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GOOD AFTERNOON, AND WELCOME 

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TO THE NIH'S WEDNESDAY AFTERNOON

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LECTURE SERIES.

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IT'S MY HONOR TO BE HERE FOR THE

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FIRST TIME AND LOOKING FORWARD 

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TO THE LECTURE.

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IT HONORS THE LEGACY OF MARGARET

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PITTMAN ESTABLISHED IN 1994 IT'S

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GIVEN BY A RESEARCHER WHO HAS 

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THE EXCELLENCE AND DRIVE THAT 

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MADE MARGARET PITTMAN A LEADER.

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IT'S MY PLEASURE TOE INTRODUCE 

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DR. CAROLYN BERTOZZI WHO WILL 

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COME OUT IN A MINUTE.

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A FORMER COLLEAGUE OF MINE FROM 

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STANFORD.

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SHE'S AN INVESTIGATOR AT THE 

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HOWARD HUGHES MEDICAL AND FROM 

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CHEM-H AND BASS PROFESSOR OF 

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CHEMISTRY AND SYSTEMS BIOLOGY 

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AND RADIOLOGY AT STANFORD.

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BEFORE I TELL YOU HER BACKGROUND

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I SHOULD LET YOU KNOW IF YOU'RE 

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ATTENDING FOR CME CREDIT THE 

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CODE IS 57692 AND IF YOU'RE 

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WATCHING ONLINE AND WOULD TO 

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SUBMIT QUESTIONS CLICK ON THE 

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SEND LIVE FEEDBACK BUTTON 

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ANYTIME DURING THE LECTURE.

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WE'RE HONORED TO HAVE 

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DR. BERTOZZI A CHEMICAL 

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BIOLOGIST AND KNOWN HER RESEARCH

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INTERESTS THAT SPAN CHEMISTRY 

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AND BIOLOGY AND WORKS ON CELL 

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SURFACE SUGARS IMPORTANT TO 

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HEALTH AND DISEASE AND HOW TO 

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USE BIO CHEMICAL CHEMISTRY AND 

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COINED THE THERM FOR 

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BIOORTHOGONAL QUICK CHEMICAL 

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REACTIONS WITH SYSTEMS AND LOOKS

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AT GLYCOSYLATION ASSOCIATED WITH

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CANCER AND INFLAMMATION AND USES

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IT TO DEVELOP NEW DIAGNOSTIC AND

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THERAPEUTIC APPROACHES IN THE 

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AAREA OF IMMUNO ONCOLOGY AND 

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RECEIVED THE NOBEL PRIZE IN 

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CHEMISTRY.

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DR. BERTOZZI WAS AWARDED AN 

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AWARD AT AGE 33 AND THE FIRST 

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WOMAN TO RECEIVE THE LEMELSON 

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M.I.T. PRIZE AND HAS MANY OTHER 

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HONORS AND POSITIONS.

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HER RESEARCH IS REFLECTED IN 

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ABOUT 440 PUBLICATIONS ACROSS 

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THE SPECTRUM OF CHEMISTRY AND 

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BIOLOGY JOURNALS AND MENTORED 81

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FORMER Ph.D. STUDENTS AND 58 

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FORMER POSTDOCTORAL FELLOWS AND 

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COMPLETED HER DEGREE FROM 

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CHEMISTRY IN HARVARD IN 1988.

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AFTER BEING IN THE FIELD OF 

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CELLULAR IMMUNOLOGY SHE JOINED 

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THE U.C. BERKELEY FACULTY IN 

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1996 AND IN 2015 JOINED THE 

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FACULTY IN STANFORD UNIVERSITY 

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AT CHEM-H WHICH STANDS FOR 

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MEDICAL CHEMICAL MEDICINE 

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APPLIED TO HEALTH.

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JOIN ME IN GIVING A WARM WELCOME

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TO DR. BERTOZZI.

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>> THANK YOU.

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HELLO.

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HELLO?

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THANK YOU SO MUCH FOR COMING 

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TODAY.

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THANK YOU, DR. BHATTACHARYA FOR 

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THE VERY KIND INVITATION AND FOR

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HOSTING ME TODAY.

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I'VE ALREADY LEARNED SO MUCH 

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JUST FROM MY FIRST MORNING HERE 

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INTERACTING WITH THE SCIENTISTS 

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AND KIND OF FINDING OUT WHAT'S 

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AT THE LEADING EDGE OF SCIENCE 

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WHICH OFTEN COMES RIGHT OUT OF 

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THE NIH.

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YOU GUYS ARE AN AMAZING GROUP OF

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PHYSICIANS AND SCIENTISTS AND 

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STAFF.

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YOU DO SO MUCH TO SERVE YOUR 

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COUNTRY.

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I'M ETERNALLY GRATEFUL FOR THE 

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SUPPORT I'VE HAD FROM THE 

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NATIONAL INSTITUTES OF HEALTH 

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AND I'LL TALK ABOUT WORK FUNDED 

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BY THE NIH STARTING WHEN I WAS A

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BRAND NEW ASSISTANT PROFESSOR AT

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THE TIME THAT WAS AT U.C. 

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BERKELEY SO THIS TAKES ME BACK 

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TO THE LATE 1990s BUT HOPEFULLY 

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BY STARTING IN THE EARLY DAYS, 

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YOU'LL GET TO UNDERSTAND THE 

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PROGRESSION OF A PROGRAM THAT 

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STARTED VERY MUCH AS A BASIC 

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SCIENCE PROJECT BUT EVENTUALLY 

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EVOLVED IN A MORE TRANSLATIONAL 

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DIRECTION TO THE POINT WHERE 

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THERE ARE NOW HUMAN THERAPEUTICS

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AND CLINICAL TRIALS THAT 

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LEVERAGE SOME OF THE CHEMISTRIES

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I'LL TALK ABOUT TODAY.

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BEFORE I GET INTO ANY OF THE 

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DETAILS, I WOULD ALSO LIKE TO 

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SORT OF SHARE THE HONOR OF 

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HELPING YOU CELEBRATE THE LIFE 

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AND CAREER AND THE IMPACT OF 

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DR. PITMAN.

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I READ A BIT ABOUT HER LAST 

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NIGHT.

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SHE CLEARLY WAS AN INCREDIBLY 

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INFLUENTIAL FIGURE AND HAD A 

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HUGE IMPACT IN HER ACADEMIC 

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POSITIONS AS WELL AS THE NIH.

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IT'S AN EXTRA HONOR FOR ME TO BE

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ON THE STAGE RECOGNIZING HER 

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CONTRIBUTIONS.

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SO WITH THAT, LET'S TALK A 

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LITTLE BIT ABOUT CHEMISTRY.

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I ALWAYS LIKE TO GET A SHOW OF 

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STANDS SO I UNDERSTAND MY 

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AUDIE

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AUDIENCE.

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HOW MANY PEOPLE HERE WOULD 

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CONSIDER THEMSELVES TO BE A 

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CHEMIST?

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ALL RIGHT.

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HOW MANY PEOPLE HERE WOULD 

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CONSIDER THEMSELVES TO BE A NOT 

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CHEMIST?

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IT'S ACTUALLY QUITE A FEW.

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THERE'S NOTHING WRONG WITH THAT.

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NOTHING TO BE ASHAMED OF 

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WHATSOEVER.

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THAT'S A JOKE FOR CHEMISTS.

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REGARDLESS OF WHETHER YOU'RE A 

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CHEMIST OR BIOLOGIST OR ANOTHER 

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TYPE OF SCIENTIST YOU'LL 

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PROBABLY RECOGNIZE THIS GADGET.

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WHEN YOU TAKE ORGANIC CHEMISTRY 

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LAB COURSES AND I THINK THE 

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LASER POINTER IS SUPPOSED TO 

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WORK BUT SEEMS TO BE SILENT.

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THERE IT IS.

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THERE IT IS.

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WHEN YOU TAKE AN ORGANIC 

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CHEMISTRY CLASS, WHICH I TEACH 

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AT STANFORD AND YOU'RE IN THE 

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LABORATORY AND DOING A CHEMICAL 

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REACTION, YOU'LL BE USING A 

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GADGET LIKE THIS ONE.

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SO THIS IS A ROUND BOTTOM FLASK.

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HIGHLY ENGINEERED GLASSWARE AND 

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THE LOGIC OF THE GLASSWARE IS IT

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ALLOWS YOU TO CONTROL EVERY 

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PARAMETER OF THE REACTION.

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SO YOU AS THE CHEMIST OR THE 

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CHEMISTRY STUDENT, YOU CONTROL 

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EXACTLY WHAT GOES INTO THIS 

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FLASK, THE CONCENTRATIONS OF THE

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REAGENTS, THE SOLVENT YOU 

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DISSOLVE THE REAGENTS IN WHICH 

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MATTERS WHEN YOU DO ORGANIC 

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CHEMISTRY AND EVEN CONTROL THE 

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ATMOSPHERE ABOVE THE LIQUID.

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SOMETIMES YOU'LL PURGE IT TO GET

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RID OF THE MOISTURE FROM THE 

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ATMOSPHERE.

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YOU EVEN CONTROL THE RATE AT 

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WHICH THE STORING OCCURS AND 

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CONTROL THE TEMPERATURE WITH 

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THIS DOWN MERE AND ALL OF THIS 

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RIGID CONTROL ALLOWS YOU TO FORM

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ALL KINDS OF BONDS USING ALL 

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KINDS OF REAGENTS AND WE HAVE 

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GIANT TELEPHONE BOOKS FULL OF 

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LISTS OF ORGANIC REACTIONS YOU 

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CAN DO IF YOU'RE DOING THEM IN 

187
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THIS KIND OF SETTING.

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BACK IN THE 1990s IN THE EARLY 

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'90s AS A POSTDOCTORAL FELLOW IN

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AN IMMUNOLOGY LAB LEARNING ABOUT

191
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THE MYSTERIES OF BIOLOGY THAT 

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WERE DIFFICULT TO ANSWER AT THE 

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TIME AND UNDERSTAND I STARTED TO

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BECOME INTERESTED IN THE IDEA OF

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DOING CHEMISTRY IN LESS 

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CONTROLLED ENVIRONMENTS AND 

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SPECIFICALLY TO DO CHEMISTRY IN 

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THE ENVIRONMENT OF LIVING 

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SYSTEMS.

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AT THE TIME I WAS THINKING ABOUT

201
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DOING CHEMISTRY ON LIVING CELLS 

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IN A DISH OR IN THE BODY OF 

203
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MODEL ORGANISMS IN THE 

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LABORATORY BUT YOU DON'T HAVE TO

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EXTRAPOLATE TOO FAR TO START 

206
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THINKING ABOUT WHAT IF YOU CAN 

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DO CHEMICAL REACTIONS TO FORM 

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NEW BONDS, NEW FORMS OF MATTER 

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INSIDE THE HUMAN BODY AND IF YOU

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COULD DO THAT, WHAT 

211
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OPPORTUNITIES MIGHT OPEN UP IN 

212
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THE WORLD OF THERAPEUTICS 

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DEVELOPMENT OR DIAGNOSTICS 

214
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TECHNOLOGIES.

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SO IT WAS THAT KIND OF THINKING 

216
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THAT ULTIMATELY LED TO THE 

217
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DEVELOPMENT TO THIS NEW BRAND OF

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CHEMISTRY WE CALL BIOORTHOGONAL 

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CHEMISTRY WHICH IS A BIT OF A 

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MOUTHFUL.

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PEOPLE OFTEN ASK WHAT'S THAT 

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MEAN AND THIS IS NOT IN THE 

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WEBSTER AS A DICTIONARY BUT SOME

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DAY MIGHT BE.

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IT MEANS CHEMISTRY BETWEEN 

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REAGENTS THAT NEITHER INTERACT 

227
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WITH NOR INTERFERE WITH A 

228
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BIOLOGICAL SETTING.

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SO THEY'RE LITERALLY ORTHOGONAL 

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TO BIOLOGY.

231
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I RECRUITED A WHOLE BRAND NEW 

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GROUP OF STUDENTS WHEN I STARTED

233
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MY FIRST FACULTY APPOINTMENT IN 

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BERKELEY AND TAKING NOTATIONS ON

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SPACE AND THERE'S CHEMISTRY FROM

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THE ELEMENTS ON THE PERIOD TRICK

237
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TABLE.

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BUT ONLY A SMALL PORTION OF 

239
00:09:02,661 --> 00:09:05,330
THOSE CHEMISTRIES OCCUR IN 

240
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BIOLOGY.

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AS VAST AS THAT BIOLOGICAL 

242
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CHEMICAL SPACE IS AND YOU COULD 

243
00:09:09,768 --> 00:09:10,702
JUST TAKE INVENTORY OF YOUR 

244
00:09:10,702 --> 00:09:12,737
BODY, ALL THE CHEMICALS IN YOUR 

245
00:09:12,737 --> 00:09:17,442
BODY ARE IN THIS GALAXY OF 

246
00:09:17,442 --> 00:09:19,711
BIOLOGICAL REACTIVITY SPACE BUT 

247
00:09:19,711 --> 00:09:21,079
IN THE UNIVERSE WE THOUGHT THERE

248
00:09:21,079 --> 00:09:24,282
COULD BE A GALAXY OF CHEMICALS 

249
00:09:24,282 --> 00:09:26,318
THAT DON'T EXIST PLANET EARTH 

250
00:09:26,318 --> 00:09:28,220
EARTH THAT ARE NOT IN THE HUMAN 

251
00:09:28,220 --> 00:09:31,323
BODY MAYBE THEY'RE CHEMICALS 

252
00:09:31,323 --> 00:09:32,591
INVENTED BY CHEMISTS NATURE 

253
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HASN'T ARISEN YET.

254
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IF WE COULD IDENTIFY REACTIONS 

255
00:09:38,597 --> 00:09:41,833
AMONGST THE BIOORTHOGONAL 

256
00:09:41,833 --> 00:09:43,969
CHEMICALS THOSE ARE WHAT WE CAN 

257
00:09:43,969 --> 00:09:45,403
DO WITHOUT INTERFERENCE IN THE 

258
00:09:45,403 --> 00:09:45,937
HUMAN BODY IN PARTICULAR.

259
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THAT WAS THE NOTION.

260
00:09:55,247 --> 00:09:57,349
AS ABSTRACT AS IT SOUNDS I WAS 

261
00:09:57,349 --> 00:09:59,184
WORKING IN THE IMMUNOLOGY LAB 

262
00:09:59,184 --> 00:10:03,355
AND MY GOAL WAS TO STUDY CHANGES

263
00:10:03,355 --> 00:10:08,660
IN THE PATTERN OF CELL SURFACE 

264
00:10:08,660 --> 00:10:09,561
GLYCOSYLATION.

265
00:10:09,561 --> 00:10:10,962
SPECIFICALLY THE SITE OF 

266
00:10:10,962 --> 00:10:11,296
INFLAMMATION.

267
00:10:11,296 --> 00:10:13,398
THIS IS MY OPPORTUNITY TO GIVE A

268
00:10:13,398 --> 00:10:14,566
TEXTBOOK DRAWING HOW PEOPLE 

269
00:10:14,566 --> 00:10:17,168
DEPICT THE SURFACE OF CELLS AND 

270
00:10:17,168 --> 00:10:19,938
THE PATTERNS OF GLYCANS ON THE 

271
00:10:19,938 --> 00:10:20,539
CELL SURFACE.

272
00:10:20,539 --> 00:10:21,806
MOST WILL KNOW CELLS ARE BOUNDED

273
00:10:21,806 --> 00:10:28,113
BY A PLASMA MEMBRANE.

274
00:10:28,113 --> 00:10:32,684
ANCHOR READY MOLECULES LIKE GLUC

275
00:10:32,684 --> 00:10:36,922
YO LIPIDS MOST ARE GLYCOPROTEINS

276
00:10:36,922 --> 00:10:38,857
AND GLYCOBIOLOGY IS AN AREA I 

277
00:10:38,857 --> 00:10:40,258
DEVELOPED AN INTEREST IN AS A 

278
00:10:40,258 --> 00:10:43,728
GRAD STUDENT BUT BLOSSOMED IN MY

279
00:10:43,728 --> 00:10:44,296
POSTDOC YEARS.

280
00:10:44,296 --> 00:10:46,164
IT TURNS OUT THE STRUCTURES OF 

281
00:10:46,164 --> 00:10:48,433
THESE GLYCANS, WHICH BY THE WAY,

282
00:10:48,433 --> 00:10:53,104
THE GLYCOSCIENTISTS USE AS A 

283
00:10:53,104 --> 00:10:55,006
SYMBOLIC LEXICON TO DESCRIBE 

284
00:10:55,006 --> 00:10:56,975
THEM AND MADE OF SIMPLE SUGAR 

285
00:10:56,975 --> 00:10:57,976
BUILDING BLOCKS ON THE TABLE.

