Elegant degradation

Transcription

>> GOOD AFTERNOON. MY NAME IS RICHARD LEADMAN, SCIENTIFIC DIRECTOR FOR THE NATIONAL INSTITUTE FOR BIOMEDICAL IMAGING AND ENGINEERING. IT IS MY GREATEST PLEASURE TODAY TO WELCOME PROFESSOR ROBERT LANGER TO THE NIH WEDNESDAY AFTERNOON LECTURE SERIES. PROFESSOR LANGER RECEIVED SO MANY PRESTIGIOUS AWARDS AND HAS HAD SUCH VAST NUMBER OF MAJOR SCIENTIFIC ACCOMPLISHMENTS IN HIS DISTINGUISHED CAREER THAT IT'S REALLY AN IMPOSSIBLE TASK TO PROVIDE ADEQUATE INTRODUCTION IN JUST A MINUTE OR SO. BUT I'LL JUST MENTION A FEW THINGS. PROFESSOR LANGER IS THE DAVID H. KOCH INSTITUTE PROFESSOR AT MUT AND IS AWARDED ONLY 14 SUCH PROFESSORS. HE RECEIVED THE HIGHEST HONOR THAT CAN BE AWARDED TO AN MIT FACULTY MEMBER. HIS RESEARCH IS AT THE ENTERTASE OF MEDICINE -- INTERFACE OF MEDICINE CANCER IN MATERIAL AND MATERIAL SCIENCE AN CANCER ENGINEERING WITH A SPECIAL FOCUS ON NANOTECHNOLOGY INCLUDING DEVELOPMENT OF NANOPARTICLES TO TREAT CANCER AND OTHER DISEASES. DR. LANGER IS CONSIDERED A PIONEER OF MANY NEW BIOTECHNOLOGIES. HIS LAB DESIGNS POLYMERS LIPIDS, POLYMER LIPIDS, HYBRID NANOCARRIERS FOR IMPROVED DRUG DELIVERY AS WELL AS CONTROLLED DELIVERY SYSTEMS FOR GENETICALLY ENGINEERED THERAPEUTIC PROTEINS AND DNA AND RNA. DR. LANGER'S RESEARCH ALSO INCLUDES CREATION OF NOVEL APPROACHES FOR THE ENGINEERING OF TISSUES AND ORGANS. THEY HELP TRANSLATE INVENTIONS INTO THE CLINIC BY FOUNDING MORE THAN 20 BIOTECH COMPANIES. DR. LANGER HAS AUTHORED MORE THAN 1200 ARTICLES AND HAD MORE THAN 800 ISSUED AND PENDING PA TENS WORLD WIDE. HE'S THE YOUNGEST PERSON IN HISTORY AT AGE 43, ONE OF A SMALL GROUP EVER, TO HAVE BEEN ELECTED TO ALL THREE OF THE UNITED STATES NATIONAL ACADEMY. INSTITUTE OF MEDICINE. NATIONAL ACADEMY OF SCIENCE AND THE NATIONAL ACADEMY OF ENGINEERING. HE WHAT'S RECEIVED MORE THAN 220 MAJOR AWARDS. THE HIGHLIGHTS OF THOSE INCLUDE THE U.S. NATIONAL MEDAL OF SCIENCE, THE U.S. MEDAL OF TECHNOLOGY AND INNOVATION, THE CHARLES STARK DRAPER PRIZE, THE ENGINEERING NOBEL PRIZE, THE MILLENNIUM TECHNOLOGY PRIZE, THE ALBANY MEDICAL CENTER PRIZE. THE PRIESTLY MEDAL WHICH IS THE HIGHEST AWARD GIVEN BY THE AMERICAN CHEMICAL SOCIETY AND LAST YEAR THE WOLF PRIZE IN CHEMISTRY. THIS YEAR HE'S ALREADY BEEN AWARDED THE $3 MILLION BREAK THROUGH PRIZE IN THE LIFE SCIENCES FOR HIS RESEARCH. IN 1999 FORBES NAMED DR. LANGER ONE OF THE 25 MOST IMPORTANT INDIVIDUALS IN BIOTECHNOLOGY IN THE WORLD. AGAIN IN 2002 FORBES SELECTED DR. LANGER AS ONE OF THE 15 INNOVATORS WORLDWIDE WHO WILL REINVENT THE FUTURE. IN 2001 BOTH TIME AND CNN NAMED HIM AS ONE OF THE 100 MOST IMPORTANT PEOPLE IN AMERICA AND ONE OF THE TOP 18 IN SCIENCE OR MEDICINE IN THE UNITED STATES. DR. LANGER EARNED HIS BACHELOR OF SCIENCE DEGREE FROM CORNELL UNIVERSITY AND SCD FROM THE MASSACHUSETTS INSTITUTE OF TECHNOLOGY BOTH IN THE FIELD OF CHEMICAL ENGINEERING. HE HOLDS 20 HONOREE DOCTORATES FROM UNIVERSITIES IN THE U.S. AND ABROAD. THE TITLE OF HIS LECTURE TODAY IS BIOMATERIALS AND BIOTECHNOLOGY. FROM THE DISCOVERY OF THE FOOD ANGIOGENESIS INHIBITORS TO DEVELOPMENT OF CONTROLLEDDED DRUG DELIVERY SYSTEMS IN THE FOUNDATION OF TISSUE ENGINEERING. DR. LANGER. [APPLAUSE] >> THANK YOU VERY MUCH, IT'S A PLEASURE TO BE HERE. I THOUGHT I WOULD START OUT AND I HAD LUNCH WITH A NUMBER OF PEOPLE HERE AND THOUGHT I WOULD START AND TELL YOU ABOUT HOW WHEN I WAS THAT AGE I ENDED UP GETTING INTO THE MEDICAL FIELD. WHEN I WAS A GRADUATE STUDENT AT MICST IN THE '70s, I WAS STUDYING CHEMICAL ENGINEERING THAT'S MY DOCTORATE IN. THAT YEAR 1974 JUST LIKE A COUPLE OF YEARS AGO THERE WAS A GAS SHORTAGE AND IT WAS ACTUALLY PROBABLY WORSE. NOT ONLY PRICE OF GAS KEEPS GOING UP BUT IF YOU LIVED IN BOSTON WHERE I LIVED YOU HAD TO WAIT IN LINE AT THE GAS STATION FOR TWO HOURS TO GET YOUR TANK FILLED. THE CONSEQUENCE OF THAT THOUGH IS IF YOU WERE A YOUNG CHEMICAL ENGINEER YOU GOT A LOT OF JOB OFFERS. PRETTY MUCH EVERY ONE OF MY FRIENDS IN MY CLASS WENT TO AN OIL COMPANY SO THAT'S WHAT I DID. I WENT AND INTERVIEWEDDED AT OIL COMPANIES. 20 OFFERS FOUR FROM EXON ALONE. , IT WASN'T LIKE I WAS THAT GREAT THEY JUST HAD A LOT OF JOB OFFERS, OPENINGS. BUT I REMEMBER ONE OF THEM MADE AN IMPACT ON ME, I REMEMBER GOING TO EXON IN BATON ROUGE, LOUISIANA AND WHEN I WAS THERE ENGINEER SAID IF YOU INCREASE THE YIELD OF THIS ONE CHEMICAL BY .1 PERCENT HE SAID THAT WOULD BE WONDERFUL. HE SAID WOULD BE WORTH BILLIONS OF DOLLARS. I REMEMBER FLYING BACK TO BOSTON THAT NIGHT THINKING TO MYSELF THAT I REALLY DIDN'T WANT TO DO THAT. AND I STARTED THINKING MORE ABOUT WHAT I DID WANT TO DO RATHER THAN JUST FOLLOW MY FRIENDS. ONE OF THE THINGS I DID WHEN I WAS A GRADUATE STUDENT AT MICST IS START AD SCHOOL FOR POOR CHILDREN AND I GOT INVOLVED IN CREATING A CHEMISTRY CURRICULUM. ONE DAY I SAW AN AD IN A CHEMISTRY JOURNAL TO BE ASSISTANT PROFESSOR CITY COLLEGE OF NEW YORK DEVELOPING NEW CHEMISTRY CURRICULA. I THOUGHT THAT'S GREAT. THAT'S WHAT I WANT TO DO SO I WROTE THEM A LETTER. APPLYING FOR THE JOB BUT THEY DIDN'T WRITE ME BACK. BUT I LIKE THED IDEA SO I FOUND ALL THE DIFFERENT UNIVERSITIES THAT HAD ASSISTANT PROFESSOR IN EDUCATION AND I WROTE THEM PROBABLY 40 ONES AND I WROTE 40 LETTERS AND NONE WROTE ME BACK. I GUESS I WASN'T IN THE RIGHT BOX, THE CHEMISTRY EDUCATION BOX. SO THAT WASN'T GOING REAL WELL SO STARTING TO THINK HOW ELSE CAN I USE MY CHEMICAL ENGINEERING BACKGROUND TO HELP PEOPLE. SO I THOUGHT ABOUT MEDICINE. I WROTE TO A LOT OF HOSPITALS AND MEDICAL SCHOOLS. AND THEY DIDN'T WRITE BACK EITHER. ONE DAY A POST-DOC IN THE LAB WHERE I WAS MENTIONED, HE SAID BOB THERE'S A SURGEON IN BOSTON AND NAMED JUDITH FAULKMAN HE SAID SOMETIMES HE HIRES UNUSUAL PEOPLE. HE ACTUALLY THOUGHT HIGHLY OF DR. VOKEMAN, I WON'T SAY WHAT HE THOUGHT ABOUT ME. AND I WROTE TO HIM AND HE WAS KIND ENOUGH TO OFFER ME POSITION. IN FACT I MET MIKE GOTTESMAN THERE. BUT ANY RATE WHEN WENT TO DR. FOALKMAN'S LAB, THE PROJECT HE ASKED ME TO WORK ON ACTUALLY WOULD BE TO SEE IF WE CAN ACTUALLY ISOLATE WHAT WOULD BE THE FIRST INHIBITOR OF ANGIOGENESIS. AND I THOUGHT I WOULD START OUT WITH A PICTURE, ACTUALLY THE NEW YORK SOMETIMES IN 1971 SHOWING DR. VOKEMAN'S VISION HOW TUMOR GROW. IT'S STILL FAIRLY ACCURATE TODAY. HIS IDEA IS SOMEHOW TUMOR CELLS BECOME ABNORMAL, THEY GROW AS A THREE DIMENSIONAL MASS TO MILLIMETER CUBED BUT THEY MIGHT NOT GO BEYOND THAT. BECAUSE TEHERAN INTO A NUTRITION PROBLEM. CELLS IN THE CENTER WOULD DIE BECAUSE THEY COULDN'T GET NUTRIENTS OR GET RID OF WASTE. BUT THE TUMOR SOLVES BY SECRETING A TAF TUMOR ANGIOGENESIS FACTOR. YOUR SURROUNDING BLOOD VESSELS ARE QUITE KYE YES, SIR SENT BUT IN THE -- QUITE QUIESCENT BUT IN THE TUMOR, IT WOULD NOURISH AND FEED IT AND THE TUMOR WOULD GROW AND METASTASIZE THROUGH BLOOD VESSELS EVENTUALLY KILLING. HIS IDEA IS IF YOU CAN STOP BLOOD VESSELS FROM GROWING MAYBE THAT WOULD BE A WAY OF THINKING ABOUT TREATING CANCER. SO HOW DO YOU THINK ABOUT ISOLATING INHIBITOR OF ANGIOGENESIS? WE BROKE IT INTO TWO PARTS. ONE IS YOU HAVE TO HAVE SUBSTANCE THAT COULD DO THIS. ONE THING WE STARTED THINKING ABOUT WAS CARTILAGE. CARTILAGE IS IN YOUR NOSE AND YOUR KNEE AND DOESN'T HAVE BLOOD VESSELS. AND BABY RABBITS ARE IN THE LAB SO MYSELF AND HENRY PROGRAM AND OTHERS GET THOSE AND P WE GOT THE CARTILAGE BUT THERE WASN'T VERY MUCH IN THE LITTLE RABBITS SO ONE THING YOU LEARN AS AN ENGINEER WAS SCALE UP SO I WENT TO COWS. AND I WENT P TO A SLAUGHTER HOUSE AND IN CAMBRIDGE AND GOT COW BONES BUT I COULDN'T GET THAT MANY SO I FOUND OUT WHERE THE COW BONES WENT TO IN THE KNOT EAST AND THEY WENT TO A MEAT PACKING PLACE AND I GOT ALL THE BONES AN BROUGHT BACK TO THE LAB THREE TIMES A WEEK AN SCRAPE OFF THE MEAT. AND I WOULD GET THIS. THIS WAS A -- I'M KIND OF PROUD OF THIS. BUT THIS IS A SCAPULAR BONE, SLICE THIS OFF AND THEN EXTRACT THE CARTILAGE WITH THINGS LIKE HYDROCHLORIDE, SO FORTH. THEN PUT THROUGH VARIOUS PURIFICATION PROCEDURES SO THE END OF A PERIOD OF TIME LIKE A COUPLE OF YEARS I MAYBE 50 OR 100 VILES OF SUBSTANCES I WANTED TO TEST. THAT BRINGS UP A SECOND QUESTION, HOW DO YOU TEST SOMETHING LIKE THIS. HOW DO YOU DEVELOP A QUANTITATIVE OR SEMIQUANTITATIVE ASSAY FOR SOMETHING LIKE ANGIOGENESIS? IF YOU LOOK BACK AT THE HISTORY OF MEDICINE, OOH LOT OF FACTORS OR SUBSTANCES THE BIOASSAY ENDS UP BEING RATE LIMITING. HOW DO YOU THINK OF DEVELOPING A QUANTITATIVE ASSAY? MIKE YIMBRONE WORKING BEFORE I DID AND HE HAD SHOWN IF YOU PUT CERTAIN TUMORS IN THE EYE OF RABBIT BLOOD VESSELS GROW FROM THE EDGE OF CORNEA TO THE TUMOR OR A TWO MONTH PERIOD. SO WE THOUGHT WHAT IF YOU CAN TAKE A POLYMER THAT A WOULD BE INERT IN THE EYE WHICH ISN'T EASY AND B, COULD DELIVER THE LARGE MOLECULES AND CARTILAGE WHICH HAD NEVER BEEN DONE BEFORE OVER A TWO MONTH PERIOD, MAYBE WE COULD DEVELOP AN ASSAY BECAUSE WE CAN USE OPTHALMIC MICROSCOPE TO MEASURE THE LENGTH OF THE LONGEST BLOOD VESSELS AND SEE HOW FAST DIFFERENT SUBSTANCES GROW TO THE TUMOR. SO THAT WAS THE IDEA. NOW THE CHALLENGE, MEDIA CHALLENGE TO THIS WAS DEVELOPING A CONTROL RELEASE POLYMER TO MEET THE TWO CRITERIA, HE WAS ON THE BOARD SCIENTIFIC ADVISORY BOARD OF THE ONE COMPANY AT THAT TIME IN THE WORLD WHO HAD DONE ANY WORK ON THESE DELIVERY SYSTEMS. THEY HAD AN OUTSTANDING SCIENTIFIC ADVISORY BOARD AND HE WENT TO ASK IF THEY COULD HELP THEY SAID NO. THEY SAID REALLY YOU JUST CAN'T RELEASE A LARGE MOLECULE THAT IF IT'S OVER 200 MOLECULAR WEIGHT IT'S NOT GOING TO BE ABLE TO DIFFUSE THROUGH THE POLYMER, IT'S LIKE SAYING COULD US WALK THROUGH THAT WALL. EVEN THE LITERATURE AT THAT TIME WOULD SAY THINGS LIKE THE POLYMER MATRICES IS VIRTUALLY RESTRICTED TO SMALL MOLECULES. SO THE ONLY THING I HAD GOING FOR ME, I DIDN'T KNOW ANY OF THAT. I TRIED ANYHOW AND I SPENT TWO YEARS WORKING IN THE LABORATORY EXPERIMENTING WITH TECHNIQUES. I FOUND FOR 200 WAYS TO GET THIS TO NOT WORK. BUT I WAS ABLE TO MAKE THESE MICROSPHERE, HERE IS ONE CUT IN HALF, AND WHAT WE WERE ABLE TO SHOW IS THAT YOU COULD RELEASE, THIS IS FROM NATURE IN 1976, RELEASE MOLECULES OF ANY SIZE OVER 100 DAYS AN LATER USING ENGINEERS APPROACHES WE WORKED OUT WAYS TO GET CONSTANT RELEASE. THIS IS ALBUMIN BEING RELEASED. IN 1976 TWO YEARS AFTER I STARTED WORK ON THIS, I ACTUALLY GOT ASKED TO GIVE THE FIRST TALK I EVER GOT ASKED TO GIVE AT A SCIENTIFIC MEETING, IT WAS A BIG POLYMER CENTER MIDDLE IN MICHIGAN. AND I WAS VERY NERVOUS ABOUT THIS TALK BEFORE THIS REALLY THE ONLY TALK I HAD GIVEN WAS IN 8TH GRADE AND THAT DIDN'T GO REAL WELL. IN 8TH GRADE I HAD TO GIVE A MINUTE AND A HALF SPEECH, I REMEMBER WRITING IT OUT AND I REHEARSED IT THREE HOURS IN FRONT OF MY PARENTS' MIRROR THE NIGHT BEFORE AND THE DAY CAME THE NEXT DAY AND I GOT UP IN FRONT OF MY CLASS, I DIDN'T BRING THE SHEET OF PAPER, I SHOULD HAVE AND I RECITED IT AND I REMEMBER LIKE FOR THE FIRST MINUTE AND TWO SECONDS I DID ALL RIGHT AND THEN I COULD NOT REMEMBER THE NEXT WORD SO I STOOD UP THERE IN FRONT OF MY CLASS FROZEN FOR THE NEXT MINUTE UNTIL FINALLY MY 8TH GRADE TEETHE TOLD ME TO SIT DOWN AND GAVE ME A NOT PARTICULARLY GOOD GRADE. I THINK IT WAS AN F ACTUALLY. SO NOW MANY YEARS LATER I WAS VERY NERVOUS GIVING THE TALK OR ANY TALK. I'M GOING TO TRY TO NOT DO THAT THIS AFTERNOON TO YOU. SO I GAVE THIS TALK, THIS WAS NOW, THIS WAS 20, 30 -- WAS IT 38 YEARS AGO? MY GOD. 38 YEARS AGO I GAVE THE TALK SO I WAS A LOT YOUNGER AND I WAS GIVING IT TO A VERY WISH DISTINGUISHED AUDIENCE OF POLYMER CHEMISTS AN ENGINEERS SO I PRACTICED THIS FOR TWO WEEKS AND WHEN I FINISHED I THOUGHT I DID BETTER. I DIDN'T STAMMERER TOO MUCH SO I THOUGHT WHEN I WAS DONE THESE CHEMISTS AND ENGINEERS BEING NICE PEOPLE WOULD WANT TO ENCOURAGE ME, THIS YOUNG GUY. WHEN I GOT DONE I STEPPED OFF THE PODIUM AM A BUNCH CAME UP AND THEY SAID WE DON'T BELIEVE ANYTHING YOU JUST SAID. THEY SAID JUST LIKE WHAT THE PEOPLE SAID A LARGE MOLECULE COULDN'T DIFFUSE THROUGH SOLID POLYMERS, WE WERE USING ORGANIC SOLVENTS AND THEY SAID THAT WOULD DESTROY WHATEVER WE PUT IN. PEOPLE -- THE FIRST PEOPLE TO REPEAT THIS I THINK WERE PEOPLE AT THE NATIONAL EYE INSTITUTE AND THEN MANY MANY MORE USING IT TO ISOLATE DIFFERENT GROWTH FACTORS. THE QUESTION WOULD SHIFT IN A COUPLE OF YEARS THE FACT IT WASN'T IMPOSSIBLE BUT HOW COULD IT WORK. I SHOULD SAY THIS HAD A PROFOUND EFFECT ON MY CAREER EARLY ON. I WAS TELLING PEEP AT LUNCH WHEN I WAS POST DOC NO CHEMICAL ENGINEERING DEPARTMENT WOULD HIRE ME AND THE DEPARTMENT THAT DID HIRE ME ORIGINALLY WITH NUTRITION ABOUT FOOD SCIENCE DEPARTMENT I REMEMBER OF I JOINED THE DEPARTMENT HEAD LEFT AND TWO ASSOCIATE DEPARTMENT HEADS AND THEY DECIDED THE GIVE ADVICE. THAT I SHOULD START LOOKING FOR ANOTHER JOB. SO I ALSO GOT LOTS OF GRANTS TURNED DOWN AND SO FORTH. SO THAT WAS LIKE SORT OF A ROCKY START. BUT PEOPLE WERE BEGAN TO REPRODUCE IT MORE AND MORE AND THE QUESTION WAS HOW IT COULD WORK. WHAT WE DID IS I TAKE TECHNIQUES USED IN PATHOLOGY USING A CRYOMICROTONE AN CUT THIN SECTIONS THROUGH THE POLYMER. HERE IS A FIVE MICRON SECTION WE USED ETHYLENE GLEE OWE ACETATE. IF YOU HAVE A MOLECULE DIFFUSE THROUGH IT OVER 200 MOLECULAR WEIGHT IT WOULDN'T BE ABLE TO DO IT. IT WOULDN'T GO FROM ONE SIDE TO THE OTHER. BUT TURNS OUT IF YOU PUT A DRUG IN, HERE IS A RED ONE, CUT A THIN SECTION WHAT YOU SEE BEFORE ANY RELEASE THIS SPACE