GOOD EVENING. I'M JOHN GALLIN THE DIRECTER OF THE CLINICAL CENTER. AND A COORGANIZER OF THIS COURSE ALONG WITH FRED WHO IS ON LEAVE, WON'T BE AT THE NIH TODAY. ON BEHALF OF THE ENTIRE FACULTY OF THE NIH, WHO WILL PARTICIPATE IN THIS COURSE, AND FACULTY FROM OUTSIDE NIH WELCOME [TECHNICAL DIFFICULTIES]. PATIENT P OP-ED RESEARCH, EPIDEMIOLOGICAL, BEHAVIORAL HAVE STUDIES AND OUTCOMES RESEARCH IN HEALTHSIS VERIES RESEARCH. SO PATIENT ORIENTED RESEARCH CAN DE WHICH IS THE ONE WE MOST FREQUENTLY THINK ABOUT IF WE'RE DOING CLINICAL RESEARCH, IS CONDUCT CANNED WITH HUMAN SUBJECTS OR MATERIAL OF HUMAN HUNDRED ORIGINS, SUCH AS TISSUE SPECIMENS AN COGNITIVE PHENOMENON OF THE TORE WHICH AN INVESTIGATOR OR COLLEAGUE DIRECTLY INTERACTS. MECHANISMS OF HUMAN DISEASE, THERAPEUTIC INTERVENTIONS AND CLINICAL TRIALS. SO THESE THREE CATEGORIES, PATIENT-ORIENTED RESEARCH EPIDEMIOLOGIC AND BEHAVIORAL STUDIES AND OUTCOMES RESEARCH AND HEALTH SERVICES RESEARCH. IS WHAT YOU'RE GOING TO BE THINKING ABOUT DURING THIS COURSE. IF I HAVE SEEN A LITTLE FURTHER IT IS BY STANDING ON THEE SHOULDERS OF GIANTS. AND HE DISCUSSED OPTIONS FOR INSTRUMENTS IN SURGERY, CONCLUDED THAT THE HAND WAS THE BEST INSTRUMENT AVAILABLE. SO YOU CAN GO TO ALL SORTS OF PLACES TO GET INSIGHTERS INTO CLINICAL RESEARCH. PERHAPS THE EARLIEST SO-CALLED TRIAL AS I'LL CALL IT, COMES FROM THE BIBLE. THE BOOK OF DANIEL. AND DANIEL SAID TEST YOUR SERVANTS FOR TEN DAYS AND LET US BE GIVEN VEGETABLES TO EAT WATER TO DRINK. US IS A GROUP OF JEWS WHO WERE CAPTURED BY THE EGYPTIANS. AND THEY DIDN'T WANT TO HAVE EAT THE NON KOSHER FOOD. SO HE WAS CLEVER. SO TO AVOID THAT, HE CONDUCT THIS TEST. SO GIVE US VEGETABLES TO EAT AND WATER TO DRINKING. AND COMPARE YOUR SERVANTS WHO WILL GET RICH FOODS. SO THEN OUR APPEARANCE AND THE APPEARANCE OF THOSE BE OBSERVED AND DEAL WITH YOUR SERVANTS. HEHARKENED TO THEM AND TESTED THEM FOR TEN DAYS. AT THE END OF TEN DAYS IT WAS SEEN THAT THEY, THE ONES WHO ATE THE VEGETABLES AND WATER, WERE BETTER IN APPEARANCE AND FATTER IN FLESH THAN ALL THE YEWs WHO ATE THE KING'S RICH FOODS. THE STEWARDS TOOK AWAY THE RESEARCH FOOD AND WINE AND GAVE THEM IN THE VEGETABLES. THIS IN IS THE BIBLE. NO INFORMED CONSENT. BUT PERHAPS THE GREATEST MIND IN EARLY MEDICINE AND CLINICAL RESEARCH WAS HI POT CONSIDERIES, IMPORTANT ABOUT 460BC, DIED ABOUT 370BC. YOU ALL KNOW ABOUT THE HIPPOCRATIC METHOD. HE ADVOCATED OB TEST TEST. FIFTH, TIME OF EFFECT MUST BE CONSIDERED. 6th, DRUGS MUST BE OBSERVED, FOR CONTINUED ACTION. AND 7th, DRUG MUST BE TESTED IN HUMANS BEFORE JUDGMENT. THIS IS AMAZING WHEN YOU THINK OF WHEN THESE CONDITIONS WERE DEFINED. SO NOW I'M GOING TO SKIP A COUPLE OF CENTURIES. AND START TALKING ABOUT ANATOMY. AND ONE OF THE GREATEST EARLY WAS LEONARDO DEVIN CHAI. THIS IS THE ONLY THEN SELF-PORTRAIT. HE DID THIS NEAR THE END OF HIS LIFE. IF YOU GO THROUGH HIS WORKS AND LOOK AT HIS DESCRIPTIONS, DRAWINGS OF THE HUMAN ANATOMY, IT'S QUITE PHENOMENAL. AND HERE ARE A COUPLE OF PICTURES. MICROSCOPE WAS AN IMPORTANT ADDITION TO MEDICINE IN CLINICAL RESEARCH. LET ME TELL YOU A LITTLE BIT ABOUT THE MICROSCOPE. IN THE FIRST CENTURY AD, GLASS WAS TESTED BY THE ROMANS THAT RECOGNIZED WHEN THICK IN THE MIDDLE, THIN AT THE EDGES YOU GOT MAGNIFICATION. [INDISCERNIBLE] WHO LIVED IN EGYPT, WAS THE FATHER OF OPTICS, ALSO A GREAT ASTRONOMER. THE 13th CENTURY EYE GLASSES WERE INVENTED. THE FIRST EYE GRASSES MADE ENGERMANY IN 1286. IN 1590, JENSEN AND HIS SON, WHO WERE DUTCH, INCENTED THE COMPOUND MICROSCOPE WITH 2 LENSES IN A CYLINDER. IN 1609, GALILEO ADDED A FOCUSING DEVICE. THAT WAS THE BEGINNING OF THE MICROSCOPE. BUT IT WAS ANTHONY WHO FIRST USED A