286
00:10:57,976 --> 00:11:00,879
EACH BUILDING BLOCK HAS A SHAPE 

287
00:11:00,879 --> 00:11:02,581
AND COLOR THAT'S DISCREET AND 

288
00:11:02,581 --> 00:11:05,817
YOU CAN SEE FROM THE CARTOONS 

289
00:11:05,817 --> 00:11:08,720
THEY GET LINKED IN PATTERNS AND 

290
00:11:08,720 --> 00:11:10,188
THE TOTALITY OF ALL THESE 

291
00:11:10,188 --> 00:11:12,591
GLYCANS ON THE SURFACE OF THE 

292
00:11:12,591 --> 00:11:19,564
CELL WE CALL THAT THE 

293
00:11:19,564 --> 00:11:20,699
GLYCOCALYX.

294
00:11:20,699 --> 00:11:31,209
I WAS CLEAR THE IS GLYCOCALYX 

295
00:11:37,349 --> 00:11:38,483
CHANGES AND THERE WERE SHIFTS IN

296
00:11:38,483 --> 00:11:40,385
THE PATTERN OF IT IN THE SETTING

297
00:11:40,385 --> 00:11:41,853
OF CANCER BUT IT WAS REALLY HARD

298
00:11:41,853 --> 00:11:43,955
TO CHARACTERIZE THESE CHANGES 

299
00:11:43,955 --> 00:11:46,458
AND NO ONE REALLY HAD ANY CLUE 

300
00:11:46,458 --> 00:11:47,959
ABOUT THE FUNCTIONAL 

301
00:11:47,959 --> 00:11:49,794
SIGNIFICANCE SO THIS WAS EARLY 

302
00:11:49,794 --> 00:11:53,798
DAYS IN THE FIELD OF CANCER 

303
00:11:53,798 --> 00:12:02,240
GLYCO SCIENCE.

304
00:12:02,240 --> 00:12:05,877
IF THEY'RE CHANGING MAYBE YOU 

305
00:12:05,877 --> 00:12:08,713
CAN DETECT A TUMOR IN THE HUMAN 

306
00:12:08,713 --> 00:12:10,682
BODY BY CT OR PET IMAGING IF YOU

307
00:12:10,682 --> 00:12:13,785
HAD A WAY TO LIGHT UP THE SUGARS

308
00:12:13,785 --> 00:12:16,154
WHICH WOULD DIFFERENTIATE THE 

309
00:12:16,154 --> 00:12:17,822
HEALTHY CELLS FROM CANCEROUS 

310
00:12:17,822 --> 00:12:18,256
CELLS.

311
00:12:18,256 --> 00:12:19,824
THERE WAS ONE PARTICULAR 

312
00:12:19,824 --> 00:12:22,827
PHENOTYPE, A GLYCOPHENOTYPE AS 

313
00:12:22,827 --> 00:12:25,563
WE WOULD SAY VERY WIDE SUPPRESS 

314
00:12:25,563 --> 00:12:29,367
AMONGST CANCERS AND IT'S THE 

315
00:12:29,367 --> 00:12:31,302
OVERPRODUCTION OF GLYCANS THAT 

316
00:12:31,302 --> 00:12:36,841
TERMINATE WITH A SIMPLE 

317
00:12:36,841 --> 00:12:41,813
MONOSACCHARIDE UNIT CALLED  

318
00:12:41,813 --> 00:12:42,947
SIALIC ACID.

319
00:12:42,947 --> 00:12:44,616
THIS IS THE CHEAT SHEET FOR THE 

320
00:12:44,616 --> 00:12:45,817
SUGARS AND SYMBOLS.

321
00:12:45,817 --> 00:12:48,086
THE ACID IS THIS PINK DIAMOND.

322
00:12:48,086 --> 00:12:53,825
AND HEALTHY CELLS WILL HAVE A 

323
00:12:53,825 --> 00:13:00,432
CERTAIN POWDER OF GLYCANS WILL 

324
00:13:00,432 --> 00:13:05,804
AND I USE MET FOAPHORS AND I WO 

325
00:13:05,804 --> 00:13:08,673
CALL THAT A GARDEN AND THAT WELL

326
00:13:08,673 --> 00:13:10,675
MANICURED GARDEN OVERGROWS AND 

327
00:13:10,675 --> 00:13:17,849
IT BECOMES A TROPICAL JUNGLE OF 

328
00:13:17,849 --> 00:13:25,824
SIALIC ACID AND CALLED IT A 

329
00:13:25,824 --> 00:13:31,062
GLY

330
00:13:31,062 --> 00:13:31,463
GLY

331
00:13:31,463 --> 00:13:34,966
GLYCOCAYLX AND IF WE CAN LIGHT 

332
00:13:34,966 --> 00:13:36,601
UP UP THAT MAY BE A WAY TO 

333
00:13:36,601 --> 00:13:38,603
DIFFERENTIATE IT FROM THE TUMOR 

334
00:13:38,603 --> 00:13:40,238
TISSUE WHICH IS A POWERFUL 

335
00:13:40,238 --> 00:13:42,907
CAPABILITY TRYING TO TREAT OR 

336
00:13:42,907 --> 00:13:45,210
MONITOR OR DIAGNOSE CANCERS.

337
00:13:45,210 --> 00:13:46,978
BACK IN THE EARLY 1990s WE DID 

338
00:13:46,978 --> 00:13:50,215
NOT HAVE A WAY OF IMAGING 

339
00:13:50,215 --> 00:13:51,716
SUGARS.

340
00:13:51,716 --> 00:13:53,384
THERE WAS ONE OF THE TOOL TO 

341
00:13:53,384 --> 00:13:56,187
LIGHT THEM UP IN LIVING SYSTEMS.

342
00:13:56,187 --> 00:13:58,356
AS IT HAPPENS, BY THE WAY, 

343
00:13:58,356 --> 00:13:59,991
SORRY, I HAVE AN A LITTLE 

344
00:13:59,991 --> 00:14:01,793
SHAMELESS PLUG, I'M GIVING A 

345
00:14:01,793 --> 00:14:05,830
TALK TOMORROW ALSO AT NCATS IN 

346
00:14:05,830 --> 00:14:06,865
ROCKVILLE AND IN THAT TALK I'LL 

347
00:14:06,865 --> 00:14:09,134
TELL YOU WHY IT HAPPENS SO DON'T

348
00:14:09,134 --> 00:14:12,737
ASK ME THAT NOW IF YOU PLAN TO 

349
00:14:12,737 --> 00:14:13,471
GO TO THE TALK TOMORROW BECAUSE 

350
00:14:13,471 --> 00:14:15,774
YOU'LL SPOIL IT.

351
00:14:15,774 --> 00:14:17,242
IN THIS TALK I'M TRYING TO TALK 

352
00:14:17,242 --> 00:14:19,811
ABOUT IMAGING AND WHY BUT COME 

353
00:14:19,811 --> 00:14:21,312
TOMORROW IF YOU WANT TO KNOW 

354
00:14:21,312 --> 00:14:21,479
WHY.

355
00:14:21,479 --> 00:14:26,484
SO I WENT TO A CONFERENCE I WAS 

356
00:14:26,484 --> 00:14:27,786
STILL A POSTDOC WORKING ON MY 

357
00:14:27,786 --> 00:14:31,689
JOB APPLICATIONS AND LANDED IN A

358
00:14:31,689 --> 00:14:33,091
CONFERENCE IN SOUTH HAMPTON, 

359
00:14:33,091 --> 00:14:33,825
ENGLAND.

360
00:14:33,825 --> 00:14:44,369
IT WAS A BOUTIQUE MIDDLEWEIGHT 

361
00:14:45,603 --> 00:14:49,874
OFF THE BEATEN TRACK AND MED 

362
00:14:49,874 --> 00:14:59,117
DR. REUTER AND HE HAD WORK 

363
00:14:59,117 --> 00:15:02,854
UNPUBLISHED THAT FOUND THE 

364
00:15:02,854 --> 00:15:09,694
PATHWAY HAS PRECURSORS AND THE 

365
00:15:09,694 --> 00:15:13,998
SUGAR KNOWN AS THIS PRECURSOR IS

366
00:15:13,998 --> 00:15:18,336
A NORMAL PRECURSOR FOR SIALIC 

367
00:15:18,336 --> 00:15:18,536
ACID.

368
00:15:18,536 --> 00:15:20,872
THERE'S SIX ACIDS THAT TRANSFORM

369
00:15:20,872 --> 00:15:23,341
IT AND A COUPLE MORE GET THAT 

370
00:15:23,341 --> 00:15:25,810
ATTACHED TO THE GLYCANS ON THE 

371
00:15:25,810 --> 00:15:36,054
CELL SURFACE.

372
00:15:38,256 --> 00:15:41,359
THEY COVERED IT IN OIL TO 

373
00:15:41,359 --> 00:15:42,527
STRETCH THE CARBON CHAIN AND AS 

374
00:15:42,527 --> 00:15:44,729
LONG AS THE MODIFICATIONS WERE 

375
00:15:44,729 --> 00:15:47,398
NOT TOO EXTRAVAGANT, ALL THE 

376
00:15:47,398 --> 00:15:48,132
ENZYMES IN THE PATHWAY WOULD 

377
00:15:48,132 --> 00:15:48,399
STAY FINE.

378
00:15:48,399 --> 00:15:56,875
FREE PASS.

379
00:15:56,875 --> 00:15:58,610
YOU FEED THE CELL WITH THIS AND 

380
00:15:58,610 --> 00:16:00,111
DUMP IT IN THE MEDIA AND WAIT A 

381
00:16:00,111 --> 00:16:01,813
COUPLE HOURS AND THE 

382
00:16:01,813 --> 00:16:03,815
CORRESPONDING ALTERED SIALIC 

383
00:16:03,815 --> 00:16:05,083
ACID WITH THE SAME SIDE CHAIN 

384
00:16:05,083 --> 00:16:09,587
APPEARS ON THE CELL SURFACE.

385
00:16:09,587 --> 00:16:11,623
WHEN I SAW THE TALK AN IDEA 

386
00:16:11,623 --> 00:16:11,823
AROSE.

387
00:16:11,823 --> 00:16:14,559
WHAT IF YOU CAN EMBED WITHIN THE

388
00:16:14,559 --> 00:16:18,897
SUGAR SOME KIND OF A CHEMICAL 

389
00:16:18,897 --> 00:16:19,297
HANDLE.

390
00:16:19,297 --> 00:16:21,232
SOMETHING INERT AND WOULD NOT 

391
00:16:21,232 --> 00:16:22,834
INTERFERE OR INTERACT WITH THE 

392
00:16:22,834 --> 00:16:23,368
CELL.

393
00:16:23,368 --> 00:16:28,072
LET THAT CHEMICAL HANDLE MAKE IT

394
00:16:28,072 --> 00:16:31,376
ITS WAY TO THE CELL SURFACE 

395
00:16:31,376 --> 00:16:33,578
SIALIC ACID WITH AN IMAGING 

396
00:16:33,578 --> 00:16:34,946
PROBE.

397
00:16:34,946 --> 00:16:37,081
I CAME BACK FROM THE CONFERENCE 

398
00:16:37,081 --> 00:16:38,850
AND SAT AND WROTE MY 

399
00:16:38,850 --> 00:16:39,550
APPLICATIONS AND THIS IS A 

400
00:16:39,550 --> 00:16:41,319
GRAPHIC FROM A JOB APPLICATION.

401
00:16:41,319 --> 00:16:42,954
YOU WRITE A PROPOSAL WHEN YOU 

402
00:16:42,954 --> 00:16:44,856
APPLY FOR FACULTY JOBS.

403
00:16:44,856 --> 00:16:46,824
BY THE WAY, THIS GRAPHIC WAS 

404
00:16:46,824 --> 00:16:49,794
VERY STATE OF THE ART CIRCA 

405
00:16:49,794 --> 00:16:49,994
1994.

406
00:16:49,994 --> 00:16:50,595
NOT SO MUCH NOW.

407
00:16:50,595 --> 00:16:52,630
BUT IN THAT PROPOSAL, I WROTE, 

408
00:16:52,630 --> 00:16:55,633
OKAY, WHAT WE'RE GOING TO DO IS 

409
00:16:55,633 --> 00:16:57,902
DEVELOP A GLYCAN IMAGING 

410
00:16:57,902 --> 00:16:59,604
TECHNOLOGY WHERE THE FIRST STEP 

411
00:16:59,604 --> 00:17:01,806
WOULD BE TO FEED CELLS A 

412
00:17:01,806 --> 00:17:05,076
CHEMICALLY ALTERED SUGAR THAT 

413
00:17:05,076 --> 00:17:06,711
MAKES ITS WAY THROUGH BIO 

414
00:17:06,711 --> 00:17:08,146
SYNTHESIS THROUGH THE GLYCAN AND

415
00:17:08,146 --> 00:17:11,382
WHEN THAT'S DONE WE'LL HAD A 

416
00:17:11,382 --> 00:17:14,519
PROMOLECULE AND THE IDEA IS A 

417
00:17:14,519 --> 00:17:15,853
CHEMICAL GROUP LET'S CALL IT X 

418
00:17:15,853 --> 00:17:20,325
FOR NOW ON THE SUGAR AND 

419
00:17:20,325 --> 00:17:21,626
COMPLEMENTARY GROUP CALL IT Y ON

420
00:17:21,626 --> 00:17:23,895
THE PROBE AND THEY'D FIND EACH 

421
00:17:23,895 --> 00:17:25,363
OTHER WITHIN THE LIVING SYSTEM 

422
00:17:25,363 --> 00:17:26,898
ON MAYBE LIVE CELLS OR ORGANISMS

423
00:17:26,898 --> 00:17:29,801
AND A CHEMICAL REACTION WOULD 

424
00:17:29,801 --> 00:17:31,035
OCCUR THAT BASICALLY ATTACHES 

425
00:17:31,035 --> 00:17:33,271
THE PROBE TO THE SUGAR AND NOW 

426
00:17:33,271 --> 00:17:34,372
YOU CAN VISUALIZE THE SUGAR.

427
00:17:34,372 --> 00:17:35,540
THAT WAS THE IDEA.

428
00:17:35,540 --> 00:17:40,945
SO I GOT THE JOB AT BERKELEY AND

429
00:17:40,945 --> 00:17:49,787
I REALIZ REALIZED IMMEDIATELY WE

430
00:17:49,787 --> 00:17:57,929
TO INVENT AND IT WOULD REQUIRE 

431
00:17:57,929 --> 00:17:59,263
BIOORTHOGONALLY AND WE HAD TO 

432
00:17:59,263 --> 00:18:00,631
INVENT WHAT WOULD BE USEFUL FOR 

433
00:18:00,631 --> 00:18:04,002
AN EXPERIMENT LIKE THIS ONE.

434
00:18:04,002 --> 00:18:08,973
THERE I WAS THIS IS U.C. 

435
00:18:08,973 --> 00:18:19,517
BERKELEY AND ME AT  THE SITE IF 

436
00:18:20,385 --> 00:18:23,321
YOU DON'T RECOGNIZE ME AND I 

437
00:18:23,321 --> 00:18:25,256
APPLIED FOR MY FIRST GRANT AT 

438
00:18:25,256 --> 00:18:27,425
NIH AND AFTER A COUPLE FALSE 

439
00:18:27,425 --> 00:18:29,027
STARTS IT WAS FUNDED BY THROUGH 

440
00:18:29,027 --> 00:18:30,428
THE NATIONAL INSTITUTE OF 

441
00:18:30,428 --> 00:18:32,797
MEDICAL SCIENCES AND THAT'S WHEN

442
00:18:32,797 --> 00:18:33,698
I LAUNCHED THIS SEARCH FOR 

443
00:18:33,698 --> 00:18:34,599
BIOORTHOGONAL CHEMICAL REACTION.

444
00:18:34,599 --> 00:18:45,043
SO THANK YOU, TO THE NIH.

445
00:18:53,885 --> 00:18:57,321
THIS WAS IN REACTION TO A FAMOUS

446
00:18:57,321 --> 00:19:02,360
CHEMIST IN THE EARLY 1800s TO 

447
00:19:02,360 --> 00:19:04,729
REACTED TO THIS GROUP WHERE 

448
00:19:04,729 --> 00:19:06,030
THERE'S THREE NITROGENS IN A ROW

449
00:19:06,030 --> 00:19:13,371
WITH THIS CHEMICAL GROUP WHICH A

450
00:19:13,371 --> 00:19:13,604
REAGENT.

451
00:19:13,604 --> 00:19:17,408
THERE'S A CHEMISTRY BY WHICH A 

452
00:19:17,408 --> 00:19:19,343
PERSON CAN REDUCE THEM AND 

453
00:19:19,343 --> 00:19:20,778
THAT'S THE REDUCTION.

454
00:19:20,778 --> 00:19:21,846
HOW MANY HERE HAVE DONE THIS 

455
00:19:21,846 --> 00:19:25,983
TYPE OF REDUCTION?

456
00:19:25,983 --> 00:19:29,387
I KNEW IT.

457
00:19:29,387 --> 00:19:31,255
IT'S AN OLDIE BUT GOODIE AND I 

458
00:19:31,255 --> 00:19:34,158
HAD DONE THIS MYSELF AS A GRAD 

459
00:19:34,158 --> 00:19:38,196
STUDENT BUT IT OCCURRED TO ME A 

460
00:19:38,196 --> 00:19:42,433
SLIGHT MODIFICATION OF THE 

461
00:19:42,433 --> 00:19:43,201
STAUDINGER REDUCTION MAY JOIN 

462
00:19:43,201 --> 00:19:44,102
THEM TOGETHER AND THAT'S WHAT 

463
00:19:44,102 --> 00:19:45,503
THIS IS.