SEPARATION, POLYMER HERE, DRUG HERE. IF YOU RELEASE THIS FOR A YEAR THEN YOU CUT A THIN SECTION, WHAT YOU SEE IS LEFT BEHIND WHERE THE DRUG WAS ARE THESE PORES. THEY WEREN'T THERE TWO SLIDES AGO. THESE PORES ARE LARGE ENOUGH SO THAT MILLIONS OF MOLECULAR WEIGHT GET THROUGH BUT PORES HAVE TIGHT CONSTRICTIONS BETWEEN THEM, THEY'RE INTERCONNECTED AND WINDING AND TORTUROUS SO IT TAKES TIME FOR THE MOLECULES TO WIND THEIR WAY THROUGH. ONE WAY I SOMETIMES EXPLAIN THIS TO PEOPLE, IT'S KIND OF LIKE LIVING IN MASSACHUSETTS, IT'S KIND OF LIKE DRIVEING A CAR THROUGH BOSTON. IN CHEMICAL ENGINEERING WE HAVE THIS TERM CALLED TORTURE'STY AND THIS HAS HIGHTOR CHURROSTY. OUR STUDENTS HAVE MODELS UNDERSTANDING HOW TO REGULATE THAT SO YOU CAN MAKE SYSTEMS RELEASE ANYWHERE FROM DAYS TO YEARS. OR ANY TIME IN BETWEEN. NOW THAT EF WE HAVE DONE THIS WORK WE CAN ADDRESS THE ANGIOGENESIS PROBLEM. HERE IS THE ASSAY. NOW WE CAN TAKE ALL THE DIFFERENT FRACTIONS AND TEST THEM. AND WE PROBABLY DID 2,000 RABBIT EYES, ENORMOUS AMOUNT OF WORK. I SHOULD SAY ALMOST EVERY FRACTION WE TESTED DID NOT WORK. AND THOSE COULD BE ALMOST CONTROLS. BUT ONE FRACTION DID. I APOLOGIZE FOR THE BLOOD BUT HERE ABOUT EIGHT WEEKS AFTER THE START OF THE EXPERIMENT, BLOOD VESSELS FROM THE EDGE OF THE CORNEA TO THE POLYMER WHICH YOU CAN NO LONGER SEE ON THE WAY TO THE TUMOR. IF YOU WAIT TWO MORE WEEKS THIS IS OF THE THIRD DIMENSION IN THE EYE, ULTIMATELY WOULD KILL BUT WE SACRIFICE GENERALLY AT THIS POINT. WITH THE INHIBITOR IN A NUMBER OF CASES, WHICH YOU NEVER SEE IN ANY CONTROLS, THE BLOOD VESSELS DID NOT INTERACT WITH THE TUMOR, IT NEVER GREW AND THEY AVOIDED THE BILL HER. SO WE PUB ACCOMPLISHED THIS IN SCIENCE, THE FIRST DEMONSTRATION THAT YOU CAN DO IN VIVO, YOU FIND SUBSTANCES THAT STOP BLOOD VESSELS FROM GROWING. IT TOOK ANOTHER 28 YEARS FROM THAT PAPER IN SCIENCE BEFORE THE FIRST ANGIOGENESIS INHIBITOR WAS APPROVED BY THE FDA. MILOS OF COMPANIES AN BILLIONS OF DOLLARS. STARTING IN 2004 WHAT HAPPENEDDED WAS MANY, MANY ANGIOGENESIS INHIBITORS WERE APPROVED NOT ONLY DIFFERENT FORMS OF CANCER BUT EYE DISEASES LIKE MACULAR DEGENERATION. I HAVE ASKED -- AVAS TAN IS PROBABLY ONE OR TWO BIGGEST SELLING BIOTECH DRUGS IN HISTORY. NOW ANGIOGENESIS INHIBITORS ARE USED IN OVER 20 MILLION PATIENTS FOR TREATING DIFFERENT DISEASES. IT ALSO SEEMED TO ME POLYMER TECHNOLOGY WE DEVELOPED MIGHT BE USEFUL NOT ONLY FOR THE IS THE STUDY IN ISOLATION OF INFORMATIONAL MACRO MOLECULES LIKEN YES GENESIS INHIBITORS BUT SLOW IN THEIR OWN RIGHT THERAPEUTICALLY BECAUSE SO MANY MOLECULES YOU WANT TO GIVE. BY INJECTION OR OTHER MEANS YOU CAN'T BECAUSE HALF LIVES ARE SO SHORT THEY'RE DESTROYED. A LOT OF MOLECULES YOU CAN'T TAKE ORALLY. SO AS PROOF OF PRINCIPLE LARRY BROWN ONE OF MY STUDENTS PUT P INSULIN IN ASPIRIN SIZE PELLET AND SHOWED YOU CAN GET IN VIVO RELEASE FOR OVER 100 DAYS. DR. FOLKMAN SAID THIS IS 1976 WE'RE AT CHILDREN'S HOSPITAL, IT'S A GOOD HOSPITAL BUT THE HOSPITAL NEVER HAD A PATENT. WE SHOULD FILE FOR A PATENT. SO WE DID. EXAMINER TURNED IT DOWN, HE TUSHD IT DOWN FIVE YEARS IN A ROW. THE LAWYER FOR THE HOSPITAL SAID BOB THIS IS CRAZY, THE GUY WILL NEVER ALLOW, HE DOESN'T UNDERSTAND IT. YOU SHOULD QUIT. I DONE LIKE TO DO THAT. SO I STARTED TO THINK HOW DO WE CONVINCE THE PATENT EXAMINER LEGALLY OF COURSE, AND I REALIZED SCIENCE WASN'T WORKING SO WELL SO I HAD THIS IDEA THAT OF ALL THESE PEOPLE WOULD TELL ME THAT WE COULDN'T DO THIS AND STUFF I WONDER IF ANYBODY WROTE ANYTHING DOWN. SO THERE'S SOMETHING THAT THEY HAD CALLED A SCIENCE CITATION INDEX WHICH MEANS I CAN TAKE A LOOK AT OUR 1976 NATURE PAPER AND SEE WHAT DIFFERENT PEOPLE SAID ABOUT IT OVER THE YEARS. SO I DID THAT AND FOUND INTERESTING THINGS, IT WAS AN INTERESTING EXERCISE TO SEE WHAT PEOPLE SAY ABOUT YOU. ANY RATE, ONE PAPER IN PARTICULAR I FOUND USEFUL FOR THIS EXERCISE. THIS IS A PAPER LOOKING BACK AT 1976 PAPER, THIS TURNED OUT FIVE TOP POLYMER CHEMISTS IN THE WORLD. HERE IS WHAT THEY WROTE. THEY'RE DESCRIBING THIS FEEL. GENERALLY THE AGENT TO BE RELEASED IS A RELATIVELY SMALL MOLECULE MOLECULAR WEIGHT NO LARGER THAN A FEW ONE HUNDRED. ONE WOULD NOT EXPECT IT COULD BE RELEASED BY SUCH A TECHNIQUE BECAUSE OF THE SMALL PERMEATION RATES THROUGH POLYMER. AND WE REPORTED ONLY SURPRISING SO THAT'S A GOOD WORD FOR A PATENT EXAMINER. RESULTS. THATCHERLY DEMONSTRATE THE OPPOSITE. SO I SHOWED THAT TO THE LAWYER AND HE WAS EXCITED, HE FLEW DOWN TO WHAT A SHOWEDDED TO THE EXAMINER AND HE SAID YOU KNOW, THAT'S VERY INTERESTING, I WILL ALLOW THIS PATENT IF DR. LANGER GETS AFFIDAVITS FROM THESE FIVE PEEP THEY WOULD WROTE THAT. SO I WROTE THEM AND THEY WERE NICE ENOUGH TO WRITE ME BACK THEY REALLY DID WRITE IT. THEN WE GOT THIS BROAD PATENT WE ACTUALLY LICENSEDDED TO SOME PLACE, I HAVE GOTTEN INVOLVED, THIS WAS MENTIONEDDED STARTING COMPANIES AND TODAY BASED ON THIS MANY DIFFERENT PRODUCTS ARE HELPING PEOPLE. FOR EXAMPLE, IF PEPTIDES LIKE ACETATE 1200 MOLECULAR WEIGHT YOU CAN'T SWALLOW OR TAKE THEM NASALLY, THEY DON'T GET IN THE BODY, IF YOU INJECT THEY'RE DESTROYED INSTANTANEOUSLY SO THEY'RE PUT IN MICROSPHERES AND WILL DELIVER THESE PEPTIDES FOR A MONTH UP TO FOUR MONTHS. THAT'S OTHERS TOO. IF SOMEBODY IS SCHIZOPHRENIC LIKE IF YOU SAW THE MOVIE A BEAUTIFUL MIND, THERE ARE DRUGS LIQUORIS PER DOLL AND USED TO BE LIKE IF YOU SAW THAT MOVIE RUSSELL CROW GOT TREATED WITH ELECTRIC SHOCKS NOW HE WOULD PROBABLY GET AN INJECTION OF ONCE OF THESE EF FEW WEEKS, THIS IS A ONCE A MONTH TREATMENT FOR ALCOHOLISM OR NARCOTIC ADDICTION, THIS IS VERY RECENTLY APPROVED SYSTEM FOR A ONCE A WEEK INJECTION OF A GLUCAGON LIKE PEPTIDE, THESE ARE USED NOW IN MILLIONS OF PATIENTS TO TREAT THESE DIFFERENT DISEASES. STILL, ALL THESE -- AND THERE'S MORE TO COME BUT ALL THESE SYSTEMS WHAT THEY DO IS THEY'RE ABLE TO CONTROL THE DRUG LEVEL AND REDUCE SIDE EFFECTS AND PROTECT THE DRUGS SO YOU CAN HAVE IT, HAVE A THERAPEUTIC EFFECT IN THE BODY. BUT WHAT THEY CAN'T DO IS ALL THESE ARE INJECTED INTRAMUSCULARLY OR SUBCUTANEOUSLY, THEY STAY THERE, SO YOU'RE NOT ABLE TO TARGET THE DRUG TO SPECIFIC CELLS OR TISSUES THAT'S GREAT THING IF YOU COULD DO IT. HOW COULD YOU THINK ABOUT THAT? WELL THESE ARE ALL MICROPARTICLES THAT YOU'RE GOING TO INJECT SUBCUTANEOUSLY INTRAMUSCULARLY. TO GET THEM TO BE TAKEN UP CELLS YOU NEED THE USE NANOPARTICLES BUT THE PROBLEM ONCE YOU PUT NANOPARTICLES OR ANY LITTLE PARTICLE IN THE BLOODSTREAM IS YOU PUT A DRUG IN IT AND MACROPHAGES ARE GOING TO EAT IT. SO WE HAD TO FIGURE A WAY TO DISGUISE THESE SO THAT THAT WOULDN'T HAPPEN OR ATHLETE IT WOULDN'T HAPPEN SO QUICKLY. SO ABOUT 20 YEARS AGO I HAD THE IDEA