MICROSCOPE IN CLINICAL RESEARCH. HE LIVED IN THE 1600S TO THE 17 HUNDREDS. AND HE WORKED IN A DRY GOODS STORE. AND HE NEEDED TO COUNT THE NUMBER OF THREADS IN AN INCH, OR IN A CERTAIN AMOUNT OF SPACE TO JUDGE THE QUALITY OF THE LINENS THAT WERE BEING PRODUCED. SO HE MADE SPECIAL SMALL LENSES WHICH COMING AN UP TO 270 POWER. AND IN THE BOTTOM OF THE SLIDE IS HIS FIRST MICROSCOPE. I GOT A FACSIMILE OF THAT THAT I FOUND IN A SMALL STORE IN MAINE, OF ALL PLACES. YOU CAN SEE THIS IS THE LENS, AND YOU CAN PUT AN OBJECT ON IT. YOU LOOK THROUGH THE OTHER SIDE, AND POSITION YOUR OBJECT WITH THIS SCREW. AND USING THIS, HE DESCRIBED THE FIRST BACTERIA, EAST, SPERM, MUSCLE, CLIFFSAL LENS OF THE EYE AND RED CELLS, AMONG OTHERS. YOU CAN IMAGINE SITTING THERE LOOKING AT A LIGHT, AND THEN MAKING DRAWINGS OF THIS. IT'S REALLY QUITE PHENOMENAL. SO HAVING DESCRIBED RED CELLS, IT MAKES ME WANT TO PREPARING TO YOUR ATTENTION WILLIAM HARVEY, WHO LIVED IN ENGLAND FROM 1578 AND HE REALLY DEFINED THE CIRCULATORY SYSTEM IN GREAT DETAIL AND ACCURACY. IN THE SAME PERIOD A LITTLE LATER, CHRISTOPHER WRENN, WHO YOU PROBABLY KNOW FOR HIS ARCHITECT, HE ALSO INVENTED THE INTRAVENOUS NEEDLE. IT WAS MADE OUT OF STERLING SILVER. AND HE CONNECTED THE BLEEDER -- THE NEEDLE TO THE URETHRA, AND INFUSES DOGS WITH OPIATES, AND WAS THE FIRST TO DESCRIBE THE EFFECTS OF INTRAVENOUS OPIATES IN A MAMMAL. HE ALSO GAVE THE NEEDLE TO A FRIEND OF HIS WHO IS SHOWN ON THE BOTTOM OF THIS SLIDE, RICHARD LAWYER, WHO IN 1667 DID THE FIRST TRANSFUSION INTO MAN USING SHEEP'S BLOOD AND THE MAN SURVIVED, PROBABLY BECAUSE HE ONLY GAVE ABOUT 10CCs OF BLOOD. A FEW MONTHS EARLIER, JOHN IN FRANCE GAVE ABOUT THE SAME -- 12-OUNCES OF SHEEP BLOOD INTO A 15-YEAR OLD BOY WHO SURVIVES. BUT THE FIRST USE OF MAN TO MAN OR MAN TO WOMAN OR TRANSFUSION WAS BY JAMES WHO IN 1828 DID A NUMBER OF TRANSFUSIONS WITHOUT ANY TYPING AND CROSS MATCHING AND ABOUT HALF OF THE 12 SUBJECTS SURVIVED. AND HE WAS ABLE TO SHOW IN THIS ETCHING, WHICH APPEARED IN LANCET IN 1828, THAT HE COULD SAVE A PERSON WHO WAS [INDISCERNIBLE] AFTER A WOMAN, AFTER A UTERINE OPERATION THAT WASN'T GOING WELL. HE SAVED HER LIFE. OF COURSE THE ADVENT OF BLOOD TYPES WAS NOT UNTIL 1900 WHEN CARL LAND STEINER, WHO WAS WORKING AT THE ROCKEFELLER UNIVERSITY, DEFINED THE ABO AND AB BLOOD TYPES. THAT WAS THE BEGINNING OF REALLY THE MODERN TRANSFUSION MEDICINE APPROACHES THAT WE HAVE. NOW, IN TERMS OF MODERN TERMINOLOGY, OR THINKING, MAYBE THE FIRST CLINICAL TRIAL WAS DONE BY JAMES WIND AND HE WORKED IN ENGLAND IN THE 17 HUNDREDS, AND AT THAT TIME SCURVY WAS THE MAJOR HEALTH PROBLEM IN THE BRITISH NAVY. WILLIAM HARVEY, WHO I MENTIONED EARLIER, HAD RECOMMENDED LEMONS TO TREAT IT BUT ARGUED THAT THE THERAPEUTIC EFFECT WAS THE RESULT OF THE ACID IN THE FRUIT. IT WAS LINDE WHO WAS AN ABLE SURGEON, CONDUCTED A CLINICAL TRIAL IN 1747 WHO ASSESS THE UTILITY OF THREE THERAPIES ON SCURVY. HE TOOK 12 SAILORS WITH CLASSICAL SCURFRY, DIVIDED INTO 6 GROUPS OF 2 EACH. ALL GIVEN IDENTICAL DIETS. THE VARIOUS GROUPS WERE SUPPLEMENTED WITH EARTH VINEGAR, DILUTE ACID, CIDER, SEA WATER, NUTMEG, GARLIC, AND HORSE RADISH MIXTURE, OR TWO ORANGES AND ONE LEMON DAILY. AND HERE ARE THE RESULTS OF ALL HIS STUDIES. THE ONLY THING THAT WORKED WAS SITRICS FRUIT. AND IT WAS NOT SIGNIFICANT. BUT THEY DIDN'T HAVE STATISTICS IN THOSE DAYS. HIGH WROTE A PAPER AND BECAME FAMOUS, BASED ON THESE DATA, SCURFY WAS PREVENTED IN THE NAVY BY GIVING PEOPLE CITRUS FRUIT. SO LET ME MOVE ON NOW TO SMALLPOX AS YOU'LL SEE AS I GO THROUGH THE REST OF THIS TALK. I HAPPEN TO HAVE A PROFOUND INTEREST IN INEFFICIENCY DISEASES, BECAUSE THAT'S MY AREA OF CLINICALLY -- CLINICALLY. AND IMMUNOLOGY. SO LET'S TALK ABOUT SMALLPOX WHICH HAS A PRETTY NEAT HISTORY. SMALLPOX WAS FIRST DESCRIBED BY AL, WHO I MENTIONED EARLIER, PROBABLY ABOUT 900AD. IN THE 11th CENTURY, THERE WERE PROTECTIVE MEASURES BEING USED THROUGHOUT THE WORLD TAKING SCABS FROM SMALLPOX PUSTULES, AND PUTTING THEM IN THE NOSTRILS OF A HEALTHY SUBJECT. AND THAT ACTUALLY OFFERED SOME PROTECTION IF YOU DIDN'T GET SMALLPOX. PEOPLE WERE WEARING THE CLOTHING OF SOMEONE WHO HAD THE DISEASE. PEOPLE IN JESTED POWDERED FLEAS FROM INFECTED COWS, MAY HAVE PERCEIVED THE RELATIONSHIP OF COW POX TO SMALLPOX. IN THE 20s, YOU WOULD TAKE A SCAB FROM A PATIENT WHO HAD SMALLPOX, REMOVE IT FROM THE SUBJECT, AND TAKE THE CONTENTS OF THAT SCAB AND SCRATCH IT INTO A HEALTHY PERSON. MOST PEOPLE GOT PROTECTED, SOME PEOPLE GOT SMALLPOX. AND LADY MARY WHO WAS BRITISH, THE WIFE OF THE BRITISH AMBASSADOR, OBSERVED IN TURKEY, THIS VIRLATION PROCESS. SHE BROUGHT IT TO LONDON AND SHE INOCULATED HER OWN TWO CHILDREN. AND A HOSPITAL FOR SMALLPOX INOCULATION WAS FOUNDED IN LONDON IN 1745 USING THIS APPROACH. THE FIRST KNOWN USE OF COW POX TO PROTECT AGAINST SMALLPOX WAS DONE BY BENJAMIN, WHO LIVED IN 1736 TO 1816. AND HE WAS A FARMER THAT LIVED IN A VILLAGE OF [INDISCERNIBLE] IN THE UNITED KINGDOM. AND HE WAS CONVINCED THAT MILK MAS WHO CONTRACTED COW POX WERE PROTECTED FROM SMALLPOX. AND IN 1774, HE INOCULATED HIMSELF, HIS WIFE AND TWO SONS WITH COW POX LYMPH THERE THE UNDER SIDE OF A COW UDDER. IN 1805 HE PUBLICLY INOCULATED HIS SON, ROBERT, WITH LIVE SMALLPOX AFTER HE HAD INOCULATED -- OR IMM UNIZED HIM. HE DEMONSTRATED HIS SON WAS PROTECTED. SO THIS WAS BEFORE JENNER. BUT WHAT JENNER DID IN 1776 WAS ACTUALLY DO A LARGE STUDY. AND HERE YOU SEE HIM VACCINATING JAMES PHILLIPS, THE FIRST PERSON WHIST VACCINATED. HE DID A LIVE STUDY AND HE RECORDED THE DATA. AND TALKED ABOUT IT. AND IT WAS AFTER JENNER'S WORK WITH SMALLPOX THAT A VACCINE THAT WAS EFFICACIOUS WAS DEVELOPED. NOW, BEFORE WE CONCLUDE SMALLPOX, I JUST WANT TO MENTION ONE HISTORICAL FACT. I DON'T WANT TO -- IS JEFFREY THE FIRST BIOLOGICAL WARFARE TAKING BLANKETS FROM PEOPLE INFECTED WITH SMALLPOX, GOOD EVENING IT TO THE INDIANS IN THE FRENCH INDIAN WAR. PRETTY HORRIBLE. BUT GEORGE WASHINGTON DID SOMETHING REMARKABLY CLEVER. IN 1775 AND 1776, WHEN THE BRITISH WERE SURROUNDING BOSTON, AND THE CONTINENTAL ARMY IN THE UNITED STATES WAS THREATENED, THE BRITISH ARMY HAD AN EPIDEMIC OF SMALLPOX, WHICH HAD NOT HIT THE CONTINENTAL ARMY. WASHINGTON MADE THE DECISION THAT HE WANTED TO DO THE VIRALATION TECHNIQUE IN THE SOLDIERS. BUT WOULDN'T DO IT WITHOUT THE CONSENT OF THE CONTINENTAL CONGRESS. HE GOT JOHN ADAMS, WHO ON JULY 3, 1776, THE DAY BEFORE THE DECLARATION OF INDEPENDENCE WAS SIGNED, HE GOT ADAMS TO GET THE CONTINENTAL CONGRESS TO GIVE APPROVAL FOR MASS IMMUNIZATION OF THE CONTINENTAL ARMY. THIS WAS TO MY KNOWLEDGE, THE FIRST EXAMPLE OF MASS IMMUNIZATION OF -- IN THE MILITARY OR PROBABLY ANYWHERE ELSE. AND IT WORKED. PROBABLY SAVED THE ARMY. ENABLED THE UNITED STATES TO BE -- OR THE CONTINENTAL ARMY TO BEAT THE BRITISH, EVENTUALLY. NOW, OF COURSE, SMALLPOX HAS ERADICATED THROUGH THE WORK OF D.A. HENDERSON, AND THE LAST CASE WAS IN 1977 AND THE WORLD HEALTH ORGANIZATION DECLARED SMALLPOX COMPLETELY ERADICATED IN 1980. SO GENETICS, WE ALL KNOW ABOUT GENETICS. WE KNOW ABOUT MENDAL WHO WAS THE FATHER OF GENETICS WORKING WITH PLANTS. AND I MAY NOT KNOW ABOUT BARBARA WHO LIVED FROM 1902 TO 1992. AND WAS A FABULOUS CYTOEGYPTICIST, DID GROUNDBREAKING RESEARCH IN DEVELOPING THE TECHNIQUE OF VISUALIZING MAZE OF CORN CHROMOSOMES. AND USED MICROSCOPIC ANALYSIS TO GENERATE MANY