACELLULAR DOMAIN OF THE BETA 1118 00:44:46,240 --> 00:44:47,680 RECEPTOR SO ANY OF THE COMMON 1119 00:44:47,680 --> 00:44:50,400 FAMILY AND HERE'S A PICTURE FOR 1120 00:44:50,400 --> 00:44:52,120 WARREN'S REVIEWS ON ALL THE 1121 00:44:52,120 --> 00:44:54,880 COMMON GAMMA CHAIN CYTOKINES SO 1122 00:44:54,880 --> 00:44:56,400 THIS INSPIRES US TO REPLACE THE 1123 00:44:56,400 --> 00:45:04,720 BETA WITH EACH OF COMMON GAMMA 1124 00:45:04,720 --> 00:45:07,400 CHAIN CYTOKINE. 1125 00:45:07,400 --> 00:45:08,560 AND THIS CHES AN INTERESTING 1126 00:45:08,560 --> 00:45:10,120 EXPERIMENT, SO THIS IS SHOWING 1127 00:45:10,120 --> 00:45:13,480 YOU ALL THE ICDs ACTIVATING 1128 00:45:13,480 --> 00:45:17,480 STAT 5, 3 AND EASY AND 6, SO 1129 00:45:17,480 --> 00:45:23,360 PREDICTABLY THE ORTHO4 RECEPTOR 1130 00:45:23,360 --> 00:45:25,680 ONLY ACTIVATES STAT 6 BUT ORTHO9 1131 00:45:25,680 --> 00:45:36,240 ACTIVATES 1, 3, AND 5. 1132 00:45:36,240 --> 00:45:38,200 SO IT'S ALMOST ACTIVATING ALL 1133 00:45:38,200 --> 00:45:39,680 THE STATS EXCEPT STAT 6. 1134 00:45:39,680 --> 00:45:43,040 THE OTHERS ARE INTERESTING TOO, 1135 00:45:43,040 --> 00:45:45,800 ORTHO7 IS A PARTIAL AGONIST FOR 1136 00:45:45,800 --> 00:45:48,200 STAT 5, BUT WE PUBLISHED IN 1137 00:45:48,200 --> 00:45:49,880 PAPER LAST YEAR [INDISCERNIBLE] 1138 00:45:49,880 --> 00:45:52,160 IS THE FIRST AUTHOR WORKING WITH 1139 00:45:52,160 --> 00:45:55,920 LEON AND CANNED CANNED--[INDIS] 1140 00:45:55,920 --> 00:45:57,920 IN KARL'S LAB BUT I WILL JUST 1141 00:45:57,920 --> 00:46:01,400 FOCUS ON 9 FOR NOW BECAUSE WHAT 1142 00:46:01,400 --> 00:46:04,680 WE ALSO FOUND WAS THAT IF WE 1143 00:46:04,680 --> 00:46:09,440 LOOK AT EFFECTOR MARKERS LIKE 1144 00:46:09,440 --> 00:46:12,200 CD62, AND STEMNESS MARKERS LIKE 1145 00:46:12,200 --> 00:46:18,400 FAST AND SCA, ORGT O 9 AND ORGT 1146 00:46:18,400 --> 00:46:20,600 O 21 SEEM TO HAVE ADVANTAGES 1147 00:46:20,600 --> 00:46:21,800 OVER THE COMMON FAMILY MEMBERS 1148 00:46:21,800 --> 00:46:23,960 ESPECIALLY WHEN IT AM CANS TO 1149 00:46:23,960 --> 00:46:30,720 STEMNESS, SO WE CHOSE ORTHO9 1150 00:46:30,720 --> 00:46:33,080 RECEPTOR TO GO DEEPER INTO THE 1151 00:46:33,080 --> 00:46:34,440 STUDIES AND THIS IS 1152 00:46:34,440 --> 00:46:35,920 [INDISCERNIBLE] WORK AND SHE 1153 00:46:35,920 --> 00:46:38,200 SHOWED THAT ORTHO9 IS ABLE TO 1154 00:46:38,200 --> 00:46:45,480 HAVE ADOPTED CELL IN THE ABSENCE 1155 00:46:45,480 --> 00:46:46,080 OF LYMPHDEPLETION. 1156 00:46:46,080 --> 00:46:49,360 AND NOT ONLY THAT BUT YOU SEE 1157 00:46:49,360 --> 00:46:50,880 BETTER INFILTRATION OF THE 1158 00:46:50,880 --> 00:46:54,920 TUMORS, YOU SEE THE TISNI SPLOT, 1159 00:46:54,920 --> 00:46:57,600 THE ORTHO9 CELLS HAVE MORE OF AN 1160 00:46:57,600 --> 00:46:58,440 ACTIVATED PHENOTYPE THAN THE 1161 00:46:58,440 --> 00:47:01,280 ORGT O 2 CELLS AND THEY'RE ALSO 1162 00:47:01,280 --> 00:47:02,840 THE STEMNESS MARKERS, THIS IS 1163 00:47:02,840 --> 00:47:06,080 ORGT O 9 RIGHT HERE, THE 1164 00:47:06,080 --> 00:47:09,520 STEMNESS MARKERS ARE UP AND 1165 00:47:09,520 --> 00:47:10,280 REDUCE EXHAUSTION MARKERS AND 1166 00:47:10,280 --> 00:47:11,800 THINGS LIKE THAT SO THIS WAS 1167 00:47:11,800 --> 00:47:18,720 REALLY SURPRISING, I MEANI IL9, 1168 00:47:18,720 --> 00:47:21,360 REALLY WE DON'T KNOW A LOT ABOUT 1169 00:47:21,360 --> 00:47:23,920 IL9, OR WHAT IT'S DOING OR THERE 1170 00:47:23,920 --> 00:47:25,600 AREN'T MANY T-CELL RESUPPORTORS 1171 00:47:25,600 --> 00:47:27,200 THAT RECEPTIVE TO IL9 BUT WHEN 1172 00:47:27,200 --> 00:47:29,680 WE TAKE IT AND PUT IT IN A NEW 1173 00:47:29,680 --> 00:47:31,080 CONTEXT IS REVEALS THESE 1174 00:47:31,080 --> 00:47:32,960 FUNCTIONS WE IN NO IDEA ABOUT 1175 00:47:32,960 --> 00:47:35,760 AND THIS IS DATA FROM KARL'S LAB 1176 00:47:35,760 --> 00:47:40,000 WHICH SUPPORTED CANNED WHAT DATA 1177 00:47:40,000 --> 00:47:41,280 IN THIS CHIMERIC--CAR T SOLID 1178 00:47:41,280 --> 00:47:44,480 TUMOR AND YOU KEY IS IN THIS 1179 00:47:44,480 --> 00:47:45,920 [INDISCERNIBLE] EXPERIMENT, HERE 1180 00:47:45,920 --> 00:47:47,520 ARE THE CAR Ts THAT ARE 1181 00:47:47,520 --> 00:47:49,120 SUPPORTED BY ORTHO2 AND HERE 1182 00:47:49,120 --> 00:47:51,840 THEY ARE WITH ORTHO9 SO THEY'RE 1183 00:47:51,840 --> 00:47:53,200 MUCH BETTER CYTOTOXICITY BY THE 1184 00:47:53,200 --> 00:47:55,360 ORTHO9 AND THEY'RE ALSO ENHANCED 1185 00:47:55,360 --> 