WITH SOME OF MY POST-DOCS THAT WE WOULD MAKE THESE LITTLE BLOCK CO-POLYMERS WITH POLYETHYLENE GLYCOL, FDA APPROVEDDED ON P THE OUTSIDE WHICH IS WATER LIKE. SO THE THINKING WAS IS THAT MAYBE THE CELLS WOULDN'T EAT THESE BECAUSE IT HAS THE WATER AND IT LOOKS LIKE WATER NORMALLY, SO MAYBE THEY CIRCUMSTANCE LIT A LONG TIME. SO THAT MIGHT AVOID THE MACROPHAGE PROBLEM TO AN EXTENT STILL YOU HAVE TO GET IT TO CELLS YOU WANT TO GO TO. SO HERE WHAT WE DID IS -- (INDISCERNIBLE) CAME TO MY LAB, PROFESSOR AT HARVARD, WHAT WE DID IS NOT ONLY PUT POLYETHYLENE GLYCOL BUT ALSO A TARGETING MOLL QUEUE WHICH COULD BE AN ANTIBODY, OPTIME, PEPTIDE OR OTHER MOLECULE. AND ACTUALLY THERE'S A LOT OF OPTIMIZATION ENGINEERING BECAUSE YOU HAVE TO GET JUST THE RIGHT DENSITY OF EACH OF THESE. I REALIZE I MAY HAVE NOT HAVE EXPLAINED THIS THAT WELL BUT I WAS LUCKY A YEAR AND A HALF AGO NO THEY EXPLAIN A LOT BETTER THAN I DO SO I'M GOING TO >> IT STARTS WITH A NANOPARTICLE OF ANTI-CANCER DRUGS. THAT GETS ENCASED IN APLITIC THAT RELEASES THE DRUG OVER TIME. THAT IN TURN GETS A SPECIAL WRAPPING THAT DISGUISES THE PACKAGE AS A WATER MOLECULE TO POOL THE TO THE DI'S IMMUNE SYSTEM. - BUT NOT LEAST THE ATRESS WHERE IT SHOULD BE DELIVERED. IT WILL ONLY FIT THE LOCK OF CANCER CELLS. >> I SHOULD TELL YOU A LOT OF CLINICS I WORK WITH TELL ME IT DOESN'T BLOW THE CELL UP QUITE LIKE THAT. BUT LIKE I SAID, I CAN'T COMPETE WITH THAT. THEY EXPLAINED IT BETTER THAN I DID. THEN WE GOT TO IT MOVE IN THIS TO THE CLINIC ONE OF THE MODELS WE USE IS AFTER WE DID THIS WORK WE STARTED -- AND I SHALL SAY THE NCI WAS VERY HELPFUL, WE GOT A CANCER NANOTECHNOLOGY GRANT AND I SHOULD A ALSO SAY MOST OF THE WORK WE HAVE HAD FUNDED BY NIBIB SO NIH IS GREAT ON A LOT OF THESE TO US. SO HERE WE SPUN OUT THIS COMPANY THAT ACTUALLY WOULD BUILD A MANUFACTURING PLANT TO MAKE NANOPARTICLES AND WE PUBLISHED ABOUT A LITTLE OVER A YEAR AGO SCIENCE TRANSLATIONAL MEDICINE FIRST HUMAN STUDIES. COUPLE OF HIGHLIGHTS. NORMALLY GIVE A DRUG BUT HERE WE PICKED ATAXATARE AND WE PICKED PSMA THAT WOULD BE OVEREXPRESSED IN TUMOR VASCULATURE. WE TARGET THAT AND IF YOU GIVE A DRUG BY ITSELF ON REGULAR NANOPARTICLE IT GOES THIS IS A LOG SCALE, IT GOES TO ZERO QUICKLY BUT IF YOU PUT IN NANOPARTICLE IT WILL CIRCULATE AROUND LONG TIME. AND WHAT YOU CAN SEE QUANTITATIVELY IS IF YOU COMPARE THE SAME DOSE IN THE NANOAS NOT THE NANOPARTICLE THE AREA UNDER THE CURVE IS 250 TIMES GREATER SO YOU'RE POUNDING THE TUMOR FOR DAYS. SO IT SEEMS SAFER AND THESE ARE JUST EFFICACY, MORE NEEDS TO BE DONE BUT THESE ARE CATS SCANS BEFORE AND 42 DAYS AFTER, BEFORE AND 42 DAY AS. THERE'S MULTIPLE CLINICAL TRIALS GOING ON PLUS THREE LARGE COMPANIES IN THE WORLD, AMGEN PFIZER AN ASTRA ZENECA ARE PUTTING THEY DRUGS IN THESE NANOPARTICLES. SO IT'S VERY EARLY BUT MY HOPE IS THAT THESE KINDS OF THINGS WILL BE USEFUL AND WE HAVE CONTINUED TO DO RELATED WORK ON THIS SOMETIMES WITH POLYMERS, SOMETIMES LIMEDS TO DELIVER DRUGS LIKE SI RNA AND mRNA, SO FORTH AND DNA. SO THIS IS ONE NANOTECHNOLOGY EXAMPLE. I'LL GIVE YOU ANOTHER. I REMEMBER ABOUT 20 YEARS AGO I WAS WATCHING THIS TELEVISION SHOW ON BEST ABOUT HOW THEY WERE MAKING CHIPS IN THE COMPUTER INDUSTRY. AND AS I WAS WATCHING AND I THOUGHT TO MYSELF WOULDN'T THIS BE A GREAT WAY TO MAKE A DRUG DELIVERY SYSTEM? NOW, IF YOU SPENT 30 YEARS OF YOUR LIFE ON DRUG DELIVERY SYSTEMS YOU MIGHT THINK THAT ABOUT ANY TV SHOW. BUT WHAT I DID, WHEN I SAW THIS, I THOUGHT WHY COULDN'T WE MAKE A SPECIAL CHIP NOT A CHIP YOU USE IN COMPUTERS BUT WITH SOME OF THE SAME IDEAS. COULD WE MAKE DIFFERENT WELLS, AND COVER THEM WITH LIKE A MEDAL WITH DRUG UNDERNEATH IT SO IT WILL BE STABLE. WHAT YOU CAN DO IS PUT DIFFERENT WELLS IN, YOU CAN PUT DIFFERENT DRUGS IN, LITERALLY HAVE A PHARMACY ON A CHIP IF POTENT ENOUGH OR DIFFERENT DOSES SAME DRUG AND SO FORTH. SO GRADUATE STUDENT JOHN SANTINI WHO WORKED ON THAT. THIS WAS AN EARLY STAGE CHIP, '04 34 WELLS TOP, 34 BOTTOM AND UNITED STATES DIME SO THIS IS LIKE A SHORT FLAT CHIP BUT WE MADE LIKE CYLINDERS SO YOU CAN HAVE INJECTABLE HIPS THROUGH THE TROUGH CAR IF YOU WANT TO CALL THEM THAT, THEY CAN BE BIGGER OR SMALLER, DO ALL KINDS OF THINGS. LET ME SHOW YOU HOW THEY WORK. HERE IS A WELL COVERED WITH GOLD OR TO BE A PLATINUM ALLOW, WE FOUND SEVERAL BIOCOMPATIBLE AND IT WOULD STAY LIKE THIS FOR YEARS. IF YOU COME ALONG AN APPLY ONE BY REMOTE CONTROL IN NANOSECONDS, THE COVER COMES OFF. WHEN IT DOES WHATEVER IS UNDERNEATH IT COMES RIGHT OUT. SO HERE IS AN EXAMPLE OF THAT FROM A -- ANOTHER PAPER IN NATURE, JOHN SANTINI MY STUDENT, YOU SEE WE PUT DIFFERENT AMOUNTS OF DRUG IN DIFFERENT WELLS AND THEY COME OUT AT DIFFERENT TIMES. IF YOU WANT TO DO THE PHARMACY ON A CHIP IDEA THERE'S MULTIPLE DRUGS IN DIFFERENT WELLS COMING OUT OF TIME, DIFFERENT TIMES. SO OVER THE YEARS WHAT WE DID IS WE MOVED THIS FROM IN VITRO TO SMALL ANIMAL TO LARGE ANIMALS AND RECENTLY THAT -- AND THEN JOHN STARTED A COMPANY ON THIS TOO. AND WHAT WAS DONE ACTUALLY A YEAR AND A HALF AGO WAS FIRST HUMAN TRIALS. THIS MIGHT SOUND LIKE SPACE AGE MEDICINE BUT LITTLE ME TELL TELL YOU WHAT WAS DONE. IN THE TRIAL PUT CHIPS IN THE HUMAN BODY AND THEY CAN COMMUNICATE OVER RAID YES FREQUENCY CALLED THE MEDICAL IMPLANT COMMUNICATION SERVICE BAND APPROVED BY THE SEC AND FDA. SOMETIMES PEOPLE ASK CAN SOMEBODY TAMPER AN CHANGE THE DOSE? I ALWAYS SAY THAT HOW ABOUT THE WORSE PROBLEM WE HAVE. WE'RE STILL TRYING TO GET THIS TO WORK. WHAT WE ALSO DID IN THIS CASE IS WE HAVE A SPECIAL COMPUTER CODE THAT ONLY THE PATIENT OR DOCTOR CAN KNOW. SO YOU HAVE TO KNOW THE RIGHT RADIO FREQUENCY, THE RIGHT CODE IF YOU WANT TO CHANGE THINGS. ALSO ONE THING INTERESTING ABOUT THIS IS WE SET IT UP SO YOU YOU HAVE A BIDIRECTIONAL COMMUNICATIONS LINK BETWEEN THE CHIP AND RECEIVER. THE RECEIVER BY THE WAY IS MANAGE LIKE THIS, COULD BE A CELL PHONE OR SOMETHING ELSE. IT GIVES YOU ALL KINDS OF INFORMATION LIKE DID YOU TAKE THE DRUG? THE BATTERY LIFE AND SO FORTH. TO THE YOUNGER PEOPLE IN THE AUDIENCE THAT MIGHT NOT SEEM IMPORTANT BUT YOURSELF MYSELF AS AN EXAMPLE, SO MY DAD DIED OF HEART ATTACK WHEN HE WAS 61. I HAVE TAKEN A STATIN DRUG NOW FOR THE LAST 15 YEARS ONCE A DAY. AND BUT WHAT'S HAPPENEDDED TO ME, I DON'T THINK I'M HAVE ALZHEIMER'S BUT WHAT HAPPENS I GO TOE -- I TAKE THE DRUG BUT MAYBE WALK BACK TO THE BATHROOM TWO HOURS LATERND LOOK AT THE VILE AND I SAY TO MYSELF DID I TAKE THE DRUG YESTERDAY OR TODAY? SO I GOT THE IDEA THAT WHAT I SHOULD DO IS WHEN I TAKE THE DRUG I WOULD TURN THE VILE UPSIDE DOWN BUT THEN STYMIES WALK INTO THE BATHROOM TWO HOURS LATER AND I LOOK AND I SAY BUT DID IT TURN THE VILE