FUNDAMENTAL IDEAS. AND DISCOVERED TRANSPOSITION AND USED IT TO DEMONSTRATE THE GENES THAT ARE RESPONSIBLE FOR TURNING PHYSICAL CHARACTERISTICS ON AND OFF. AND IN 1983, SHE WON THE NHLBI PRIZE FOR HER DISCOVERIES -- NOBLE PRIZE FOR DISCOVERIES OF HER GENETIC ELEMENTS. YOU KNOW ABOUT DARWIN, IN 1859, PUBLISHED HIS BOOK ON THE ORIGIN OF THE SPECIES . YOU MAY NOT KNOW HE CREATED THE FIRST TISSUE BANK. DURING HIS TRAVELS HE TOOK TISSUES FROM ALL THE DIFFERENT SPECIES HE STUDIED AND ACTUALLY CREATED A TISSUE BANK. SO CLINICAL MEDICINE DEPENDS ON EPIDEMIOLOGY FOR MUCH OF THE WORK. I WANT TO JUST MENTION JOHN SNOW WHO WAS AN ANTHIAZOLES 450 LIVED FROM 1813 TO 1858 WHO WAS BRITISH. AND HE WAS A REAL MEDICAL HYGIENE PIONEER AND REALLY, THE FATHER OF MODERN EPIDEMIOLOGY FOR WORK TRACING THE SOURCE OF A EPIDEMIC IN ENGLAND IN 1854. AND HE CREATED THIS SPOT MAP IN THE CITY OF LONDON AND SOHO TO ILLUSTRATE EACH CASE OF CHOLERA DURING THIS EPIDEMIC. HE DEMONSTRATED IT ALL CENTERED AROUND A WATER PUMP. AND HE ILLUSTRATED THIS CONNECTION BETWEEN THE QUALITY OF WATER SOURCE AND THE CHOLERA CASES. HE SAID REMOVE THE WATER PUMP AND YOU'LL GET RID OF THE CHOLERA, AND THEY DID. THEN THE COMMUNITY WENT BALLISTIC, BECAUSE THEY HAD TO WALK LONG DISTANCES TO GET THE WATER SO THEY REOPENED IT. THE CHOLERA CAME BACK. SO HE REALLY PROVED HIS POINT. THEN THEY CLOSED THE PUMP AND THE EPIDEMIC SUBSIDED. SO THIS WAS A MAJOR EVENT IN PUBLIC HEALTH HISTORY. MAYBE THE GREATEST PUBLIC HEALTH INVENTION IN THE 1800S WAS BY , WHO I'LL TELL YOU ABOUT IN A MINUTE. BUT REMEMBER WHAT I TOLD YOU, THERE WAS ADVOCATION OF STERILIZATION OF WOUNDS AND HI POCK ACCURATEYS PROMOTED CLEAN HANDS. BUT IT WAS THIS MAN WHO REALLY SOLIDIFIED THE IMPORTANCE OF SANITATION IN MEDICINE. AND HE LIVED FROM 1848 TO 1863, A SHORT LIFE. HE STUDIED SEPSIS OVER THE PROTEST OF HIS CHIEF. HE WAS AN ANESTHESIOLOGIST. HE ADD NOTED THAT 2 SEPSIS RATE WAS 3 TIMES HIGHER IN DIVISION ONE IN HIS HOSPITAL THAN DIVISION TWO. THESE TWO DIVISIONS WERE IDENTICAL, EXCEPT MEDICAL STUDENTS WORKED IN DIVISION ONE. MID WIVES IN DIVISION TWO. HE HAD A DEAR FRIEND WHO DIED FOLLOWING INFECTION OF AN AUTOPSY. THAT HESS FRIEND DID, HE WAS A PATHOLOGIST. AND IT WAS -- AUTOPSY IN A PATIENT WHO HAD A WOUND SIMILAR TO PURPLE SEPSIS. AND THIS LED HIM TO THE PRIMARY HYPOTHESIS THAT THE INFECTION THAT WAS SEEN IN THE WOMEN WHO WERE DELIVERING BABIES CAME FROM THE AUTOPSY ROOM BY THE MEDICAL STUDENTS TO THESE WOMEN WHO WERE GIVING BIRTH. SO HE SAID STUDENTS HAD TO WASH THEIR HANDS AND HE USED CHLORINATED LIME SOLUTION. AND WHEN HE DID THAT, THE MORTALITY RATE DROPPED FROM 18% TO 1% PER YEAR. IN SOME MONTHS, IN 1848, IT WAS 0. THESE ARE THE DATA THAT HE PUBLISHED AND YOU CAN SEE BY THIS YELLOW LINE WHICH IS THE NUMBER OF WOMEN WHO HAD SEPSIS, WHO DIED. AND THE RED ARROW IS WHEN HE STARTED HAVING THEM WASH THEIR HANDS. IMMEDIATELY PLUMMETED. SO HE TOLD HIS CHIEF ABOUT THIS. AND THE CHIEF DIDN'T BELIEVE HIS DATA. AND HE WAS FIRED. SO THEN HE LOVED TO BUDAPEST WHERE HE -- EMOVED TO BUDAPEST. HE WROTE A PAPER, AND IT WAS REJECTED BY THE VIENNA MEDICAL JOURNAL. AND ULTIMATELY, HE HAD PEW PAY TO GET THIS WORK PUBLISHED BUT IT WAS PUBLISHED. AND I CAN TELL YOU, HE HAD A SAD OUTCOME. HE WENT CRAZY. BECAUSE NOBODY BELIEVED HIM. AND HE WAS ADMITTED TO A MENTAL HOSPITAL. AND HE CUT HIS LEG ON THE EDGE OF A BED AND HE DIED OF PURPLE SEPSIS. NOW, HIS WORK WAS KNOWN BY SOME FOLKS IN THE UNITED STATES AND I'LL TELL YOU ABOUT THAT IN A SECOND. BUT IN THE INTERESTRAM, IN -- INTRIEM, JOSEPH LISTER WAS ALSO WORKING ON THE IMPORTANCE OF SEPSIS IN THE OPERATING ROOM. HE USED SPRAYS TO CLEAN WOUNDS, OPEN WOUNDS