00:47:59,120 EFFECTOR FUNCTIONS AND ALSO THE 1186 00:47:59,120 --> 00:48:01,240 STEMNESS AND THIS IS NOW IN A 1187 00:48:01,240 --> 00:48:04,520 SOLID TUMOR MODEL SO REALLY THE 1188 00:48:04,520 --> 00:48:08,160 ORTHO9 SYSTEM IS SUPER 1189 00:48:08,160 --> 00:48:09,240 INTERESTING AND WE'RE LOOKING 1190 00:48:09,240 --> 00:48:11,880 DEEPER INTO IT AS PERHAPS THE 1191 00:48:11,880 --> 00:48:16,720 NEXT GEN BEYOND ORTHO2, AND--BUT 1192 00:48:16,720 --> 00:48:18,280 THERE'S 1 LIABILITY OF THE 1193 00:48:18,280 --> 00:48:20,040 ORTHO9 SYSTEM COMPARED TO ORTHO2 1194 00:48:20,040 --> 00:48:22,960 WHICH IS ORTHO2 THE CELLS EXPAND 1195 00:48:22,960 --> 00:48:25,360 TREMENDOUSLY IN THE SYSTEMIC 1196 00:48:25,360 --> 00:48:26,440 CIRCULATION, ORTHO9 DOES NOT 1197 00:48:26,440 --> 00:48:29,080 HAVE A STRONG PROLIFERATIVE 1198 00:48:29,080 --> 00:48:30,720 SIGNAL SO WHAT LEON SUH HASSA 1199 00:48:30,720 --> 00:48:33,200 BEEN DOING IN MY LAB IS SHE'S 1200 00:48:33,200 --> 00:48:36,480 TAKING A HARD LOOK AT THE IL9 1201 00:48:36,480 --> 00:48:38,000 RECEPTOR INTRANSLATIONAL 1202 00:48:38,000 --> 00:48:38,680 RESEARCH CELLULAR DOMAIN 1203 00:48:38,680 --> 00:48:40,600 TYROSEENS AND HE'S BEEN MUTATING 1204 00:48:40,600 --> 00:48:42,360 THEM AND DOG PROTEIN ENGINEERING 1205 00:48:42,360 --> 00:48:44,040 ON THE EXTRA CELLULAR DOMAIN AND 1206 00:48:44,040 --> 00:48:44,880 YOU CAN SEE WHENY WOO BEING 1207 00:48:44,880 --> 00:48:46,880 LOAMACY THEA THE STAT 5 1208 00:48:46,880 --> 00:48:48,880 SIGNALING, STAT 5, 3, AND 1, 1209 00:48:48,880 --> 00:48:50,400 DON'T FOCUS IN ON THE DETAILS 1210 00:48:50,400 --> 00:48:56,560 HERE, JUST LOOK AT HERE'S ORTHO2 1211 00:48:56,560 --> 00:48:57,320 VERSUS ORTHOWILD-TYPE AND YOU 1212 00:48:57,320 --> 00:48:59,160 CAN SEE IT LOOKS LIKE AS WE'VE 1213 00:48:59,160 --> 00:49:00,640 SHOWN EARLIER ORTHO9 ACTIVATES 1214 00:49:00,640 --> 00:49:03,200 ALL OF THEM BUT LEON HAS MADE 1215 00:49:03,200 --> 00:49:04,600 VERSIONS WHICH NOW CONTUNE THE 1216 00:49:04,600 --> 00:49:11,760 DEGREE OF STAT ACTIVATION OF THE 1217 00:49:11,760 --> 00:49:14,160 DIFFERENT STATTINGS AND AT THE 1218 00:49:14,160 --> 00:49:16,480 SAME TIME OF RESCUING THE ASSAYS 1219 00:49:16,480 --> 00:49:19,360 HE'S BEEN ABLE TO RESCUE THE 1220 00:49:19,360 --> 00:49:21,360 ILOORKS 9, IT'S NOT AS GOOD AS 1221 00:49:21,360 --> 00:49:23,440 IL2 BUT IT'S STILL SOMETHING 1222 00:49:23,440 --> 00:49:24,720 WHILE ALSO PRESERVING THE 1223 00:49:24,720 --> 00:49:27,240 STEMNESS PROPERTIES TO DIFFERENT 1224 00:49:27,240 --> 00:49:27,720 DEGREES. 1225 00:49:27,720 --> 00:49:33,520 AND SO WE'RE BEGINNING TO WORK 1226 00:49:33,520 --> 00:49:35,440 WITH MIKE MILONE AND THE SAME 1227 00:49:35,440 --> 00:49:37,280 TESTING AND TUMOR VARIANTS ABOUT 1228 00:49:37,280 --> 00:49:41,600 ASKING WHAT IS REALLY THE BEST 1229 00:49:41,600 --> 00:49:49,320 COMBINATION OF SIGNALS HERE FROM 1230 00:49:49,320 --> 00:49:54,240 THE 2 MUTANTS HERE AND THE 1231 00:49:54,240 --> 00:50:04,160 TUNABILITY FOR THERAPEUTICS. 1232 00:50:04,160 --> 00:50:05,800 I'LL VIEW THIS SECTION HERE, ALL 1233 00:50:05,800 --> 00:50:06,760 THESE CELL FATE DECISIONS ARE 1234 00:50:06,760 --> 00:50:08,960 MADE IN THE CONTEXT OF A 1235 00:50:08,960 --> 00:50:15,200 CYTOKINE MILIEU AND WE THINK 1236 00:50:15,200 --> 00:50:15,920 THAT THESE EXPERIMENTS REALLY 1237 00:50:15,920 --> 00:50:18,160 OPEN UP A LOT OF POSSIBILITY OF 1238 00:50:18,160 --> 00:50:19,440 TUNING CYTOKINES EARLY IN THESE 1239 00:50:19,440 --> 00:50:21,280 FATE DETERMINE NATION PATHWAYS 1240 00:50:21,280 --> 00:50:25,720 AND POSSIBLY CREATING NEW CELL 1241 00:50:25,720 --> 00:50:29,920 FATES OR ALTERING BAIT CHOICES 1242 00:50:29,920 --> 00:50:32,440 IN ADDITION TO THE 1243 00:50:32,440 --> 00:50:33,320 DIFFERENTIATED CELL TYPES I'VE 1244 00:50:33,320 --> 00:50:34,720 TALKED ABOUT SO FAR. 1245 00:50:34,720 --> 00:50:36,080 SO THAT'S KIND OF WHERE WE'RE 1246 00:50:36,080 --> 00:50:37,680 GOING, I WANT TO FINISH UP HERE 1247 00:50:37,680 --> 00:50:39,360 GETTING BACK TO MECHANISM, YOU 1248 00:50:39,360 --> 00:50:41,360 KNOW AFTER A LONG, YOU KNOW I 1249 00:50:41,360 --> 00:50:42,200 STARTED WORKING ON THE JACK 1250 00:50:42,200 --> 00:50:44,560 STRUCTURE WHILE I WAS A POST DOC 1251 00:50:44,560 --> 00:50:47,200 AT SCRIPS AND FINALLY IN 2022, 1252 00:50:47,200 --> 00:50:49,160 THROUGH CRYOEM, A TEAM OF PEOPLE 1253 00:50:49,160 --> 00:50:57,760 IN MY LAB, CALEB, KEVIN, 1254 00:50:57,760 --> 00:51:00,080 RECENTLY, NATHANIEL, WE MANAGED 1255 00:51:00,080 --> 00:51:01,520 TO STRUCTURE A FULL LEJT JACK 1256 00:51:01,520 --> 00:51:02,880 AND SO IN THIS STRUCTURE IN THE 1257 00:51:02,880 --> 00:51:07,200 1 IN THE LEFT HERE, THE KINASE 1258 00:51:07,200 --> 00:51:11,040 DOMAINS HERE WERE A PART ASK WE 1259 00:51:11,040 --> 00:51:14,240 KNOW THAT WHEN THE JACK--SO THIS 1260 00:51:14,240 --> 00:51:15,960 IS THE INTRACELLULAR DOMAIN. 