UPSIDE DOWN YESTERDAY OR TODAY SO ACTUALLY HAVING A PERMANENT RECORD OF THIS THAT YOU'D ALWAYS HAVE WHEN YOU TOOK THE DRUG AND SO FORTH, WHAT TIME, EVERYTHING, U THINK WILL BE USEFUL. LET ME TELL YOU THE TRIAL. IT WAS DONE IN DENMARK, THERE WERE EIGHT PATIENTS. WE WANT TO PICK A SITUATION THAT WE FELT A COULD HAVE CLINICAL IMPACT BUT BE A TOUGH TEST. PEOPLE USUALLY WILL TELL YOU WHY YOUR IDEA WON'T WORK T.EST REASON PEOPLE TOLD US THIS DIDN'T WORK IS FIBRIN ENCAPSULATION THAT SHUTS OFF RELEASE OF SUBSTANTIALLY SIZE MOLECULE SO WE PICKED A LARGE MOLECULE, PARATHYROID HORMONE, WE FELT COULD HAVE A CLINICAL IMPACT BECAUSE 77% OF THE WOMEN TWEAK THIS AS INJECTIONS DROP OUT DELIVER CON ON THE WOWSLY, THAT ACTUAL HUH CAUSES WORSE OSTEOPOROSIS, YOU WANT TO GIVE IT IN A PULSE TILE ACTION. SO WE THOUGHT IT DOCTORS WOULD DO A LITTLE OFFICE PROCEDURE TO DO THE IMPLANT, TAKES 20 -- WHAT HAPPENED IN THE TRIAL IS THERE WAS LESS VARIABILITY WHICH I DON'T THINK IS IMPORTANT HERE BUT MIGHT BE IMPORTANT IN SOME CASES AND THERE'S THREE MEASURES WHETHER YOU TREAT OSTEOPOROSIS AND COLLAGEN AND DIFFERENT FRAGMENTS AND THEY WERE THE SAME AS PARATHYROID HORMONE LEVELS ONCE YOU PULSE IT DAY 60, 68, 76 AND 84. SUPERIMPOSABLE. THIS IS ACTUALLY IF YOU LOOK AT IT, HERE IS A CHIP INSIDE OF IT THERE WAS A BATTERY, A COMPUTER PROGRAM, ON THIS SIDE YOU CAN'T EVEN SEE ON THE END WE IMPRINTED AN ANTENNA THAT'S HOW YOU COMMUNICATE SO THERE'S IMPRINT OF ANTENNA, WE ARE NOW MAKING MUCH SMALLER CHIPS BUT THIS IS A -- BUT ACTUALLY DONE, YOU CAN SEE A COUPLE OF THINGS, ONE YOU DO GET FIBRIN ENCAPSULATION, IT'S ABOUT 1/20 WHAT A PACEMAKER GETS. IF YOU LOOK AT HISTOLOGY, IT IS NOT BAD, NO INFLAMMATORY CELLS SO FORTH. WE'RE MOVING IN MULTIPLE DIRECTIONS. WE'RE ACTUALLY DESIGNING TWO YEAR CHIPS. SECOND THING THAT'S VERY INTERESTING IS BILL GATES CAME TO SEE ME YEAR AND A HALF AGO AND YOU MAY KNOW HE AND HIS WIFE ARE INTERESTED IN BIRTH CONTROL WHERE THE WOMAN IS EMPOWEREDDED TO ACTUALLY CONTROL IT. SO THEY ASK COULD WE MAKE A BIRTH CONTROL DEVICE THAT COULD BE IMPLANTED THAT COULD LAST FOR 16 YEARS THAT THE WOMAN COULD TURN ON AND OFF WHENEVER SHE WANED IN THAT'S NOT AN EASY THING TO DO WITH ANY REGULAR BIRTH CONTROL IMPLANT BUT WITH THIS IT'S FAIRLY I DON'T WANT TO SAY STRAIGHT FORWARD BUT DOABLE BECAUSE YOU HAVE THIS CONTROLLER. YOU CAN MAKE EACH WELL LAST A MONTH SHUT ON OR OFF WHENEVER YOU WANT SO WE'RE DOING THAT, THEY HAVE GIVEN US WELL OVER $6 MILLION TO DO THIS AND HOPEFULLY MORE TO BRING THIS TO PATIENTS. FINALLY WE'RE LOOKING AT SOME DAY, WE HAVE ALREADY DONE PART OF THIS, YOU CAN ENVISION SENSORS ON THESE CHIPS. SO YOU CAN SENSE SIGNALS IN THE HUMAN BODY AND TELL THE CHIP HOW MUCH DRUG TO DELIVER. FROM Z I TALKED HOW WE CAN TAKE MATERIALS THAT EXIST IN NATURE AND DO THINGS WITH ENGINEERING TO DO THINGS THEY NEVER DID BEFORE. WHAT ABOUT MATERIALSES THEMSELVES? SO I WAS CURIOUS ABOUT THIS WHEN I KNOW WORKED IN CHILDREN'S HOSPITAL AND OTHER PLACES, HOW DID MATERIALS FIND THEIR WAY INTO MEDICINE? CHEMIST, CHEMICAL ENGINEERS? IT ALMOST NEVER WAS. THE DRIVING FORCE FOR BRINGING MATERIALS TO MEDICINE ALMOST ALWAYS FOR MEDICAL DOCTORS WHO URGENTLY SOLVE A MEDICAL PROBLEM, THEY GENERALLY GO TO THEIR HOUSE TO FIND SOME OBJECT THAT SEMIABLE THE TISSUE THEY WANT TO FIX AND THEY USE IT FOR PATIENT. LET ME GIVE SOME EXAMPLES. THE FIRST WAS HERE. SO THEY WANTED SOMETHING WITH A GOOD FLEX LIFE SO THEY PICKED OUT A LADY'S GIRDLE BECAUSE IT HAS A FLEX LIFE. THAT'S WHAT'S IN THE ARTIFICIAL HEART TODAY BUT SOMETIMES YOU GET CLOTTING WHEN THE BLOOD SURFACES THE ARTIFICIAL HEART CLOTS GO TO PATIENT BRAIN AND THEY GET A STROKE AND DIE. DIALYSIS WITH SAUSAGE CASING VASCULAR GRAPH IS SURGEON GOING TO A CLOSEDDED DOOR TO SEW WELL, BREAST IMPLANTS ONE WAS LUBRICANT, ANOTHER IS A MATTRESS STUFFING, THINK OF THE LOGIC. SO ONE THING YOU LEARN IN CHEMICAL ENNEARING IS CHEMICAL ENGINEERING DESIGN. THAT IS WE'RE GOING TO I THOUGHT RATHER THAN TAKE THIS APPROACH, TAKE SOMETHING FROM YOUR HOUSE, WHY COULDN'T WE ASK THE QUESTION? CHEMISTRY STANDPOINT AND BIOLOGY STAND POINT AND SYNTHESIZE FROM FIRST PRINCIPLES. WE PICKD AN EXAMPLE. FOR IMPLANTATION DEGRADABLE WHERE WERE POLYsTURE SUE CHU, THEY LOOK LIKE THIS AND GET SPONGY AND PALPATE. IT'S O O FOR SOME DRUGS BUT IF YOU HAVE ANTI-CANCER DRUG ORINASE LINS, DUMP THE DRUG AND IT CAN BE FATAL. SO WE SAID FROM ENGINEERING STANDPOINT THAT'S NOT WHAT WE WANT. WHAT WE WANT IS TO PREVENT THE DUTCHING POTENTIAL SURFACE EROSION, CAN WE MAKE A POLYMER THAT DOES THIS. HOW DO YOU DO THE THIS? FIRST I SHOULD SHOW YOU WHAT DOES POLYMER LOCK LIKE? THEY'RE MONOMERS WHICH COULD BE ANYTHING CONNECTED BY BONDS. WOE SAID IF WE WANT TO MAKE SOMETHING SURFACE EROSION, SHOULD IT BE ENZYMES WATER OR SOMETHING ELSE? ALL OF YOU HAVE DIFFERENT ENZYME LEVELS, CELLULAR RESPONSE AROUND IMPLANT WILL CHANGE OVER TIME, AGAIN CHANGING THE ENZYME LEVELS BUT ALL OF YOU HAVE EXCESS WATER SO WE SAID IF WE WANT THE MAKE THIS REPRODUCIBLE FOR EVERYBODY LET'S MAKE WATER THE CATALYST, LET'S BUILD THAT IN THE POLYMER WE DESIGN. THEN WE ASKED THE NEXT QUESTION. IF WE DO THAT AND WE WANT TO SURFACE EROSION WE HAVE TO MAKE MONOMERS HYDROPHOBIC TO MAKE THESE -- BONDS TO BREAK WHEN THE WATER HITS IT SO WE WENT TO ORGANIC CHEMISTRY. TO LOOK AT DIFFERENT VULNERABLE. I SAY AT M I CANT I SHOW A SLIDE I FOUND A GOOD USE FOR ORGANIC CHEMISTRY ANDCAL CAN YOULATED UP HERE TO THE HYDRIDE BOND. SO WE PROPOSE THE IDEA OF HYDROPHOBIC POLYHYDRIDES. NOW WE HAVE TO FIGURE WHAT THESE R GROUPS WERE SO I STARTED TALKING TO CHEMISTS AND TOXICOLOGISTS AT MIT. NOTABLY MIKE MARLETTO A GOOD FRIEND OF MINE NOW HEAD OF SCRIPPS WHO WAS HELPFUL TOWS. WE PICKED MONOMERS THAT I FELT COULD MAKE POLYMERS OUT OF BUT THAT HE FELT WOULDN'T BE TOXIC ONCE THEY BROKE DOWN. VERY HYDROPHOBIC CARBOXYPROPANE, SLIGHTLY LESS PHOBIC THAN BAY SIX ACID AND SYNTHESIZED IT. NOT ONLY DID THEY COME CLOSE TO SURFACE EROSION BUT BY CHANGING THE RATIO FROM 0% BASIC ACID TO 79% YOU DIAL IN DIFFERENT RATIOS YOU MAKE THESE LAST DIFFERENT LENGTHS OF TIME FROM SAY TWO WEEKS TO MANY YEARS. SO NOW IF YOU HAVE THIS YOU CAN BEGIN TO THINK ABOUT USING THESE POLYMERS AGAIN FOR DIFFERENT MEDICAL APPLICATIONS. IN 1985, HENRY BRADLEY YOUNG NEUROSURGEON AT JOHNS HOPKINS CAME TO SEE ME, HE'S CHIEF OF NEUROSURGERY HERE TODAY AND HE WAS LOOKING FOR A BETTER WAY TO TREAT GLIOBLASTOMA MULTI-FORMING WHICH IS A UNIFORMLY FATAL DISEASE, MEAN LIFE SPAN LESS THAN A YEAR. THE DRUG AT THAT TIME THE ONLY DRUG THAT WAS REALLY USED WAS BCNU. WE STARTED TALKING ABOUT HAVING A DIFFERENT PARADIGM, RATHER THAN A DRUG LIKE THIS