AND HE SHOWED THAT THIS WOULD REDUCE INFECTION. SO THE PERSON WHO ADVOCATEED FOR HIM WAS THE FATHER OF THE GREAT SUPREME COURT JUSTICE IN THE UNITED STATES, WHO WAS AN OBSTETRICIAN WHO WORKED AT MASSACHUSETTS GENERAL HOSPITAL. AND HE DIDN'T REPEAT THE EXPERIMENTS, BUT HE BELIEVED THEM AND HE WENT AROUND AND SPOKE THIS UP, AND CERTAINLY GOT CLEAN HANDS AND WASHING HANDS AS AN INTEGRAL PART OF THE PUBLIC HEALTH OF HOSPITALS. SADLY, IT'S STILL A HUGE PROBLEM. AND I CAN TELL YOU IN THIS HOSPITAL, AT THE NIH CLINICAL CENTER, A FEW YEARS AGO WE HAD AN EPIDEMIC OF A MUSCLE DRAWING RANT INFECTION. IT WAS CLEARLY LENGTHED TO PEOPLE NOT WASHING THEIR HANDS IN AN AGGRESSIVE ENOUGH FASHION. SO SOMETHING AS SIMPLE AS WASHING HANDS WITH PHENOMENALLY IMPORTANT. LET ME TELL YOU MORE ABOUT SURGERY, MORE MODERN SURGERY. I CAN'T ESCAPE TELLING YOU ABOUT JOHN HUNTER WHO LIVED IN 1728 TO 1793, WHO REALLY CHANGED THE NATURE OF SURGERY. HE WAS THE SCOTTISH ANATMIST AND SURGEON. HIS OLDER BROTHER WAS AN ESTABLISHED SURGEON, HIS MOTHER DIDN'T KNOW WHAT TO DO WITH HIM. SHE SENT HIM TO WORK WITH HIS BROTHER. HIS BROTHER, WHO WAS A SURGEON, TOLD HIM TO ROB GRAVES. AND HE BECAME -- THEY WOULD TAKE THESE CORPSES AND TEACH ANATOMY TO PEOPLE WHO WERE INTERESTED. AND HE BECAME QUITE THE SKILLED ANATMIST AND THEN SURGEON. AND ONE OF THE THINGS HE DID IS DETERMINE THE NATURE OF VENEARIAL DISEASE. HE INOCULATED HIMSELF WITH AN INFECTED MATERIAL FROM SOMEONE WHO HAD SYPHILIS. AND HE GOT SYPHILIS. AND HE EVENTUALLY HAD HEART DAMAGE FROM THE SYPHILIS. A GREAT BOOK CALLED THE NICE MAN, IF YOU'RE INTERESTED, I SUGGEST YOU READ IT. IT'S A VERY COLORFUL BOOK ABOUT HIS LIFE. ANESTHESIA, WE CAN'T MENTION WITHOUT MENTIONING WILLIAM T.J. MORTON WHO WAS THE DENTIST, LIVED FROM 1890 TO 1868. HE DEMONSTRATED THAT ETHER, WORKED. AND HE DID HIS DEMONSTRATION 1846, OCTOBER 16, AT MASS GENERAL HOSPITAL IN BOSTON. DEMONSTRATING THAT SURGERY COULD BE CONDUCTED ON A PERSON WHILE THEY ARE AASLEEP WITH NO PAIN. SO WITH THAT BACKGROUND, ETHICAL LET ME BRING YOU STORIES ABOUT THE PHARMACEUTICAL INDUSTRY. I WOULD LIKE TO START THAT WITH MENTIONING CLAWED BERNARD, WHO WAS FRENCH. LIVED FROM 1813 TO 1878. AMONG HIS ACCOMPLISHMENTS, HE RECOGNIZED THE PANCREAS WAS IMPORTANT IN DIGESTION. HE DESCRIBED THE GLYCOGENIC FUNCTION OF THE LIVER. DESCRIBED THE ADVISO MOTOR SYSTEM AND CONSTRUCTER NERVES, AND HE DISCOVERED JER RARI AND APPLICATIONS IN MEDICINE. RUDOLPH, LIVED FROM 1821 TO 1902, POLISH, HE DEFINED LEUKEMIA. AND HE WROTE EVERY CELL ORIGINATES FROM ANOTHER CELL. SO HE DEFINED STEM CELLS, PROBABLY THE FIRST PERSON. HE ALSO DEFINED PULMONARY EMBOLI AS RELATED TO THROMBOSIS AND.BOLISM. ONE OF MY HEROES IS PASTIER, WHO LIVED FROM 1822 TO 1895. IF YOU LOOK CAVALLY AT THIS PICTURE YOU'LL NOTE HIS RIGHT ARM IS HANGING LOOSE. AND THAT WAS BECAUSE OF THE YOUNG AGE HE HAD A STROKE AND COULDN'T USE HIS RIGHT ARM. AND DESPITE THAT WAS ABLE TO MAKE HIS PHENOMENAL DISCOVERIES. INCLUDING THE GERM BASIS OF FERMENTATION, GERM THEORY OF INFECTIOUS DEDISEASES. HE DESCRIBED STREPTO CAUCUS AS THE CAUSE OF PURPLE SEPSIS, THE DISEASE THAT WAS PREVIOUSLY TALKED ABOUT. HE MADE THE FIRST VACCINE FOR ANTHRAX, AND THE EVACUATION FOR RABIES. COKE, WHO LIVED IN A SIMILAR ERA, FROM 1843 TO 1910, DEVELOPED THE PETE R DISH AND USE OF PLATES TO CULTURE BACTERIA. HE WAS THE FIRST TO DESCRIBE ANTHRAX INFECTION BEFORE PASTURE MADE THE VACCINE. HE DESCRIBED AND CULTURED TUBERCULOSIS. THE FIRST PERSON TO DO THAT. HE DEVELOPED A TB SKIN TEST. HE DESCRIBED WATER BOURNE EPIDEMICS. HE MADE HIS POSTULATES AND IN 1905 WAS AWARDED THE NOBLE PRIZE FOR HIS WORK ON TUBERCULOSIS. AND IF YOU LOOK IN