464
00:19:45,503 --> 00:19:47,438
THIS IS A CHEMISTRY YOU CAN DO 

465
00:19:47,438 --> 00:19:48,906
ON CELLS, NO PROBLEM, THERE'S NO

466
00:19:48,906 --> 00:19:51,909
HARM TO THE CELL, NO 

467
00:19:51,909 --> 00:19:53,377
INTERFERENCE WITH ANY OF THE 

468
00:19:53,377 --> 00:19:58,216
BIOLOGICAL CHEMICALS, AZIDES AND

469
00:19:58,216 --> 00:20:01,352
PHOSPHINES WERE MADE BY HUMANS.

470
00:20:01,352 --> 00:20:02,420
THEY'RE NOT NATURAL CHEMICAL 

471
00:20:02,420 --> 00:20:02,954
GROUPS.

472
00:20:02,954 --> 00:20:04,889
THIS CHEMISTRY WAS SO WELL 

473
00:20:04,889 --> 00:20:07,058
TOLERATED IN BIOLOGICAL SETTINGS

474
00:20:07,058 --> 00:20:08,726
WE COULD EVEN PERFORM THIS IN 

475
00:20:08,726 --> 00:20:11,429
THE BODY OF A MOUSE AND WE 

476
00:20:11,429 --> 00:20:12,630
PUBLISHED -- THIS IS THE WORK OF

477
00:20:12,630 --> 00:20:14,966
TWO FORMER STUDENTS A PROFESSOR 

478
00:20:14,966 --> 00:20:18,536
NOW AT U.C. IRVINE, ANOTHER AT 

479
00:20:18,536 --> 00:20:20,004
BODEN COLLEGE AND SHOWED YOU CAN

480
00:20:20,004 --> 00:20:24,408
INJECT A PRECURSOR OF THE SIALIC

481
00:20:24,408 --> 00:20:27,011
ACID WITH THE AZIDE AND THE 

482
00:20:27,011 --> 00:20:27,945
SUGAR WOULD GET METABOLIZED IN 

483
00:20:27,945 --> 00:20:29,814
THE BODY OF THE MOUSE.

484
00:20:29,814 --> 00:20:33,017
A COUPLE DAYS LATER YOU'D FIND 

485
00:20:33,017 --> 00:20:39,090
THE GLYCANS AND INTRODUCE YOUR 

486
00:20:39,090 --> 00:20:40,091
PHOSPHINE PROBE.

487
00:20:40,091 --> 00:20:41,325
IT'S HERE AND THAT WILL REACT 

488
00:20:41,325 --> 00:20:44,128
WITH THE AZIDE AND THE REST IS 

489
00:20:44,128 --> 00:20:45,663
JUST A PROBE.

490
00:20:45,663 --> 00:20:47,665
SOMETHING YOU CAN FIND AND QUANT

491
00:20:47,665 --> 00:20:49,800
TIGHT ON THE CELLS AFTER THE 

492
00:20:49,800 --> 00:20:51,636
REACTION IS COMPLETE.

493
00:20:51,636 --> 00:20:52,503
SO WE SPENT MANY YEARS PLAYING 

494
00:20:52,503 --> 00:20:54,272
WITH THE CHEMISTRY, DOING 

495
00:20:54,272 --> 00:20:54,906
INTERESTING THINGS AND 

496
00:20:54,906 --> 00:20:56,340
PUBLISHING WITH IT AND SO ON BUT

497
00:20:56,340 --> 00:20:58,276
WE REALIZED PRETTY QUICKLY THAT 

498
00:20:58,276 --> 00:21:01,179
THIS WAS NOT THE IDEAL CHEMISTRY

499
00:21:01,179 --> 00:21:04,148
FOR IMAGING APPLICATIONS.

500
00:21:04,148 --> 00:21:07,485
FOR THE SIMPLE REASON IT'S A 

501
00:21:07,485 --> 00:21:08,152
RATHER SLUGGISH REACTION AND 

502
00:21:08,152 --> 00:21:09,220
GOES A LITTLE BIT TOO SLOW.

503
00:21:09,220 --> 00:21:11,289
IT'S FINE FOR REACTIONS TO GO 

504
00:21:11,289 --> 00:21:13,024
SLOWLY IN THE ROUND BOTTOM FLASK

505
00:21:13,024 --> 00:21:14,859
BECAUSE YOU CAN HEAT THEM UP AND

506
00:21:14,859 --> 00:21:16,460
LET THEM GO FOR DAYS AND DAYS.

507
00:21:16,460 --> 00:21:19,664
IN A MOUSE, YOU CAN'T HEAT IT 

508
00:21:19,664 --> 00:21:21,799
UP, OR YOU SHOULDN'T, ANYWAYS 

509
00:21:21,799 --> 00:21:23,301
AND FURTHERMORE YOU CAN'T JUST 

510
00:21:23,301 --> 00:21:25,236
WAIT FOR DAYS AND DAYS AND DAYS 

511
00:21:25,236 --> 00:21:26,370
BECAUSE THE MOUSE WILL CLEAR 

512
00:21:26,370 --> 00:21:28,673
THESE REAGENTS OUT OF ITS BODY 

513
00:21:28,673 --> 00:21:30,141
BECAUSE THE CHEMISTRY'S HAD A 

514
00:21:30,141 --> 00:21:31,609
CHANCE TO OCCUR IF THE REACTION 

515
00:21:31,609 --> 00:21:32,977
IS TOO SLOW.

516
00:21:32,977 --> 00:21:36,247
SO IN THE EARLY 2000s WE WENT 

517
00:21:36,247 --> 00:21:37,715
BACK IT THE DRAWING BOARD AND 

518
00:21:37,715 --> 00:21:39,784
STARTED THINKING ABOUT OTHER 

519
00:21:39,784 --> 00:21:43,287
CHEMISTRIES WE COULD PERFORM 

520
00:21:43,287 --> 00:21:44,822
PRESERVING THE AZIDE AS AS A 

521
00:21:44,822 --> 00:21:46,624
PARTNER BECAUSE WE LOVED IT.

522
00:21:46,624 --> 00:21:48,960
IT'S SMALL AND HAS GREAT 

523
00:21:48,960 --> 00:21:51,262
STABILITY IN BIOLOGICAL SYSTEMS.

524
00:21:51,262 --> 00:21:53,631
LOTS OF HUMAN MEDICINES HAVE 

525
00:21:53,631 --> 00:21:55,933
AZIDES IN THEM SO WE KNOW A LOT 

526
00:21:55,933 --> 00:21:59,337
ABOUT THE METABOLISM AND THEY'RE

527
00:21:59,337 --> 00:22:02,974
INERT IN THE BODY AND IT TURNS 

528
00:22:02,974 --> 00:22:05,109
OUT THEY HAVE ACTIVITIES WITH 

529
00:22:05,109 --> 00:22:06,811
OTHER GROUPS ONE BEING ALKINES.

530
00:22:06,811 --> 00:22:12,416
NOW ALKINES WERE WELL KNOWN ALSO

531
00:22:12,416 --> 00:22:16,988
SOME FOUNDATIONAL CHEMISTRY FROM

532
00:22:16,988 --> 00:22:21,058
GERMANY IN THE '50s AND '60s AND

533
00:22:21,058 --> 00:22:26,964
FORMED A TRIAZOL.

534
00:22:26,964 --> 00:22:29,800
THIS WAS WELL KNOWN TO THE 

535
00:22:29,800 --> 00:22:31,636
CHEMICAL COMMUNITY BUT NOT IDEAL

536
00:22:31,636 --> 00:22:33,971
FOR BIOORTHOGONAL APPLICATIONS 

537
00:22:33,971 --> 00:22:35,640
BECAUSE IT'S EVEN SLOWER THAN 

538
00:22:35,640 --> 00:22:39,810
THE STAUDINGER CHEMISTRY ON ITS 

539
00:22:39,810 --> 00:22:40,011
FACE.

540
00:22:40,011 --> 00:22:45,816
BUT IN THE YEAR 2002 THESE TWO 

541
00:22:45,816 --> 00:22:48,152
SYNTHETIC ORGANIC CHEMISTS, 

542
00:22:48,152 --> 00:22:53,691
DR. MEIDAL AND SHARPLESS 

543
00:22:53,691 --> 00:22:55,593
INDEPENDENTLY AND SIMULTANEOUSLY

544
00:22:55,593 --> 00:22:57,595
ZORCHD YOU CAN SPEED IT UP BY 

545
00:22:57,595 --> 00:23:01,565
ADDING A COPPER CATALYST AND 

546
00:23:01,565 --> 00:23:05,569
THIS AZIDE CYCLE EDITION BECAME 

547
00:23:05,569 --> 00:23:08,973
POPULARLY KNOWN AS CLICK 

548
00:23:08,973 --> 00:23:09,707
CHEMISTRY.

549
00:23:09,707 --> 00:23:13,544
WE LEARNED FOR THE BIOLOGISTS IN

550
00:23:13,544 --> 00:23:14,812
THE AUDIENCE YOU PROBABLY NOT 

551
00:23:14,812 --> 00:23:17,114
HEARD OF ANY OTHER REACTION BY 

552
00:23:17,114 --> 00:23:20,217
NAME OTHER THAN CLICK CHEMISTRY.

553
00:23:20,217 --> 00:23:22,653
HOW MANY HEARD OF THIS?

554
00:23:22,653 --> 00:23:24,522
AND HOW MANY HAVE DONE CLICK 

555
00:23:24,522 --> 00:23:25,022
CHEMISTRY?

556
00:23:25,022 --> 00:23:25,356
YEAH.

557
00:23:25,356 --> 00:23:27,992
THIS IS ONE OF THE FEW CHEMICAL 

558
00:23:27,992 --> 00:23:29,794
RAKES THAT EVEN A BIOLOGIST CAN 

559
00:23:29,794 --> 00:23:31,262
DO IN THE LABORATORY.

560
00:23:31,262 --> 00:23:39,904
BUT THAT SAYS SOMETHING.

561
00:23:39,904 --> 00:23:42,640
IT'S FOOL PROOF AND YOU CAN SPIT

562
00:23:42,640 --> 00:23:44,575
ON THE REACTION, AND THAT'S AN 

563
00:23:44,575 --> 00:23:45,710
INSIDE CHEMISTRY JOKE.

564
00:23:45,710 --> 00:23:48,679
WHEN THE PAPER CAME OUT WE GOT 

565
00:23:48,679 --> 00:23:50,981
EXCITED BECAUSE IT'S SUCH A FAST

566
00:23:50,981 --> 00:23:51,248
REACTION.

567
00:23:51,248 --> 00:23:52,283
IT DOESN'T TAKE DAYS BUT 

568
00:23:52,283 --> 00:23:52,650
MINUTES.

569
00:23:52,650 --> 00:23:54,218
MAYBE AN HOUR AT MOST.

570
00:23:54,218 --> 00:23:56,153
THE PROBLEM WAS THE COPPER 

571
00:23:56,153 --> 00:23:57,021
CATALYST.

572
00:23:57,021 --> 00:23:57,955
THAT COPPER CATALYST IS TOXIC TO

573
00:23:57,955 --> 00:24:02,460
CELLS.

574
00:24:02,460 --> 00:24:03,794
SO WHILE CLICK CHEMISTRY IS 

575
00:24:03,794 --> 00:24:05,663
USEFUL TO JOIN THINGS TOGETHER 

576
00:24:05,663 --> 00:24:08,165
IN VERY COMPLEX EVEN BIOLOGICAL 

577
00:24:08,165 --> 00:24:09,567
SETTINGS, IT'S NOT USEFUL IF THE

578
00:24:09,567 --> 00:24:12,503
OBJECTIVE IS TO STUDY SOMETHING 

579
00:24:12,503 --> 00:24:15,039
THAT IS ALIVE WHETHER IT'S CELLS

580
00:24:15,039 --> 00:24:16,640
OR ORGANISMS OKAY, SO THAT 

581
00:24:16,640 --> 00:24:17,441
WASN'T GOING TO SOLVE THE 

582
00:24:17,441 --> 00:24:18,709
PROBLEM FOR US.

583
00:24:18,709 --> 00:24:20,378
BUT IT TURNS OUT THERE ARE OTHER

584
00:24:20,378 --> 00:24:25,750
WAYS OF ACCELERATING THE RATE OF

585
00:24:25,750 --> 00:24:30,654
AN AZIDE ALKINE CYCLE EDITION 

586
00:24:30,654 --> 00:24:31,922
THAT DON'T REQUIRE THE CATALYST 

587
00:24:31,922 --> 00:24:34,191
AND THE STRATEGY WAS TO TAKE THE

588
00:24:34,191 --> 00:24:36,427
TRIPLE BOND ALKINE AND CONFINE 

589
00:24:36,427 --> 00:24:40,998
IT IN AN EIGHT MEMBER DRAIN AND 

590
00:24:40,998 --> 00:24:44,135
YOU INDUCE RING STRAIN AND THE 

591
00:24:44,135 --> 00:24:46,604
CHEMISTS WILL KNOW WHEN THINGS 

592
00:24:46,604 --> 00:24:47,972
ARE CONSTRAINED THEY'RE 

593
00:24:47,972 --> 00:24:48,305
UNCOMFORTABLE.

594
00:24:48,305 --> 00:24:50,641
MOLECULES WANT TO RELEASE IT AND

595
00:24:50,641 --> 00:24:54,879
WHEN THIS REACTS WITH THE AZIDE 

596
00:24:54,879 --> 00:24:58,916
TO FORM THE TRIZOLE THAT DRIVES 

597
00:24:58,916 --> 00:25:00,751
THE KINETICS AND THE COPPER FREE

598
00:25:00,751 --> 00:25:04,688
CLICK CHEMISTRY AS WE CALL IT IS

599
00:25:04,688 --> 00:25:06,190
SOMETHING YOU CAN DO IN LIVING 

600
00:25:06,190 --> 00:25:06,957
SYSTEMS WITHOUT HAVING TO WORRY 

601
00:25:06,957 --> 00:25:11,662
ABOUT TEXASES.

602
00:25:11,662 --> 00:25:20,171
 -- TOXICITIES AND BADGE  -- 

603
00:25:20,171 --> 00:25:22,573
BARRY AND MYSELF AND OTHERS WERE

604
00:25:22,573 --> 00:25:24,842
RECOGNIZED WITH A NOBEL PRIZE 

605
00:25:24,842 --> 00:25:26,544
FOR THIS IN 2022.

606
00:25:26,544 --> 00:25:30,681
WE HAD A NEW BIOORTHOGONAL 

607
00:25:30,681 --> 00:25:32,049
CHEMISTRY AND THE OBJECTIVE WAS 

608
00:25:32,049 --> 00:25:35,252
TO GET THEM IN MOLECULES, CELLS,

609
00:25:35,252 --> 00:25:37,154
ORGANISMS IN THE SUGAR AROUND 

610
00:25:37,154 --> 00:25:39,089
INTRODUCE THE PROBES WITH 

611
00:25:39,089 --> 00:25:41,492
FLUORESCENT DIES OR IMAGING 

612
00:25:41,492 --> 00:25:43,527
PROBES MORE BROADLY AND LET THEM

613
00:25:43,527 --> 00:25:44,695
CLICK TOGETHER AND IMAGE THE 

614
00:25:44,695 --> 00:25:49,333
PRODUCTS.

615
00:25:49,333 --> 00:25:51,669
IT TURNED OUT TO BE THE EASIEST 

616
00:25:51,669 --> 00:25:54,772
PART BECAUSE WE HAD THIS GREAT 

617
00:25:54,772 --> 00:25:57,608
PRECEDENT FROM THE PROFESSOR'S 

618
00:25:57,608 --> 00:25:58,442
EARLIER WORK.

619
00:25:58,442 --> 00:26:00,311
WE HAD IT ON THE PRECURSOR.

620
00:26:00,311 --> 00:26:02,012
WE FED THAT TO CELLS, THE CELLS 

621
00:26:02,012 --> 00:26:08,953
DID THE HARD WORK AND BUILT A 

622
00:26:08,953 --> 00:26:12,323
SIALIC ACID AND YOU CAN DO THIS 

623
00:26:12,323 --> 00:26:15,292
PRETTY MUCH ANY SUGAR.

624
00:26:15,292 --> 00:26:18,195
YOU CAN PUT IT IN THE GLUCOSE.

625
00:26:18,195 --> 00:26:21,799
THAT'S ANOTHER INTERESTING SUGAR

626
00:26:21,799 --> 00:26:27,538
BIOLOGICALLY AND INTO GALNAC AND

627
00:26:27,538 --> 00:26:32,042
FOLKS WHO STUDY THE MUSIN FAMILY

628
00:26:32,042 --> 00:26:33,110
MAY HAVE AVEILED THEMSELVES OF 

629
00:26:33,110 --> 00:26:35,513
THIS TECHNOLOGY.

630
00:26:35,513 --> 00:26:38,782
WHO HERE HAS FED CELLS GALNAZ.