1261 00:51:15,960 --> 00:51:19,480 WHEN IT BINDS AND KIND OF--THE 1262 00:51:19,480 --> 00:51:20,600 CYTOKINE BRINGS THESE TOGETHER, 1263 00:51:20,600 --> 00:51:23,440 THESE KINASE DOMAINS HAVE TO 1264 00:51:23,440 --> 00:51:24,720 TRANSPHOSPHORYLATE TO ACTIVATE 1265 00:51:24,720 --> 00:51:28,240 TURGTER SIGNALING SO RECENTLY, 1266 00:51:28,240 --> 00:51:30,440 NATHANIEL AND BOBBY SAX TON AND 1267 00:51:30,440 --> 00:51:34,200 MY LAB, [INDISCERNIBLE] MANAGED 1268 00:51:34,200 --> 00:51:36,240 TO TRAP AIAN CONFIRMATION OF THE 1269 00:51:36,240 --> 00:51:37,520 CLUSTER DOMAINS WHERE THEY'RE IN 1270 00:51:37,520 --> 00:51:38,840 COMMUNICATION WITH EACH OTHER. 1271 00:51:38,840 --> 00:51:42,080 SO NOW THIS IS THE ACTIVE 1272 00:51:42,080 --> 00:51:44,560 TRANSFORFORALATING POSE OF THIS 1273 00:51:44,560 --> 00:51:46,760 1 AND THE MESSAGE HERE THERE'S A 1274 00:51:46,760 --> 00:51:48,840 LOT OF FLEXIBILITY IN THESE 1275 00:51:48,840 --> 00:51:49,800 KINASE DOMAINS AND YOU WOULD 1276 00:51:49,800 --> 00:51:52,440 IMAGINE THERE HAS TO BE BECAUSE, 1277 00:51:52,440 --> 00:51:54,720 YOU KNOW THESE INTRACELLULAR 1278 00:51:54,720 --> 00:51:57,480 DOMAIN TAILS KIND OF HANG OFF 1279 00:51:57,480 --> 00:51:58,720 HERE AND KIND OF WIND THEIR WAY 1280 00:51:58,720 --> 00:52:00,840 DOWN TO THE KINASE DOMAINS AND 1281 00:52:00,840 --> 00:52:03,080 THE KINASE DOMAIN VS TO BE ABLE 1282 00:52:03,080 --> 00:52:05,040 TO ACCESS DIFFERENT TYROSEENS ON 1283 00:52:05,040 --> 00:52:05,760 THE DIFFERENT CELLULAR DOMAINS 1284 00:52:05,760 --> 00:52:08,880 AND THEY NEED TO BE SOMEWHAT 1285 00:52:08,880 --> 00:52:10,760 MOBILE AND SO WE'RE CONTINUING 1286 00:52:10,760 --> 00:52:12,000 TO ESCALATE OUR STRUCTURAL 1287 00:52:12,000 --> 00:52:14,480 STUDIES NOW TO TRAP A STAT 1288 00:52:14,480 --> 00:52:16,480 COMPLEX WITH THE JACK. 1289 00:52:16,480 --> 00:52:22,400 BUT WHAT I WANT TO ALSO SHOW YOU 1290 00:52:22,400 --> 00:52:25,160 TODAY IS WHAT WE LEARNED ABOUT 1291 00:52:25,160 --> 00:52:27,000 ONCOGENIC MUTATIONS FROM THE 1292 00:52:27,000 --> 00:52:27,240 STRUCTURE. 1293 00:52:27,240 --> 00:52:31,000 SO THERE'S THIS CLASSIC MUTATION 1294 00:52:31,000 --> 00:52:34,280 IN JACKS CALLED V17 F WHICH 1295 00:52:34,280 --> 00:52:35,840 RESPONSIBLE FOR MANY CLASSES, 1296 00:52:35,840 --> 00:52:38,000 IT'S A CONSTITTATIVE ACTIVATING 1297 00:52:38,000 --> 00:52:39,160 MUTATION IN THE PSEUDOKINASE 1298 00:52:39,160 --> 00:52:41,200 DOMAIN AND THIS IS A FIGURE FROM 1299 00:52:41,200 --> 00:52:44,520 THE ORIGINAL PAPER, APOLOGIES I 1300 00:52:44,520 --> 00:52:45,680 DON'T HAVE A REFERENCE HERE BUT 1301 00:52:45,680 --> 00:52:47,320 THIS IS SEVERAL GROUPS DETERMINE 1302 00:52:47,320 --> 00:52:49,800 THIS ABOUT THE SAME TIME ABOUT 1303 00:52:49,800 --> 00:52:52,640 15 YEARS AGO AND THIS MUTATION 1304 00:52:52,640 --> 00:52:54,600 MAPS RIGHT INTO THIS DIMER 1305 00:52:54,600 --> 00:52:58,760 INTERFACE RIGHT THERE BETWEEN 1306 00:52:58,760 --> 00:53:01,800 THE PSEUDOKINASE DOMAINS AND 1307 00:53:01,800 --> 00:53:02,840 IT'S AVAILING TO 1308 00:53:02,840 --> 00:53:03,680 [INDISCERNIBLE], SO WHAT IT DOES 1309 00:53:03,680 --> 00:53:06,480 IF YOU LOOK AT THE WILD-TYPE 1310 00:53:06,480 --> 00:53:07,640 INTERFACE BETWEEN THE 1311 00:53:07,640 --> 00:53:09,720 PSEUDOKINASE DOMAINS, IT'S A 1312 00:53:09,720 --> 00:53:10,800 VERY POORLY PACKED INTERFACE AND 1313 00:53:10,800 --> 00:53:13,640 SO IN THIS MODEL, THE CYTOKINE 1314 00:53:13,640 --> 00:53:14,680 IS REALLY RESPONSIBILITY FOR 1315 00:53:14,680 --> 00:53:16,280 BRINGING THE 2 RECEPTORS WITH 1316 00:53:16,280 --> 00:53:18,800 THEIR JACKS TOGETHER, TO FORM IN 1317 00:53:18,800 --> 00:53:19,000 DIMER. 