HIS BOOK, AND I HAVE A COPY OF HIS BOOK, THESE ARE ALL HAND DRAWINGS. HERE HE WAS -- DREW THE ANTHRAX. BEARING. LIVED IN GERMANY FROM 1854 TO 1917, DISCOVERED ANTIBODIES, FIRST PERSON TO DESCRIBE THEM, TIP THEY'RIA. HE WAS THE FIRST TO USE PASSIVE IMMUNIZATION TO TREAT A PERSON WHO HAD BEEN EXPOSED. AND HE WON THE NOBLE PRIZE IN 1901. PAUL, WHO WAS POLISH, DESCRIBED -- HE WAS A MEDICAL STUDENT, DESCRIBED THE COMPLEMENT PATHWAY AND HUMORAL IMMUNITY SYSTEM. HE ALSO DEVELOPED THE FIRST ANTIBIOTIC TO STREET SYPHILIS. HE WORKED WITH HIS TECHNICIAN AND THEY DEVELOPED WHAT HOX CALLED -- IT HAD 32% ARSE SENIC, AND WAS TOXIC. LATER THEY DEVELOPED A COMPOUND LESS TOXIC, CALLED COMPOUND 914. HE SAID WE NEED MAGIC BULLETS. WE MUST SEARCH FOR MAGIC BULLETS. WE MUST STRIKE THE PARASITES AND THE PARASITES ONLY IF POSSIBLE. TO DO THIS, YOU MUST LEARN TO AIM WITH CHEMICAL SUBSTANCES. SO THIS WAS THE FIRST DESCRIPTION OF THE NEED FOR ANTIBIOTICS. OF COURSE FLEMING, WHO -- IN 1928 WHILE WORKING ON INFLUENZA VIRUS, OBSERVED MOLD ON A STAPH CULTURE PLATE WITH A BACTERIA-FREE CIRCLE AROUND IT. MOST PEOPLE WOULD HAVE PROBABLY THROWN IT OUT. HE ASKED WHY THERE WERE NO BACTERIA AROUND THIS MOLD. AND HE DISCOVERED PENICILLIN. AND WON THE NOBLE PRIZE IN 1945. INSULIN IS AN INTERESTING STORY. IT GETS TO A LITTLE BIT ABOUT SCIENTIFIC ETHICS. IN THE SUMMER OF 1928 -- 21, MATERIAL EXTRACTED FROM THIS [INDISCERNIBLE] CALLED INSULIN FROM LATIN FOR ISLAND, WAS GIVEN TO A DICK DOG T RESULT WAS THAT ABNORMALLY HIGH BLOOD SUGAR LEVELS WERE LOWERED. WITHIN 6 WEEKS, BANTING AND BEST, BANTING WAS A JUNIOR SCIENTIST AND BEST WAS A TECHNICIAN. THEY HAD PURIFIED INSULIN AND GAVE IT TO A 14-YEAR OLD BOY WHO WAS DYING OF DIABETES. AND THEY BASICALLY SAVED THIS KID'S LIFE. THEIR BOSS, OR THEIR PAPERWORK WAS PUBLISHED IN 1922 BUT THEIR BOSS IN 1923 SHARED -- HIS NAME WAS MCLEOD, SHARED THE NOBLE PRIZE WITH BANTING, AND MCLEOD WAS AWAY DURING THE WHOLE TIME THAT THIS STUDY WAS DONE. HE WAS ON VACATION. SUMMER VACATION. IT WAS IN HIS LAB. SO MCLEOD WON THE NOBLE PRIZE WITH BANTING, AND BEST, WHO WAS THE TECHNICIAN, DIDN'T GET ANYTHING. TECHNICIANS DIDN'T WIN NOBLE PRIZES IN THOSE DAYS. THE GOOD NEWS IS THAT MCLEOD AND BANTING SHARED ALL THEIR MONEY WITH THE FOLKS IN THE LAB WHO DID THE WORK. BUT THE CREDIT FROM THE NOBLE COMMITTEE WENT TO BANTING AND MCLEOD. IT WAS VERY SAD THAT BEST DIDN'T RECEIVE THE NOBLE PRIZE, WHICH HE CLEARLY DESERVED. POLIO. YOU'VE ALL HEARD OF [INDISCERNIBLE], BUT THE NOBLE PRIZE WENT TO ENDERS, WELLER, AND ROBINS. WHO DEVELOPED THE TECHNIQUE FOR CULTURING THE POLE YANGTE RIVER VIRUS, WHICH -- POLIO VIRUS WHICH LED TO THE VACCINE. AND IT WAS THE FIRST, AND IT USED INACTIVATED POLIO VIRUS THAT WAS GIVEN TO SUBJECTS. AND THERE WAS A SERIOUS BAD INCIDENT WITH THE DEVELOPMENT OF THIS VACCINE THAT WAS A LAB MANUFACTURING AREA BY CUTTER, WHEN THEY WERE INACTIVATING THE VIRUS. THEY EXTRAPOLATED, RATHER THAN GETTING DATA, TO THE CRITICAL DOSE NEEDED, MINUTE 348 DOSE CAN ACTIVATE THE VIRUS. THEY GAVE POLIO, I THINK, TO THE FIRST THOUSAND OR SO PEOPLE WHO RECEIVED THE VACCINE. BUT THEN THAT WAS FIXED, AND THEN THE EVACUATION WAS DEVELOPED. SABIN'S VACCINE IS PROBABLY BETTER, IT'S A LIVE VIRUS VACCINE. YOU GET IMMUNITY. ONE CHILD IN A CLASSROOM GETS THE VACCINE, THE WHOLE CLASSROOM WILL GET IT. IT'S SORT OF A PERFECT VACCINE. SABIN WORKED WITH RUSSIAN COLLEAGUES TO PREVENT THIS VACCINE IN THE LATE 1950s, AND YOU KNOW THAT IT WORKED MARVELOUSLY. I HAVEN'T MENTIONED TOO MUCH ABOUT WOMEN, BECAUSE THERE WARRANTY MANY WOMAN DOING -- OTHERE WEREN'T TOO MANY WOMEN DOING SCIENCE IN THE OLD DAYS. LET ME MENTION A FEW SUPERSTARS