631
00:26:38,782 --> 00:26:48,025
ALL RIGHT, DR. HANOVER.

632
00:26:48,025 --> 00:26:50,427
AND THE ORGANISM WE STARTED WITH

633
00:26:50,427 --> 00:26:54,565
IS POPULAR FOR OPTICAL 

634
00:26:54,565 --> 00:27:03,107
MICROSCOPY IS ZEBRAFISH THEY'RE 

635
00:27:03,107 --> 00:27:04,108
TRANSLUCENT AND THEY'RE 

636
00:27:04,108 --> 00:27:05,142
VERTEBRATES ARE SIMILAR TO 

637
00:27:05,142 --> 00:27:08,913
HUMANS AND AS PEOPLE ARE AWARE, 

638
00:27:08,913 --> 00:27:12,283
THE PROGRAMS OF EMBRYO GENESIS 

639
00:27:12,283 --> 00:27:14,251
VERY MUCH MIRROR THE PROGRAMS OF

640
00:27:14,251 --> 00:27:15,286
CANCER DEVELOPMENT AND 

641
00:27:15,286 --> 00:27:15,619
DISSEMINATION.

642
00:27:15,619 --> 00:27:18,889
MANY OF THE SAME GENES WE 

643
00:27:18,889 --> 00:27:21,625
ASSOCIATE WITH MALIGNANCIES ARE 

644
00:27:21,625 --> 00:27:23,861
EXPRESSED AND THAT'S TRUE FOR 

645
00:27:23,861 --> 00:27:25,162
THE CELL SURFACE GLYCANS.

646
00:27:25,162 --> 00:27:26,797
IT'S A GOOD PLACE TO START.

647
00:27:26,797 --> 00:27:29,667
FOR THOSE WHO HAVE NOT SPENT 

648
00:27:29,667 --> 00:27:31,035
TIME LOOKING AT ZEBRAFISH 

649
00:27:31,035 --> 00:27:32,536
EMBRYOS IT ALL STARTS WITH A 

650
00:27:32,536 --> 00:27:36,106
SINGLE CELL YOU FERTILIZE IN A 

651
00:27:36,106 --> 00:27:38,642
DISH, IN VITRO FERTILIZATION AND

652
00:27:38,642 --> 00:27:40,844
THE EMBRYO STARTS TO DEVELOP AND

653
00:27:40,844 --> 00:27:42,046
AT THE END OF EIGHT DAYS YOU 

654
00:27:42,046 --> 00:27:44,248
HAVE A YOUNG ADULT FISH AND CAN 

655
00:27:44,248 --> 00:27:46,650
WATCH THE DEVELOPMENTAL PROGRAM 

656
00:27:46,650 --> 00:27:48,452
UNFOLD IN REAL TIME DURING THE 

657
00:27:48,452 --> 00:27:49,086
FIVE-DAY PERIOD.

658
00:27:49,086 --> 00:27:50,688
SO SO WE STARTED DOING 

659
00:27:50,688 --> 00:27:52,089
EXPERIMENTS OF THIS TYPE WHERE 

660
00:27:52,089 --> 00:27:55,292
WE WOULD TAKE THESE EMBRYOS AND 

661
00:27:55,292 --> 00:27:57,428
WE WOULD BATHE THEM IN MEDIA 

662
00:27:57,428 --> 00:28:01,131
THAT HAD SUGARS WITH AZIDES IN 

663
00:28:01,131 --> 00:28:01,332
THEM.

664
00:28:01,332 --> 00:28:05,035
WE WOULD LET THOSE SUGARS GET 

665
00:28:05,035 --> 00:28:13,110
TAKEN UP AND INTO THE GLYCANS 

666
00:28:13,110 --> 00:28:20,384
AND ADD DYE AND THIS HAPPENS TO 

667
00:28:20,384 --> 00:28:22,553
BE A TYPE AND DO IT AGAIN AND 

668
00:28:22,553 --> 00:28:24,088
AGAIN TO YOUR HEART'S DESIRE.

669
00:28:24,088 --> 00:28:25,856
TAKE THE FISH AND DO A WASHING 

670
00:28:25,856 --> 00:28:29,093
STEP AND THEN BATHE THEM IN A 

671
00:28:29,093 --> 00:28:30,694
NEW BATCH OF SUGAR INTRODUCING A

672
00:28:30,694 --> 00:28:32,997
NEW BATCH OF AZIDES AND THEN YOU

673
00:28:32,997 --> 00:28:35,966
CAN CLICK ON A DIFFERENT COLOR.

674
00:28:35,966 --> 00:28:37,434
THROUGH THIS EXPERIMENTATION YOU

675
00:28:37,434 --> 00:28:38,836
CAN LOOK AT DIFFERENT SUGARS AND

676
00:28:38,836 --> 00:28:40,404
TIME POINTS THROUGH THE COURSE 

677
00:28:40,404 --> 00:28:40,938
OF DEVELOPMENT.

678
00:28:40,938 --> 00:28:44,274
SO IMAGES LIKE THESE BECAME LIKE

679
00:28:44,274 --> 00:28:46,276
THE DOMINATING DATA SETS IN OUR 

680
00:28:46,276 --> 00:28:47,344
LAB AROUND THOSE YEAR.

681
00:28:47,344 --> 00:28:50,147
THIS NOW TAKES ME UP TO 2004 

682
00:28:50,147 --> 00:28:51,148
THROUGH 2008.

683
00:28:51,148 --> 00:28:54,118
UP HERE IS THE HEAD OF A 

684
00:28:54,118 --> 00:28:55,386
FIVE--DAY-OLD ZEBRAFISH THAT WAS

685
00:28:55,386 --> 00:28:56,286
LABELLED WITH THREE DIFFERENT 

686
00:28:56,286 --> 00:28:57,221
SUGARS AT DIFFERENT TIME POINTS.

687
00:28:57,221 --> 00:28:59,957
YOU CAN SEE THE COLORS ARE 

688
00:28:59,957 --> 00:29:01,725
DISTRIBUTED IN INTERESTING WAYS.

689
00:29:01,725 --> 00:29:05,829
YOU CAN DISTINGUISH THE PATTERNS

690
00:29:05,829 --> 00:29:09,667
OF GLYCOSYLATION IN THE UPPER 

691
00:29:09,667 --> 00:29:11,001
RESPIRATORY TRACT IN THE NOSE 

692
00:29:11,001 --> 00:29:13,570
WHICH IS DIFFERENT FROM THE 

693
00:29:13,570 --> 00:29:14,371
EPIDERMIS OR OTHER TISSUE.

694
00:29:14,371 --> 00:29:17,841
YOU CAN BACK UP TO EARLY STAGES 

695
00:29:17,841 --> 00:29:18,942
OF EMBRYO GENESIS.

696
00:29:18,942 --> 00:29:21,378
THE BALL OF CELLS IS A 24-HOUR 

697
00:29:21,378 --> 00:29:24,281
OLD EMBRYO AND A LOT OF CELL 

698
00:29:24,281 --> 00:29:27,017
DIVISION IS HAPPENING IN THE 

699
00:29:27,017 --> 00:29:27,851
EARLY STAGES.

700
00:29:27,851 --> 00:29:30,688
CELLS ARE MAKING THEIR DISHES 

701
00:29:30,688 --> 00:29:31,655
ABOUT WHAT TISSUE FATE THEY WILL

702
00:29:31,655 --> 00:29:33,223
ADOPT AND WE CAPTURED 

703
00:29:33,223 --> 00:29:33,857
INTERESTING PHENOMENA.

704
00:29:33,857 --> 00:29:36,360
FOR EXAMPLE, EVERY TIME WE FOUND

705
00:29:36,360 --> 00:29:39,530
A CELL GOING THROUGH A ROUND OF 

706
00:29:39,530 --> 00:29:41,598
MITOSIS WE DISCOVERED THE CELL 

707
00:29:41,598 --> 00:29:42,866
SURFACE SUGARS WERE 

708
00:29:42,866 --> 00:29:43,867
REDISTRIBUTING THEMSELVES AND 

709
00:29:43,867 --> 00:29:45,936
BELOW IS A BLOWUP OF ONE OF 

710
00:29:45,936 --> 00:29:47,805
THESE EVENTS OF MITOSIS.

711
00:29:47,805 --> 00:29:50,541
TO SEE IF I CAN GET THIS TO 

712
00:29:50,541 --> 00:29:50,741
PLAY.

713
00:29:50,741 --> 00:29:53,977
SO THIS IS A BLOWUP OF A MOTHER 

714
00:29:53,977 --> 00:29:57,081
CELL WHO HAS DUPLICATED HER 

715
00:29:57,081 --> 00:29:58,882
CHROMOSOMES AND DIVIDED TO TWO 

716
00:29:58,882 --> 00:29:59,450
DAUGHTER CELLS.

717
00:29:59,450 --> 00:30:00,417
IT'S THE SAME FRAME IN EACH OF 

718
00:30:00,417 --> 00:30:05,823
THE PANELS BUT WE'RE LOOKING AT 

719
00:30:05,823 --> 00:30:06,790
DIFFERENT MOLECULES WITH 

720
00:30:06,790 --> 00:30:07,691
DIFFERENT DYES.

721
00:30:07,691 --> 00:30:10,861
ON THE LEFT ARE CELLS IN WHICH 

722
00:30:10,861 --> 00:30:11,995
THE FLUORESCENT DYE IS ON THE 

723
00:30:11,995 --> 00:30:14,264
DNA AND YOU'RE LOOKING AT THE 

724
00:30:14,264 --> 00:30:17,501
CHROMOSOMES AND HERE THEY 

725
00:30:17,501 --> 00:30:21,371
DUPLICATED, CLASSIC MICROTUBIAL 

726
00:30:21,371 --> 00:30:22,439
DISCRIMINATION.

727
00:30:22,439 --> 00:30:23,574
THAT'S WHAT IT LOOKS LIKE AND 

728
00:30:23,574 --> 00:30:26,276
JUMP OVER THE PANEL IN THIS 

729
00:30:26,276 --> 00:30:28,812
FRAME WITH WE HAVE A MEMBRANE 

730
00:30:28,812 --> 00:30:31,448
WITH A GENETIC FUSION YOU CAN 

731
00:30:31,448 --> 00:30:33,851
SEE THE MEMBRANE STARTS AS 

732
00:30:33,851 --> 00:30:35,285
BASICALLY CIRCLES THE MOTHER 

733
00:30:35,285 --> 00:30:38,155
CELL AND AS IT DIVIDES YOU GET 

734
00:30:38,155 --> 00:30:39,289
NEW MEMBRANE FORMING BETWEEN 

735
00:30:39,289 --> 00:30:41,191
ULTIMATELY TWO DAUGHTER CELLS.

736
00:30:41,191 --> 00:30:42,426
THAT IS WHAT CELL DIVISION LOOKS

737
00:30:42,426 --> 00:30:43,026
LIKE THROUGH THE LENS OF THE 

738
00:30:43,026 --> 00:30:45,129
MEMBRANE.

739
00:30:45,129 --> 00:30:47,464
NOW FOR THE FIRST TIME WE GOT TO

740
00:30:47,464 --> 00:30:48,098
SEE WHAT CELL DIVISION LOOKS 

741
00:30:48,098 --> 00:30:51,235
LIKE THROUGH THE LENS OF A CELL 

742
00:30:51,235 --> 00:30:52,870
SURFACE GLYCANS.

743
00:30:52,870 --> 00:30:53,837
AND WHAT'S KIND OF SURPRISING 

744
00:30:53,837 --> 00:30:57,241
YOU SEE THEY LOOK LIKE A FUZZY 

745
00:30:57,241 --> 00:30:58,175
HALO.

746
00:30:58,175 --> 00:30:59,376
PICTURE ALL THE TREES IN THE 

747
00:30:59,376 --> 00:31:01,545
GRASS AND LANDSCAPING ON THE 

748
00:31:01,545 --> 00:31:02,546
CELL SURFACE.

749
00:31:02,546 --> 00:31:04,448
AS THE CELL GETS TO THE LATE 

750
00:31:04,448 --> 00:31:06,483
STAGES OF CELL DIVISION THE 

751
00:31:06,483 --> 00:31:08,585
GLYCANS ARE NO LONGER UNIFORMLY 

752
00:31:08,585 --> 00:31:08,919
DISTRIBUTED.

753
00:31:08,919 --> 00:31:09,853
THEY START TO PILE UP AT THE 

754
00:31:09,853 --> 00:31:11,388
JUNCTION BETWEEN THE TWO 

755
00:31:11,388 --> 00:31:13,323
DAUGHTER CELLS AND TURNS OUT 

756
00:31:13,323 --> 00:31:14,825
THEY ARE CONTRIBUTING TO 

757
00:31:14,825 --> 00:31:16,593
SEGREGATION AT THIS STAGE OF 

758
00:31:16,593 --> 00:31:17,327
CELL DIVISION.

759
00:31:17,327 --> 00:31:19,363
AND WE SPUN OUT A WHOLE PROJECT 

760
00:31:19,363 --> 00:31:20,998
SORT OF STUDYING THE FUNDAMENTAL

761
00:31:20,998 --> 00:31:24,802
CONTRIBUTION OF THE GLYCAN TO 

762
00:31:24,802 --> 00:31:26,170
LATE STAGES OF CELL DIVISION.

763
00:31:26,170 --> 00:31:28,305
IT'S LIKE YOU TURN ON YOUR 

764
00:31:28,305 --> 00:31:29,840
SPOTLIGHT AND YOU SHINE IT IN 

765
00:31:29,840 --> 00:31:32,342
PLACE AND SEE A NEW THING.

766
00:31:32,342 --> 00:31:37,114
THAT WAS OUR EXPERIENCE USING 

767
00:31:37,114 --> 00:31:37,648
THESE BIOORTHOGONAL TOOLS.

768
00:31:37,648 --> 00:31:38,682
BY THE WAY, THE LAST PANEL WAS 

769
00:31:38,682 --> 00:31:43,654
JUST AN OVERLAY OF THE THREE 

770
00:31:43,654 --> 00:31:44,922
PANELS WHERE THEY'RE JUST 

771
00:31:44,922 --> 00:31:45,155
COLORED.

772
00:31:45,155 --> 00:31:48,091
SUFFICE IT SAY AT THIS POINT WE 

773
00:31:48,091 --> 00:31:49,560
DEVELOPED A TECHNOLOGY, A 

774
00:31:49,560 --> 00:31:51,528
STRATEGY FOR IMAGING SUGARS ON 

775
00:31:51,528 --> 00:31:53,130
THE SURFACE OF CELLS.

776
00:31:53,130 --> 00:31:54,765
WE DEVELOPED SOME TOOLS WE COULD

777
00:31:54,765 --> 00:31:58,335
USE IN ANIMAL MODELS AND WE SPUN

778
00:31:58,335 --> 00:31:59,503
OUT A LOT OF THESE TECHNOLOGIES 

779
00:31:59,503 --> 00:32:01,471
INTO COMPANIES, SOME WERE 

780
00:32:01,471 --> 00:32:02,272
LICENSED BY COMPANIES INTERESTED

781
00:32:02,272 --> 00:32:04,074
IN CLINICAL DIAGNOSTICS, A FEW 

782
00:32:04,074 --> 00:32:06,210
COMPANIES I CO-FOUNDED WITH SOME

783
00:32:06,210 --> 00:32:07,444
STUDENTS FROM MY LAB.

784
00:32:07,444 --> 00:32:09,246
BUT I THOUGHT IT WOULD BE FUN TO

785
00:32:09,246 --> 00:32:11,114
FAST FORWARD AND TELL YOU A 

786
00:32:11,114 --> 00:32:12,749
RECENT STORY ALSO BASIC SCIENCE 

787
00:32:12,749 --> 00:32:16,019
DISCOVERY THAT WAS ENABLED BY 

788
00:32:16,019 --> 00:32:17,487
BIOORTHOGONAL CHEMISTRY AND IT 

789
00:32:17,487 --> 00:32:21,258
TAKES ME BACK TO THE GLYCOCALYX 

790
00:32:21,258 --> 00:32:23,093
OR THE CELL SURFACE.

791
00:32:23,093 --> 00:32:24,528
EVERY TEXT YOU READ WILL TELL 

792
00:32:24,528 --> 00:32:27,598
YOU THERE'S TWO KINDS OF 

793
00:32:27,598 --> 00:32:30,133
GLYCOMOLECULES ON THE SURFACE, 

794
00:32:30,133 --> 00:32:31,668
GLYCOLIPIDS AND PROTEINS.

795
00:32:31,668 --> 00:32:32,836
OKAY.

796
00:32:32,836 --> 00:32:35,172
THAT HAS BEEN THE STANDARD STATE

797
00:32:35,172 --> 00:32:36,840
OF THE ART OF KNOWLEDGE FOR MORE

798
00:32:36,840 --> 00:32:38,308
ETHAN 100 YEARS NOW.

799
00:32:38,308 --> 00:32:39,243
EVERY TEXTBOOK WILL TELL YOU 

800
00:32:39,243 --> 00:32:40,310
THIS.

801
00:32:40,310 --> 00:32:43,313
IT TURNS OUT THAT'S NOT ALL.