1318 00:53:19,000 --> 00:53:19,920 HOWEVER, WHENEVER THE 1319 00:53:19,920 --> 00:53:23,160 VALENTINEDENT IS MUTATED TO A 1320 00:53:23,160 --> 00:53:24,360 [INDISCERNIBLE] LIKE IN V617 F 1321 00:53:24,360 --> 00:53:27,360 AND IT FILLS THE GAPS AND 1322 00:53:27,360 --> 00:53:28,400 IMPROVES THE SHAPE 1323 00:53:28,400 --> 00:53:29,120 COMPLEMENTARITY BETWEEN THE 1324 00:53:29,120 --> 00:53:30,320 DOMAINS AND WHEN THAT HAPPENS 1325 00:53:30,320 --> 00:53:32,840 NOW, THE JACKS ARE ABLE TO 1326 00:53:32,840 --> 00:53:33,960 DIMERIZE WITHOUT THE REQUIREMENT 1327 00:53:33,960 --> 00:53:36,520 OF THE CYTOKINE BRINGING THE 2 1328 00:53:36,520 --> 00:53:38,760 RECEPTORS TOGETHER. 1329 00:53:38,760 --> 00:53:40,120 SO IT'S ESSENTIALLY AN 1330 00:53:40,120 --> 00:53:41,520 ONMECHANISM MUTATION THAT JUST 1331 00:53:41,520 --> 00:53:43,280 SERVES TO CEMENT THIS DIMER 1332 00:53:43,280 --> 00:53:47,960 TOGETHER IN A CYTOKINE 1333 00:53:47,960 --> 00:53:48,320 INDEPENDENT WAY. 1334 00:53:48,320 --> 00:53:51,120 AND WE DID SOME EXPERIMENTS WITH 1335 00:53:51,120 --> 00:53:53,640 [INDISCERNIBLE] USING A SINGLE 1336 00:53:53,640 --> 00:53:56,920 MOLECULE TURF SEVERAL YEARS AGO 1337 00:53:56,920 --> 00:53:59,080 AND [INDISCERNIBLE] AND HIS 1338 00:53:59,080 --> 00:54:01,840 GROUP SHOWED THAT THIS 1339 00:54:01,840 --> 00:54:02,440 CONSTITTATIVE HOMER 1340 00:54:02,440 --> 00:54:04,560 DIMERIZATION, THE ABSENCE OF 1341 00:54:04,560 --> 00:54:08,200 LIGAND IS HOW B617 F WORKS SO 1342 00:54:08,200 --> 00:54:10,680 FOR INSTANCE HERE'S TFO RECEPTOR 1343 00:54:10,680 --> 00:54:12,080 AND EPO RECEPTOR ASK HAD IS JUST 1344 00:54:12,080 --> 00:54:13,840 ANOTHER WOR FORWARD 1345 00:54:13,840 --> 00:54:14,480 DIMERIZATIONOT CELL SURFACE AND 1346 00:54:14,480 --> 00:54:16,560 YOU CAN SEE WHEN THE WILD-TYPE 1347 00:54:16,560 --> 00:54:19,960 JACK IS MUTATED BOTH RECEPTORS 1348 00:54:19,960 --> 00:54:21,640 NOW DIMER ICE IN A LIGAND 1349 00:54:21,640 --> 00:54:22,080 INDEPENDENT FASHION. 1350 00:54:22,080 --> 00:54:23,120 SO NOW WITH THE STRUCTURE WE'RE 1351 00:54:23,120 --> 00:54:24,720 ABLE TO KIND OF PUT ALL THIS 1352 00:54:24,720 --> 00:54:26,720 TOGETHER, AND THIS LIGAND 1353 00:54:26,720 --> 00:54:28,920 INDEPENDENT DIMERIZATION IS DUE 1354 00:54:28,920 --> 00:54:30,800 TO THIS INCREASED SHAPE 1355 00:54:30,800 --> 00:54:32,320 COMPLEMENTARITY AS A RESULT OF 1356 00:54:32,320 --> 00:54:34,800 THIS MUTATION WHICH FORMS KIND 1357 00:54:34,800 --> 00:54:39,560 OF A GLUE BETWEEN THE JACKS TO 1358 00:54:39,560 --> 00:54:40,960 HOLD THEM TOGETHER AND THERE'S 1359 00:54:40,960 --> 00:54:42,800 ALL KINDS OF OTHER MUTATIONS IN 1360 00:54:42,800 --> 00:54:45,480 JACKS OUTSIDE OF THIS B617 F 1361 00:54:45,480 --> 00:54:46,960 THAT ARE ALSO ACTIVATES THAT 1362 00:54:46,960 --> 00:54:49,040 DON'T WORK THROUGH DIMERIZE AND 1363 00:54:49,040 --> 00:54:50,480 THIS IS ANOTHER FIGURE FROM THE 1364 00:54:50,480 --> 00:54:53,480 PAPER WHERE HERE WE HAVE THESE 1365 00:54:53,480 --> 00:54:54,880 CONSTITTATIVE ACTIVATING JACK 1366 00:54:54,880 --> 00:54:57,800 MUTATIONS, THEY DON'T CAUSE 1367 00:54:57,800 --> 00:54:59,080 DIMERIZATION AND SO WE'RE REALLY 1368 00:54:59,080 --> 00:55:05,160 INTERESTED IN THIS AND YOU KNOW 1369 00:55:05,160 --> 00:55:06,360 THESE JACK PAPERS 1370 00:55:06,360 --> 00:55:09,440 [INDISCERNIBLE] THERE AT NIH AND 1371 00:55:09,440 --> 00:55:10,720 CONGRATULATIONS TO JOHN, HE WAS 1372 00:55:10,720 --> 00:55:13,600 JUST SELECTED TO THE NATIONAL 1373 00:55:13,600 --> 00:55:13,800 ACADEMY. 1374 00:55:13,800 --> 00:55:14,680 JOHN REALLY PILOT PROJECT OR 1375 00:55:14,680 --> 00:55:17,040 NEARED THE DEVELOPMENT OF THESE 1376 00:55:17,040 --> 00:55:19,040 JACK INHIBITORS TO INHIBIT THESE 1377 00:55:19,040 --> 00:55:23,880 KINASE DOMAINS AND TREAT MILE O 1378 00:55:23,880 --> 00:55:25,400 PROLIFERATIVE NEOPLASMS, WELL 1379 00:55:25,400 --> 00:55:26,800 THAT'S LIKE A STANDARD OF CARE 1380 00:55:26,800 --> 00:55:28,840 IN THE CLINIC NOW, IT'S A PILLAR 1381 00:55:28,840 --> 00:55:29,120 OF THERAPY. 