THAT LIVED FROM THE 1800S ON. FLORENCE NIGHTINGALE WAS THE FIRST. SHE WAS A GREAT MATHEMATICIAN. HER PARENTS TOLD HER NOT TO GO INTO MATH, DIDN'T THINK IT WAS A LADY LIKE THING TO GO. THEY TOLD HER SHE HAD 250 GO INTO NURSING, BUT SHE WAS A MATHEMATICIAN. SHE USED THIS SKILL IN THE WAR, SHE SHOWED THAT OVERCROWDED HOSPITALS, SHE WORKED OUT THE MATH MATTEDICS FOR HOW CROWDING WOULD LEAD TO TRANSMISSION OF INFECTION. YOU HAD GOOD VENTILATION, SPREAD THE BEDS APART. DO THAT, SHE REDUCED THE INTRAHOSPITAL INFECTION RATE DRAMATICALLY. MARIE CURRY, AN AMAZING STORY. SHE DISCOVERED RADIUM. SHE REALIZE THAT HAD RADIO ACTIVITY IS AN INTRINSIC ATOMIC PROPERTY OF MATTER. YOU MAY NOT KNOW SHE PIONEER ADD MOBILE X-RAY UNIT FOR THE FRENCH ARMY IN WORLD WAR I AND FOUNDED A RADIOLOGICAL SCHOOL FOR NURSES. WITH HER HUSBAND, SHE WAS AWARDED HALF THE NOBLE PRIZE IN PHYSICS IN 1903 FOR THEIR STUDY IN TO THE SPONTANEOUS RADIATION DISCOVERED BY BECKERAL, AWARDED THE OTHER HALF OF THE PRIZE. SHE WON A SECOND NOBLE PRIZE IN 1911, HER HUSBAND HAD DIED. FOR HER WORK IN RADIO ACTIVITY. HER DAUGHTER WAS ALSO AWARDED A NOBLE PRIZE FOR WORK WITH HER HUSBAND ON THE DISCOVERY OF ARTIFICIAL RADIO ACTIVITY. SO THIS IS THE FIRST EXAMPLE OF A PARENT CHILD NOBLE LAUREATES. WHATEVER THAT'S WORTH. AND THEN ROSELYNE, WHO WAS A MEDICAL PHYSICIST, COLLABORATED WITH SOLOMON AND INVENTED THE RADIO IMMUNE ASSAY. AND HE DIE SOD HE DIDN'T WIN THE NOBLE PRIZE, BUT ROSELYNE DID IN 1977. SHE WAS THE FIRST FEMALE AND FIRST NUCLEAR PHYSICIST TO WIN THE LACKER AWARD AS WELL. JANET, WHO DIED JUST A FEW YEARS AGO, WAS AN AMERICAN GENETICIST IN THE 1907s, THE -- 1970s, THE FIRST SCIENTIST TO IDENTIFY CHROMOSOMEAL, THE CAUSE OF LEUKEMIA. SHE DISCOVERED THE PHILADELPHIA CHROMOSOME, AND SHE WON THE NATIONAL MEDAL OF SCIENCE, THE PRESIDENTIAL MEDAL OF FREEDOM AND LACKER AWARD. LASKER AWARD. I WANT TO SAY A FEW COMMENTS IN THE REMAINING TIME ABOUT SOME STATISTICAL APPROACHES AND WE'LL START WITH BLIND STUDIES. YOU MAY NOT REALIZE THAT THE FIRST PERSON TO USE A BLIND STUDY WAS BENJAMIN FRANKLIN. IN 17 '84, KING LOUIE THE 16th OF FRANCE ASKED FRANKLIN TO STUDY A UPON HE HAD WHERE HIS PEOPLE IN PARIS WERE HUGGING THE TREES, AND THEY WERE CONVINCED IT MADE THEM BETTER, CARED ALL THEIR ILLS. SO THE KING DIDN'T LIKE THAT. SO HE ASKED FRANKLIN TO APPOINT A COMMITTEE AND HE DID. ON THAT COMMITTEE WERE ALL SORTS OF FAMOUS PEOPLE, SUCH AS GUILLOTINE OF THE KNIGHTS, AND OTHERS. AND THEY WENT TO AND HUGGED THE TREES, THIS COMMITTEE, AND COULDN'T DECIDE WHETHER IT MADE ANY DIFFERENCE, SO THEY DECIDED TO BRING IN VOLUNTEERS, BLINDFOLD THEM AND GIVE THEM OBJECTS TO HOLD. SOME OF WHICH WERE TREE LYMPHS, PIECES OF THE TREES. AND THEY CONCLUDED THAT IT DIDN'T WORK. AND -- BUT FRANKLIN WAS OBSERVANT. HE IDENTIFIED THE PLACEBO EFFECT. THIS WAS THE DISCOVERY OF THE PLACEBO EFFECT. THE FIRST PAPER USING BLINDED APPROACHES TO DO CLINICAL RESEARCH AND IDENTIFYING A PLACEBO EFFECT WAS DONE BY FRANKLIN AND THE PAPER -- I HAVE A COPY OF IT, IF ANYBODY IS INTERESTED, IS KNOWN HERE ON THE RIGHT. PROBABLY DIDN'T KNOW THAT ABOUT FRANKLIN. NOW, PLACEBO -- OR BLINDING WAS SORT OF IGNORED THEN. A FEW HUNDRED YEARS LATER, FOALMAN, A GREAT STATISTICIAN, THOUGHT IT MIGHT BE A SOLUTION TO INVESTIGATOR BIAS, THAT WAS ABOUT 1930. THEN BLINDFOLD TESTS WERE WIDELY USED BY ADVERTISERS AND CONSUMERS GROUPS IN THE 1930s AND 40s. THE FIRST USE OF STATISTICS WAS A BORROWED IDEA, BORROWED FROM SIREN THAT WOULD FISHER. WHO APPLIED STATISTICS FOR AGRICULTURE USE AND INTRODUCED THE APPLICATION OF STATISTICS IN EXPERIMENTAL DESIGN. AND FOR FARMING AND PLANT FERTILITY, THE CONCEPT OF RANDOMIZATION WAS