802
00:32:43,313 --> 00:32:46,250
A COUPLE YEARS AGO WE DISCOVERED

803
00:32:46,250 --> 00:32:48,418
THAT THERE'S ANOTHER BIO 

804
00:32:48,418 --> 00:32:49,820
MOLECULE THAT ALSO GETS 

805
00:32:49,820 --> 00:32:50,787
GLYCOSYLATED AND ALSO PRESENTED 

806
00:32:50,787 --> 00:32:53,423
ON THE CELL SURFACE AND IT'S 

807
00:32:53,423 --> 00:32:55,459
RNA.

808
00:32:55,459 --> 00:32:57,828
SO CHECK THIS OUT.

809
00:32:57,828 --> 00:33:00,230
A FORMER POSTDOC IN MY LAB CAME 

810
00:33:00,230 --> 00:33:02,599
FROM A Ph.D. TRAINING IN HOWARD 

811
00:33:02,599 --> 00:33:05,969
CHANG'S LAB AT STANFORD WHO IS A

812
00:33:05,969 --> 00:33:09,773
VERY FAMOUS RNA BIO CHEMIST NOW 

813
00:33:09,773 --> 00:33:13,243
HEAD OF RESEARCH FOR AMGEN AND 

814
00:33:13,243 --> 00:33:17,814
RECENTLY LEFT STANFORD TO AMGEN 

815
00:33:17,814 --> 00:33:21,485
AND CAME WITH DEEP EXPERTISE AND

816
00:33:21,485 --> 00:33:23,620
ASKED ME HOW COME ALL THE OTHER 

817
00:33:23,620 --> 00:33:25,889
MOLECULE GLYCOSYLATED BUT NOT 

818
00:33:25,889 --> 00:33:27,758
RNA AND I SAID THAT'S THE WAY IT

819
00:33:27,758 --> 00:33:33,163
IS AND HOW LIFE EVOLVED AND HE 

820
00:33:33,163 --> 00:33:37,234
SAID HAS ANYONE LOOKED?

821
00:33:37,234 --> 00:33:39,236
AS FAR AS I KNOW NO ONE THOUGHT 

822
00:33:39,236 --> 00:33:45,842
TO LOOK AND THE CELL BIOLOGIST 

823
00:33:45,842 --> 00:33:50,080
WHY WOULD YOU LOOK AND WE KNOW 

824
00:33:50,080 --> 00:33:54,751
WHERE IT IS IN THE LUMEN OF THE 

825
00:33:54,751 --> 00:33:57,154
ER AND GOLGI COMPARTMENT AND 

826
00:33:57,154 --> 00:33:59,089
THEY TWO WORLDS DON'T TOUCH EACH

827
00:33:59,089 --> 00:33:59,823
OTHER.

828
00:33:59,823 --> 00:34:03,327
WHY WOULD YOU THINK RNA COULD BE

829
00:34:03,327 --> 00:34:05,228
GLYCOSYLATED.

830
00:34:05,228 --> 00:34:07,531
FORTUNATELY, RYAN THOUGHT IF NO 

831
00:34:07,531 --> 00:34:10,200
ONE'S LOOKED, LET ME BE THE ONE 

832
00:34:10,200 --> 00:34:11,935
AND ANSWER THE QUESTION ONCE AND

833
00:34:11,935 --> 00:34:14,371
FOR ALL.

834
00:34:14,371 --> 00:34:18,175
HE USED AZIDE SUGARS AND SAID IF

835
00:34:18,175 --> 00:34:21,345
I GET IT IN MY RNA MAYBE IT'S 

836
00:34:21,345 --> 00:34:24,281
GLYCOSYLATED AND HE DID THAT AND

837
00:34:24,281 --> 00:34:27,351
TOOK CELLS AND TOOK THE SUGARS 

838
00:34:27,351 --> 00:34:32,823
AND ACID AND DID RNA EXTRACTION 

839
00:34:32,823 --> 00:34:35,559
AND PURIFICATION STEPPED AND 

840
00:34:35,559 --> 00:34:37,828
CLICKED ON A BIO TIN PROBE USING

841
00:34:37,828 --> 00:34:41,465
THE COPPER CLICK CHEMISTRY AND 

842
00:34:41,465 --> 00:34:42,666
ANALYZED THE CHEMISTRY USING 

843
00:34:42,666 --> 00:34:44,201
VARIOUS GELS AND BLOTTING 

844
00:34:44,201 --> 00:34:46,603
TECHNIQUES AND WAS SURPRISED TO 

845
00:34:46,603 --> 00:34:49,272
SEE THERE WAS A SPECIES THERE 

846
00:34:49,272 --> 00:34:52,576
THAT IS RNA CARRYING THE SUGAR.

847
00:34:52,576 --> 00:34:56,279
HE RAN A SUCROSE GRADIENT TO 

848
00:34:56,279 --> 00:34:59,116
SEPARATE THEM OUT AND FOUND THE 

849
00:34:59,116 --> 00:35:00,150
SUGAR LABELLED RNA, IT'S 

850
00:35:00,150 --> 00:35:03,086
ACTUALLY MAPPING WITH THE SMALL 

851
00:35:03,086 --> 00:35:05,722
RNAs BUT IT WAS ON A GEL LIKE A 

852
00:35:05,722 --> 00:35:06,990
LARGE RNA.

853
00:35:06,990 --> 00:35:09,359
IT HAS AN ANOMALOUS MIGRATION ON

854
00:35:09,359 --> 00:35:10,127
THE GEL.

855
00:35:10,127 --> 00:35:12,929
COULD IT BE GLYCOSYLATED RNA?

856
00:35:12,929 --> 00:35:15,332
FOR THE NEXT TWO YEARS WE 

857
00:35:15,332 --> 00:35:16,767
BASICALLY SPENT EVERY DAY 

858
00:35:16,767 --> 00:35:19,469
THINKING HOW TO SHOOT DOWN THE 

859
00:35:19,469 --> 00:35:20,437
HYPOTHESIS BECAUSE IT SEEMED 

860
00:35:20,437 --> 00:35:23,740
IMPOSSIBLE BUT WE PROVED TO 

861
00:35:23,740 --> 00:35:26,777
OURSELVES AND ULTIMATELY THE 

862
00:35:26,777 --> 00:35:28,045
COMMUNITY THERE'S GLYCORNAs ON 

863
00:35:28,045 --> 00:35:29,880
THE SURFACE OF THE CELLS.

864
00:35:29,880 --> 00:35:31,148
IN THE FIRST SET OF EXPERIMENTS 

865
00:35:31,148 --> 00:35:35,385
THE TYPE WE IDENTIFIED WERE ALL 

866
00:35:35,385 --> 00:35:43,927
SMALL STRUCTURED RNAs LIKE Y-RA 

867
00:35:43,927 --> 00:35:50,167
RNAs AND T RNAS AND THEY WERE 

868
00:35:50,167 --> 00:35:53,970
HIGHLY BRANCHED GLYCANS AND WE 

869
00:35:53,970 --> 00:35:55,739
PUBLISHED THIS IN '21 AND IT 

870
00:35:55,739 --> 00:35:57,340
TOOK FOUR ROUNDS OF REVIEWERS 

871
00:35:57,340 --> 00:35:58,875
AND SEVEN REVIEWERS TO GET IT 

872
00:35:58,875 --> 00:36:00,010
PUBLISHED IN CELL.

873
00:36:00,010 --> 00:36:01,945
ONE THING WE REPORT IN THE PAPER

874
00:36:01,945 --> 00:36:04,448
IS THE INTRIGUING OBSERVATION 

875
00:36:04,448 --> 00:36:10,153
THAT GLYCO RNAs ON THE CELL 

876
00:36:10,153 --> 00:36:12,322
SURFACE CAN ENGAGE A FAMILY OF 

877
00:36:12,322 --> 00:36:14,024
IMMUNE CHECKPOINT RECEPTORS.

878
00:36:14,024 --> 00:36:17,094
IT'S EARLY DAYS BUT WE SUSPECT 

879
00:36:17,094 --> 00:36:23,033
IT MAY BE PART OF AN IMMUNE 

880
00:36:23,033 --> 00:36:25,602
MODULATORY OR TRAINING EFFECT 

881
00:36:25,602 --> 00:36:28,271
AND MAY PLAY A ROLE IN 

882
00:36:28,271 --> 00:36:28,572
REGULATION.

883
00:36:28,572 --> 00:36:29,806
THAT'S AN OPEN QUESTION.

884
00:36:29,806 --> 00:36:32,242
MOST IMPORTANTLY IS WE PUT WORK 

885
00:36:32,242 --> 00:36:34,177
INTO IDENTIFYING THE SPECIFIC 

886
00:36:34,177 --> 00:36:36,113
CHEMICAL LINKAGE THAT CONNECTS 

887
00:36:36,113 --> 00:36:37,080
THE GLYCOAND RNA.

888
00:36:37,080 --> 00:36:40,984
ONE OF THE LINKAGES WE 

889
00:36:40,984 --> 00:36:49,392
IDENTIFIED WAS BASICALLY GLY

890
00:36:49,392 --> 00:36:53,163
GLYCOSYLATION OF RTRNs AND THE 

891
00:36:53,163 --> 00:36:55,799
ACP3U MODIFIED BASE WHICH HAS 

892
00:36:55,799 --> 00:36:59,236
THE BIG CHEMICAL NAME AND IN A 

893
00:36:59,236 --> 00:37:03,373
NUTSHELL WE THE ACP3U RESIDUES 

894
00:37:03,373 --> 00:37:06,710
HIGHLY CONSERVED IN YOUR tRNA 

895
00:37:06,710 --> 00:37:08,044
AND VARIES FROM SPECIES TO 

896
00:37:08,044 --> 00:37:10,914
SPECIES BUT IN MAMMALS IT'S 

897
00:37:10,914 --> 00:37:12,816
ALWAYS IN THIS PARTICULAR LOOP.

898
00:37:12,816 --> 00:37:15,952
HIRES THE CHEMICAL STRUCTURE.

899
00:37:15,952 --> 00:37:18,588
IT'S THIS EXTRA AMINO ACID ABOUT

900
00:37:18,588 --> 00:37:21,992
IT HANGING OFF OF IT AND THERE'S

901
00:37:21,992 --> 00:37:26,630
A BIO SYNTHETIC PATHWAY WHEN 

902
00:37:26,630 --> 00:37:29,032
IT'S ALREADY IN THE TRNA SO YOU 

903
00:37:29,032 --> 00:37:31,201
GET THE MODIFICATION.

904
00:37:31,201 --> 00:37:35,372
WITH A COLLABORATOR CALLED BEN 

905
00:37:35,372 --> 00:37:44,381
GARCIA A WORLD CLASS MASS 

906
00:37:44,381 --> 00:37:45,015
SPECTOMETERRIST THEY WERE ABLE 

907
00:37:45,015 --> 00:37:46,850
TO LINK IT AND HERE'S THE BASE, 

908
00:37:46,850 --> 00:37:49,519
HERE'S THE MODIFIED BASE AND 

909
00:37:49,519 --> 00:37:52,355
THERE'S AN AMINO GROUP AND FROM 

910
00:37:52,355 --> 00:37:55,392
THEN ON IT LOOKS LIKE A GLYCAN 

911
00:37:55,392 --> 00:37:57,027
YOU FIND ON YOUR FAVORITE 

912
00:37:57,027 --> 00:37:57,494
NEIGHBORHOOD PROTEIN.

913
00:37:57,494 --> 00:38:01,164
SHOCKING.

914
00:38:01,164 --> 00:38:03,233
AND RYAN HAS NOW DONE A LOT MORE

915
00:38:03,233 --> 00:38:05,168
WORK ON THIS AND IS NOW A YOUNG 

916
00:38:05,168 --> 00:38:06,369
PROFESSOR AT HARVARD UNIVERSITY 

917
00:38:06,369 --> 00:38:08,939
AND HE IS BASICALLY BUILDING OUT

918
00:38:08,939 --> 00:38:13,276
THE STORY OF GLYCORNA BIO 

919
00:38:13,276 --> 00:38:14,878
SYNTHESIS, TRAFFICKING, HOW THEY

920
00:38:14,878 --> 00:38:19,049
DO THEY GET IN THE LUMEN AND 

921
00:38:19,049 --> 00:38:21,351
THAT'S WHY THEY'RE GETTING 

922
00:38:21,351 --> 00:38:22,085
GLYCOSYLATED?

923
00:38:22,085 --> 00:38:24,721
IS A PRIMORDIAL FORM LATER 

924
00:38:24,721 --> 00:38:27,357
MIMICKED BY PROTEINS WITH THEIR 

925
00:38:27,357 --> 00:38:29,492
RESIDUES OR THE OTHER WAY 

926
00:38:29,492 --> 00:38:29,726
AROUND?

927
00:38:29,726 --> 00:38:33,363
I MEAN, ACP3U IS HIGHLY 

928
00:38:33,363 --> 00:38:35,332
CONSERVED IN ALL DOMAINS OF 

929
00:38:35,332 --> 00:38:36,433
LIFE.

930
00:38:36,433 --> 00:38:37,801
THIS MAY BE SOMETHING ANCIENT.

931
00:38:37,801 --> 00:38:39,936
HIS LAB IS PICKING THIS APART 

932
00:38:39,936 --> 00:38:45,342
AND IF YOU DO A PUB MED SEARCH 

933
00:38:45,342 --> 00:38:49,913
OF GLYCORNA YOU'LL GET 40.

934
00:38:49,913 --> 00:38:53,483
HE HAS A PIPELINE COMING OUT 

935
00:38:53,483 --> 00:38:55,318
NEXT MONTH WHICH WILL BLOW YOUR 

936
00:38:55,318 --> 00:38:57,254
MIND AND THE IMMUNE SYSTEM IS 

937
00:38:57,254 --> 00:38:58,054
PART OF THIS.

938
00:38:58,054 --> 00:38:59,589
HOPEFULLY YOU'LL SEE THIS IS A 

939
00:38:59,589 --> 00:39:00,957
BASIC SCIENCE DISCOVERY THAT CAN

940
00:39:00,957 --> 00:39:02,559
COME WHEN YOU HAVE A TOOL THAT 

941
00:39:02,559 --> 00:39:05,729
ALLOWS YOU TO OPEN A WINDOW TO A

942
00:39:05,729 --> 00:39:06,196
NEW TYPE OF MOLECULE.

943
00:39:06,196 --> 00:39:06,396
OKAY.

944
00:39:06,396 --> 00:39:08,498
SO LET'S REVISE THE TEXTBOOKS.

945
00:39:08,498 --> 00:39:09,432
HOPEFULLY IN THE NEXT GENERATION

946
00:39:09,432 --> 00:39:13,270
OF TEXTBOOKS YOU WON'T JUST SEE 

947
00:39:13,270 --> 00:39:16,339
THE GLYCOPROTEINS AND 

948
00:39:16,339 --> 00:39:21,344
GLYCOLIPIDS BUT GLYCORNAs AND 

949
00:39:21,344 --> 00:39:24,414
ANCHORED BY RNA BINDING 

950
00:39:24,414 --> 00:39:24,681
PROTEINS.

951
00:39:24,681 --> 00:39:27,450
SO IN THE LAST PART I'LL GIVE A 

952
00:39:27,450 --> 00:39:30,754
COUPLE VIGNETTES THAT ILLUSTRATE

953
00:39:30,754 --> 00:39:33,423
HOW BIOORTHOGONAL AND CLICK 

954
00:39:33,423 --> 00:39:36,693
CHEMISTRIIES STARTED TRANSLATIN 

955
00:39:36,693 --> 00:39:39,262
INTO THE WORLD OF THERAPEUTICS.

956
00:39:39,262 --> 00:39:41,364
YOU CAN GOOGLE WEBSITES AND A 

957
00:39:41,364 --> 00:39:43,700
NUMBER OF COMPANIES WILL 

958
00:39:43,700 --> 00:39:44,501
ADVERTISE THEMSELVES AS USING 

959
00:39:44,501 --> 00:39:45,568
BIOORTHOGONAL CHEMISTRY AS A 

960
00:39:45,568 --> 00:39:45,835
PLATFORM.

961
00:39:45,835 --> 00:39:50,373
A VERY POPULAR APPLICATION IS IN

962
00:39:50,373 --> 00:39:53,710
MAKING NEXT GENERATION ANTIBODY 

963
00:39:53,710 --> 00:39:57,447
DRUG CONJUGATES AND AN AREA MY 

964
00:39:57,447 --> 00:39:58,481
LAB HAS WORKED IN AND SOME 

965
00:39:58,481 --> 00:40:05,822
COMPANIES ARE USING THEM TO MAKE

966
00:40:05,822 --> 00:40:06,656
VACCINES FOR PNEUMOCOCCUS AND 

967
00:40:06,656 --> 00:40:11,494
PEOPLE WHO MAKE ANY KIND OF 

968
00:40:11,494 --> 00:40:12,796
COMPLEX CONJUGATE PROBABLY ARE 

969
00:40:12,796 --> 00:40:15,031
AVAILING THEMSELVES OF THESE 

970
00:40:15,031 --> 00:40:18,501
CLICK CHEMISTRIES AND 

971
00:40:18,501 --> 00:40:21,004
BIOORTHOGONAL CHEMISTRIES.