1382 00:55:29,120 --> 00:55:33,360 WE THINK ABOUT OTHER WAYS TO DO 1383 00:55:33,360 --> 00:55:37,760 THIS AND 1 WAY IS THROUGH 1384 00:55:37,760 --> 00:55:38,880 RECRUITING PHOSPHATASES TO THE 1385 00:55:38,880 --> 00:55:41,040 RECEPTOR, SO IN THIS CASE, THE 1386 00:55:41,040 --> 00:55:43,480 B617 F WOULD BE SIGNALING 1387 00:55:43,480 --> 00:55:44,920 CONSTITTATIVELY, IF WE CAN BRING 1388 00:55:44,920 --> 00:55:46,200 A FOZ TO TAISS--SYNTH TO THE 1389 00:55:46,200 --> 00:55:48,040 RECEPTOR AND HAVE THE 1390 00:55:48,040 --> 00:55:49,000 INTRACELLULAR DOMAIN ON THE 1391 00:55:49,000 --> 00:55:51,040 FOSTER NURSED TO TAISS--SYNTH 1392 00:55:51,040 --> 00:55:52,240 DIRECTLY DEPHOSPHORYLATE THE 1393 00:55:52,240 --> 00:55:53,400 RECEPTOR INSTEAD OF DIRECT 1394 00:55:53,400 --> 00:55:55,600 INHIBITION OF THE KINASE, WE 1395 00:55:55,600 --> 00:55:57,880 MIGHT GET MORE SPECIFICITY 1396 00:55:57,880 --> 00:56:00,840 BECAUSE YOU DO THIS WITH A 1397 00:56:00,840 --> 00:56:02,120 BI-SPECIFIC ANTIBODY SPECIFIC TO 1398 00:56:02,120 --> 00:56:03,760 THE RECEPTOR, SPECIFIC TO THE 1399 00:56:03,760 --> 00:56:04,960 SPECIFIC RECEPTOR AND SO THAT'S 1400 00:56:04,960 --> 00:56:06,040 KIND OF 1 THING WE'RE WORKING ON 1401 00:56:06,040 --> 00:56:10,040 THAT I WILL LEAVE YOU WITH AND 1402 00:56:10,040 --> 00:56:12,320 PRELIMINARY DATA THAT WE CALL 1403 00:56:12,320 --> 00:56:13,960 THE RIPPER MOLECULE IS ABLE TO 1404 00:56:13,960 --> 00:56:15,520 INHIBIT PROLIFERATION OF CELLS 1405 00:56:15,520 --> 00:56:18,080 BEARING THIS JACK 2 BF MUTATION, 1406 00:56:18,080 --> 00:56:23,000 YOU KNOW ALMOST EFFECTIVELY, AS 1407 00:56:23,000 --> 00:56:24,280 GOOD AS THE JACK INHIBITOR SO 1408 00:56:24,280 --> 00:56:26,160 THIS IS A PROOF OF CONCEPT 1409 00:56:26,160 --> 00:56:30,280 EXPERIMENT THAT WE CAN 1410 00:56:30,280 --> 00:56:31,480 DEPHOSPHORYLATE THAT JACK. 1411 00:56:31,480 --> 00:56:33,400 AND YOU KNOW WE'RE JUST SORT OF 1412 00:56:33,400 --> 00:56:34,560 THE BEGINNING HERE OF TRYING TO 1413 00:56:34,560 --> 00:56:38,160 EXPLAIN THIS AS A NEW WAY OF 1414 00:56:38,160 --> 00:56:39,320 INHIBITING THE ONCOGENIC 1415 00:56:39,320 --> 00:56:39,600 RECEPTORS. 1416 00:56:39,600 --> 00:56:41,240 SO I WILL END HERE AND JUST, YOU 1417 00:56:41,240 --> 00:56:44,240 KNOW TELL YOU THAT WE'RE 20 1418 00:56:44,240 --> 00:56:47,000 YEARS LATER, MY LAB IS MORE 1419 00:56:47,000 --> 00:56:50,000 EXCITED ABOUT CYTOKINE RECEPTORS 1420 00:56:50,000 --> 00:56:50,400 THAN EVER. 1421 00:56:50,400 --> 00:56:53,080 THIS IS KIND OF OUR MENU OF 1422 00:56:53,080 --> 00:56:54,280 CANDIDATES HERE WHEN YOU THINK 1423 00:56:54,280 --> 00:56:56,840 ABOUT THE DIVERSITY OF THE EXTRA 1424 00:56:56,840 --> 00:57:07,320 CELLULAR DOMAINS, THEIR TISSUE 1425 00:57:07,800 --> 00:57:08,400 EXPRESSION--CYTOKINE RECEPTORS 1426 00:57:08,400 --> 00:57:10,280 JUST LIKE ARTISTS HOW THE COLORS 1427 00:57:10,280 --> 00:57:12,160 THAT WE CAN MIX AND MATCH AND 1428 00:57:12,160 --> 00:57:13,080 DIFFERENT COMBINATIONS AND 1429 00:57:13,080 --> 00:57:14,800 CREATE NOW SHADES AND NEW HUGHES 1430 00:57:14,800 --> 00:57:18,120 AND SO WE'RE HAVING A LOT OF FUN 1431 00:57:18,120 --> 00:57:19,480 WITH THAT NOW AND HOPEFULLY WE 1432 00:57:19,480 --> 00:57:22,360 WILL HAVE NEW THINGS TO TELL YOU 1433 00:57:22,360 --> 00:57:22,760 ABOUT SOON. 1434 00:57:22,760 --> 00:57:25,640 SO I WANT TO FINISH LIE 1435 00:57:25,640 --> 00:57:26,960 ACKNOWLEDGING ALL THE PEOPLE WHO 1436 00:57:26,960 --> 00:57:27,640 DID THIS WORK. 1437 00:57:27,640 --> 00:57:29,040 I TRIED TO MENTION NAMES ALONG 1438 00:57:29,040 --> 00:57:30,640 THE WAY, SO I DON'T REALLY NEED 1439 00:57:30,640 --> 00:57:33,440 TO GO INTO DETAIL ON THIS SLIDE, 1440 00:57:33,440 --> 00:57:37,280 YOU PROBABLY HAVE SEEN THE NAMES 1441 00:57:37,280 --> 00:57:39,840 MENTIONED HERE OR THEIR 1442 00:57:39,840 --> 00:57:41,120 PUBLICATIONS AND SO, I WANT TO 1443 00:57:41,120 --> 00:57:43,720 THANK ALL THESE PEOPLE FOR THEIR 1444 00:57:43,720 --> 00:57:49,840 CONTRIBUTIONS OVER THE YEARS AND 1445 00:57:49,840 --> 00:57:50,720 ALSO AGAIN SYNTHEKINE IS 1446 00:57:50,720 --> 00:57:52,360 CREATING MOST OF THE MOLECULES I 1447 00:57:52,360 --> 00:57:53,000 SHOWED TODAY. 1448 00:57:53,000 --> 00:57:54,560 SO I WILL STOP HERE AND HAPPY TO 1449 00:57:54,560 --> 00:57:59,320 TAKE ANY QUESTIONS. 1450 00:57:59,320 --> 00:57:59,680 >>HEY, CHRIS. 1451 00:57:59,680 --> 00:58:00,600 THANK YOU VERY MUCH FOR FACAS 1452 00:58:00,600 --> 00:58:01,280 WONDERFUL TALK. 1453 00:58:01,280 --> 00:58:04,440 LET ME REMIND PEOPLE TO SEND 1454 00:58:04,440 --> 00:58:06,720 LIVE FEEDBACK WITH QUESTIONS SO 1455 00:58:06,720 --> 00:58:09,040 THAT WE CAN SEE THEM IN THE 1456 00:58:09,040 --> 00:58:09,360 CHAT. 1457 00:58:09,360 --> 00:58:12,640 LET ME START WITH 1 QUESTION, 1458 00:58:12,640 --> 00:58:18,640 CHRIS, BESIDES IL2, AND MAKING 1459 00:58:18,640 --> 00:58:20,040 AN ORTHOIL2 MOLECULE DO YOU HAVE 1460 00:58:20,040 --> 00:58:21,920 TD SENSE THAT OTHER 1461 00:58:21,920 --> 00:58:24,760 ORTHOCYTOKINES WOULD BE OF VALUE 1462 00:58:24,760 --> 00:58:26,040 TO CREATE SOMETHING OF A 1463 00:58:26,040 --> 00:58:27,640 PARALLEL SYSTEM WHERE YOU WOULD 1464 00:58:27,640 --> 00:58:30,040 PUT IN A DIFFERENT CYTOKINE 1465 00:58:30,040 --> 00:58:34,440 RECEPTOR AND HAVE THE DIFFERENT 1466 00:58:34,440 --> 00:58:36,120 PAIRED CYTOKINE. 