SYSTEMICALLY LIKE IV THROUGHOUT THE BODY MAKE GIVE LOCALLY, ALLOW THE NEUROSURGEON LIKE HENRY TO OPERATE ON THE PATIENT AND BEFORE HE CLOSINGS THE PATIENT'S BRAIN UP LINE THE CAVITY WITH WAFERS CONTAINING THIS. IT LASTS NORMALLY 12 MINUTES HALF LIFE BUT IN THE POLYMER TO PROTECT IT IT LASTS AS LONG AS THE POLYMER LASTS. WHAT THEY WANTED WAS A POLYMER THAT WOULD LAST A MONTH AND WE COULD DO THAT. THEY ALSO WANT IT SURFACE ERODING TO NOT DUMP THE DRUG. THE POLYMER PROTECTS IT FROM DEGRADATION AND YOU GET THIS BENEFIT, HIGH CONCENTRATIONS IN THE BRAIN WHERE YOU WANT TO BE AND LOW IN THE REST OF THE BODY WHERE IT CAUSES HARM. IF YOU'RE A YOUNG PROFESSOR WITH THESE IDEAS YOU HAVE TO RAISE MONEY AND WE WRITE GRANTS TO NIH AND NSF AND OTHER PLACES, WE DIDN'T DO WELL. TO MAKE IT CLEAR WHEN WE WRITE GRANTS TO NIH IT'S PROFESSORS AT OTHER UNIVERSITY WHOSE REVIEW THEM, NOT PEOPLE AT NIH SO YOU HAVE THESE STUDY SECTIONS PROFESSORS FROM OTHER UNIVERSITIES. WHEN WE HAVE -- THIS WOULD BE TRUE AT NSF TOO. THESE ARE REVIEWS WHEN WE CAME BACK. 1981 CHEMISTS SAID YOU COULD NERVE SYNTHESIZE THE POLYMERS BUT I HAD A GOOD P DOC WHO BECAME PRESIDENT OF THE (INAUDIBLE) CORPORATION A $12 BILLION COMPANY SOLD TO JOHNSON AND JOHNSON BUT HE'S ALSO A MEMBER OF THE NATIONAL ACADEMY OF ENGINEERING AND HE SYNTHESIZED IT, SENT IT BACK AND REVIEWERS PEOPLE SAID WE STILL NEVER GET THIS WORK BECAUSE WE HAVE AN HYDRIDE BONDS AND POLYMERS REACT WITH ANY DRUG YOU PUT IN. BUT WE DIDN'T THINK IT WAS TRUE BECAUSE IT WAS IN A POLYMER FORM AND I HAD ANOTHER COUPLE OF POST-DOCS BOB LYNNHART COPSLATION PROFESSOR AT CAMERON YOUNG JAMES DUKE PROFESSOR BIOENGINEERING AT DUKE UNIVERSITY ALSO MEMBER OF NATIONAL ACADEMY EVENING FLOORING SHOWING KNOW REACTION. SENT IT BACK AGAIN, REVIEWER SAID THE POLYMERS WERE LOW MOLECULAR WEIGHT AND FRAGILE BUT ANOTHER COUPLE OF POST DOCS ARCVICS DONE CHAIR OR BECAME CHAIR OF MEDICINAL CHEMISTRY AT HEBREW UNIVERSITY AND EDITH (INDISCERNIBLE) FULL PROFESSOR BIOENGINEERING AT BROWN UNIVERSITY, THEY MADE POLYMERS HIGH MOLECULAR WEIGHT AND THEY WERE FINE. NEXT ISSUE WAS THE POLYMER WOULD BE TOXIC. ANOTHER GRADUATE STUDENT KAY TOE LAWRENCE, HE BECAME DEAN OF MEDICINE UNIVERSITY OF CONNECTICUT BOTH INSTITUTE OF MEDICINE AND NATIONAL ACADEMY OF ENGINEERING AND HE SHOWING THE POLYMERS WOULD BE QUITE SAFE THIS KEPT GOING ON AND ON P UNTIL 1996 WHEN THE FDA APPROVED IT. FIRST TIME IN OVER 20 YEARS THE FDA APPROVED A NEW TREATMENT FOREBRAIN CANCER AND FIRST TIM THEY APPROVED THIS IDEA WITH LOCALIZED POLYMER CHEMOTHERAPY, I'M PROUD OF HOW WELL ALL THE M MIT GRADUATE STUDENTS AND POST-DOCS BECAME CHAIRS MEMBERS OF NATIONAL ACADEMY OF ENGINEERING AND CHAIR PEOPLE OF CORPORATIONS, AD WHEREAS AT OTHER UNIVERSITIES THEY DIDN'T DO SO WELL. I SHOULD SAY THOUGH, I AS AN ASIDE, THAT IN SPITE OF THIS I STILL THINK THE NIH REVIEW PROCESS IS THE BEST ONE OF ANY AGENCIES BECAUSE YOU GET FEEDBACK AND UNFORT MATILY, WE'RE CERTAINLY GOING TO SEE THIS NOW, IS WHEN MONEY IS TIGHT WHAT HAPPENS IS REVIEWERS USUALLY LOOK TO THINGS THEY BECOME MORE CRITICAL, LOOK AT WHY THINGS CAN'T WORK. AND I THINK IT JUST MAKE IT IS THE WHOLE PROCESS MORE DIFFICULTFUL RATHER THAN GIVING PEOPLE A CHANCE TO DREAM AND DO GREAT THINGS. SO UNFORTUNATE WHEN MONEY IS TITER AND TIGHTER. I DO WANT TO SHOW YOU WHAT WHAT THE OPERATION LOOKS LIKE BUT IF ANYBODY IS SQUEAMISH AND DOESN'T LIKE SIGHT OF BLOOD YOU SHOULDN'T LOOK. HERE IS A WAFER INTO THE BRAIN. USUALLY 6 OR 7 AND CLOSE THE BRAIN. IT'S VERY HARD TO GIVE GOOD ADVICE WHEN YOU GIVE A TALK BUT ABOUT 12 YEARS AGO I REMEMBER GIVING A LECTURE TO A GROUP OF CHEMICAL ENGINEERS AT MIT AND MY WIFE CAME TO THE LECTURE. AT THE END I SAID LAURA WHAT DID YOU THINK? AND SHE SAID BOB, SHE SAID THE TALK WAS ALL RIGHT. THAT BY THE WAY IS INCREDIBLY HIGH PRAISE. BUT SHE SAID I DON'T KNOW IF YOU WERE LOOKING AT THE CHEMICALS ENGINEERS WHEN SHOWING SLIDES BUT A LOT WERE TURNING GREEN. AND LOOKING AT THE FLOOR. SO AFTER THAT I DID WHAT I DID TODAY O GAVE A WARNING AND SHOWED QUICKLY BUT I WANT THE TELL YOU THE SEQUEL. IS TWO YEARS AFTER THAT I GOT ASKED TO GIVE A DINNER SPEECH. BUT THIS WAS TO A GROUP OF NEUROSURGEONS AND AT THE END OF THE SPEECH A NUMBER OF THEM CAME UP TO ME AND HE SAID YOU KNOW THE BLOODY SLIDES YOU SHOWED NO PROBLEM, YOU COULD HAVE LEFT THOSE ON AS LONG AS YOU WANT. THEY SAID BUT THOSE CHEMICAL FORMULAS. TO LEAVE THOSE ON FOR A NEUROSURGEON IS REALLY BAD. FROM SO ANYHOW, THIS WAS SOME OF THE PHASE 3 DATA IN EUROPE AND YOU DO SEE A PROLONGATION OF -- NOT A CURE BY ANY MEANS BUT PROLONGATION OF LIFE AN THIS IS NOW STILL USED. 18 YEARS AFTER ITS APPROVAL IN 50 COUNTRIES, FAIRLY NARROW SITUATION WHERE PEOPLE WILL USE IT IN FAIRLY LOCALIZED TUMORS. BUT IT'S STILL BEEN USED PROBABLY NEARLY 100,000 PATIENTS. ALSO THE PRINCIPLE OF LOCALIZED POLYMER CHEMOTHERAPY, MOST WIDELY USED IS NOT IN CANCER BUT INTERVENTIONAL CARDIOLOGY, SOME OF THIS WAS DONE BY ANOTHER STUDENT, PROFESSOR AT HARVARD AND MIT AS WELL AS A NUMBER OF COMPANIES. THE WHOLE IDEA IS THAT IF SOMEBODY GETS HEART DISEASE YOU PUT IN A STINT LIKE A CHINESE FINGER PUZZLE TO KEEP THE BLOOD VESSEL OPEN BUT 50% IT CLOSES OFF BECAUSE OF SMOOTH MUSCLE PROLIFERATION SO NOW YOU TAKE A DIFFERENT ANTI-CANCER DRUG IN THIS CASE TAX OOL QUOTED WITH A POLYMER AND IT CORALLY DELIVERS IT AND -- LOCALLY DELIVERS IT AN THESE ARE USED IN ABOUT A MILLION PATIENTS EVERY YEAR. LAST THING I WANT TO TALK ABOUT BRIEFLY IS USING MATERIALS NOT TO DELIVER DRUGS BUT CELLS THAT CREATE NEW TISSUES AND ORGANS. I'LL BE BRIEF BUT CERTAINLY EXCITING AREA AND I WILL SHOW YOU A LITTLE BIT. HERE IS A PATIENT OF ONE OF MY COLLEAGUES JAY PICANTI. THIS BOY IS DIAGNOSE OF LIVER FAILURE. THERE'S NO WAY FOR HIM TO BE TREATED EXCEPT SOMEBODY ELSE HAS TO DIE AND THEY DO A TRANSPLANT. HE CAME TO SEE ME, MUST HAVE BEEN OVER 30 YEARS AGO AND WE START TALKING TO COME UP WITH A BETTER WAY TO DO IT. THE IDEA WE CAME UP WITH WAS SHOWN FROM A PAPER WE WROTE IN SCIENCE IS HERE, WE YET WROTE THIS BEFORE PEOPLE TALKED ABOUT STEM CELLS. BUT YOU CAN ISOLATE DIFFERENT CELL TYPES INJECT AT RANDOM NOT MUCH HAPPENS BUT IF YOU TAKE THE SAME CELLS PUT THEM CLOSE ENOUGH TOGETHER THEY HAVE THE ABILITY TO FORM STRUCTURES. PEOPLE ARE SHOWN THAT BEFORE US AT BERKELEY PEOPLE WERE SHOPE YOU CAN TAKE MAMMARY EPITHELIAL CELLS PUT THEM TOGETHER AND THEY FORM ARCSINI AND MAKE MILK. OUR THOUGHT WAS TO CREATE A POLYMER SCAFFOLD THAT WOULD BE DEGRADABLE TO ALLOW THE REORGANIZATION TO OCCUR BUT THEN THE POLYMER WOULD GO AWAY. ALSO WHAT'S CRITICAL, I PROBABLY WON'T TWO INTO THAT TOO MUCH NOW IS THE WAY YOU GROW THE CELLS, IT'S