972
00:40:21,004 --> 00:40:22,706
THERE'S CONJUGATES BETWEEN A 

973
00:40:22,706 --> 00:40:24,574
TUMOR FIGHTING ANTIBODY AND 

974
00:40:24,574 --> 00:40:26,843
TOXIC PAY LOAD CONNECTED BY A 

975
00:40:26,843 --> 00:40:27,610
CHEMICAL LIQUOR.

976
00:40:27,610 --> 00:40:29,546
THIS IS AN AREA I'VE BEEN 

977
00:40:29,546 --> 00:40:31,448
FOLLOWING SINCE IT CAUGHT FIRE 

978
00:40:31,448 --> 00:40:33,083
BACK IN THE 1990s AND FDA 

979
00:40:33,083 --> 00:40:36,953
APPROVALS IN THE 2000s.

980
00:40:36,953 --> 00:40:41,758
RIGHT NOW THERE'S AT LEAST A 

981
00:40:41,758 --> 00:40:43,793
DOZEN ANTIBODY DRUG CONJUGATES 

982
00:40:43,793 --> 00:40:46,730
BY THE FDA AND CLINICAL TRIALS 

983
00:40:46,730 --> 00:40:49,099
IN CHINA ARE IN THE THOUSANDS 

984
00:40:49,099 --> 00:40:50,500
FOR NEXT GENERATION.

985
00:40:50,500 --> 00:40:52,535
PEOPLE SPENT THE LAST 30 YEARS 

986
00:40:52,535 --> 00:40:53,069
SYSTEMICALLY SOLVING THE 

987
00:40:53,069 --> 00:40:53,803
PROBLEMS.

988
00:40:53,803 --> 00:40:56,039
WE FIGURED OUT HOW TO MAKE 

989
00:40:56,039 --> 00:40:58,141
BETTER ANTIBODIES.

990
00:40:58,141 --> 00:41:01,111
WE FIGURED OUT WHAT PAY LOADS 

991
00:41:01,111 --> 00:41:02,412
WORK BEST.

992
00:41:02,412 --> 00:41:06,316
WE KIND CLEVER LINKERS STABLE IN

993
00:41:06,316 --> 00:41:09,119
SERUM BUT FALL APART INSIDE 

994
00:41:09,119 --> 00:41:10,720
CANCER CELLS BUT THE AREA THAT 

995
00:41:10,720 --> 00:41:12,122
HASN'T BEEN DISRUPTED YET TO MY 

996
00:41:12,122 --> 00:41:14,624
MIND IS HOW YOU DO THE CHEMISTRY

997
00:41:14,624 --> 00:41:17,293
BETWEEN THE PROTEINS WHICH COMES

998
00:41:17,293 --> 00:41:19,562
FROM RECOMBINANT PRODUCTION AND 

999
00:41:19,562 --> 00:41:20,497
THE LINKER DRUG FROM CHEMICAL 

1000
00:41:20,497 --> 00:41:20,697
SYNTHESIS.

1001
00:41:31,674 --> 00:41:35,145
AND SOME ARE DOING IT ON SISTINE

1002
00:41:35,145 --> 00:41:37,213
SIDE CHAINS WITHOUT MUCH CONTROL

1003
00:41:37,213 --> 00:41:45,088
OVER THE SITES AND STOICY STOIC 

1004
00:41:45,088 --> 00:41:45,722
METRY.

1005
00:41:45,722 --> 00:41:46,890
THIS IS WHAT IT'S WELL 

1006
00:41:46,890 --> 00:41:48,491
POSITIONED TO SOLVE.

1007
00:41:48,491 --> 00:41:49,826
IF YOU HAVE AN ANTIBODY WHICH 

1008
00:41:49,826 --> 00:41:54,597
MIGHT TYPICALLY HAVE 70 OR 80 

1009
00:41:54,597 --> 00:42:03,306
SURFACE EXPOSED LYSISES AND YOU 

1010
00:42:03,306 --> 00:42:04,507
CAN'T HAVE 60 OR 70 BECAUSE 

1011
00:42:04,507 --> 00:42:05,809
YOU'LL KILL THE MOLECULE.

1012
00:42:05,809 --> 00:42:08,711
IF THERE'S A WAY TO INTRODUCE A 

1013
00:42:08,711 --> 00:42:10,013
NEW CHEMICAL GROUP, 

1014
00:42:10,013 --> 00:42:12,282
BIOORTHOGONAL GROUP THAT NEITHER

1015
00:42:12,282 --> 00:42:15,018
INTERACTS OR INTERFERES WITH ANY

1016
00:42:15,018 --> 00:42:16,286
OTHER SIDE CHAIN YOU CAN DIRECT 

1017
00:42:16,286 --> 00:42:18,655
THE CHEMISTRY WHERE YOU WANT IT.

1018
00:42:18,655 --> 00:42:20,990
YOU CAN PUT THE PAY LOAD HERE OR

1019
00:42:20,990 --> 00:42:21,825
HERE OR HERE OR HERE AS LONG AS 

1020
00:42:21,825 --> 00:42:24,561
YOU HAVE A WAY TO INTRODUCE THE 

1021
00:42:24,561 --> 00:42:25,929
CHEMICAL GROUP AT THE SITES AND 

1022
00:42:25,929 --> 00:42:30,033
WITH THE RATIO OF INTEREST.

1023
00:42:30,033 --> 00:42:32,202
SO, WE PUT THOUGHT INTO HOW TO 

1024
00:42:32,202 --> 00:42:33,169
LEVERAGE BIOORTHOGONAL CHEMISTRY

1025
00:42:33,169 --> 00:42:34,237
THIS WAY AND ULTIMATELY 

1026
00:42:34,237 --> 00:42:37,474
DEVELOPED A TECHNIQUE WE CALL 

1027
00:42:37,474 --> 00:42:43,112
THE ALDAHIDE TAG FOR MAKING SITE

1028
00:42:43,112 --> 00:42:46,549
SPECIFIC ANTIBODY DRUG 

1029
00:42:46,549 --> 00:42:50,053
CONJUGATES STARTING WITH AN 

1030
00:42:50,053 --> 00:42:52,355
ENZYME WHICH WILL OXIDIZE IT IN 

1031
00:42:52,355 --> 00:42:54,257
A SHORT SEQUENCE ONLY FIVE 

1032
00:42:54,257 --> 00:43:01,831
RESIDUES AND CONVERT IT TO WHAT 

1033
00:43:01,831 --> 00:43:04,133
HAS AN ALDEHYDE AND CLONE THAT 

1034
00:43:04,133 --> 00:43:07,036
INTO YOUR PROTEIN OF INTEREST 

1035
00:43:07,036 --> 00:43:10,206
YOUR SITE OF INTEREST, THIS WILL

1036
00:43:10,206 --> 00:43:13,810
INTRODUCE AN ALDEHYDE AND YOU 

1037
00:43:13,810 --> 00:43:15,478
CAN DO CHEMISTRY THAT DOESN'T 

1038
00:43:15,478 --> 00:43:16,679
INTERFERE WITH THE REST OF THE 

1039
00:43:16,679 --> 00:43:17,247
PROTEIN.

1040
00:43:17,247 --> 00:43:18,915
ON THE GROUND WHAT WE WOULD DO 

1041
00:43:18,915 --> 00:43:20,984
WITH AN ANTIBODY IS CLONE THAT 

1042
00:43:20,984 --> 00:43:22,552
MOTIF INTO THE GENE SEQUENCE OF 

1043
00:43:22,552 --> 00:43:25,054
EITHER THE HEAVY CHAIN OR THE 

1044
00:43:25,054 --> 00:43:26,789
LIGHT CHAIN, DEPENDING WHERE YOU

1045
00:43:26,789 --> 00:43:27,457
WANT IT.

1046
00:43:27,457 --> 00:43:30,159
EXPRESS THE PLASMIDS IN CELLS 

1047
00:43:30,159 --> 00:43:34,797
WITH A PLASMID THAT BOOSTS THIS 

1048
00:43:34,797 --> 00:43:36,199
ENZYME'S EXPRESSION AND THE 

1049
00:43:36,199 --> 00:43:38,501
CELLS WILL SECRETE THE ANTIBODY 

1050
00:43:38,501 --> 00:43:41,237
WITH ALDEHYDES READY TO GO AT 

1051
00:43:41,237 --> 00:43:43,072
THE SITES YOU ENGINEER.

1052
00:43:43,072 --> 00:43:45,475
WE DEVELOPED A CHEMISTRY ALSO 

1053
00:43:45,475 --> 00:43:48,311
BASED ON ANCIENT GERMAN 

1054
00:43:48,311 --> 00:43:49,679
CHEMISTRY I WON'T GO INTO BUT 

1055
00:43:49,679 --> 00:43:51,648
ALLOWS YOU TO ATTACH A LINKER 

1056
00:43:51,648 --> 00:43:52,849
AND PAY LOAD DIRECTLY TO THE 

1057
00:43:52,849 --> 00:43:57,020
SITES AND FOR THE CHEMISTS HERE 

1058
00:43:57,020 --> 00:44:00,256
SOMEBODY ALWAYS ASKS WHAT'S THE 

1059
00:44:00,256 --> 00:44:01,824
MECHANISM?

1060
00:44:01,824 --> 00:44:04,894
BASICALLY THIS REACTS AND YOU 

1061
00:44:04,894 --> 00:44:06,596
GET AN INTRAMOLECULAR 

1062
00:44:06,596 --> 00:44:09,499
SUBSTITUTION AND THE PEOPLE IN 

1063
00:44:09,499 --> 00:44:13,803
THE AUDIENCE HARDCORE CHEMISTS 

1064
00:44:13,803 --> 00:44:16,406
WILL RECOGNIZE THIS AND THAT 

1065
00:44:16,406 --> 00:44:18,207
FORMS A CARBON LINKED PRODUCT 

1066
00:44:18,207 --> 00:44:19,943
THAT'S ROCK STABLE.

1067
00:44:19,943 --> 00:44:21,477
WILL NOT FALL A PART EVEN IN THE

1068
00:44:21,477 --> 00:44:24,247
HUMAN BODY.

1069
00:44:24,247 --> 00:44:26,749
WE FOUND A COMPANY BY MYSELF AND

1070
00:44:26,749 --> 00:44:29,218
MY FORMER STUDENT AND EVENTUALLY

1071
00:44:29,218 --> 00:44:30,720
THAT COMPANY WAS ACQUIRED AND 

1072
00:44:30,720 --> 00:44:33,590
NOW THIS IS ONE OF THE OFFERINGS

1073
00:44:33,590 --> 00:44:35,558
OF IT.

1074
00:44:35,558 --> 00:44:36,726
THEY PARTNERED WITH COMPANY WHO 

1075
00:44:36,726 --> 00:44:39,329
WANT TO MAKE ADCs.

1076
00:44:39,329 --> 00:44:41,064
YOU E-MAIL THEM THE SEQUENCE OF 

1077
00:44:41,064 --> 00:44:42,465
YOUR HEAVY CHAIN AND LIGHT CHAIN

1078
00:44:42,465 --> 00:44:44,667
AND FROM THERE THEY'LL MAKE THE 

1079
00:44:44,667 --> 00:44:48,938
ADC AND SOME MOLECULES IN THE 

1080
00:44:48,938 --> 00:44:49,205
CLINIC.

1081
00:44:49,205 --> 00:44:50,540
WHAT ABOUT CELLS?

1082
00:44:50,540 --> 00:44:52,542
WE CAN DO CHEMISTRY ON CELLS.

1083
00:44:52,542 --> 00:44:54,310
WE ALREADY KNOW THAT.

1084
00:44:54,310 --> 00:44:55,478
MAYBE WE CAN ADD SOMETHING TO 

1085
00:44:55,478 --> 00:44:58,481
THE WORLD OF CELLULAR 

1086
00:44:58,481 --> 00:44:58,815
THERAPEUTICS.

1087
00:44:58,815 --> 00:45:00,883
SO CAR-Ts.

1088
00:45:00,883 --> 00:45:02,485
EVERYONE'S EXCITE ABOUT THIS NEW

1089
00:45:02,485 --> 00:45:04,487
FORM OF IMMUNE THERAPY.

1090
00:45:04,487 --> 00:45:06,522
IT'S EXPENSIVE AND HARD TO SCALE

1091
00:45:06,522 --> 00:45:09,058
AND VERY BESPOKE.

1092
00:45:09,058 --> 00:45:10,493
THE TYPICAL PROTOCOL INVOLVES 

1093
00:45:10,493 --> 00:45:12,295
FIRST REMOVING BLOOD FROM THE 

1094
00:45:12,295 --> 00:45:15,498
CANCER PATIENT, TAKING THEIR T 

1095
00:45:15,498 --> 00:45:20,737
CELLS EX VIVO AND INTRODUCE A 

1096
00:45:20,737 --> 00:45:21,537
CHIMERIC RECEPTOR SO AFTER YOU 

1097
00:45:21,537 --> 00:45:27,176
GROW THE CELLS AND REINTRODUCE 

1098
00:45:27,176 --> 00:45:28,611
THEM IN THE PATIENT IN THE 

1099
00:45:28,611 --> 00:45:30,647
PERFECT WORLD THEY HOLD TO THE 

1100
00:45:30,647 --> 00:45:31,848
TUMOR AND KILL IT AND IT'S 

1101
00:45:31,848 --> 00:45:33,416
REMARKABLE WHEN THEY WORK AND 

1102
00:45:33,416 --> 00:45:35,251
FOR CERTAIN BLOOD CANCERS YOU 

1103
00:45:35,251 --> 00:45:38,588
CAN GET A CURE WITH A CAR-T 

1104
00:45:38,588 --> 00:45:40,323
THERAPY BUT LIKE I SAID, IT'S 

1105
00:45:40,323 --> 00:45:41,524
EXPENSIVE AND DOESN'T SCALE AND 

1106
00:45:41,524 --> 00:45:43,092
IS PATIENT BY PATIENT BY 

1107
00:45:43,092 --> 00:45:43,693
PATIENT.

1108
00:45:43,693 --> 00:45:46,362
MOST PEOPLE DON'T HAVE ACCESS TO

1109
00:45:46,362 --> 00:45:46,763
THIS TECHNOLOGY.

1110
00:45:46,763 --> 00:45:51,100
EVEN PATIENTS WITH CANCERS THAT 

1111
00:45:51,100 --> 00:45:51,868
COULD BENEFIT.

1112
00:45:51,868 --> 00:45:54,370
WELL, ONE OF MY FORMER STUDENTS 

1113
00:45:54,370 --> 00:45:56,272
FORMED A STUDENT OF WHICH I 

1114
00:45:56,272 --> 00:45:58,608
SERVE ON THE BOARD OF DIRECTORS 

1115
00:45:58,608 --> 00:46:01,477
THAT IS USING BIOORTHOGONAL 

1116
00:46:01,477 --> 00:46:03,346
CHEMISTRY TO CHEMICALLY ENGINEER

1117
00:46:03,346 --> 00:46:06,683
T CELLS TO HOME TO TUMORS RATHER

1118
00:46:06,683 --> 00:46:07,250
THAN GENETICALLY ENGINEER.

1119
00:46:07,250 --> 00:46:09,452
AS A CONSEQUENCE THEY CAN TAKE 

1120
00:46:09,452 --> 00:46:12,689
OFF THE SHELF T CELLS THE 

1121
00:46:12,689 --> 00:46:14,857
SO-CALLED GAMMA DELTA T CELLS 

1122
00:46:14,857 --> 00:46:19,095
THAT ARE GENERALLY WELL 

1123
00:46:19,095 --> 00:46:21,330
TOLERATED IN ALLOGENEIC FOLKS SO

1124
00:46:21,330 --> 00:46:22,732
THEY DON'T GET REJECTED.

1125
00:46:22,732 --> 00:46:27,503
SO TAY TAKE THE OFF THE SHELF T 

1126
00:46:27,503 --> 00:46:29,539
CELLS AND DO BIOORTHOGONAL CHEM 

1127
00:46:29,539 --> 00:46:33,509
TRY TO INTRODUCE THE ANTIBODY 

1128
00:46:33,509 --> 00:46:35,311
FROM THE OUTSIDE AND IN EARLY 

1129
00:46:35,311 --> 00:46:37,814
CLINICAL DATA THEY'RE EFFECTIVE 

1130
00:46:37,814 --> 00:46:39,916
AT HOMING TO AND KILLING BLOOD 

1131
00:46:39,916 --> 00:46:41,818
CANCERS IN PATIENTS.

1132
00:46:41,818 --> 00:46:43,853
HOPEFULLY IT WILL MAKE A CAR T 

1133
00:46:43,853 --> 00:46:44,787
LIKE THERAPEUTIC CHEAPER AND 

1134
00:46:44,787 --> 00:46:46,589
MORE AVAILABLE TO A BROADER 

1135
00:46:46,589 --> 00:46:48,524
SPECTRUM OF PATIENTS.