1467 00:58:36,120 --> 00:58:37,240 SO NOT OVERLAPPING ORTHOCYTOKINE 1468 00:58:37,240 --> 00:58:39,240 SO CAN YOU SELECTIVELY ACTIVATE 1469 00:58:39,240 --> 00:58:43,280 2, 2 DIFFERENT PATHWAYS. 1470 00:58:43,280 --> 00:58:45,880 >>YEAH. 1471 00:58:45,880 --> 00:58:46,800 >>EIGHTY-THREE, YEAH, 1472 00:58:46,800 --> 00:58:47,400 ABSOLUTELY ORTHOGONALITY, I 1473 00:58:47,400 --> 00:58:50,960 THINK PEOPLE ARE WAKING UP TO 1474 00:58:50,960 --> 00:58:52,360 ORTHOLINALLITY AND ALL THE 1475 00:58:52,360 --> 00:58:58,120 THERAPEUTIC IMPLICATIONS IT HAS. 1476 00:58:58,120 --> 00:58:59,400 YOU KNOW ORTHOGONALITY IN 1477 00:58:59,400 --> 00:59:01,000 PRACTICE MADE IT SOUND DIFFICULT 1478 00:59:01,000 --> 00:59:02,080 BUT IT'S VERY DIFFICULT TO,A 1479 00:59:02,080 --> 00:59:05,000 CHIEF TO FIEBD A PROTEIN THAT 1480 00:59:05,000 --> 00:59:08,480 WILL HAVE NO ACTIVITY TO ANY 1481 00:59:08,480 --> 00:59:11,280 EXISTING PROTEIN IN THE BODY SO 1482 00:59:11,280 --> 00:59:13,280 IT'S NONTRIVIAL TO MAKE 1483 00:59:13,280 --> 00:59:14,000 ORTHOGONAL INTERACTIONS BUT IF 1484 00:59:14,000 --> 00:59:15,440 YOU CAN IT'S POWERFUL SO WHAT 1485 00:59:15,440 --> 00:59:17,280 WE'RE DOING NOW, I HAVE A NEW 1486 00:59:17,280 --> 00:59:19,400 POST DOC IN MY LAB, HE IS TRYING 1487 00:59:19,400 --> 00:59:25,120 TO MAKE THE DOUBLE ORTHO, NOT 1488 00:59:25,120 --> 00:59:28,240 JUST ORTHO AGAINST BETA BUT 1489 00:59:28,240 --> 00:59:29,000 ORTHO AGAINST GAMMA. 1490 00:59:29,000 --> 00:59:34,560 SO INSTEAD OF BEING LIMITED TO 1 1491 00:59:34,560 --> 00:59:36,040 ICD-CHANGE WE CAN NOW LOOK AT 1492 00:59:36,040 --> 00:59:37,840 ALL THE DIFFERENT THE CYTOKINE 1493 00:59:37,840 --> 00:59:38,120 RECEPTORS. 1494 00:59:38,120 --> 00:59:39,480 >>THIS THE CHA THE THERE ARE 2 1495 00:59:39,480 --> 00:59:42,360 QUESTIONS THAT ARE THE SAME, 1496 00:59:42,360 --> 00:59:44,880 WHAT ABOUT THE IMMUNO 1497 00:59:44,880 --> 00:59:47,800 GENERATEDISSITY RELATED TO THE 1498 00:59:47,800 --> 00:59:49,160 VARIOUS MODIFIED CYTOKINES. 1499 00:59:49,160 --> 00:59:49,440 >>RIGHT. 1500 00:59:49,440 --> 00:59:55,600 WELL, THAT'S A GOOD QUESTION, 1501 00:59:55,600 --> 00:59:57,680 AND IS DEFINITELY THE IT'S 1502 00:59:57,680 --> 00:59:58,600 DEFINITELY TOP OF MIND WHEN YOU 1503 00:59:58,600 --> 01:00:01,800 GO INTO THE CLINIC ON THESE 1504 01:00:01,800 --> 01:00:05,760 THINGS BUT I THINK WE'RE 1505 01:00:05,760 --> 01:00:07,080 STARTING TO--THERE ARE A LOT OF 1506 01:00:07,080 --> 01:00:08,360 CLINICAL TRIALS GOING ON RIGHT 1507 01:00:08,360 --> 01:00:11,800 NOW WITH DIFFERENT VERSIONS OF 1508 01:00:11,800 --> 01:00:12,960 ENGINEERED CYTOKINES, AND I 1509 01:00:12,960 --> 01:00:15,200 REALLY CAN'T SAY ANYTHING ABOUT 1510 01:00:15,200 --> 01:00:17,480 OUR PARTICULAR CYTOKINE AT THIS 1511 01:00:17,480 --> 01:00:19,040 TIME BUT IT'S TURNING OUT TO BE 1512 01:00:19,040 --> 01:00:22,680 NOT AS BIG OF A PROBLEM AS 1 1513 01:00:22,680 --> 01:00:25,000 MIGHT HAVE IMAGINE THAT IMMUNO 1514 01:00:25,000 --> 01:00:27,880 GENERATEDISSITY IS NOT ALWAYS 1515 01:00:27,880 --> 01:00:28,280 DUE TO MUTATIONS. 1516 01:00:28,280 --> 01:00:28,960 IT'S MOST OFTEN DUE TO THE 1517 01:00:28,960 --> 01:00:32,360 BEHAVIOR OF THE PROTEIN THAT 1518 01:00:32,360 --> 01:00:34,120 YOU'RE PUTTING INTO PEOPLE AND 1519 01:00:34,120 --> 01:00:37,640 SO, VERY WELL BEHAVED PROTEINS 1520 01:00:37,640 --> 01:00:45,080 THAT HAVE MUTATION TEND TO BE 1521 01:00:45,080 --> 01:00:46,880 PRETTY WELL TOLERATED. 1522 01:00:46,880 --> 01:00:48,640 >>SOMEONE ASKED HOW'S ORTHOIL2 1523 01:00:48,640 --> 01:00:50,800 DIFFERENT FROM IL15 IF IT IS IN 1524 01:00:50,800 --> 01:00:54,200 TERMS OF SIGNALING AND OVERALL 1525 01:00:54,200 --> 01:00:54,840 BIOLOGICAL EFFECTS? 1526 01:00:54,840 --> 01:00:58,000 >>YEAH, SO I DIDN'T GET INTO 1527 01:00:58,000 --> 01:00:59,880 THAT BUT THE DICHOTOMY BETWEEN 1528 01:00:59,880 --> 01:01:02,280 IL2 AND 15 IS INTERESTING. 