MORE THAN REGULAR TISSUE CULTURE, SOMETIMES YOU HAVE TO APPLY THE RIGHT STRESSES AND THERE'S BIOENGINEERING IN THAT. AND THEN YOU CAN MAKE THE TISSUE. WE SYNTHESIZE POLYMERS, WE MIGHT USE GLYCOLLIC ACID CO-POLYMER BUT SOME CASES CERTAIN CELLS WILL NOT ADHERE TO IT SO WE CREATED NEW POLYMERS LIKE POLYGLYCOLIC ACID GLYCENE, YOU CAN LOOK AT DIFFERENT AMINO ACIDS LEATHER SEQUENCES LIKE RGD SO WE CAN CONTROL WHAT THE CELLS DO. WE INFORM THEM TO DIFFERENT STRUCTURES LIKE FIBERS LIKE THIS AND WE HAVE GONE FURTHER LIKE (INDISCERNIBLE) ONE OF MY POST DOCS NOW RUNS A BIG INSTITUTE IN GERMANY, POLYMERS YOU CAN BEGIN TO USE CAD CAM TECHNIQUES LIKE COMPUTER AIDED DESIGN THE MAKE SHAPES IN ANY SHAPE YOU WANT AND JUST SPECULATE WITH YOU, 30 YEARS FROM FROM NOW, MAYBE SOMEBODY WILL GO TO A PLASTIC SURGEON AND SAY I WOULD LIKE A NEW NOSE. MY SPECULATION IS COMPUTER SCREEN WITH PICTURES OF 30 NOSES AND YOU CAN TAKE YOUR PICK. TO THAT END HE'S USED THE COMPUTER AIDED DESIGN ALONG WITH VARIOUS APPROACHES LIKE 3-D PRINTING OR DIFFERENT METHODS MAKING PHONES AND HERE IS LIKE THE REGULAR NOSE. AND YOU CAN PUT CARTILAGE CELLS ON IT. FROM Z THIS IS A REGULAR NOSE BUT SAY SOMEBODY WANTS UPTURNED NOSE, IT WOULDN'T BE HARD TO DO. YOU TAKE THIS OFF. SAY SOMEBODY WANT AD HOOK NOSE, PROBABLY WOULDN'T BUT IF THEY DID WE WOULD GIVE MORE, TAKE THE CELLS AND MAKE -- GIVE YOU AN EXAMPLE OF THAT IN A MINUTE. SO I THOUGHT I WOULD GIVE YOU TWO EXAMPLES TO END THE TALK BUT THEY'RE PROBABLY 20 OR SO WE'RE WORKING ON. FIRST IS CARTILAGE, WE WORKED ON THIS WITH CHUCK MCCONTY, JAY'S BROTHER AND YOU CAN TAKE NUDE MICE AND WE MADE A SCAFFOLD AND WE REDID THIS GUY'S SKULL. WE REDID THIS GUY'S CHEEK. IF YOU OPEN THE ANIMALS AN LOOK AT THEM, WHAT YOU SEE IS THIS PURE WHITE GLYCERIN CARTILAGE, I DIDN'T BRING IT BUT LOOKING AT HISTOLOGY IT LOOKS IDENTICAL TO TEXTBOOK CARTILAGE BUT IT'S NOT. TURNS OUT THE LEVELS OF GLYCO GUY CANS AN TYPE 2 COLLAGEN IS LESS AN MECHANICAL PROPERTIES ARE NOT AS GOOD SO E EAR NOT AT POINT TO HELP PEOPLE WITH ATHLETIC JURIES BUT THERE ARE COSMETIC THINGS YOU CAN DO, BIG PROJECT WITH JAY AND MELINDA GRIFFITH, FORMER POST-DOC WITH THE ARMY. SEE IF WE CAN MAKE BODY PART FOR SOLARS WHO MIGHT RETURN FROM AFGHANISTAN OR IRAQ AND ONE IS LIKE AN P EAR, TO THEM LYNN THE MADE A SCAFFOLD IN THE FORM OF HUMAN EAR,. HERE IS SCANNING MICROGRAPH OF THE POLYMER FIBERS. HERE ARE THE KENDRACYTES MULTIPLYING MAKING EXTRA CELLULAR MATRIX OVER TIME THE POLYMER WILL FULLY DISSOLVE AND YOU GET ALL CELLS AN EXTRA CELLULAR MATRIX. CHUCK PUT THIS ON A RABBIT. AND WE HAVE NOT PUT IT ON PATIENTS YET BUT WHAT HAPPENED IS JAY -- WE HAVE DONE JAY AND OTHERS HAVE DONE CLINICAL TRIALS AND I'LL GIVE YOU AN EXAMPLE, HERE IS 12-YEAR-OLD BOY AT THE TIME BUT IF YOU LOOK, HE'S GOT NO CHEST COVERING HIS HEART BUT LIKE OTHER 12-YEAR-OLD BOYS HE LIKE IT IS PLAY BASE BARK IMAGINE IF HE GOT HIT IN THE CHEST WITH A BASEBALL HE COULD DIE SO JAY PARTICIPANTED ON HIM, HE MADE A POLYMER SCAFFOLD AND MADE HIM A NEW CHEST, SO HE'S NOW SIX FETAL AND DOING WELL. THE LAST EXAMPLE IS ONE WE LICENSED SOMETHING TO COMPANY BUT THEY CAN MAKE NEW SKIN FOR BURN VICTIMS WHO HAVE OR FOR PATIENTS WITH DIABETIC SKIN ULCERS, THESE ARE FDA APPROVED FAIRLY WIDELY USED. LET ME SHOW A PICTURE OF THAT. HERE IS A 2-YEAR-OLD BOY WHO IS VERY, VERY BADLY BURNED. THE PRODUCT NOW WITH NEONATAL SKIN FIBROBLAST, PUT IT ON THE POLYMER, YOU CAN EVEN CRYOPRESERVE THESE AND PUT IT ON THE CHILD AT THE TIME OF INJURY, IT LOOKS LIKE THIS IF YOU COME BACK THREE WEEKS LATER HE LOOKS LIKE THIS IF YOU COME BACK SIX MONTHS LATER HE LOOKS LIKE THIS. AND AS I MENTIONED THESE ARE NOW FDA APPROVED FOR BOTH DIABETIC SKIN ULCERS AN P BIRD VICTIMS. I WILL END HERE, WE'RE WORKING ON A BUNCH OF OTHER IT SHALL SHOES AN ORGANS SOME FUNDED BY NIH AND I WOULD SORT OF MAKE TWO COMMENTS IN CLOSING. ONE, I GET ASKED TO GIVE LECTURES BUT WHEN NIH ASKS I FEEL VERY GRATEFUL TO NIH OVER THE YEARS, THEY HAVE BEEN OUR NUMBER ONE FUNDING SOURCE AND NONE OF THESE WOULD HAVE HAPPENED NONE OF THESE PRODUCTS WOULD HAVE HAPPENED IF THEY DIDN'T GET THEIR GENESIS HERE. SECOND THING I WOULD SAY, THIS IS REALLY THE P TIP OF THE ICEBERG I BELIEVE THAT BIOENGINEERING IS STILL IN INFANCY. THE KINDS OF THINGS I TALKED ABOUT WE PROBABLY RAISED MORE QUESTIONS THAN WE HAVE ANSWERED. I BELIEVE AS WE MOVE FORWARD TO THIS CENTURY THERE'S GOING TO BE SO MANY THINGS THAT CAN BE DONE BY COMBINING ENGINEERING BIOLOGY AND MEDICINE ALL KINDS OF THINGS CAN BE DONE BY STUDENTS AND POST DOCS OF THE FUTURE THAT RELIEVE SUFFERING AND PROLONG LIFE. THANK YOU VERY MUCH FOR HAVING ME HERE. [APPLAUSE] >> THANK YOU VERY MUCH FOR A WONDERFUL TALK. QUESTIONS. >> THIS IS THE LATTER PART OF YOUR PRESENTATION OF TISSUE ENGINEERING. THE EXAMPLES YOU HAVE SHOWN OR WE READ IN THE NEWSPAPERS, THEY'RE STRUCTURAL, STRUCTURE OF SKIN, CAN YOU IMAGINE IN THE FUTURE WE WILL BE ABLE TO IMPACT WITH BIOLOGICAL MOLECULES SO THEY HAVE MAGIC ACTIVITIES. REAL BIOLOGICAL ACTIVITIES? >> CAN WE BUILD BIOLOGICAL ACTIVITY INTO THESE MATERIAL? FROM YES. >> SURE. SOMETIMES WE TO WHAT WE CALL BIOMIMETIC MATERIALS SO YOU CAN BUILD THEM. IN FACT ONE THING I ALLUDED TO, I DIDN'T GO INTO IT MUCH IS THE FACT THAT YOU CAN MAKE POLYMERS AND TAKE SPECIFIC AMINO ACID SEQUENCES TO RECREATE SURFACES THAT AID ADHERENCE BUT ALSO BRING IN OTHER FEATURES TOO IF YOU WANT TO. ABSOLUTELY. >> CREATING NEURONSES, CAN THAT HAPPEN, FUNCTIONAL NEURON? >> I'M NOT THE EXPERT -- THE QUESTIONNAIRE IS COULD ONE TALK STEM CELLS AN DIFFERENTIATE TO NEURONS. I THINK PEOPLE HAVE DONE THINGS ALONG THOSE LINES THE QUESTION IS WHETHER YOU -- HOW FAR YOU WANT TO GO. >> BITTY SHOENING NEARING -- BY TISSUE ENGINEERING. >> REGENERATING. I GUESS I TAKE A BROAD DEFINITION OF TISSUE ENGINEERING, IN OTHER WORDS IN FACT WE LOOKED AT SPINAL CORD REPAIR AND OTHERS. WHAT YOU WANT TO DO FROM MEDICAL STANDPOINT, IF I CAN GET NEURONS FROM STEM CELLS, NEURONAL STEM CELLS THAT'S ONE THING WE LOOKED AT, I'M HAPPY TO USE THOSE. YOU HAVE TO FIND THE RIGHT MATERIAL TO DO THE THINGS YOU WANT TO DO IT WITH. HAD BEEN PROBABLY SMART ENOUGH TO DO OUT SOMETIME IF THEY GET FUNDING AN SMART ENOUGH. PROBABLY IT'S NOT US. >> THANK YOU FOR WONFUL TALK. CAN YOU GIVE LESSON LEARNED OR TIPS HOW TO DO BETTER TRANSLATIONAL SCIENCE TO BUSINESS TO COMMERCIALIZATION? WELL, I'M NOT SURE I'M AN EXPERT ON THAT BUT I GUESS THERE'S A COUPLE OF DIFFERENT THINGS. THE ENVIRONMENT AT MIT IS GOOD IN TERMS OF TRANSLATION. I MEAN, MIT IS TO ME IF YOU GET -- RAISE THE TYPES OF DOLLARS IT TAKE AND GET THE ORGANIZATION IT TAKES TO MAKE PRODUCTS YOU NEED MONEY. SO