1136
00:46:48,524 --> 00:46:50,526
AND THEN FINALLY I MENTIONED 

1137
00:46:50,526 --> 00:46:52,962
EARLY ON WE HAD THIS DREAM OF 

1138
00:46:52,962 --> 00:46:55,898
TAKING CHEMISTRY OUT OF THE 

1139
00:46:55,898 --> 00:46:57,266
ROUND BOTTOM FLASK AND ONTO THE 

1140
00:46:57,266 --> 00:46:58,568
CELL BUT CAN WE GO ALL THE WAY 

1141
00:46:58,568 --> 00:47:00,103
TO THE CHEMISTRY IN THE HUMAN 

1142
00:47:00,103 --> 00:47:01,437
BODY AND THE ANSWER IS YES.

1143
00:47:01,437 --> 00:47:02,772
THIS IS NOW HAPPENING IN THE 

1144
00:47:02,772 --> 00:47:07,810
HANDS OF A COMPANY IN THE BAY 

1145
00:47:07,810 --> 00:47:08,244
AREA.

1146
00:47:08,244 --> 00:47:15,518
SO THEY'RE USING A CHEMISTRY 

1147
00:47:15,518 --> 00:47:19,155
CALLED TETRAZINE LIGATION AND 

1148
00:47:19,155 --> 00:47:22,759
USES A HIGHLY STRAINED REAGENT 

1149
00:47:22,759 --> 00:47:30,299
BUT IT'S A TRANS CYCLE OCTINE 

1150
00:47:30,299 --> 00:47:33,536
AND THEY'LL REACT WITH REAGENTS 

1151
00:47:33,536 --> 00:47:34,737
AND YOU CAN MANEUVER THE 

1152
00:47:34,737 --> 00:47:36,839
CHEMISTRY SO AT THE SAME TIME 

1153
00:47:36,839 --> 00:47:38,074
THESE TWO THINGS ARE CLICKING 

1154
00:47:38,074 --> 00:47:40,243
TOGETHER THERE'S THE RELEASE OF 

1155
00:47:40,243 --> 00:47:41,577
THIS SIDE CHAIN.

1156
00:47:41,577 --> 00:47:44,814
SO YOU CAN USE THE CHEMISTRY TO 

1157
00:47:44,814 --> 00:47:47,316
NOT ONLY CLICK BUT RELEASE WHICH

1158
00:47:47,316 --> 00:47:51,988
MAKES IT NICE FOR A PRODRUG 

1159
00:47:51,988 --> 00:47:52,321
APPLICATION.

1160
00:47:52,321 --> 00:47:59,262
TET -- THEY HAVE TAKEN DRUGS 

1161
00:47:59,262 --> 00:48:08,671
THAT'S AN OLDER BUT GOODIE.

1162
00:48:08,671 --> 00:48:12,441
AND TAKE IT TO A PLACE WHERE IT 

1163
00:48:12,441 --> 00:48:14,644
INACTIVATE THE DRUG AND THEY'LL 

1164
00:48:14,644 --> 00:48:18,481
INTERJECT INTO THE INTRATUMORAL 

1165
00:48:18,481 --> 00:48:21,551
ENVIRONMENT WITH THE TETRAZINE 

1166
00:48:21,551 --> 00:48:23,052
ANCHORED TO IT AND THAT IS 

1167
00:48:23,052 --> 00:48:25,822
INSERT IN THE HUMAN BODY AND 

1168
00:48:25,822 --> 00:48:28,324
LATER WHEN YOU INFUSE THIS DRUG 

1169
00:48:28,324 --> 00:48:31,327
WHENEVER THAT DRUG ENCOUNTER THE

1170
00:48:31,327 --> 00:48:32,595
TUMOR IT CAN REACT WITH THE 

1171
00:48:32,595 --> 00:48:37,800
CLICK TO RELEASE AND SPIT OUT AT

1172
00:48:37,800 --> 00:48:41,571
HIGH LOSE LOCALLY IN THE TUMOR.

1173
00:48:41,571 --> 00:48:43,806
YOU CAN HAVE THIS DRUG COURSING 

1174
00:48:43,806 --> 00:48:46,576
THROUGH THE BODY BUT IT'S NOT 

1175
00:48:46,576 --> 00:48:51,547
TOXIC ONLY AS IT'S RELEASED IN 

1176
00:48:51,547 --> 00:48:53,082
THE MICROTISSUE ENVIRONMENT AND 

1177
00:48:53,082 --> 00:48:57,920
THEY'RE DOING A STUDY TO TREAT 

1178
00:48:57,920 --> 00:48:59,121
SOFT TISSUE SARCOMA.

1179
00:48:59,121 --> 00:49:01,290
WHAT STARTED AS A SOLUTION TO A 

1180
00:49:01,290 --> 00:49:03,259
SPECIFIC PROBLEM TO IMAGE CELL 

1181
00:49:03,259 --> 00:49:04,727
SURFACE SUGARS TOOK OFF AND 

1182
00:49:04,727 --> 00:49:06,362
FOUND ALL KIND OF INTERESTING 

1183
00:49:06,362 --> 00:49:06,696
APPLICATIONS.

1184
00:49:06,696 --> 00:49:08,531
SOME IN MY LAB BUT MOST OUTSIDE 

1185
00:49:08,531 --> 00:49:11,968
IN OTHER SETTINGS AND MOST 

1186
00:49:11,968 --> 00:49:13,703
EXCITINGLY NOW IN WAYS THAT WILL

1187
00:49:13,703 --> 00:49:14,871
HOPEFULLY TRANSLATE TO 

1188
00:49:14,871 --> 00:49:20,776
TREATMENTS FOR HUMAN DISEASES.

1189
00:49:20,776 --> 00:49:22,111
SO THERE'S A LOT OF NEW 

1190
00:49:22,111 --> 00:49:26,082
APPLICATIONS AND I LOVE SEEING 

1191
00:49:26,082 --> 00:49:26,949
HOW THE COMMUNITY HAS RUN WITH 

1192
00:49:26,949 --> 00:49:28,951
THIS KIND OF SCIENCE.

1193
00:49:28,951 --> 00:49:32,121
WE CAN'T PREDICT THE FUTURE BUT 

1194
00:49:32,121 --> 00:49:38,361
I THINK BIOORTHOGONAL AND CLICK 

1195
00:49:38,361 --> 00:49:39,061
CHEMISTRY WILL BE USEFUL TO YOU 

1196
00:49:39,061 --> 00:49:40,329
AND IF YOU SEE SOMETHING YOU 

1197
00:49:40,329 --> 00:49:43,132
WANT TO TRY, SEND ME AN AGENT 

1198
00:49:43,132 --> 00:49:45,768
AND WE'LL SEND YOU WHATEVER 

1199
00:49:45,768 --> 00:49:48,070
REAGENTS WE HAVE, OF COURSE.

1200
00:49:48,070 --> 00:49:50,640
FOR THAT, THANK YOU VERY MUCH 

1201
00:49:50,640 --> 00:49:51,607
AND I CAN'T THANK EVERYONE 

1202
00:49:51,607 --> 00:49:54,744
BECAUSE IT'S ABOUT MANY OVER THE

1203
00:49:54,744 --> 00:49:56,812
DECADES BUT I'M INDEBTED TO MY 

1204
00:49:56,812 --> 00:49:58,180
POSTDOCS FOR DOING THE WORK WITH

1205
00:49:58,180 --> 00:49:58,981
ME AND HAPPY TO ANSWER 

1206
00:49:58,981 --> 00:49:59,248
QUESTIONS.

1207
00:49:59,248 --> 00:49:59,515
THANK YOU.

1208
00:49:59,515 --> 00:49:59,582
 

1209
00:50:11,394 --> 00:50:15,331
>> FOLKS, USE THE MICS.

1210
00:50:15,331 --> 00:50:15,665
>> HI.

1211
00:50:15,665 --> 00:50:18,401
SUPER COOL.

1212
00:50:18,401 --> 00:50:21,637
THE THING I'M THINKING ABOUT THE

1213
00:50:21,637 --> 00:50:24,807
ENTIRE I'M WATCHING IS THE EIGHT

1214
00:50:24,807 --> 00:50:25,141
MEMBER THING.

1215
00:50:25,141 --> 00:50:26,242
WHERE DOES THAT COME FROM?

1216
00:50:26,242 --> 00:50:29,111
DO YOU HAVE TO MAKE IT?

1217
00:50:29,111 --> 00:50:32,148
IS IT UNSTABLE AND EXPENSIVE?

1218
00:50:32,148 --> 00:50:33,649
THAT'S WHAT I WAS SWEATING 

1219
00:50:33,649 --> 00:50:33,883
ABOUT?

1220
00:50:33,883 --> 00:50:36,752
>> IN THE EARLY DAYS THERE

1221
00:50:36,752 --> 00:50:40,589
REALLY WASN'T MUCH LITERATURE ON

1222
00:50:40,589 --> 00:50:43,426
CYCLE OCTINES AND THERE WERE A 

1223
00:50:43,426 --> 00:50:44,293
COUPLE PAPERS AND PEOPLE PLAYED 

1224
00:50:44,293 --> 00:50:47,463
WITH THEM BACK THEN.

1225
00:50:47,463 --> 00:50:51,267
WE DEVELOP SYNTHETIC ROUTES TO 

1226
00:50:51,267 --> 00:50:53,703
TUNE THEIR REACTIVITIES OVER 

1227
00:50:53,703 --> 00:50:57,640
MANY ORDERS OF MAGNITUDE AND 

1228
00:50:57,640 --> 00:50:58,941
NOWADAYS YOU CAN BUY THEM FROM 

1229
00:50:58,941 --> 00:51:03,646
SOURCES AND THAT WAS A MOM AND 

1230
00:51:03,646 --> 00:51:06,882
POP SHOP OUT OF GEORGIA SELLING 

1231
00:51:06,882 --> 00:51:10,152
THEM AND THEY GOT ACQUIRED BY 

1232
00:51:10,152 --> 00:51:11,620
VECTOR LABS WHICH NOW SELLS THEM

1233
00:51:11,620 --> 00:51:16,025
BUT YOU CAN BUY FROM THERMAL 

1234
00:51:16,025 --> 00:51:18,461
FISHER ALL THIS STUFF IS NOW 

1235
00:51:18,461 --> 00:51:19,595
TOTALLY COMMERCIALIZED.

1236
00:51:19,595 --> 00:51:22,965
YOU MAY HAVE USED THEM AS 

1237
00:51:22,965 --> 00:51:25,334
REAGENT A, B AND C.

1238
00:51:25,334 --> 00:51:26,836
>> ARE THEY STABLE?

1239
00:51:26,836 --> 00:51:28,004
>> YOU CAN MAKE THEM
STABLE.

1240
00:51:28,004 --> 00:51:31,674
THE ONES WE USE ARE VERY STABLE.

1241
00:51:31,674 --> 00:51:34,243
WE STORE THEM ROOM TEMP ON THE 

1242
00:51:34,243 --> 00:51:37,179
BENCH TOP.

1243
00:51:37,179 --> 00:51:38,714
THE MORE REACTIVE THEY ARE THE 

1244
00:51:38,714 --> 00:51:41,117
LESS STABLE SO YOU CAN SOUP THEM

1245
00:51:41,117 --> 00:51:43,786
UP SO THEY'RE SUPER FAST BUT 

1246
00:51:43,786 --> 00:51:46,288
THEN THEY DON'T HAVE A GOOD 

1247
00:51:46,288 --> 00:51:47,023
SHELF LIFE.

1248
00:51:47,023 --> 00:51:48,891
THE ONES WE USE ARE FAST ENOUGH 

1249
00:51:48,891 --> 00:51:49,158
AND FINE.

1250
00:51:49,158 --> 00:51:51,494
YEAH.

1251
00:51:51,494 --> 00:51:53,529
WE DON'T TREAT THEM IN A SPECIAL

1252
00:51:53,529 --> 00:51:55,865
WAY WITH KID GLOVES OR ANYTHING 

1253
00:51:55,865 --> 00:51:57,566
AND AFTERWARDS BY THE WAY, COME 

1254
00:51:57,566 --> 00:52:00,336
LOOK AT MY EARRINGS IF YOU CAN'T

1255
00:52:00,336 --> 00:52:01,804
TELL FROM THERE.

1256
00:52:01,804 --> 00:52:05,908
>> CAROLYN, BEAUTIFUL
TALK.

1257
00:52:05,908 --> 00:52:09,045
THIS IS ABOUT NEW BIOORTHOGONAL 

1258
00:52:09,045 --> 00:52:09,311
REACTION.

1259
00:52:09,311 --> 00:52:12,415
THERE'S SO MUCH CHEMICAL 

1260
00:52:12,415 --> 00:52:13,816
REACTIVITY DATA PEOPLE ARE DOING

1261
00:52:13,816 --> 00:52:14,383
SYNTHESIS.

1262
00:52:14,383 --> 00:52:15,251
WE'RE USING A.I.

1263
00:52:15,251 --> 00:52:21,624
I'M CURIOUS IS THERE A WAY TO 

1264
00:52:21,624 --> 00:52:24,160
GET THE REACTIVITY DATA AND USE 

1265
00:52:24,160 --> 00:52:25,795
THE KNOWN BIOORTHOGONAL 

1266
00:52:25,795 --> 00:52:27,029
REACTIONS TO PREDICT WHAT COULD 

1267
00:52:27,029 --> 00:52:28,831
BE NEW REACTIONS.

1268
00:52:28,831 --> 00:52:30,332
DO YOU THINK THAT CAN BE DONE OR

1269
00:52:30,332 --> 00:52:31,100
IS BEING DONE 

1270
00:52:31,100 --> 00:52:32,001
>> ABOUT QUESTION.

1271
00:52:32,001 --> 00:52:35,738
LOTS OF PEOPLE NOWADAYS MORE 

1272
00:52:35,738 --> 00:52:36,405
HARDCORE CHEMISTRY LABS ARE 

1273
00:52:36,405 --> 00:52:39,642
INTERESTED IN DEVELOPING NEXT 

1274
00:52:39,642 --> 00:52:42,912
GENERATIONS OF BIOORTHOGONAL 

1275
00:52:42,912 --> 00:52:43,212
CHEMISTRIES.

1276
00:52:43,212 --> 00:52:45,815
WHERE THEY COULD BE MOST USEFUL 

1277
00:52:45,815 --> 00:52:49,452
IS ORTHOGONAL TO THE CURRENT SET

1278
00:52:49,452 --> 00:52:51,420
WITHOUT CROSS REACTIVITY.

1279
00:52:51,420 --> 00:52:53,656
MOST THE WORK I'VE SEEN HAS 

1280
00:52:53,656 --> 00:52:57,126
TAKEN THE SAME THEME WE TOOK 

1281
00:52:57,126 --> 00:52:59,962
WHICH IS DIAL THE CLOCK BACK TO 

1282
00:52:59,962 --> 00:53:03,466
THE 1950s AND '60s WHERE 

1283
00:53:03,466 --> 00:53:07,269
PHYSICAL AND ORGANIC CHEMISTRY 

1284
00:53:07,269 --> 00:53:11,006
WAS THE THEME AND YOU COULD FIND

1285
00:53:11,006 --> 00:53:12,274
PEARLS FROM THAT LITERATURE AND 

1286
00:53:12,274 --> 00:53:14,343
BRING IT UP AND USE IT THIS WAY.

1287
00:53:14,343 --> 00:53:17,146
THE FIELD IS SHIFTING NOW MORE 

1288
00:53:17,146 --> 00:53:18,914
TOWARDS USING MODERN 

1289
00:53:18,914 --> 00:53:21,183
COMPUTATIONAL METHODS BECAUSE WE

1290
00:53:21,183 --> 00:53:23,819
HAVE THE ABILITY NOW TO SIMULATE

1291
00:53:23,819 --> 00:53:26,989
TRANSITION STATES AND THIS IS 

1292
00:53:26,989 --> 00:53:29,992
ALL ABOUT TRANSITION STATES.

1293
00:53:29,992 --> 00:53:33,496
HAVE YOU TWO YOU WANT TO BIND 

1294
00:53:33,496 --> 00:53:35,231
TOGETHER THAN WHAT THEY COULD 

1295
00:53:35,231 --> 00:53:37,333
ACHIEVE WITH A BIOLOGICAL 

1296
00:53:37,333 --> 00:53:37,700
CHEMICAL.

1297
00:53:37,700 --> 00:53:39,168
THAT'S THE SELECTIVITY.

1298
00:53:39,168 --> 00:53:40,970
I KNOW SOME PEOPLE MODELLING 

1299
00:53:40,970 --> 00:53:45,808
LIKE IF I TAKE THIS REAGENT 

1300
00:53:45,808 --> 00:53:47,309
WHICH MAY FORM A LOW ENERGY 

1301
00:53:47,309 --> 00:53:48,144
TRANSITION STATE.

1302
00:53:48,144 --> 00:53:49,712
I THINK THAT'S AN INTERESTING 

1303
00:53:49,712 --> 00:53:51,547
AND POTENTIALLY EXCITING WAY TO 

1304
00:53:51,547 --> 00:53:53,816
BREAK OPEN NEW INNOVATION IN 

1305
00:53:53,816 --> 00:53:55,384
THIS SPACE.