1529 01:01:02,280 --> 01:01:05,720 SO, AND WE PUBLISHED ON THIS 1530 01:01:05,720 --> 01:01:07,240 WITH WARREN, YOU KNOW THEY USE 1531 01:01:07,240 --> 01:01:09,840 THE SAME RECEPTORS SO IL15 AND 1532 01:01:09,840 --> 01:01:12,040 IL2 USE IL2 R BETA AND COMMON 1533 01:01:12,040 --> 01:01:15,560 GAMMA CHAIN AND THEY SIGNAL 1534 01:01:15,560 --> 01:01:21,080 VERY, VERY--IN A VERY SIMILAR 1535 01:01:21,080 --> 01:01:25,600 WAY AND SO, NOW ORTHO2 DIFFERS 1536 01:01:25,600 --> 01:01:26,840 FROM IL15 IN THAT IT'S 1537 01:01:26,840 --> 01:01:31,560 COMPLETELY SPECIFIC FOR THE 1538 01:01:31,560 --> 01:01:32,760 ORTHAGOREAN NOLL RECEPTOR 1539 01:01:32,760 --> 01:01:34,560 WHEREAS IL15 IS SPECIFIC FOR THE 1540 01:01:34,560 --> 01:01:37,320 NATURAL RECEPTORS JUST LIKE IL2. 1541 01:01:37,320 --> 01:01:39,640 SO IL15 TO ME IS KIND OF ANOTHER 1542 01:01:39,640 --> 01:01:42,160 WAY OF DELIVERING AN IL2 LIKE 1543 01:01:42,160 --> 01:01:47,800 SIGNAL, BUT IT DOESN'T SOLVE THE 1544 01:01:47,800 --> 01:01:48,560 SPECIFICITY ISSUE. 1545 01:01:48,560 --> 01:01:51,560 >>CHRIS, LET ME ASK YOU A JACK 1546 01:01:51,560 --> 01:01:54,880 RELATED QUESTION THAT I KNOW YOU 1547 01:01:54,880 --> 01:01:55,720 THOUGHT ABOUT. 1548 01:01:55,720 --> 01:01:58,040 NOT ALL JACKS ARE NATURALLY 1549 01:01:58,040 --> 01:02:00,600 PAIRED WITH EACH OTHER IN 1550 01:02:00,600 --> 01:02:03,600 RESPONSE TO CYTOKINES LIKE ALL 1551 01:02:03,600 --> 01:02:04,960 HOMODIMERIC RECEPTORS ACT 1552 01:02:04,960 --> 01:02:07,160 THROUGH JACK 2, THE COMMON GAMMA 1553 01:02:07,160 --> 01:02:08,680 CHAIN, USE JACK 1 AND JACK 3, 1554 01:02:08,680 --> 01:02:12,880 BUT NOT EVERY PAIR IS 1555 01:02:12,880 --> 01:02:18,400 PHYSIOLOGICAL USED AND SO TO 1556 01:02:18,400 --> 01:02:21,120 WHAT DEGREE IS IT THAT THEY WORK 1557 01:02:21,120 --> 01:02:24,600 BETTER VERSUS THAT THEY JUST 1558 01:02:24,600 --> 01:02:28,960 WEREN'T COMBINED IN THE WAY--THE 1559 01:02:28,960 --> 01:02:31,080 WAY YOU DEVELOPED IT? 1560 01:02:31,080 --> 01:02:31,760 >>IT'S A FASCINATING REQUESTY 1561 01:02:31,760 --> 01:02:34,120 THAT DRIVES A LOT OF THE WAY I 1562 01:02:34,120 --> 01:02:34,680 THINK ABOUT THIS. 1563 01:02:34,680 --> 01:02:37,240 I HAVE A SLIDE WHERE I SHOW THE 1564 01:02:37,240 --> 01:02:37,960 MISSING JACK [INDISCERNIBLE] 1565 01:02:37,960 --> 01:02:39,120 THAT NATURE DID NOT PROVIDE FOR 1566 01:02:39,120 --> 01:02:44,040 AND I SPENT A LOT OF TIME 1567 01:02:44,040 --> 01:02:46,720 THINKING ABOUT THAT. 1568 01:02:46,720 --> 01:02:48,440 ONE POSSIBLE INTERPRETATION IS 1569 01:02:48,440 --> 01:02:50,120 NATURE TRIED THOSE COMBINATIONS 1570 01:02:50,120 --> 01:02:52,720 AND FOR WHATEVER REASON, THEY 1571 01:02:52,720 --> 01:02:57,600 WERE NOT GOOD FOR THE HOST AND 1572 01:02:57,600 --> 01:02:59,000 THEY WERE EVOLVED AGAINST, 1573 01:02:59,000 --> 01:02:59,760 THAT'S A POSSIBILITY. 1574 01:02:59,760 --> 01:03:02,560 I DON'T REALLY BELIEVE THAT. 1575 01:03:02,560 --> 01:03:08,560 WE HAVE NOW CREATED USING 1576 01:03:08,560 --> 01:03:09,840 SYNTHEKINES THOSE NONNATURAL 1577 01:03:09,840 --> 01:03:11,000 PAIRINGS FOR INSTANCE THERE'S NO 1578 01:03:11,000 --> 01:03:12,440 JACK 2 OR THRESHOLD PAIR NOTHING 1579 01:03:12,440 --> 01:03:14,080 98 IRB. 1580 01:03:14,080 --> 01:03:16,960 THERE IS NO TICK 2 JACK 1. 1581 01:03:16,960 --> 01:03:21,240 AND SO, WE'VE CREATED THOSE 1582 01:03:21,240 --> 01:03:24,240 PAIRINGS ARTIFICIALLY USING THE 1583 01:03:24,240 --> 01:03:25,960 ORTHOGONAL RECEPTOR SYSTEM AND 1584 01:03:25,960 --> 01:03:26,920 THEY HAVE INTERESTING SIGNALING 1585 01:03:26,920 --> 01:03:28,240 PROPERTIES AND SO NOW WE'RE 1586 01:03:28,240 --> 01:03:30,160 TRYING TO MAKE LIGANDS TO 1587 01:03:30,160 --> 01:03:31,200 ENFORCE THOSE PAIRINGS AS WELL 1588 01:03:31,200 --> 01:03:33,880 BECAUSE I REALLY THINK THERE'S 1589 01:03:33,880 --> 01:03:34,600 SOMETHING, THERE'S SOMETHING 1590 01:03:34,600 --> 01:03:36,200 HAPPENING THERE THAT'S GOING TO 1591 01:03:36,200 --> 01:03:38,280 BE VERY INTERESTING. 1592 01:03:38,280 --> 01:03:40,720 >>THERE ARE MORE QUESTIONS IN 1593 01:03:40,720 --> 01:03:43,240 THE CHAT, APOLOGIES, I WASN'T 1594 01:03:43,240 --> 01:03:45,720 NAMING PEOPLE BUT RUSS 1595 01:03:45,720 --> 01:03:47,120 [INDISCERNIBLE] ASKS, I FOUND 1596 01:03:47,120 --> 01:03:48,960 THE ABILITY TO REENGINEER THE 1597 01:03:48,960 --> 01:03:51,200 CYTOPLASM PORTIONS OF ENGINEERED 1598 01:03:51,200 --> 01:03:51,920 ILRECEPTORS EXCITING DO YOU 1599 01:03:51,920 --> 01:03:56,200 EXPECT THAT THE ABILITY TO 1600 01:03:56,200 --> 01:04:01,600 CHANGE THE CYTO[INDISCERNIBLE] 1601 01:04:01,600 --> 01:04:03,000 EXTRA CELLULAR PORTION TO BE 1602 01:04:03,000 --> 01:04:05,840 WIDELY APPLICABLE WHAT ABOUT 1603 01:04:05,840 --> 01:04:07,200 OTHER TYPES IMMUNORECEPTORS. 