THEREFORE YOU HAVE TO HAVE INCENTIVE, CREATE INCENTIVE FOR PEOPLE TO WANT TO INVEST IN IT. WHETHER COMPANIES OR INVESTORS LIKE VENTURE CAPITAL. THE FIST THING YOU NEED, YOU NEED A RELAY GOOD IDEA THAT IS -- REALLY GOOD IDEA. THAT IS IMPORTANT. SECONDLY YOU NEED A GOOD PATENT. I DON'T THINK IN THE BIOLOGICAL AREA MEDICAL AREA PEOPLE WILL INVEST UNLESS YOU HAVE GOOD INTELLECTUAL PROPERTY. THIRD YOU NEED GOOD IN VIVO DATA AND ALSO WANT TO GET YOURSELF ASSOCIATED WITH REALLY GOOD BUSINESS PEOPLE. THAT I WOULD THINK IN TERMS OF COMMERCIALIZATION. IN TERMS OF TRANSLATION, THAT MAY NOT BE REQUIRED. I MEAN, IF YOU WORK WITH GOOD CLINICS THAT ALSO -- WE HAVE BEEN FOR GNAT AGAIN HAVING CHURN'S HOSPITAL MASS GENERAL WITH JOHNS HOPKINS AND YOU HAVE THINGS HERE, THERE'S MORE AND MORE I THINK WITH BIOMEDICAL ENGINEERING GOOD COLLABORATIONS BETWEEN BIOENGINEERS AND CLINICIANS GOING BOTH WAYS. MY LAB I HAVE TEN CLINICIANS. ONE THING NICE ABOUT THESE PLACES IS YOU HAVE FELLOWS WHO COME FOR THREE YEARS, THEY'RE FANTASTIC. WE HAVE FELLOWS FROM ALL KINDS OF DISCIPLINES GASTROENTEROLOGY NEUROSUFFER SURGERY, DERMATOLOGY, ON MALLMOLOGY, PAIN. SO I THINK HAVING -- OPHTHALMOLOGY. SO I THINK HAVING THE TRANSLATION REALLY REQUIRES THE INTERFACE BETWEEN SCIENCE AND CLINICS WHO WANT TO MAKE HAPPEN ON THE OTHER. >> DURING YOUR TALK YOU COMMENTED HOW DIFFICULT FOR NIH TO REVIEW RESEARCH PROPOSALS AND STILL END UP CHOOSING THE INNOVATIVE ONES. COULD YOU COMMENT ON THAT FURTHER WHAT YOU MIGHT SEE WE SHOULD DO? >> I DON'T KNOW THAT IT'S NIH. I THINK THE SAD THING, WHAT I WATCH, AND I WAS ON A STUDY SECTION FOR SIX YEARS SO I CAN SPEAK FROM PERSONAL EXPERIENCE. WHAT I HAVE SEEN, THE STUDY SECTIONS HAVE YOU CAN DO IT ONE OR TWO WAYS, YOU CAN USE WHAT I CALL BENEVOLENT DICTATOR APPROACH MEANING SOMEBODY IS IN CHARGE OF VISION AND DECIDE WHAT THEY WANT TO DO. SOMETIMES THEY'RE EAR PLACES LIKE DARPA, I DON'T KNOW THEY NECESSARILY DO THAT RIGHT EITHER BUT SOMETIMES THE PROGRAM MANAGER CAN JUST SORT OF DO THAT. I ACTUALLY PREFER WHAT NIH DOES. I LIKE TO HAVE PEER REVIEW. I LIKE THE FACT THAT PEOPLE SIT AROUND A ROOM AND YOU GET A SCIENTIFIC REVIEW. SO I THINK THAT PART IS GOOD. BUT I'LL GIVE A COUPLE OF SUGGESTIONS. SOMETIMES I KNOW TODAY I GET A CALL FROM PEOPLE AT NIH AND THEY SAY COULD YOU BE ON A STUDY SECTION TWO WEEKS OR THREE WEEKS FROM NOW. SORT OF HARD TO DO THAT IN SUCH A SHORT TIME. SO I THINK THAT YOU LOSE A LOT OF REVIEWERS ALONG THOSE LINES BY MAKING THINGS SO QUICK. BUT THE BIGGEST PROBLEM TO ME IS THE MONEY. WHAT I HAVE WATCHED, WHEN I WAS INVOLVED IN THESE THINGS, THINGS ARE FUNDED UP TO THE 30th PERCENTILE, PEOPLE WILL SIT AROUND THE ROOM AND THEY'LL TAKE MORE CHANCES. THIS IS THE PROFESSORS AT THE UNIVERSITIES. THINGS ARE FUNNED TO 27 OR 10 PERCENTILE, PEOPLE WANT -- THERE'S JUST A NATURAL HUMAN TENDENCY TO SAY WHAT CAN GO WRONG. BOY F YOU'RE DOING SOMETHING SPECULATIVE AND EARLY A LOT CAN GO WRONG. SO I THINK THAT TO ME, IT'S THE NATURE OF THE BEAST WHEN PAY LINES ARE REALLY LOW, THE CONSERVATIVES AT LEAST IN MY EXPERIENCE HAS BECOME GREATER. WHEN PAY LINES ARE HIGHER, I THINK ALLKINE OF GOOD THINGS GET FUNDED. SO TO ME THE WAY IT WOULD BE FIXED IS THE GOVERNMENT GIVE YOU MORE MONEY. THEN YOU CAN GIVE IT TO US. [APPLAUSE] I'M SAYING IT FROM PERSONAL EXPERIENCE, I HAVE BEEN INVOLVED IN THOSE STUDY SECTIONS, IN OTHER WORDS YOU GUYS PROBABLY AROUND AREN'T BUT YOU MIGHT SEE THEM, BUT YOU SIT THERE THREE DAYS AND YOU SEE WHAT THE DIFFERENT MEMBERS SAY AND SOME OF THE COMMENTS, WHAT I SHOWED YOU ON MINE WAS NOTHING. IT'S LIKE YOU SEE SOME OF THESE COMMENTS PEOPLE GET ULTRA CONSERVATIVE. WHEN MONEY IS TIGHT THAT'S THE MOST NATURAL HUMAN TENDENCY. AND I WOULD ADD WHAT'S MORE IMPORTANT THAN FUNDING THE STUFF WE ALL DO, THAT'S SUPER HIGH PRIORITY SO I THINK WHEN THE PAY LINES ARE REALLY TIGHT THAT MAKES IT VERY,VERY HARD. PEOPLE ARE HUMAN. OTHER QUESTIONS? >> GOOD QUESTION. GOING FORWARD DO YOU SEE LIMIT TO COMPLEXITY OF TISSUE ORGANS THAT COULD BE ENGINEERS IN THE LAB? BECAUSE YOU HAVE ALL THESE DIFFERENT CELL TYPES, IN THE RIGHT PLACE. >> I THINK YOU'RE RIGHT. CERTAINLY THERE'S HUGE ISSUES AS YOU INCREASE COMPLEXITY. LIVER HAS AT LEAST FIVE CELLS AND ALL KINDS OF INTERESTING STRUCTURES, THE HEART, I THINK THERE'S NO QUESTION THINGS GET MORE COMPLEX. SO RIGHT NOW WE'RE AT THE STAGE WE TRY TO PUT THINGS EASY, MAYBE ONE CELL TYPE MAYBE DOING STRUCTURAL THING LIKE SKIN OR CARTILAGE MAYBE BUT P AND EVEN THAT'S VERY, VERY HARD. I THINK WE'RE AT -- AND IF ONE DOES A LIVER MAYBE ONE TRIES TO JUST DO ONE CELL TYPE THAT MIGHT CURE ENZYME DEFICIENCY DISEASE OR SOMETHING ELSE SO THERE'S NO QUESTION THE COMPLEXITY IS HUGE. NONETHELESS, IF WE G I WOULDN'T KNOW WHERE TO STOP, 50, 100 YEARS IN THE FUTURE PEOPLE WILL PROBABLY FIGURE THIS OUT BUT YOU START -- YOU TAKE SMALL STEPS, YOU MAKE ADVANCES, PEOPLE MAKE GREATER UNDERSTANDING IN THE BIOLOGY AND ENGINEERING AREA, THEY'LL PUT TOGETHER AND BUILD ON THINGS THAT DONE. SO THAT'S WHAT I MEANT WHEN I ENED THE LECTURE, I THINK WE'RE STILL IN INFANCY SO I THINK IF WE HAD THE SAME LECTURE 100 YEARS FROM NOW THERE WILL -- THE KIND OF THINGS YOU SAID THERE WILL BE VERY SIGNIFICANT ADVANCES ON BUT IT WILL COME FROM NOT ONLY THE KINDS OF THINGS I TALKED ABOUT BUT FUNDAMENTAL ADVANCES IN CELL BIOLOGY AND ENGINEERING AS WELL. (OFF MIC) >> CONTINUING ON THIS TOPIC, WOULD YOU THINK -- GIVEN COMPLEXITY OF THE BODY, GIVING ALL THE DIFFERENT IT SHALL SHOES, SHOULD WE PLAY ON THE ABILITY OF THE BODY TO HEAL ITSELF IN TERMS OF FOR EXAMPLE IF THERE IS CHRONIC DISEASE OF INFLAMMATION WE TAKE CARE VERY SPECIFICALLY ABOUT DIRECTING INFLAMMATION, NOT NECESSARILY SUPPRESSING IT BUT DIRECTING IT TO THE WAY THAT WILL ALLOW THE BODY TO REBUILD ITSELF, SOME HELP MAYBE FROM OUTSIDE BUT NOT COMPLETELY RELYING ON BUILDING EVERYTHING FROM SCRATCH. WHAT DO YOU THINK ABOUT THIS? Q. I AGREE WITH THAT. EVEN WHEN WE DO SOME MATERIAL, MOM WAYS WE INDUCE VASCULARIZATION SOME MATERIALS WILL CREATE VASCULAR RESPONSE JUST BY IMPLANTING THEM THERE BUT THE WAY I LOOK AT IT AND MAYBE I WAS TRYING TO SAY THIS BEFORE, I'LL TAKE ANY HELP I CAN GET. THESE THINGS ARE HARD PROBLEMS SO MATERIALS CAN DO THINGS LIKE BRING IN BLOOD VESSELS SO IF YOU HAVE A NATURAL RESPONSE THAT HELPS YOU LIKE YOU'RE SAYING, I THINK THAT'S A GOOD THING. >> I WOULD LIKE TO -- FIRST LET ME TELL YOU THERE WILL BE A RECEPTION IN THE LIBRARY, EVERYBODY IS INVITED TO MEET THERE FOR FURTHER CHAT WITH THE SPEAKER. I WOULD LIKE TO THANK OUR SPEAKER AGAIN FORGIVING SUCH A -- FOR GIVING A WONDERFUL THOUGHT PROVOKING ELEGANT LECTURE TO US. THANK YOU. [APPLAUSE]