1306
00:53:55,384 --> 00:53:55,851
>> THANK YOU.

1307
00:53:55,851 --> 00:53:58,187
>> I'LL SNEAK IN ONE
QUESTION 

1308
00:53:58,187 --> 00:53:58,888
FROM ONLINE IN THE FRONT ROW.

1309
00:53:58,888 --> 00:53:59,555
OVER HERE.

1310
00:53:59,555 --> 00:54:01,857
>> I CAN'T FIND YOU.

1311
00:54:01,857 --> 00:54:03,692
>> IT COMES FROM ONLINE
THOUGH 

1312
00:54:03,692 --> 00:54:05,928
SO YOU DON'T HAVE TO STARE 

1313
00:54:05,928 --> 00:54:08,831
ANYWHERE WHERE WHEN YOU ANSWER.

1314
00:54:08,831 --> 00:54:12,301
AZIDES ARE KNOWN TO BE TOXIC TO 

1315
00:54:12,301 --> 00:54:14,637
HUMANS SO HOW WOULD YOU STUDY 

1316
00:54:14,637 --> 00:54:15,704
AZIDES IN HUMANS?

1317
00:54:15,704 --> 00:54:17,806
>> THIS IS MY FIRST GRANT 

1318
00:54:17,806 --> 00:54:20,676
APPLICATION BACK IN 1999.

1319
00:54:20,676 --> 00:54:23,946
SO AZIDE AND THE SALT IS TOXIC.

1320
00:54:23,946 --> 00:54:27,116
IT'S USED AS A METABOLIC POISON.

1321
00:54:27,116 --> 00:54:30,753
WE PUT IT TO PREVENT BACTERIAL 

1322
00:54:30,753 --> 00:54:32,221
GROWTH BUT WHERE THE N3 IS 

1323
00:54:32,221 --> 00:54:34,323
ATTACHED TO AN ORGANIC MOLECULE 

1324
00:54:34,323 --> 00:54:36,792
NOT A NEGATIVE CHARGE BUT BOND 

1325
00:54:36,792 --> 00:54:38,794
TO A CARBON ARE HARMLESS, 

1326
00:54:38,794 --> 00:54:39,461
TOTALLY FINE.

1327
00:54:39,461 --> 00:54:41,130
FOR EXAMPLE, THE DRUG AZT, THAT 

1328
00:54:41,130 --> 00:54:43,032
WAS ONE OF THE FIRST GENERATION 

1329
00:54:43,032 --> 00:54:46,735
AIDS DRUGS, THAT IS AN AZIDE.

1330
00:54:46,735 --> 00:54:49,605
PEOPLE TAKE GRAMS OR PEOPLE TOOK

1331
00:54:49,605 --> 00:54:54,109
GRAMS PER DAY AND 

1332
00:54:54,109 --> 00:54:55,911
GLAXOSMITHKLINE DID THE STUDY 

1333
00:54:55,911 --> 00:54:59,682
AND IT COMES OUT IN THE URINE.

1334
00:54:59,682 --> 00:55:01,817
IT'S VERY SAFE AS LONG AS 

1335
00:55:01,817 --> 00:55:07,456
THEY'RE BIOORGANIC.

1336
00:55:07,456 --> 00:55:08,357
IT'S A TRANSPORT CHAIN.

1337
00:55:08,357 --> 00:55:11,927
>> EXCELLENT TALK.

1338
00:55:11,927 --> 00:55:18,300
THE REACTION OF A CLICK REACTION

1339
00:55:18,300 --> 00:55:19,702
HAS THE REACTION WHO INTRODUCED 

1340
00:55:19,702 --> 00:55:19,868
IT?

1341
00:55:19,868 --> 00:55:23,172
>> WHO INVENTED IT?

1342
00:55:23,172 --> 00:55:33,182
>> [INDISCERNIBLE].

1343
00:55:33,182 --> 00:55:34,950
OF COURSE IT WAS A CLICK 

1344
00:55:34,950 --> 00:55:37,987
REACTION AT ROOM TEMPERATURE.

1345
00:55:37,987 --> 00:55:41,890
AND SO YOU SET IT UP BEAUTIFUL.

1346
00:55:41,890 --> 00:55:46,195
FANTASTIC WITH THE CHEMISTRY BUT

1347
00:55:46,195 --> 00:55:50,266
THE ANTIBODY DRUG CONJUGATION WE

1348
00:55:50,266 --> 00:55:53,569
USE THE ENZYMES TO CONNECT THE 

1349
00:55:53,569 --> 00:55:54,970
SUGARS BASED ON THE STRUCTURE 

1350
00:55:54,970 --> 00:56:01,810
MUTATED SO IT CAN BE BASICALLY 

1351
00:56:01,810 --> 00:56:05,214
CONNECTED VIA SUGARS, GLYCAN 

1352
00:56:05,214 --> 00:56:05,547
SUGARS.

1353
00:56:05,547 --> 00:56:11,086
YOU DID NOT INCLUDE THAT S&P
--.

1354
00:56:11,086 --> 00:56:12,321
>> OTHER PEOPLE HAVE.

1355
00:56:12,321 --> 00:56:14,957
YOU MAY ASK WHY DIDN'T WE PUT AN

1356
00:56:14,957 --> 00:56:16,892
AZIDE ON THE PROTEIN?

1357
00:56:16,892 --> 00:56:20,129
BECAUSE METHODS FOR INTRODUCING 

1358
00:56:20,129 --> 00:56:24,667
AZIDES LIKE AN UNNATURAL AMINO 

1359
00:56:24,667 --> 00:56:27,236
ACID EXIST.

1360
00:56:27,236 --> 00:56:27,736
PET

1361
00:56:27,736 --> 00:56:29,805
PET

1362
00:56:29,805 --> 00:56:33,742
PET

1363
00:56:33,742 --> 00:56:41,083
PETER SCHULTZ' LAB DID THAT AND 

1364
00:56:41,083 --> 00:56:43,185
YOU HAVE TO DO THAT WITH 

1365
00:56:43,185 --> 00:56:45,688
UNNATURAL AMINO ACIDS SO WE 

1366
00:56:45,688 --> 00:56:47,356
THOUGHT THIS WAS AN EASIER WAY 

1367
00:56:47,356 --> 00:56:49,692
TO DO IT WHERE IT'S NOT 

1368
00:56:49,692 --> 00:56:51,727
UNNATURAL BUT REPURPOSED 

1369
00:56:51,727 --> 00:56:52,461
POST-TRANSLATIONAL MODIFICATION 

1370
00:56:52,461 --> 00:56:53,929
THAT CREATES A DIFFERENT KIND OF

1371
00:56:53,929 --> 00:56:56,565
CHEMICAL GROUP SO HONESTLY WE 

1372
00:56:56,565 --> 00:56:58,400
THOUGHT WE COULD GET TO SITE 

1373
00:56:58,400 --> 00:57:01,804
SPECIFIC ADCs ON SCALE FASTER 

1374
00:57:01,804 --> 00:57:04,340
THIS WAY.

1375
00:57:04,340 --> 00:57:05,541
BUT OTHER PHARMACEUTICALS IF I 

1376
00:57:05,541 --> 00:57:09,078
GO BACK TO THAT SLIDE WITH LOGOS

1377
00:57:09,078 --> 00:57:15,818
ON IT -- THIS COMPANY, THEY'RE 

1378
00:57:15,818 --> 00:57:18,787
MAKING ANTIBODY DRUG CONJUGATES 

1379
00:57:18,787 --> 00:57:21,657
WITH COPPER-FREE CLICK CHEMISTRY

1380
00:57:21,657 --> 00:57:23,726
AND PATENTED IT AND ANOTHER IS 

1381
00:57:23,726 --> 00:57:30,532
MAKING SITE-SPECIFIC ADCs AND 

1382
00:57:30,532 --> 00:57:33,268
THREES ARE DOING THAT BUT WE 

1383
00:57:33,268 --> 00:57:35,704
HAVE A DIFFERENT CHEMISTRY.

1384
00:57:35,704 --> 00:57:43,812
>> AND THE ENZYME IS BEING
USED.

1385
00:57:43,812 --> 00:57:47,249
THERE'S TRANSFERASE.

1386
00:57:47,249 --> 00:57:52,121
>> IN FACT SYNOFIX DOES IT
WITH 

1387
00:57:52,121 --> 00:57:54,022
THE ANTIBODY WITH THE ACID.

1388
00:57:54,022 --> 00:57:55,357
>> I'D LIKE TO SQUEEZE IN
THREE 

1389
00:57:55,357 --> 00:57:56,825
MORE QUESTIONS ONLINE.

1390
00:57:56,825 --> 00:57:59,895
ONE AND TWO AND THREE.

1391
00:57:59,895 --> 00:58:00,863
WE'RE AT THE HOUR NOW.

1392
00:58:00,863 --> 00:58:03,399
>> SO MAYBE I MISSED THIS
BUT ON

1393
00:58:03,399 --> 00:58:05,701
ONE OF THE -- HI.

1394
00:58:05,701 --> 00:58:09,805
ON ONE OF THE LAST SLIDES WHEN 

1395
00:58:09,805 --> 00:58:15,411
YOU'RE TALKING ABOUT THE 

1396
00:58:15,411 --> 00:58:16,645
TETRAZINE LOCATION WHAT ABOUT 

1397
00:58:16,645 --> 00:58:17,813
THE ENVIRONMENT CAUSE THE 

1398
00:58:17,813 --> 00:58:19,214
BINDING AND RELEASE.

1399
00:58:19,214 --> 00:58:20,616
>> SORRY, I WENT THROUGH
THAT SO

1400
00:58:20,616 --> 00:58:21,884
QUICKLY IN THE INTEREST OF TIME 

1401
00:58:21,884 --> 00:58:23,752
BUT SINCE YOU ASKED, NOW I CAN 

1402
00:58:23,752 --> 00:58:24,186
USE MORE TIME.

1403
00:58:24,186 --> 00:58:27,756
THE IDEA IS THIS.

1404
00:58:27,756 --> 00:58:32,661
SO, THIS IS A HYDROGEL POLYMER A

1405
00:58:32,661 --> 00:58:36,932
FORM OF HYALURONIC ACID.

1406
00:58:36,932 --> 00:58:41,804
WHICH IS JUVADERM AND THEY 

1407
00:58:41,804 --> 00:58:44,440
MODIFY IT AND INJECT IT IN THE 

1408
00:58:44,440 --> 00:58:46,608
TUMOR SO IT'S A PROBLEM IN THE 

1409
00:58:46,608 --> 00:58:47,142
TUMOR SITTING THERE DOING 

1410
00:58:47,142 --> 00:58:53,282
NOTHING.

1411
00:58:53,282 --> 00:58:55,651
WHEN IT ENCOUNTERS THE DRUG THEY

1412
00:58:55,651 --> 00:58:57,319
FIND EACH OTHER AND BOOM THE 

1413
00:58:57,319 --> 00:58:59,054
REACTION HAPPENS SPONTANEOUSLY.

1414
00:58:59,054 --> 00:59:01,657
WHEN THAT OCCURS ALL THE 

1415
00:59:01,657 --> 00:59:05,527
UNRAVELLING HAPPENS AND YOU 

1416
00:59:05,527 --> 00:59:07,830
LIBERATE THIS MOLECULE WHICH IS 

1417
00:59:07,830 --> 00:59:09,565
NOW TOXIC AND CONCENTRATED IN 

1418
00:59:09,565 --> 00:59:10,065
THE MICROENVIRONMENT.

1419
00:59:10,065 --> 00:59:11,934
>> TO MORE AND WE'LL HAVE
A 

1420
00:59:11,934 --> 00:59:12,201
RECEPTION.

1421
00:59:12,201 --> 00:59:12,534
>> HELLO.

1422
00:59:12,534 --> 00:59:16,905
THIS IS A REALLY GENERAL 

1423
00:59:16,905 --> 00:59:20,108
QUESTION, BUT TO THE POINT ABOUT

1424
00:59:20,108 --> 00:59:25,280
THE SPACE OF BIOLOGICALLY 

1425
00:59:25,280 --> 00:59:26,949
OCCURRING CHEMICAL REACTIONS I'M

1426
00:59:26,949 --> 00:59:29,818
WONDERING WHAT IS KNOWN ABOUT 

1427
00:59:29,818 --> 00:59:33,422
HOW QUICKLY BIOLOGICAL SYSTEMS 

1428
00:59:33,422 --> 00:59:36,825
EVOLVE TO EXPLORE NEW -- 

1429
00:59:36,825 --> 00:59:37,860
>> IF WE WAIT LONG ENOUGH 

1430
00:59:37,860 --> 00:59:39,194
REACTIONS EVOLVE IN NATURE.

1431
00:59:39,194 --> 00:59:39,895
GREAT QUESTION.

1432
00:59:39,895 --> 00:59:47,135
ONE THING I'VE LEARNED IS  IT'S 

1433
00:59:47,135 --> 00:59:48,537
UNWISE TO SAY NATURE DOESN'T DO 

1434
00:59:48,537 --> 00:59:49,638
X.

1435
00:59:49,638 --> 00:59:52,574
BECAUSE WHAT WE KNOW ABOUT WHAT 

1436
00:59:52,574 --> 00:59:55,444
NATURE DOES AND DOESN'T DO IS A 

1437
00:59:55,444 --> 00:59:59,314
SCRATCH ON THE SURFACE OF 

1438
00:59:59,314 --> 00:59:59,548
REALITY.

1439
00:59:59,548 --> 01:00:00,716
WHO KNOWS WHAT EXISTS THAT WE 

1440
01:00:00,716 --> 01:00:01,750
DON'T KNOW ABOUT YET.

1441
01:00:01,750 --> 01:00:04,419
AND ALL THE MORE REASON TO STUDY

1442
01:00:04,419 --> 01:00:05,821
HUMAN BIOLOGY WITH CHEMICAL 

1443
01:00:05,821 --> 01:00:09,525
TOOLS, I GUESS.

1444
01:00:09,525 --> 01:00:13,362
>> SO THIS IS ALSO VERY
BROAD 

1445
01:00:13,362 --> 01:00:14,863
QUESTION BUT WITH ALL THESE 

1446
01:00:14,863 --> 01:00:15,397
BEAUTIFUL MOLECULES AND 

1447
01:00:15,397 --> 01:00:17,799
EVERYTHING AND THESE REACTIONS, 

1448
01:00:17,799 --> 01:00:20,636
ONCE THEY ACTUALLY OCCUR AND 

1449
01:00:20,636 --> 01:00:22,638
REACT, WHAT'S HAPPENING 

1450
01:00:22,638 --> 01:00:24,973
CLEARANCE WISE WITH THE BIO 

1451
01:00:24,973 --> 01:00:26,308
AZIDES MAINLY CLEARED BUT ARE 

1452
01:00:26,308 --> 01:00:27,876
THERE COMMON CLEARANCE PATHWAYS 

1453
01:00:27,876 --> 01:00:30,846
FOR A LOT OF THESE OR HAS THAT 

1454
01:00:30,846 --> 01:00:32,681
NOT BEEN EXPLORED?

1455
01:00:32,681 --> 01:00:34,283
>> I WISH I HAD MORE OF 

1456
01:00:34,283 --> 01:00:35,751
SUBSTANCE TO SAY IN RESPONSE TO 

1457
01:00:35,751 --> 01:00:36,585
THAT QUESTION.

1458
01:00:36,585 --> 01:00:38,253
THE TRUTH IS WE DON'T REALLY 

1459
01:00:38,253 --> 01:00:40,589
KNOW HOW THE ADDUCTS WE MAKE ARE

1460
01:00:40,589 --> 01:00:42,057
GETTING METABOLIZED.

1461
01:00:42,057 --> 01:00:44,760
THEY GET CLEARED AND DISAPPEAR 

1462
01:00:44,760 --> 01:00:46,795
AND PRESUMABLY BROKEN DOWN TO A 

1463
01:00:46,795 --> 01:00:48,063
FRAGMENT THAT GETS CLEARED FROM 

1464
01:00:48,063 --> 01:00:49,731
THE LIVER OR MAYBE KIDNEYS AND 

1465
01:00:49,731 --> 01:00:52,267
SECRETED OUT IN THE URINE BUT 

1466
01:00:52,267 --> 01:01:02,811
I -- EXCRETED THROUGH THE URINE.

1467
01:01:05,280 --> 01:01:06,448
IT THANKS FOR EXPOSING THE 

1468
01:01:06,448 --> 01:01:06,782
IGNORANCE.

1469
01:01:06,782 --> 01:01:08,584
>> WE'RE GOING TO WRAP IT
UP.

1470
01:01:08,584 --> 01:01:10,886
I INVITE YOU TO ATTEND A 

1471
01:01:10,886 --> 01:01:12,220
RECEPTION ACROSS THE HALL IN THE

1472
01:01:12,220 --> 01:01:13,789
NIH LIBRARY AND PLEASE JOIN ME 

1473
01:01:13,789 --> 01:01:16,658
IN THANKING DR. BERTOZZI FOR AN 

1474
01:01:16,658 --> 01:01:17,793
AMAZING LECTURE.

1475
01:01:17,793 --> 01:01:28,036
>> THANK YOU.