1604 01:04:07,200 --> 01:04:08,080 >>YEAH, ABSOLUTELY, LIKE I SAID 1605 01:04:08,080 --> 01:04:11,720 WE WANT TO MAKE THE DOUBLE 1606 01:04:11,720 --> 01:04:14,000 ORTHO, SO WE CAN SAMPLE ALL THE 1607 01:04:14,000 --> 01:04:16,160 DISCIPLINARY MERRIC COMBINATIONS 1608 01:04:16,160 --> 01:04:17,000 INCLUDING NONNATURAL JACK 1609 01:04:17,000 --> 01:04:18,080 PAIRINGS AND IT'S BEEN DONE IN 1610 01:04:18,080 --> 01:04:20,320 OTHER SYSTEMS AS WELL. 1611 01:04:20,320 --> 01:04:22,160 I MEAN PHIL GREEN BERG WAS 1612 01:04:22,160 --> 01:04:23,360 MAKING SO CALLED SWITCH 1613 01:04:23,360 --> 01:04:25,240 RECEPTORS QUITE A FEW YEARS AGO 1614 01:04:25,240 --> 01:04:28,640 WHERE HE WAS MAKING CHIMERIC 1615 01:04:28,640 --> 01:04:33,000 RECEPTORS, YOU KNOW FOR 1616 01:04:33,000 --> 01:04:35,280 INSTANCE, GCSF, INTERRACELLULAR 1617 01:04:35,280 --> 01:04:36,120 DOMAIN, INTERLEUKIN 2 EXTRA 1618 01:04:36,120 --> 01:04:37,760 CELLULAR DOMAIN SO THE CONCEPT'S 1619 01:04:37,760 --> 01:04:39,680 BEEN OUT THERE AND AROUND FOR A 1620 01:04:39,680 --> 01:04:42,840 WHILE AND MAKE THEM COMPLETELY 1621 01:04:42,840 --> 01:04:44,160 ORTHOGONAL AND I THINK IN CELL 1622 01:04:44,160 --> 01:04:44,680 THERAPY AND ACTIVITIES AND 1623 01:04:44,680 --> 01:04:46,160 PROJECTS THEY--THE IS WHERE THE 1624 01:04:46,160 --> 01:04:47,480 ACTION IS RIGHT NOW IS USING 1625 01:04:47,480 --> 01:04:49,240 THESE TYPES OF SYSTEMS TO 1626 01:04:49,240 --> 01:04:53,880 DELIVER NEW SIGNALING TO CELLS. 1627 01:04:53,880 --> 01:04:56,240 >>THERE'S A QUESTION BY 1628 01:04:56,240 --> 01:04:57,320 [INDISCERNIBLE] NICE HIT ON 1629 01:04:57,320 --> 01:04:59,000 CANCER MODELS HAVE YOU TRIED 1630 01:04:59,000 --> 01:05:02,200 ENGINEERED IL2 AND OTHER 1631 01:05:02,200 --> 01:05:03,600 CYTOKINES IN HIV? 1632 01:05:03,600 --> 01:05:04,320 >>WE HAVE NOT. 1633 01:05:04,320 --> 01:05:06,000 WE HAVE NOT. 1634 01:05:06,000 --> 01:05:07,480 I'M PARTICULARLY INTERESTED IN A 1635 01:05:07,480 --> 01:05:15,280 NEW KIND OF IL2 WE MADE THAT HAS 1636 01:05:15,280 --> 01:05:18,040 WE BROUGHT IN A IL3 MODEL AND 1637 01:05:18,040 --> 01:05:19,320 THAT WE'RE PARTICULARLY 1638 01:05:19,320 --> 01:05:20,840 INTERESTED IN TRYING THAT, I 1639 01:05:20,840 --> 01:05:26,880 WANT TO TRY THAT IN MODELS WHERE 1640 01:05:26,880 --> 01:05:28,560 T-CELL EXHAUSTION IS HAPPENING 1641 01:05:28,560 --> 01:05:29,240 IN THE MODELS. 1642 01:05:29,240 --> 01:05:32,360 Y SO WE HAVEN'T TRIED IT BUT I'M 1643 01:05:32,360 --> 01:05:32,880 INTERESTED. 1644 01:05:32,880 --> 01:05:35,040 >>CAN A QUESTION, CAN YOU 1645 01:05:35,040 --> 01:05:36,400 EXPAPPEDOT BEHAVIOR OF THE 1646 01:05:36,400 --> 01:05:39,840 PROTEIN THAT IMPACT ON IMIEWP O 1647 01:05:39,840 --> 01:05:40,560 GENERATEDISSITY. 1648 01:05:40,560 --> 01:05:41,960 >>IT'S MAINLY AGGREGATED 1649 01:05:41,960 --> 01:05:42,480 PROTEINS. 1650 01:05:42,480 --> 01:05:43,800 PROTEINS THAT DON'T BEHAVE WELL, 1651 01:05:43,800 --> 01:05:46,120 THAT DOESN'T HELP YOU MUCH BUT 1652 01:05:46,120 --> 01:05:48,640 FOR A BIOCHEMIST, YOU SAY A 1653 01:05:48,640 --> 01:05:49,800 PROTEIN DOESN'T BEHAVE WELL, YOU 1654 01:05:49,800 --> 01:05:51,040 KNOW WHICH WAY THE WIND IS 1655 01:05:51,040 --> 01:05:54,320 BLOWING AND SO WELL BEHAVED 1656 01:05:54,320 --> 01:05:55,880 PROTEINS, YOU KNOW MONODISPERSED 1657 01:05:55,880 --> 01:05:58,720 REALLY HAPPY, WELL EXPRESSED 1658 01:05:58,720 --> 01:06:01,120 PROTEINS, TEND TO NOT BE AS 1659 01:06:01,120 --> 01:06:02,880 IMMUNOGENIC AS MORE AGGREGATED 1660 01:06:02,880 --> 01:06:04,400 PROTEINS AND IT'S NOT A HARD 1661 01:06:04,400 --> 01:06:08,120 SCIENCE, BUT THAT'S KIND OF WHAT 1662 01:06:08,120 --> 01:06:17,800 THE DATA'S SHOWING US. 1663 01:06:17,800 --> 01:06:28,400 >>OKAY, I THINK THIS IS REALLY 1664 01:06:29,320 --> 01:06:31,000 WONDERFUL AND RISK RECEPTION 1665 01:06:31,000 --> 01:06:32,480 AFTERWARDS BUT WE WILL HOPEFULLY 1666 01:06:32,480 --> 01:06:33,800 THANK YOU. 1667 01:06:33,800 --> 01:06:34,440 >>THANKS A LOT AND THANKS TO 1668 01:06:34,440 --> 01:06:36,600 EVERYONE FOR THE QUESTIONS. 1669 01:06:36,600 --> 00:00:00,000 >>THANK YOU.