DEVELOPED BY HIM. AND THEN IT WAS LATER AMID TO MEDICINE. APPLIED TO MEDICINE. THE FIRST MODERN EXAMPLE OF A CONTROLLED CLINICAL TRIAL WAS DONE BY SIR AUSTIN BRADFORD IN 1948, WHO DID A STUDY TO SHOW THAT STREPTOMYCIN WAS AN EFFECTIVE DRUG FOR PULMONARY TUBERCULOSIS. THIS WAS A BEAUTIFUL STUDY AND CLEARLY SHOWED THE IMPORTANCE OF A RANDOMIZED CONTROL GROUP TO PROVE THAT STREPTOMYCIN WAS AN EFFECTIVE THERAPY FOR TB. OKAY. MEDICAL ETHICS. YOU PROBABLY HEARD OF GERHART HANSON, WHO DISCOVERED THE CAUSE OF LEPROSY IN 1874. BUT THIS CLAIM WAS NOT WELL RECEIVED AT THE TIME. AND HE BECAME DESPERATE TO PROVE THAT IT REALLY WAS THE CAUSE OF LEPROSY. WITHOUT TELLING SOME NURSES, HE INOCULATED THEM WITH LIVE LEPROSY, AND HE GAVE THEM LEPROSY. AND HE WAS SUED. AND HE LOST. AND HE WAS REMOVED FROM HIS POSITION BUT FOR REASONS THAT ARE NOT COMPLETELY WELL, HE WAS SO WELL RECOGNIZED IN HIS INSTITUTION THAT HE WAS ALLOWED TO STILL WORK. BUT HE COMMITTED WHAT WOULD BE CONSIDERED A GRAVE VIOLATION OF ETHICAL PRINCIPLES. IN 1998. WILLIAM, AT A -- 1898, WILLIAM AT A MEETING SAID TO [INDISCERNIBLE], WHO HAD SCOFFED THE ETIOLOGIC AGENT FOR YELLOW FEVER, SOMEWHAT SIMILAR TO WHAT HANSON DID, INJECTED THE AGENT INTO VOLUNTEERS. GAVE THEM YELLOW FEVER. HE SAID INJECT THE POISON OF KNOWN DEGREE OF VIRLANCY INTO HUMAN BEINGS, UNLESS YOU OBTAIN A MAN'S CONSENT IS CRIMINAL. AND THAT WAS THE END OF HIS CAREER. UNLIKE HANSON M. , SO THAT WAS THE BEGINNING OF INFORMED CONSENT. I'M GOING TO JUMP AHEAD TO 153, THE DAY -- 19536789 WITHIN DAYS OF THE CLINICAL CENTER OPENING HERE AT NIH. WHEN THE MEDICAL BOARD IN THE FIRST MEETING UNDER DR. LUTHER TERRY, WHO WAS CHAIR OF THAT BOARD, SAID THAT THEY HAD TO PROVIDE EACH PATIENT WITH A REASONABLE UNDERSTANDING OF HIS ROLE IN A STUDY PROJECT AND THE MEANS OF OBTAINING EVIDENCE TO SUCH UNDERSTANDING AN CONSENT. THIS POLICY AT THE CLINICAL CENTER HAD A BIG EFFECT. IT HAD A BIG EFFECT ON CONGRESS, AND THE HARRIS AMENDMENT TO THE FDA LAW. STIPULATED THAT SUBJECTS MUST BE TOLD WHETHER A DRUG IS BEING USED FOR INVESTIGATIONAL PURPOSES, AND THE UNITED STATES SURGEON GENERAL ISSUED A POLICY SAYING THAT ANY FEDERAL MONEY USED TO SUPPORT RESEARCH USING DRUG DEVELOPMENT REQUIRED REVIEW BY AN INSTITUTIONAL REVIEW BOARD TO MAKE SURE THAT IT WAS ETHICAL. AND THAT WAS ON ALL PUBLIC HEALTH SERVICE GRANTS. IN 1967, RELATIVELY RECENTLY, THE FDA REQUIRED ALL NEW DRUG SPONSORS OBTAIN INFORMED CONSENT FOR USE OF INVESTIGATIONAL DRUGS IN HUMANS. YOU'LL HEAR ABOUT ETHICS AND THE HISTORY OF ETHICS FROM CHRISTINE GRADY AND OTHERS. AND YOU'LL LEARN MORE ABOUT THE BACKGROUND AND CURRENT POLICIES. SO THIS IS MY LAST SLIDE. AND I WANTED TO LEAVE YOU WITH THE MESSAGE, IF YOU HAVEN'T FIGURED IT OUT, THAT THE BUSINESS OF CLINICAL RESEARCH HAS BEEN AN INTERNATIONAL BUSINESS. WITH GREAT PEOPLE, LITERALLY IN EVERY CULTURE, AND WE'RE ALL THE BENEFICIARIES OF THAT. AND WHAT WE DO TODAY, I THINK, IS JUST CAPITALIZING ON WHAT AN AWFUL LOT OF PEOPLE HAVE DONE BEFORE US. SO I HOPE THE COURSE THAT YOU'RE GOING DO SIT THROUGH AND -- THROUGHOUT THE NEXT WEEKS PROVES TO BE INTERESTING TO YOU AND HELPFUL. YOU'RE GOING TO LEARN A LOT ABOUT STATISTICS AND STUDY DESIGN. YOU'RE GOING TO LEARN ABOUT HOW TO APPLY FOR MONEY, LEARN HOW TO REVIEW, LEARN ABOUT THE ETHICAL LEGAL AND SOCIAL ISSUES, AND THE FACULTY ARE PHENOMENALLY DEDICATED AND HOPE THAT YOU ENJOY THE COURSE AS MUCH AS WE ENJOY TEACHING IT. PLEASE FILL OUT YOUR FORMS AS YOU HEAR THE LECTERS AND HELP US MAKE THE COURSE BETTER EACH YEAR. SO THANK YOU VERY MUCH. [APPLAUSE] IF THERE ARE ANY QUESTIONS HERE IN THIS ROOM I'D BE HAPPY TO ENTERTAIN THEM. IF NOT, WE'RE ADJOURNED.